Adnan Nagrial

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Purpose To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome. Patients and Methods Consecutive BRAF-tested Australian patients with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted. Results Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor. Conclusion V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.

The analysis of T-cell antigens in long-term survivors of pancreatic ductal adenocarcinoma suggests that neoantigen immunogenicity and quality, not purely quantity, correlate with survival. A small percentage of patients with pancreatic cancer survive beyond five years, but the reason for their relative longevity remains uncertain. In this retrospective analysis, Vinod Balachandran et al. evaluate the immune mechanisms of long-term survival in human pancreatic cancer. The analysis shows that survival correlates with high mutation load in conjunction with increased infiltration of cytolytic T cells and polyclonal T-cell responses and that mutations at the tumour antigen MUC16 locus are enriched in long-term survivors. Additionally, patients with high predicted neoantigen–microbial cross-reactivity scores tended to live longest. The authors provide evidence that the quality rather than quantity of neoantigens determines survival. Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling. The genomes of 102 primary pancreatic neuroendocrine tumours have been sequenced, revealing mutations in genes with functions such as chromatin remodelling, DNA damage repair, mTOR activation and telomere maintenance, and a greater-than-expected contribution from germ line mutations. Pancreatic neuroendocrine tumours (PanNETs) are the second most common epithelial neoplasm of the pancreas. Aldo Scarpa, Sean Grimmond and colleagues report whole-genome sequencing of 102 primary PanNETs and present analysis of their mutational signatures as part of the International Cancer Genome Consortium. They find frequent mutations in genes with functions that include chromatin remodelling, DNA damage repair, activation of mTOR signalling, and telomere maintenance. They also identify mutational signatures, including one resulting from inactivation of the DNA repair gene MUTYH, and report a larger than expected germline contribution to PanNET development.

Abstract We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE‐158 (NCT02628067; phase 2) and KEYNOTE‐028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD‐L1)‐positive tumors were required for eligibility in KEYNOTE‐028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE‐158) or 10 mg/kg every two weeks (KEYNOTE‐028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE‐158 enrolled 104 patients and KEYNOTE‐028 enrolled 24 patients. Median (range) follow‐up was 7.5 months (0.6‐34.3) in KEYNOTE‐158 and 5.7 months (0.6‐55.4) in KEYNOTE‐028. In KEYNOTE‐158, ORR was 5.8% (6/104; 95% CI, 2.1%‐12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2‐26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5‐9.6) and 2.0 (1.9‐2.1) months. Among PD‐L1‐expressers (n = 61) and PD‐L1‐nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE‐028, ORR was 13.0% (3/23; 95% CI, 2.8%‐33.6%); median DOR was NR (range, 21.5‐53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1‐9.8) and 1.8 (1.4‐3.1) months. Grade 3 to 5 treatment‐related adverse events occurred in 13.5% of patients in KEYNOTE‐158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE‐028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD‐L1 expression, and has manageable toxicity.

BackgroundCurrent staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 (CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used.MethodsWe assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC.ResultsBy specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P = 0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels >90 U/ml did not benefit from adjuvant chemotherapy (P = 0.7194) compared with those with a CA19.9 of ≤90 U/ml (median 26.0 vs 16.7 months, P = 0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P = 0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%.ConclusionsPerioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation.

Fine-tuned manipulation of tumor tension and vasculature enhances response to chemotherapy and impairs metastatic spread in pancreatic cancer.

Personalized medicine strategies using genomic profiling are particularly pertinent for pancreas cancer. The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was initially designed to exploit results from genome sequencing of pancreatic cancer under the auspices of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed small subsets of patients with aberrations in their tumor genome that could be targeted with currently available therapies.The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumor specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable timeframe. We screened for three molecular targets: HER2 amplification; KRAS wild-type; and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM).Tumor biopsy and archived tumor samples were collected from 93 patients and 76 were screened. To date 22 candidate cases have been identified: 14 KRAS wild-type, 5 cases of HER2 amplification, 2 mutations in BRCA2, and 1 ATM mutation. Median time from consent to the return of validated results was 21.5 days. An inability to obtain a biopsy or insufficient tumor content in the available specimen were common reasons for patient exclusion from molecular analysis while deteriorating performance status prohibited a number of patients from proceeding in the study.Documenting the feasibility of acquiring and screening biospecimens for actionable molecular targets in real time will aid other groups embarking on similar trials. Key elements include the need to better prescreen patients, screen more patients, and offer more attractive clinical trial options.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer. Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer. Pancreatic ductal adenocarcinoma has a 5-year survival of <5%, with therapies offering only incremental benefit,1Vogelzang N.J. et al.J Clin Oncol. 2012; 30: 88-109Crossref PubMed Scopus (85) Google Scholar potentially due to the diversity of its genomic landscape.2Bailey P. et al.Nature. 2016; 531: 47-52Crossref PubMed Scopus (1973) Google Scholar, 3Biankin A.V. et al.Nature. 2012; 491: 399-405Crossref PubMed Scopus (1379) Google Scholar, 4Waddell N. et al.Nature. 2015; 518: 495-501Crossref PubMed Scopus (1466) Google Scholar Recent reports link high mutation burden with response to immune checkpoint inhibitors in several cancer types.5Le D.T. et al.N Engl J Med. 2015; 372: 2509-2520Crossref PubMed Scopus (6099) Google Scholar Defining tumors that are hypermutated with an increased mutation burden and understanding the underlying mechanisms in pancreatic cancer has the potential to advance therapeutic development, particularly for immunotherapeutic strategies. Whole genome sequencing (WGS, n = 180) and whole exome sequencing (n = 205) of 385 unselected predominantly sporadic pancreatic ductal adenocarcinoma (Supplementary Table 1) defined a mean mutation load of 1.8 and 1.1 mutation per megabase (Mb), respectively (Supplementary Table 2). Outlier analysis identified 20 tumors with the highest mutation burden (5.2%, 15 WGS and 5 exome) (Table 1 and Supplementary Figure 1A), 5 of which were considered extreme outliers and classified as hypermutated as they contained ≥12 somatic mutations/Mb, the defined threshold for hypermutation in colorectal cancer.6Cancer Genome Atlas NetworkNature. 2012; 487: 330-337Crossref PubMed Scopus (5894) Google Scholar Immunohistochemistry for mismatch repair (MMR) proteins (MSH2, MSH6, MLH1, and PMS2) identified 4 MMR-deficient tumors, all of which were hypermutated (n = 180, Figure 1).Table 1Clinical and Histologic Features and Proposed Etiology for Highly Mutated Pancreatic Ductal Adenocarcinoma Tumors (n = 20)Sample IDPersonal and family history of malignancyHistologyMutation load, mutations/MbIHC resultMSIsensor scoreKRAS mutationPredominant mutation signature (mutations/Mb)SV subtype (no. of events)Proposed etiologyHypermutation (extreme outliers) ICGC_0076aSample sequenced by WGS, other samples by exome sequencing.NoneMixed signet ring, mucinous and papillary adenocarcinoma38.55Absent MLH1 and PMS228.3p.G12VMMR (18.3)Scattered (131)MMR deficiency: >280 kb somatic homozygous deletion over MSH2. ICGC_0297aSample sequenced by WGS, other samples by exome sequencing.NoneUndifferentiated adenocarcinoma60.62Absent MSH2 and MSH627.33WTMMR (33.4)Scattered (75)MMR deficiency: Somatic MLH1 promoter hypermethylation. ICGC_0548aSample sequenced by WGS, other samples by exome sequencing.NoneDuctal adenocarcinoma, moderately differentiated30.13Absent MSH2 and MSH617.47WTMMR (16.6)Stable (49)MMR deficiency: >27 kb somatic inversion rearrangement disrupting MSH2. ICGC_0328aSample sequenced by WGS, other samples by exome sequencing.NoneDuctal adenocarcinoma16.63Normal3.2p.G12DUnknown (11.9)Scattered (110)Cell line with signature: etiology unknown. ICGC_00901 FDR, father CRCDuctal adenocarcinoma, moderately differentiated12.9Absent MSH2 and MSH60.21p.G12CNANAMMR deficiency: somatic MSH2 splice site c.2006G>A.Highly mutated tumors ICGC_0054aSample sequenced by WGS, other samples by exome sequencing.NoneDuctal adenocarcinoma, poorly differentiated6.52Normal0.01p.G12VHR deficiency (1.3)Unstable (310)HR deficiency: no germline or somatic cause found. ICGC_0290aSample sequenced by WGS, other samples by exome sequencing.NoneDuctal adenocarcinoma, poorly differentiated6.54Not available0.07p.G12VHR deficiency (3.1)Unstable (558)HR deficiency: Germline BRCA2 mutation c.7180A>T, p.A2394*. Somatic CN-LOH. ICGC_0215aSample sequenced by WGS, other samples by exome sequencing.2 FDR lung cancer, 2 FDR prostate cancer. Previous CRC and melanomaDuctal adenocarcinoma, moderately differentiated6.27Normal0.01p.G12VHR deficiency (1.9)Scattered (111)HR deficiency: Germline ATM mutation c.7539_7540delAT, p.Y2514*. Somatic CN-LOH. ICGC_0324NoneDuctal adenocarcinoma, moderately differentiated6.24Normal0p.G12DNANAUndefined ICGC_0034aSample sequenced by WGS, other samples by exome sequencing.NoneDuctal adenocarcinoma, poorly differentiated6.09Normal4.02p.G12DHR deficiency (3.4)Unstable (366)HR deficiency: Germline BRCA2 mutation c.5237_5238insT, p.N1747*. Somatic CN-LOH. ICGC_0131aSample sequenced by WGS, other samples by exome sequencing.Lung cancer after PCDuctal adenocarcinoma, moderately differentiated5.63Normal0p.G12DT>G at TT sites (3.0)Focal (147)T>G at TT sites signature: etiology potentially associated with DNA oxidation ICGC_0006aSample sequenced by WGS, other samples by exome sequencing.1 FDR, father lung cancerAdenocarcinoma arising from IPMN, moderately differentiated5.29Normal0.01p.G12DHR deficiency (1.2)Unstable (211)HR deficiency: Somatic BRCA2 c.5351dupA, p.N1784KfsTer3. Somatic CN-LOH. ICGC_0321aSample sequenced by WGS, other samples by exome sequencing.2 FDR, mother and cousin breast cancerDuctal adenocarcinoma, poorly differentiated4.79Not available0p.G12DHR deficiency (2.1)Unstable (286)HR deficiency: Germline BRCA2 c.6699delT, p.F2234LfsTer7. Somatic CN loss- 1 copy. ICGC_0309aSample sequenced by WGS, other samples by exome sequencing.NoneAdenocarcinoma arising from IPMN, moderately differentiated4.74Normal0.03p.G12VT>G at TT sites (3.1)Unstable (232)T>G at TT sites signature: etiology potentially associated with DNA oxidation ICGC_0005aSample sequenced by WGS, other samples by exome sequencing.1 FDR, mother CRCDuctal adenocarcinoma, poorly differentiated4.72Not available1p.G12VHR deficiency (1.1)Focal (95)HR deficiency: No germline or somatic cause found. ICGC_0016aSample sequenced by WGS, other samples by exome sequencing.NoneDuctal adenocarcinoma, poorly differentiated4.61Normal3.03p.G12VHR deficiency (1.7)Unstable (447)HR deficiency: potentially linked to Somatic RPA1 c.273G>T, p.R91S ICGC_00461 FDR, brother PCDuctal adenocarcinoma, poorly differentiated4.3Normal0p.Q61HNANAUndefined GARV_0668aSample sequenced by WGS, other samples by exome sequencing.NoneDuctal adenocarcinoma, poorly differentiated4.3Not available2.19p.G12VHR deficiency (1.6)Unstable (464)HR deficiency: Germline BRCA2 c.7068_7069delTC, p.L2357VfsTer2. Somatic CN loss - 1 copy. ICGC_0291NoneDuctal adenocarcinoma, well differentiated3.84Not available0.03p.G12RNANAHR deficiency: Somatic BRCA2 c.7283T>A, p.L2428*. ICGC_0256NoneDuctal adenocarcinoma, poorly differentiated3.72Not available0.06p.G12DNANAUndefinedCRC, colorectal cancer; FDR, first-degree relative; IHC, immunohistochemistry; IPMN, intraductal papillary mucinous neoplasm; CN-LOH, copy neutral loss of heterozygosity; CN, copy number; PC, pancreatic cancer; NA, not applicable to exome data.a Sample sequenced by WGS, other samples by exome sequencing. Open table in a new tab CRC, colorectal cancer; FDR, first-degree relative; IHC, immunohistochemistry; IPMN, intraductal papillary mucinous neoplasm; CN-LOH, copy neutral loss of heterozygosity; CN, copy number; PC, pancreatic cancer; NA, not applicable to exome data. KRAS mutation status and histopathologic characteristics have been associated with MMR-deficient pancreatic tumors.7Goggins M. et al.Am J Pathol. 1998; 152: 1501-1507PubMed Google Scholar Of the 4 MMR-deficient tumors in our cohort, 2 were KRAS wild-type; 3 had undifferentiated to moderately differentiated histology and one had a signet-ring component. These features were not predictive of MMR deficiency in our cohort, as 11 additional non−MMR-deficient tumors had a signet-ring cell component or colloid morphology, and 131 of 347 assessable tumors had poorly or undifferentiated histology. Mutational signature analysis can detect MMR deficiency indirectly based on the pattern of somatic mutations.8Alexandrov L.B. et al.Nature. 2013; 500: 415-421Crossref PubMed Scopus (6213) Google Scholar An MMR-deficient signature dominated the MMR-deficient tumors (with WGS), and was minimal in MMR intact tumors (Supplementary Figure 1). In addition, microsatellite instability (MSI), a hallmark of MMR deficiency in colorectal cancer, was detected in all three MMR deficient tumors with WGS using MSIsensor9Niu B. Ye K. et al.Bioinformatics. 2014; 30: 1015-1016Crossref PubMed Scopus (294) Google Scholar (Supplementary Table 2). MSI was not identified for the fourth MMR deficient sample potentially due to the reduced number of microsatellite loci in exome data. The underlying causes of MMR deficiency in the 4 cases were private somatic events. For 2 cases, MSH2 was disrupted by different structural rearrangements, 1 case contained a missense MSH2 mutation and the last, methylation of the MLH1 promoter (Figure 1). The missense mutation caused an MSH2 splice acceptor site mutation that alters the same nucleotide results in a pathogenic skipping of exon 13 in germline studies.10Thompson B.A. et al.Nat Genet. 2014; 46: 107-115Crossref PubMed Scopus (346) Google Scholar Hypermethylation of the MLH1 promoter is the predominant mechanism of MSI in sporadic colon cancer.11Boland C.R. et al.Gastroenterology. 2010; 138: 2073-2087 e3Abstract Full Text Full Text PDF PubMed Scopus (1359) Google Scholar The remaining hypermutated tumor contained an intact MMR pathway, and was a cell line (ATCC, CRL-2551) with an unidentified mutational signature, therefore the high mutation burden in this sample may be the result of long-term cell culture. The 15 samples (11 WGS and 4 exome) identified in the outlier analysis with high mutation burden, but not hypermutated (∼4 to 12 mutations/Mb) contained no evidence of MMR deficiency. Mutational signature analysis of the WGS samples indicated homologous recombination (HR) repair deficiency as the most substantial (range, 1.0–3.4 mutations/Mb) contributor to the mutation burden for 8 WGS mutation load outlier tumors. In support of a HR defect4Waddell N. et al.Nature. 2015; 518: 495-501Crossref PubMed Scopus (1466) Google Scholar; 7 of these tumors contained high levels of genomic instability with >200 structural variants and mutations in genes involved in HR were present for 6 of 8 cases (Supplementary Table 2). In addition, 1 case that had undergone exome sequencing had a somatic BRCA2 nonsense mutation that likely contributed to HR deficiency in this case. A mutational signature associated with T>G mutations at TT sites previously described in other cancers, including esophageal cancer12Nones K. Waddell N. Wayte N. et al.Nat Commun. 2014; : 5Google Scholar was the major contributor (>3 mutations/Mb) in 2 samples. For these 2 and the remaining 4 cases, no potential causative event could be identified. Although germline defects in MMR genes are well reported in pancreatic cancer13Grant R.C. Selander I. et al.Gastroenterology. 2015; 148: 556-564Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar in our cohort, they did not contribute to MMR deficiency even in those with familial pancreatic cancer or a personal or family history of Lynch-related tumors. A germline truncating variant was detected in PMS2 in 1 case, but did not have loss of the second allele, had normal immunohistochemistry staining and did not display a MMR mutational signature (Supplementary Table 2). MMR deficiency is important in the evolution in a small, but meaningful proportion of pancreatic cancers with a prevalence of 1% (4 of 385) in our cohort. This is consistent with recent studies using the Bethesda polymerase chain reaction panel,14Laghi L. et al.PLoS One. 2012; 7: e46002Crossref PubMed Scopus (55) Google Scholar and with previous estimates of MSI prevalence of 2%−3%.15Nakata B. et al.Clin Cancer Res. 2002; 8: 2536-2540PubMed Google Scholar However, in tumors with low epithelial content that underwent exome sequencing, the sensitivity of somatic mutation detection is reduced, which will affect mutation burden and signature analysis. While cognizant of small numbers, immunohistochemistry was the most accurate in defining MMR due to multiple genomic mechanisms of MMR gene inactivation. Multiple methods to define MMR deficiency may be required for clinical trials that aim to recruit MMR-deficient participants to assess the potential efficacy of checkpoint inhibitors or other therapies in pancreatic cancer. Homologous recombination-deficient tumors, and those with a novel signature seen in esophageal cancer had an increased mutation burden, and need further evaluation as potential patient selection markers for clinical trials of checkpoint inhibitor and other therapies that target tumors with a high mutation burden. The authors would like to thank Cathy Axford, Deborah Gwynne, Mary-Anne Brancato, Clare Watson, Michelle Thomas, Gerard Hammond, and Doug Stetner for central coordination of the Australian Pancreatic Cancer Genome Initiative, data management, and quality control; Mona Martyn-Smith, Lisa Braatvedt, Henry Tang, Virginia Papangelis, and Maria Beilin for biospecimen acquisition; and Sonia Grimaldi and Giada Bonizzato of the ARC-Net Biobank for biospecimen acquisition. For a full list of contributors see Australian Pancreatic Cancer Genome Initiative: http://www.pancreaticcancer.net.au/apgi/collaborators. The cohort consisted of 385 patients with histologically verified pancreatic exocrine carcinoma, prospectively recruited between 2006 and 2013 through the Australian Pancreatic Cancer Genome Initiative (www.pancreaticcancer.net.au) as part of the International Cancer Genome Consortium.1Hudson T.J. et al.Nature. 2010; 464: 993-998Crossref PubMed Scopus (1689) Google Scholar Ethical approval was granted at all treating institutions and individual patients provided informed consent upon entry to the study. The clinicopathologic information for the cohort is described in (Supplementary Table 1), and the global mutation profile has previously been reported for some of these tumors (Supplementary Table 2). Tumor and normal DNA were extracted after histologic review from fresh frozen tissue samples collected at the time of surgical resection or biopsy, as described previously.2Biankin A.V. et al.Nature. 2012; 491: 399-405Crossref PubMed Scopus (1513) Google Scholar Tumor cellularity was determined from single-nucleotide polymorphism array data using qpure.3Song S. et al.PLoS One. 2012; 7: e45835Crossref PubMed Scopus (85) Google Scholar Tumors with epithelial content ≥40% underwent WGS lower cellularity tumors underwent whole exome sequencing. DNA from patient-derived pancreas cell lines and matched normal was also extracted. Exome and WGS were performed using paired 100-bp reads on the Illumina HiSeq 2000, as described previously.2Biankin A.V. et al.Nature. 2012; 491: 399-405Crossref PubMed Scopus (1513) Google Scholar, 4Waddell N. et al.Nature. 2015; 518: 495-501Crossref PubMed Scopus (1686) Google Scholar Regions of germline and somatic copy number change were detected using Illumina SNP BeadChips with GAP.5Popova T. et al.Genome Biol. 2009; 10 (R128−R128)Crossref PubMed Scopus (151) Google Scholar Somatic structural variants were identified from WGS reads using the qSV tool.4Waddell N. et al.Nature. 2015; 518: 495-501Crossref PubMed Scopus (1686) Google Scholar, 6Patch A.M. et al.Nature. 2015; 521: 489-494Crossref PubMed Scopus (930) Google Scholar Single nucleotide variants were called using 2 variant callers: qSNP7Kassahn K.S. et al.PLoS One. 2013; 8: e74380Crossref PubMed Scopus (52) Google Scholar and GATK.8McKenna A. et al.Genome Res. 2010; 20: 1297-1303Crossref PubMed Scopus (14755) Google Scholar Mutations identified by both callers or, those that were unique to a caller but verified by an orthogonal sequencing approach, were considered high confidence and used in all subsequent analyses. Small indels (<200 bp) were identified using Pindel9Ye K. et al.Bioinformatics. 2009; 25: 2865-2871Crossref PubMed Scopus (1391) Google Scholar and each indel was visually inspected in the Integrative Genome Browser. The distribution of the total number of small somatic mutations (coding and noncoding single nucleotide and indel variants) identified per megabase for exome and WGS sequence data were analyzed separately. The group of samples with high mutation load, at the top of each distribution, were defined as the upper distribution outliers for mutations per megabase, that is, ≥75th centile + (1.5× interquartile range). The threshold for detecting outliers in the exome and WGS groups was 3.4 and 4.2 mutations/Mb, respectively. From within the highly mutated set of tumors, hypermutated samples were identified as those with a mutation rate exceeding the thresholds for extreme distribution outliers (≥75th centile + [5× interquartile range]) of 7.4 and 8.1 mutations/Mb for exome and WGS sequencing, respectively. MSIsensor was used to detect microsatellite instability by directly comparing microsatellite repeat lengths between paired normal and tumor sequencing data.10Niu B. et al.Bioinformatics. 2014; 30: 1015-1016Crossref PubMed Scopus (378) Google Scholar A MSIsensor score of >3.5% of somatic microsatellites with repeat length shifts was the detection threshold used to indicate microsatellite instability as published for endometrial cancer.10Niu B. et al.Bioinformatics. 2014; 30: 1015-1016Crossref PubMed Scopus (378) Google Scholar This correlated well with the 5 and 7 microsatellite panels recommended in the Bethesda guidelines.10Niu B. et al.Bioinformatics. 2014; 30: 1015-1016Crossref PubMed Scopus (378) Google Scholar, 11Umar A. et al.J Natl Cancer Inst. 2004; 96: 261-268Crossref PubMed Scopus (2461) Google Scholar Tissue microarrays were constructed using at least three 1-mm formalin-fixed, paraffin-embedded tumor cores. Immunohistochemistry for MSH6 and PMS2 proteins was performed on tissue microarray sections as a screen for MMR deficiency due to MMR proteins forming heterodimers with concordant mismatch repair loss (ie, loss of MLH1 and PMS2 or loss of MSH2 and MSH6).12Hall G. et al.Pathology. 2010; 42: 409-413Abstract Full Text PDF PubMed Scopus (98) Google Scholar Immunohistochemistry on full tumor sections for MSH2, MLH1, MSH6, and PMS2 was performed in those with abnormal staining in core sections. The immunohistochemistry was performed as described previously12Hall G. et al.Pathology. 2010; 42: 409-413Abstract Full Text PDF PubMed Scopus (98) Google Scholar and scored by a senior pathologist. Somatic mutational signatures were extracted from the whole genome sequenced samples using the framework described previously.13Alexandrov L.B. et al.Cell Rep. 2013; 3: 246-259Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar High confidence somatic substitutions were classified by the substitution change and sequence context, that is, the type of immediately neighboring bases to the variant. The framework processes the counts of somatic mutations at each context within each sample using non-negative factorization to produce the different signature profiles that are present in the data. The profiles identified were matched against reported signatures from the Cancer of Somatic Mutations in Cancer (http://cancer.sanger.ac.uk/cosmic/signatures). The major contributory signatures, defined as the mutational signature with the highest number of contributing somatic substitution variants, is reported for highly mutated whole genome samples. Bisulfite-converted whole-genome amplified DNA was hybridized to Infinium Human Methylation 450K Beadchips according to the manufacturers protocol (Illumina). Methylation arrays were performed on DNA from 174 pancreatic ductal adenocarcinoma samples, which were compared to DNA from 29 adjacent nonmalignant pancreata. A subset of the methylation data has been published previously.14Nones K. et al.Int J Cancer. 2014; 135: 1110-1118Crossref PubMed Scopus (156) Google Scholar We examined the data for evidence of tumor-specific hypermethylation of the promoter region of MLH1 and MSH2 genes. The methylation array data have been deposited into the International Cancer Genome Consortium data portal (dcc.icgc.org, project PACA-AU). Download .xlsx (.08 MB) Help with xlsx files Supplementary Tables 1 and 2

<h3>Importance</h3> Biliary tract cancers represent a rare group of malignant conditions with very limited treatment options. Patients with advanced disease have a poor outcome with current therapies. <h3>Objective</h3> To evaluate the efficacy and safety of combination immunotherapy with nivolumab and ipilimumab in patients with advanced biliary tract cancers. <h3>Design, Setting, and Participants</h3> The CA209-538 prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced rare cancers including patients with biliary tract cancers. This subgroup analysis evaluated 39 patients from CA209-538 with biliary tract cancers who were enrolled from December 2017 to December 2019. Most of the patients (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research. <h3>Interventions</h3> Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks and continued for up to 96 weeks until disease progression or the development of unacceptable toxic events. <h3>Main Outcomes and Measures</h3> The primary end point was disease control rate (complete remission, partial remission, or stable disease) as assessed by RECIST 1.1. <h3>Results</h3> Among the 39 patients included in this subgroup analysis of a phase 2 clinical trial (20 men, 19 women; mean [range] age, 65 [37-81] years), the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17); all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Responses were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma. The median duration of response was not reached (range, 2.5 to ≥23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Immune-related toxic events were reported in 49% of patients (n = 19), with 15% (n = 6) experiencing grade 3 or 4 events. <h3>Conclusions and Relevance</h3> This subgroup analysis of a phase 2 clinical trial found that combination immunotherapy with nivolumab and ipilimumab was associated with substantial positive outcomes patients with advanced biliary tract cancers. This treatment compares favorably to single-agent anti–programmed cell death protein 1 (anti–PD-1) therapy and warrants further investigation. Ongoing translational research is focused on identifying biomarkers that can predict treatment response. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02923934

<h2>Abstract</h2><h3>Background</h3> In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. <h3>Materials and methods</h3> Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of <i>KRAS</i> in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. <h3>Results</h3> Of 112 patients consented pre-operatively, 81 (72%) underwent resection. <i>KRAS</i> mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (<i>N</i> = 42), <i>KRAS</i> mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; <i>P</i> = 0.002)] and OS (HR 4.1; <i>P</i> = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; <i>P</i> < 0.0001) and OS (HR 4.0; <i>P</i> = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. <h3>Conclusion</h3> ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab.Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Abstract Purpose: Combination immunotherapy with anti–CTLA-4 and anti–PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs. Patients and Methods: CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease). Results: Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7–10.5] and overall survival was 14.8 months (95% CI: 4.1–21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events. Conclusions: Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.

Purpose Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. Patients and Methods We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. Results Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34; 95% CI, 1.69 to 6.62; P &lt; .001) and both validation cohorts (HR, 5.65; 95% CI, 2.77 to 11.5; P &lt; .001 and HR, 2.78; 95% CI, 1.25 to 7.17; P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis; two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome; and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. Conclusion Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.

Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC).An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum.HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.

4079 Background: Antitumor activity with pembro, an anti–PD-1 antibody, has been observed in patients (pts) with advanced/metastatic biliary tract cancers (BTC), who have limited treatment options. We present follow-up data from pts with advanced BTC treated with pembro in the KN158 (NCT02628067; phase 2) and KN028 (NCT02054806; phase 1) studies. Methods: Eligible pts ≥18 y in the KN158/KN028 BTC cohorts had histologically/cytologically confirmed incurable advanced BTC that progressed after/failed any number of prior standard treatment regimens, measurable disease per RECIST v1.1, ECOG PS of 0/1, and no prior immunotherapy. PD-L1–positivity (membranous PD-L1 expression in ≥1% of tumor and associated inflammatory cells or positive staining in stroma) was required for eligibility in KN028, but not KN158. Pts received pembro 200 mg Q3W (KN158) or 10 mg/kg Q2W (KN028) for up to 2 y. Radiographic imaging occurred Q9W for 12 mo (KN158) or Q8W for 6 mo (KN028) and Q12W thereafter. Primary efficacy endpoint in both studies was ORR by RECIST 1.1. Response assessed by independent central review is reported. Results: Median (range) follow-up was 7.5 (0.6–29.5) mo in the 104 pts from KN158 and 6.5 (0.6–33.1) mo in the 24 pts from KN028 with BTC. All pts in KN028 and 61 in KN158 had PD-L1–positive tumors. No pt had MSI-H tumors (not assessed in KN028). In KN158, ORR was 5.8% (6/104, all PR [including 1 pt with PD-L1–negative tumor]; 95% CI, 2.1%–12.1%) and median duration of response (DOR) was not reached (NR; range, 6.2 to 23.2+ mo). Median OS and PFS were 7.4 mo (95% CI, 5.5–9.6) and 2.0 mo (95% CI, 1.9–2.1). 12-mo OS rate was 32.7%. In KN028, ORR was 13.0% (3/23, all PR; 95% CI, 2.8%‒33.6%) and median DOR was NR (range, 21.5 to 29.4+ mo). Median OS and PFS were 6.2 mo (95% CI, 3.8‒10.3) and 1.8 mo (95% CI, 1.4‒3.7), respectively. 12-mo OS rate was 27.6%. Grade 3–5 treatment-related AEs occurred in 13.5% in KN158 (1 pt had grade 5 renal failure) and 16.7% of pts in KN028 (no grade 5). 18.3% in KN158 and 20.8% of pts in KN028 had an immune-mediated AE or infusion reaction. Conclusions: Pembro provides durable antitumor activity, regardless of PD-L1 expression, and manageable toxicity in a subset of pts with advanced BTC. Clinical trial information: NCT02054806 and NCT02628067.

Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4.Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens).Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach.This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.

Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options. Over the past few decades, many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review attempts to synthesise all the randomised data available to help better inform patient and clinician decision-making when dealing with this difficult disease.To assess the effect of chemotherapy, radiotherapy or both for first-line treatment of advanced pancreatic cancer. Our primary outcome was overall survival, while secondary outcomes include progression-free survival, grade 3/4 adverse events, therapy response and quality of life.We searched for published and unpublished studies in CENTRAL (searched 14 June 2017), Embase (1980 to 14 June 2017), MEDLINE (1946 to 14 June 2017) and CANCERLIT (1999 to 2002) databases. We also handsearched all relevant conference abstracts published up until 14 June 2017.All randomised studies assessing overall survival outcomes in patients with advanced pancreatic ductal adenocarcinoma. Chemotherapy and radiotherapy, alone or in combination, were the eligible treatments.Two review authors independently analysed studies, and a third settled any disputes. We extracted data on overall survival (OS), progression-free survival (PFS), response rates, adverse events (AEs) and quality of life (QoL), and we assessed risk of bias for each study.We included 42 studies addressing chemotherapy in 9463 patients with advanced pancreatic cancer. We did not identify any eligible studies on radiotherapy.We did not find any benefit for chemotherapy over best supportive care. However, two identified studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated.Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate-quality evidence), PFS (HR 1.47, 95% CI 1.12 to 1.92) and QoL. On the other hand, two studies showed FOLFIRINOX was better than gemcitabine for OS (HR 0.51 95% CI 0.43 to 0.60, moderate-quality evidence), PFS (HR 0.46, 95% CI 0.38 to 0.57) and response rates (RR 3.38, 95% CI 2.01 to 5.65), but it increased the rate of side effects. The studies evaluating CO-101, ZD9331 and exatecan did not show benefit or harm when compared with gemcitabine alone.Giving gemcitabine at a fixed dose rate improved OS (HR 0.79, 95% CI 0.66 to 0.94, high-quality evidence) but increased the rate of side effects when compared with bolus dosing.When comparing gemcitabine combinations to gemcitabine alone, gemcitabine plus platinum improved PFS (HR 0.80, 95% CI 0.68 to 0.95) and response rates (RR 1.48, 95% CI 1.11 to 1.98) but not OS (HR 0.94, 95% CI 0.81 to 1.08, low-quality evidence). The rate of side effects increased. Gemcitabine plus fluoropyrimidine improved OS (HR 0.88, 95% CI 0.81 to 0.95), PFS (HR 0.79, 95% CI 0.72 to 0.87) and response rates (RR 1.78, 95% CI 1.29 to 2.47, high-quality evidence), but it also increased side effects. Gemcitabine plus topoisomerase inhibitor did not improve survival outcomes but did increase toxicity. One study demonstrated that gemcitabine plus nab-paclitaxel improved OS (HR 0.72, 95% CI 0.62 to 0.84, high-quality evidence), PFS (HR 0.69, 95% CI 0.58 to 0.82) and response rates (RR 3.29, 95% CI 2.24 to 4.84) but increased side effects. Gemcitabine-containing multi-drug combinations (GEMOXEL or cisplatin/epirubicin/5FU/gemcitabine) improved OS (HR 0.55, 95% CI 0.39 to 0.79, low-quality evidence), PFS (HR 0.43, 95% CI 0.30 to 0.62) and QOL.We did not find any survival advantages when comparing 5FU combinations to 5FU alone.Combination chemotherapy has recently overtaken the long-standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab-paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patients.

PURPOSE Lifirafenib is an investigational, reversible inhibitor of B-RAF V600E , wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF– or K-RAS/N-RAS–mutated solid tumors. METHODS During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF–mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAF V600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAF V600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAF V600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF–mutated non–small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS–mutated endometrial cancer and K-RAS codon 12–mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS–mutated colorectal cancer (n = 20). CONCLUSION Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAF V600 –mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.

<h3>Background</h3> Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study. <h3>Patients and methods</h3> Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints. <h3>Results</h3> Thirty-nine patients were enrolled in DE [<i>n</i> = 14 (cohort 1); <i>n</i> = 17 (cohort 2); <i>n</i> = 8 (cohort 3)] and 134 in DC [<i>n</i> = 40 (arm A); <i>n</i> = 40 (arm B); <i>n</i> = 40 (arm C); <i>n</i> = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR. <h3>Conclusions</h3> Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.

Australia has one of the highest rates of asbestos-associated diseases. Mesothelioma remains an area of unmet need with a 5-year overall survival of 10%. First-line immunotherapy with ipilimumab and nivolumab is now a standard of care for unresectable pleural mesothelioma following the CheckMate 743 trial, with supportive data from the later line single-arm MAPS2 trial. RIOMeso evaluates survival and toxicity of this regimen in real-world practice.Demographic and clinicopathologic data of Australian patients treated with ipilimumab and nivolumab in first- and subsequent-line settings for pleural mesothelioma were collected retrospectively. Survival was reported using the Kaplan-Meier method and compared between subgroups with the log-rank test. Toxicity was investigator assessed using Common Terminology Criteria for Adverse Events version 5.0.A total of 119 patients were identified from 11 centers. The median age was 72 years, 83% were male, 92% had Eastern Cooperative Oncology Group less than or equal to 1, 50% were past or current smokers, and 78% had known asbestos exposure. In addition, 50% were epithelioid, 19% sarcomatoid, 14% biphasic, and 17% unavailable. Ipilimumab and nivolumab were used first line in 75% of patients. Median overall survival (mOS) was 14.5 months (95% confidence interval [CI]: 13.0-not reached [NR]) for the entire cohort. For patients treated first line, mOS was 14.5 months (95% CI: 12.5-NR) and in second- or later-line patients was 15.4 months (95% CI: 11.2-NR). There was no statistically significant difference in mOS for epithelioid patients compared with nonepithelioid (19.1 mo [95% CI: 15.4-NR] versus 13.0 mo [95% CI: 9.7-NR], respectively, p = 0.064). Furthermore, 24% of the patients had a Common Terminology Criteria for Adverse Events grade greater than or equal to 3 adverse events, including three treatment-related deaths. Colitis was the most frequent adverse event.Combination immunotherapy in real-world practice has poorer survival outcomes and seems more toxic compared with clinical trial data. This is the first detailed report of real-world survival and toxicity outcomes using ipilimumab and nivolumab treatment of pleural mesothelioma.

Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer.We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative.The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P<0.0001). Older patients (aged ≥70) were less likely to receive adjuvant chemotherapy (51.5% vs 29.8%; P<0.0001). Older patients had a particularly poor outcome when adjuvant therapy was not delivered (median survival=13.1 months; HR 1.89, 95% CI: 1.27-2.78, P=0.002).Patients aged ≥70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer.

Abstract Background: MEK1 mutations in melanoma can confer resistance to BRAF inhibitors, although preexisting MEK1P124 mutations do not preclude clinical responses. We sought to determine whether recurrent, preexisting MEK1P124 mutations affected clinical outcome in BRAF inhibitor–treated patients with melanoma. Methods: Data from four published datasets were analyzed to determine whether preexisting MEK1P124 mutations affect radiologic response or progression-free survival (PFS) in patients with BRAFV600-mutant metastatic melanoma treated with vemurafenib or dabrafenib. The effects of MEK1P124 mutations on MAPK pathway activity and response to BRAF inhibition were also investigated in a series of cell models. Results: In a pooled analysis of 123 patients, the presence of a pretreatment MEK1P124 mutation (N = 12, 10%) was associated with a poorer RECIST response (33% vs. 72% in MEK1P124Q/S vs. MEK1P124 wild-type, P = 0.018), and a shorter PFS (median 3.1 vs. 4.8 months, P = 0.004). Furthermore, MEK1P124Q/S mutations were shown to have independent kinase activity and introduction of these mutations into a BRAF-mutant melanoma cell line diminished inhibition of ERK phosphorylation by dabrafenib and enhanced clonogenic survival in the presence of dabrafenib compared with cells ectopically expressing wild-type MEK1. Consistent with these data, two BRAF-mutant cell lines with endogenous MEK1P124 mutations showed intermediate sensitivity to dabrafenib, but were highly sensitive to downstream inhibition of MEK or ERK. Conclusion: Taken together, our data indicate that preexisting MEK1P124 mutations are associated with a reduced response to BRAF inhibitor therapy and identify a subset of patients with BRAF-mutant melanoma likely to benefit from combination therapies involving MEK or ERK inhibitors. Clin Cancer Res; 21(1); 98–105. ©2014 AACR.

BACKGROUND Inherited predisposition to pancreatic cancer contributes significantly to its incidence and presents an opportunity for the development of early detection strategies. The genetic basis of predisposition remains unexplained in a high proportion of patients with familial PC (FPC). METHODS Clinicopathologic features were assessed in a cohort of 766 patients who had been diagnosed with pancreatic ductal adenocarcinoma (PC). Patients were classified with FPC if they had ≥1 affected first‐degree relatives; otherwise, they were classified with sporadic PC (SPC). RESULTS The prevalence of FPC in this cohort was 8.9%. In FPC families with an affected parent‐child pair, 71% in the subsequent generation were 12.3 years younger at diagnosis. Patients with FPC had more first‐degree relatives who had an extrapancreatic malignancy (EPM) (42.6% vs 21.2; P &lt;.0001), particularly melanoma and endometrial cancer, but not a personal history of EPM. Patients with SPC were more likely to be active smokers, have higher cumulative tobacco exposure, and have fewer multifocal precursor lesions, but these were not associated with differences in survival. Long‐standing diabetes mellitus (&gt;2 years) was associated with poor survival in both groups. CONCLUSIONS FPC represents 9% of PC, and the risk of malignancy in kindred does not appear to be confined to the pancreas. Patients with FPC have more precursor lesions and include fewer active smokers, but other clinicopathologic factors and outcome are similar to those in patients with SPC. Furthermore, some FPC kindreds may exhibit anticipation. A better understanding of the clinical features of PC will facilitate efforts to uncover novel susceptibility genes and the development of early detection strategies. Cancer 2014;120:3669–3675. © 2014 American Cancer Society .

Background: Biliary tract cancers (BTC) are often diagnosed at an advanced stage, with standard gemcitabine plus cisplatin combination chemotherapy providing limited benefit. The phase 2, multicohort KEYNOTE-158 study (NCT02628067) evaluated antitumor activity and safety of pembrolizumab (pembro), an anti–PD-1 antibody in patients (pts) with advanced BTC. Methods: Pts aged ≥18 y with histologically/cytologically confirmed unresectable or metastatic BTC and prior progression/intolerance on standard therapy were enrolled if they had measurable disease per RECIST v1.1, ECOG PS ≤ 1, and tumor sample for evaluation of PD-L1 (PD-L1 IHC 22C3 pharmDx assay [Agilent Technologies]) and other biomarkers. Pts received pembro 200 mg Q3W for up to 2 y or until disease progression or unacceptable AEs. The primary endpoint was ORR; DOR, PFS, OS and safety were secondary endpoints. Response was assessed every 9 wks in year 1, then every 12 wks (RECIST v1.1, independent central review). DOR, PFS, and OS were evaluated using the Kaplan-Meier method. AE severity was graded per NCI CTCAE v4.0. PD-L1 combined positive score (CPS; ≥1 or < 1) was determined. Results: At data cutoff (Jan 15, 2018), 104 pts with BTC (49% male; median age, 63 y [range, 34–81]; ≥2 prior therapies, 52%) were enrolled (median follow-up, 9.3 mo [range, 0.6–23.6]). ORR was 5.8% (95% CI, 2.1–12.1; 6 PR, 0 CR); 17 pts (16%) had SD. Median DOR was not reached (range, 6.2–15.7+ mo); 2 pts had DOR ≥15 mo. ORR was 6.6% (95% CI, 1.8–15.9) and 2.9% (95% CI, 0.1–15.3) among those with PD-L1 CPS ≥1 (n = 61) and CPS <1 (n = 34), respectively. Median PFS was 2.0 mo (95% CI, 1.9–2.1) and median OS was 9.1 mo (95% CI, 5.6–10.4). Median PFS was 1.9 mo (95% CI, 1.8–2.0) vs 2.1 mo (95% CI, 1.9–2.6) and median OS was 7.2 mo (95% CI, 5.3–11.0) vs 9.6 mo (95% CI, 5.4–12.8) among pts with PD-L1 CPS ≥1 vs < 1, respectively. 99 pts (including all responders) were evaluated for MSI status; none were MSI-H. Overall, 55% of pts had treatment-related AEs (most commonly fatigue [14%], rash [12%], pruritus [9%]); 13% had grade 3–5 AEs, and 16% had immune-mediated AEs. Treatment-related AEs led to discontinuation in 6 pts. Conclusions: Pembro shows durable antitumor activity in a subset of pts with advanced BTC regardless of PD-L1 CPS and had manageable toxicity. Clinical trial identification: NCT02628067. Editorial acknowledgement: Medical writing and editorial assistance was provided by Sheri Arndt, PharmD, of C4 MedSolutions, LLC (Yardley, PA), a CHC Group company. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study: Merck Sharp & Dohme Corp. Funding: Merck Sharp & Dohme Corp. Disclosure: M. Ueno: Honoraria and research funding: Taiho Pharmaceutical, Shire, AZ; Honoraria: Yakult Honsha, Novartis, Lilly, Teijin Pharma, Ono Pharmaceutical (OP); Research funding: Daiichi Sankyo, Eisai, OP, MSD, Merck Serono, NanoCarrier, Dainippon Sumitomo Pharma, Incyte. H.C. Chung: Consultant/advisor: Taiho, Celltrion, MSD, Lilly, Quintiles, BMS, Merck-Serono; Speaker: Merck-Serono, Lilly, Foundation Medicine; Research funding: Lilly, GSK, MSD, Merck-Serono, BMS-Ono, Taiho. A. Nagrial: Consultant/advisor for MSD, AstraZeneca, Shire; Speaker: AstraZeneca, Roche, BMS, MSD. A. Marabelle: Honoraria: Merck, BMS, Roche, Genentech; Research funding: Merus; Travel/accommodation: Roche, BMS, Amgen; Consultant/advisor: Roche, Genentech, Novartis, Amgen; Speaker: BMS, Amgen, Roche, Merck. R.K. Kelley: Advisory board: Bayer, Debiopharm Group; Steering committee: Agios, AZ, BMS; Research funding: Lilly, Exelixis, Regeneron, Celgene, Tekmira, Sanofi, Novartis, BMS, MedImmune, MSD, Agios, AZ, Adaptimmune, Taiho Pharmaceutical, Target Pharmasolutions, Bayer. L. Xu, S.K. Pruitt: Employee: Merck Sharp & Dohme Corp. J. Mahoney: Employee: ExecuPharm, King of Prussia, PA, USA, working under contract at Merck Sharp & Dohme Corp. D-Y. Oh: Research funding: AstraZeneca.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. A first-line standard of care, sorafenib results in median overall survival of 12 months in patients with Child-Pugh class A disease and 6 months in patients with Child-Pugh class B disease with objective response rates (ORRs) not exceeding 19%. These low efficacy rates have driven research on alternative therapeutic options, particularly immune-checkpoint inhibitors (ICIs). We reviewed the response rates (estimated by RECIST 1.1 criteria) across patients with advanced HCC treated with ICIs in phase I-IV clinical trials published between December 2012 to December 2020; 17 reports were identified as eligible and included in the quantitative analysis. Within the selected studies, pembrolizumab + lenvatinib reached the highest absolute ORR (36%), with first-line atezolizumab + bevacizumab showing the second highest ORR (27.3%). With regard to second-line therapy, nivolumab + ipilimumab reached an ORR of 32%, and pembrolizumab alone resulted in an ORR of 17% among sorafenib-experienced patients with advanced HCC. In summary, current studies show high response rates of ICIs in patients with advanced HCC. Nonetheless, further studies are required in the second-line setting to further evaluate ICI therapeutic superiority. Finally, it is of particular interest to examine the therapeutic potential of ICIs for patients with decompensated liver disease (Child-Pugh class C), currently not eligible for any systemic therapy. IMPLICATIONS FOR PRACTICE: Immune-checkpoint inhibitors (ICIs) can provide high objective response rates (ORR, estimated with RECIST 1.1. criteria) when used as first-line treatment in advanced hepatocellular carcinoma, particularly pembrolizumab + lenvatinib (ORR 36%) or atezolizumab + bevacizumab (ORR 27.3%). In sorafenib-experienced patients, nivolumab + ipilimumab (ORR 32%) provided the highest ORR among ICI-based regimens. These findings emphasize high therapeutic potential of ICI-based therapies in patients with advanced hepatocellular carcinoma, although further studies are required to further validate and define their role in this context.

The Rho/ROCK pathway is involved in numerous pivotal cellular processes that have made it an area of intense study in cancer medicine, however, Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are yet to make an appearance in the clinical cancer setting. Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm. This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents. ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy. As such, repurposing of these agents as adjuncts to standard treatments may significantly improve outcomes for patients with cancer. A deeper understanding of the controlled and dynamic regulation of the key components of the Rho pathway may lead to effective use of the Rho/ROCK inhibitors in the clinical management of cancer.

We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection.Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease.In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram.High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables.Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.

104 Background: BMS-986156 is a fully human IgG1 agonist mAb that binds GITR and promotes T effector cell activation and possible reduction/inactivation of T regulatory cells. Preclinical data show enhanced antitumor T-cell activity with anti-GITR + anti–programmed death-1 (PD-1). Here we describe preliminary dose escalation data from a phase I/IIa study of BMS-986156 ± nivolumab (anti–PD-1 mAb) in pts with advanced solid tumors (NCT02598960). Methods: During dose escalation, pts received BMS-986156 (10–800 mg) or BMS-986156 (30–800 mg) + nivolumab (240 mg) every 2 weeks. Objectives included safety (primary), immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of Dec 12, 2016, 66 pts were treated with BMS-986156 (n = 29) or BMS-986156 + nivolumab (n = 37).No dose-limiting toxicities (DLTs) were reported during dose escalation. The most common treatment-related adverse events reported with BMS-986156/BMS-986156 + nivolumab included pyrexia (21%/30%), chills (10%/16%), and fatigue (14%/14%); events were G1/2 in all pts except for 4 pts (6%) treated with the combination (G3 lipase [n = 1], G3 lung infection [n = 1], G3 fatigue [n = 1], and G3 aspartate aminotransferase with G4 creatine phosphokinase [n = 1; leading to discontinuation of treatment]). Preliminary data indicate that the incidence of immunogenicity to BMS-986156 was low when BMS-986156 ± nivolumab was administered. Preliminary data also indicate that BMS-986156 ± nivolumab exhibits linear PK with dose proportionality after a single dose, and BMS-986156 ± nivolumab is biologically active in PD analyses in peripheral blood. Initial antitumor activity has been observed in several pts treated with the combination; these data will be reported. Conclusions: This is the first report of clinical data with an anti-GITR mAb ± a PD-1 inhibitor.BMS-986156 ± nivolumab was well tolerated, with no DLTs and low immunogenicity. Antitumor activity was observed with BMS-986156 + nivolumab at doses predicted to be biologically active. Further evaluation of this combination in pts with advanced solid tumors is ongoing. Clinical trial information: NCT02598960.

Abstract Background Immunotherapy with or without chemo has improved survival vs chemo in 1L aNSCLC. NIVO + chemo showed encouraging activity in a phase 1 study in this setting. CheckMate 227 is a multi-part, randomized, open-label, phase 3 study evaluating NIVO-based regimens vs chemo. We present final results from Part 2, which evaluated NIVO + chemo vs chemo in 1L aNSCLC. Methods Pts (N = 755) with chemo-naive, stage IV or recurrent NSCLC, ECOG PS 0–1, and no sensitizing EGFR/ALK alterations were randomized 1:1 to receive every 3 weeks NIVO 360 mg + chemo or chemo. Pts were stratified by histology (squamous [SQ] vs non-squamous [NSQ]), sex, and PD-L1 expression ( Results Baseline characteristics were generally balanced. Minimum follow-up was 19.5 mo. In pts with NSQ NSCLC, no statistically significant improvement in OS was seen with NIVO + chemo vs chemo (HR, 0.86 [95.62% CI, 0.69–1.08; P=0.1859]); median OS was 18.8 mo vs 15.6 mo; 12-mo OS rates were 67.3% vs 59.2%. HR for OS was 0.81 (95% CI, 0.67–0.97) in all randomized pts; 0.69 (95% CI, 0.50–0.97) in pts with SQ NSCLC. Progression-free survival and objective response rates favored NIVO + chemo in NSQ, SQ, and all randomized pts (table). Grade 3–4 tx-related adverse events occurred in 45% and 35% of all pts treated with NIVO + chemo and chemo, respectively.TableLBA3 Efficacy outcomes with 1L NIVO + chemo vs chemo in pts with NSQ NSCLC, SQ NSCLC, and in all randomized ptsTableNSQ NSCLCSQ NSCLCAll Randomized PtsNIVO + chemoChemoNIVO + chemoChemoNIVO + chemoChemon=270n = 273n=107n = 105n=377n = 378OSEvents, n (%)156 (57.8)164 (60.1)68 (63.6)75 (71.4)224 (59.4)239 (63.2)Median, mo18.815.618.312.018.314.7HR (95% CI)0.86 (0.69–1.08)aP = 0.18590.69 (0.50–0.97)0.81 (0.67–0.97)12-mo OS rate, %67.359.266.148.566.956.2PFSEvents, n (%)187 (69.3)200 (73.3)79 (73.8)82 (78.1)266 (70.6)282 (74.6)Median, mo8.75.87.14.48.45.5HR (95% CI)0.67 (0.55–0.82)0.51 (0.37–0.70)0.62 (0.52–0.73)12-mo PFS rate, %39.525.731.79.337.321.3Objective response rate, n (%)130 (48.1)80 (29.3)64 (59.8)34 (32.4)194 (51.5)114 (30.2)a95.62% CI Conclusion CheckMate 227 Part 2 did not meet the primary endpoint of OS for NIVO + chemo vs chemo in NSQ NSCLC. Descriptive analyses showed longer OS with NIVO + chemo in all randomized pts and SQ NSCLC. No new safety signals were observed. Clinical trial identification NCT02477826; Release date: June 23, 2015. Editorial acknowledgement Writing and editorial assistance was provided by Namiko Abe, PhD, of Caudex, funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure L. Paz-Ares: Honoraria (self): Roche, MSD, Lilly, Novartis, Boehringer Ingelheim, AstraZeneca, Amgen, Sanofi, Pharmamar, Pfizer, Bristol-Myers Squibb, Merck, Takeda, Celgene, Servier, Sysmex, Incyte, Ipsen, Adacap, Bayer, Blueprint; Leadership role: Altum Sequencing; Research grant / Funding (institution): MSD, AstraZeneca, Pfizer, Bristol-Myers Squibb; Officer / Board of Directors: Genomica. T.E. Ciuleanu: Advisory / Consultancy: Astellas, Janssen, Bristol-Myers Squibb, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Lilly, AstraZeneca, MSD, Sanofi, Novartis, Servier, AD Pharma. A. Pluzanski: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche; Speaker Bureau / Expert testimony: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche, Takeda; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche. A. Nagrial: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; Research grant / Funding (institution): Astra Zeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche. R. Kowalyszyn: Advisory / Consultancy: Astellas, Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, MSD, Novartis; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Lilly, MSD, Pfizer, Roche. C. Audigier-Valette: Honoraria (self): AbbVie, Pfizer; Honoraria (institution): Roche, MSD, Bristol-Myers Squibb, AstraZeneca; Advisory / Consultancy: Roche, MSD, Bristol-Myers Squibb, AstraZeneca, AbbVie, Pfizer. Y-L. Wu: Honoraria (self): AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, BMS, Roche; Non-remunerated activity/ies: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche. H. Borghaei: Honoraria (self): University of Pennsylvania, CAR T Program, Takeda [Data and Safety Monitoring Board]; Advisory / Consultancy: Bristol-Myers Squibb, Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bio, GLG; Research grant / Funding (self): Millennium, Merck/Celgene, Bristol-Myers Squibb/Lilly. M.D. Hellmann: Advisory / Consultancy: Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, Syndax, Shattuck Labs, Immunai, Nektar, Blueprint Medicines; Research grant / Funding (institution): Bristol-Myers Squibb; Travel / Accommodation / Expenses: Bristol-Myers Squibb, AstraZeneca; Shareholder / Stockholder / Stock options: Shattuck Labs, Immunai. J. Brahmer: Advisory / Consultancy: Bristol-Myers Squibb, AstraZeneca, Genentech, Merck, Amgen. M. Reck: Honoraria (self): AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Advisory / Consultancy: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. S. Ramalingam: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Roche/Genentech, Loxo, Tesaro, Merck, Daichi; Advisory / Consultancy: Amgen, AbbVie, Lilly, Genentech, Takeda; Research grant / Funding (institution): Bristol-Myers Squibb, Amgen, AstraZeneca, Takeda, Advaxis, Tesaro, Merck. L. Zhang: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: AstraZeneca, Bristol-Myers Squibb, MSD, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Pfizer, Henrui Pharm. P. Bhagavatheeswaran: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F.E. Nathan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. K.J. O'Byrne: Advisory / Consultancy: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim, Novartis, Teva, Janssen-Cilag, Natera; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim, Janssen-Cilag, Mundipharma; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim; Shareholder / Stockholder / Stock options: Carp Pharmaceuticals, Carpe Vitae Phaemaceuticals; Licensing / Royalties: Various patents issues with licensee as listed. Queensland University of Technology and Trinity College Dublin. All other authors have declared no conflicts of interest.

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.

There remains uncertainty regarding the optimal second-line chemotherapy in advanced pancreatic ductal adenocarcinoma (PDAC). The current recommendation of 5-fluorouracil and oxaliplatin may not be relevant in current practice, as FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) has become a more popular first line therapy in fit patients. The majority of studies in this setting are single-arm Phase II trials with significant heterogeneity of patient populations, treatments and outcomes. In this review, we sought to systematically review and synthesise all prospective data available for the second-line treatment of advanced PDAC.

Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population.Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks.Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3-28.9).Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia.ClinicalTrials.gov Identifier: NCT02492789.

Predictive biomarkers for poor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is an area of ongoing research. This multicentre retrospective study sought to determine the impact of programmed death-ligand 1 (PD-L1) tumour proportional score (TPS) on outcome in EGFR TKI treated patients.Patients with Stage IIIB/IV lung adenocarcinoma harbouring a sensitising EGFR mutation treated with first-line TKI at five metropolitan hospitals were included. PD-L1 TPS was determined using the Ventana anti-PD-L1 (SP263) assay. High PD-L1 expression was defined as TPS ≥ 50 %. Determinants of progression and survival hazards were modelled using Cox regression.A total of 186 patients were included. Mean age was 67 years, 66 % were female and 54 % were Asian. Patients with high PD-L1 expression (n = 23; 12 %) had significantly shorter progression free survival (6.6 vs 13.0 months, hazard ratio (HR) 2.6 95 % CI 1.6-4.2, p < 0.0001) and overall survival (11.5 vs 32.9 months, HR 3.3, 95 % CI 1.9-5.7, p < 0.0001) compared to patients with PD-L1 low/negative tumours. This remained significant in multivariate analyses. High PD-L1 in post-TKI progression biopsies was not associated with poorer survival.In this large, real-world cohort of EGFR-mutant lung adenocarcinoma patients, high PD-L1 expression was associated with early resistance to 1st generation EGFR TKIs and shorter survival, regardless of ethnicity.

Over the past decade, ALK tyrosine kinase inhibitors have delivered unprecedented survival for individuals with ALK-positive (ALK+) lung cancers. Real-world data enhance the understanding of optimal drug sequencing and expectations for survival.Multicenter real-world study of individuals with pretreated advanced ALK+ lung cancers managed on a lorlatinib access program between 2016 and 2020. Key outcomes were lorlatinib efficacy, tolerability, and treatment sequencing. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method among all individuals (PFSa and OSa), with at least 30 days (one-cycle) lorlatinib exposure (PFSb and OSb), and with good performance status (PFSc and OSc). Subgroups of interest were analyzed to assess signals of potential clinical applicability. Two OS index dates were analyzed, from lorlatinib initiation and advanced ALK+ diagnosis.The population (N = 38, 10 sites) was heavily pretreated (23 had ≥2 previous treatment lines) with a high disease burden (26 had 2-4 sites and 11 had >4 sites of metastatic disease, 19 had brain metastases). The overall response rate was 44% and the disease control rate was 81%. Lorlatinib dose reduction (18%), interruption (16%), and discontinuation (3%) were consistent with the trial experience. From advanced ALK+ diagnosis, the median OS for populations a, b, and c was 45.0 months, 69.9 months and 61.2 months respectively. From lorlatinib initiation, the median PFSa, PFSb and PFSc was 7.3 months, 13.2 months and 27.7 months and the median OSa, OSb and OSc was 19.9 months, 25.1 months and 27.7 months. The median PFSa with versus without brain metastases was 34.6 months versus 5.8 months (p = 0.09). The intracranial median PFS was 14.2 months. Previous good response versus poor response to the first ALK-directed therapy median PFSa was 27.7 months versus 4.7 months with a hazard ratio of 0.3 (p = 0.01).Lorlatinib is a potent, highly active brain-penetrant third-generation ALK tyrosine kinase inhibitors with benefits for most individuals in the later-line setting in a real-world evaluation, consistent with clinical trial data.

To develop effective combination therapy against pancreatic ductal adenocarcinoma (PDAC) with a combination of chemotherapy, CHK1 inhibition, and EGFR-targeted radioimmunotherapy.Maximum tolerated doses were determined for the combination of gemcitabine, the CHK1 inhibitor PF-477736, and Lutetium-177 ((177)Lu)-labeled anti-EGFR antibody. This triple combination therapy was investigated using PDAC models from well-established cell lines, recently established patient-derived cell lines, and fresh patient-derived xenografts. Tumors were investigated for the accumulation of (177)Lu-anti-EGFR antibody, survival of tumor-initiating cells, induction of DNA damage, cell death, and tumor tissue degeneration.The combination of gemcitabine and CHK1 inhibitor PF-477736 with (177)Lu-anti-EGFR antibody was tolerated in mice. This triplet was effective in established tumors and prevented the recurrence of PDAC in four cell line-derived and one patient-derived xenograft model. This exquisite response was associated with the loss of tumor-initiating cells as measured by flow cytometric analysis and secondary implantation of tumors from treated mice into treatment-naïve mice. Extensive DNA damage, apoptosis, and tumor degeneration were detected in the patient-derived xenograft. Mechanistically, we observed CDC25A stabilization as a result of CHK1 inhibition with consequent inhibition of gemcitabine-induced S-phase arrest as well as a decrease in canonical (ERK1/2 phosphorylation) and noncanonical EGFR signaling (RAD51 degradation) as a result of EGFR inhibition.Our study developed an effective combination therapy against PDAC that has potential in the treatment of PDAC.

Comprehensive characterization of signaling in pancreatic ductal adenocarcinoma (PDAC) promises to enhance our understanding of the molecular aberrations driving this devastating disease, and may identify novel therapeutic targets as well as biomarkers that enable stratification of patients for optimal therapy. Here, we use immunoaffinity-coupled high-resolution mass spectrometry to characterize global tyrosine phosphorylation patterns across two large panels of human PDAC cell lines: the ATCC series (19 cell lines) and TKCC series (17 cell lines). This resulted in the identification and quantification of over 1800 class 1 tyrosine phosphorylation sites and the consistent segregation of both PDAC cell line series into three subtypes with distinct tyrosine phosphorylation profiles. Subtype-selective signaling networks were characterized by identification of subtype-enriched phosphosites together with pathway and network analyses. This revealed that the three subtypes characteristic of the ATCC series were associated with perturbations in signaling networks associated with cell-cell adhesion and epithelial-mesenchyme transition, mRNA metabolism, and receptor tyrosine kinase (RTK) signaling, respectively. Specifically, the third subtype exhibited enhanced tyrosine phosphorylation of multiple RTKs including the EGFR, ERBB3 and MET. Interestingly, a similar RTK-enriched subtype was identified in the TKCC series, and 'classifier' sites for each series identified using Random Forest models were able to predict the subtypes of the alternate series with high accuracy, highlighting the conservation of the three subtypes across the two series. Finally, RTK-enriched cell lines from both series exhibited enhanced sensitivity to the small molecule EGFR inhibitor erlotinib, indicating that their phosphosignature may provide a predictive biomarker for response to this targeted therapy. These studies highlight how resolution of subtype-selective signaling networks can provide a novel taxonomy for particular cancers, and provide insights into PDAC biology that can be exploited for improved patient management.

Durvalumab following concurrent chemoradiotherapy is standard treatment for unresectable stage III non-small-cell lung cancer based on the results of the PACIFIC trial. Based on trial criteria, not all patients are eligible for durvalumab in routine clinical practice.We evaluated eligibility for durvalumab in a real-world clinical setting and the impact of eligibility on outcomes. Consecutive patients treated with concurrent chemoradiotherapy at two tertiary centers between January 2015 and June 2022 were assessed. Clinical characteristics and outcomes were evaluated based on eligibility criteria for the PACIFIC trial.A total of 126 patients were included. Seventy patients (56%) were eligible for durvalumab. Ineligibility was associated with shorter progression-free survival of 9.7 months versus 18.4 months (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.39-0.95, p = 0.029) and overall survival of 26.4 months versus 58.7 months (HR 0.47, 95% CI 0.28-0.80, p = 0.005). Common reasons for ineligibility were history of previous malignancy (32%) and progressive disease or death during chemoradiotherapy (25%). Ineligible patients who received durvalumab had similar outcomes to eligible patients who received durvalumab.In a real-world cohort, adjuvant durvalumab is safe and beneficial in a substantial proportion of patients who would not have been eligible for the PACIFIC trial.

Increasing evidence strongly supports the key role of the tumour microenvironment in response to systemic therapy, particularly immune checkpoint inhibitors (ICIs). The tumour microenvironment is a complex tapestry of immune cells, some of which can suppress T-cell immunity to negatively impact ICI therapy. The immune component of the tumour microenvironment, although poorly understood, has the potential to reveal novel insights that can impact the efficacy and safety of ICI therapy. Successful identification and validation of these factors using cutting-edge spatial and single-cell technologies may enable the development of broad acting adjunct therapies as well as personalised cancer immunotherapies in the near future. In this paper we describe a protocol built upon Visium (10x Genomics) spatial transcriptomics to map and characterise the tumour-infiltrating immune microenvironment in malignant pleural mesothelioma. Using ImSig tumour-specific immune cell gene signatures and BayesSpace Bayesian statistical methodology, we were able to significantly improve immune cell identification and spatial resolution, respectively, improving our ability to analyse immune cell interactions within the tumour microenvironment.

Vibostolimab, a humanized, antagonist monoclonal antibody, binds to the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and blocks its interaction with its ligands, CD112 and CD155. In the first-in-human, phase 1 dose-finding study (NCT02964013), vibostolimab monotherapy plus pembrolizumab was well tolerated, with a manageable safety profile across all doses tested in patients with advanced solid tumors in the dose-escalation/confirmation phase. Promising antitumor activity was observed in a heavily pretreated population across multiple tumor types. We present results of the dose-expansion/confirmation phase in patients with non–small cell lung cancer (NSCLC) naive to prior anti–PD-1/PD-L1 therapy (anti–PD-1/PD-L1-naive). Patients with anti–PD-1/PD-L1-naive advanced NSCLC, regardless of PD-L1 status, received vibostolimab (200 or 210 mg) plus pembrolizumab (200 mg) on day 1 of each 3-week cycle for up to 35 cycles. Primary end points were safety and tolerability. Secondary and exploratory end points included ORR, DOR, and PFS based on investigator review per RECIST v1.1. Database cutoff was March 3, 2020. In the 41 patients enrolled with anti–PD-1/PD-L1-naive NSCLC, 73% had received ≥1 prior line of therapy. Median age was 62 years; 68% were male and 83% had an ECOG performance status of 1. Median follow-up was 11 months (range, 7-18). Treatment-related adverse events (TRAEs) occurred in 34 patients (83%); pruritus (34%), hypoalbuminemia (29%), and pyrexia (20%) were the most frequent (≥20%). Grade 3-4 TRAEs occurred in 6 patients (15%); no deaths due to TRAEs were reported. ORR and PFS are reported in the table. Median DOR for all patients was not reached (range, 4 to 17+ months).Table:All Patients N = 41TPS ≥1% n = 13TPS <1% n = 12ORR, % (95% CI)29 (16-46)46 (19-75)25 (5-57)Median PFS, months (95% CI)5.4 (2.1-8.2)8.4 (3.9-10.2)4.1 (1.9-NR)16 patients did not have available PD-L1 data. Open table in a new tab Vibostolimab in combination with pembrolizumab was well tolerated and demonstrated promising antitumor activity in patients with advanced NSCLC naive to anti–PD-1/PD-L1 therapy.

Background. Colorectal cancer (CRC) is the fourth most deadly cancer worldwide. Unfortunately, a quarter of the patients are diagnosed at late stages, when surgical options are limited. Targeted therapies, particularly immune-checkpoint inhibitors (ICIs), are the latest addition and have been studied herein regarding their efficacy outcomes. Methods. Clinical studies were identified through the PubMed, Scopus and Cochrane databases. Any trial that evaluated ICIs in patients with metastatic CRC (mCRC) and reported the objective response rate was deemed eligible. Data analysis was performed by employing the random-effects model in STATA v.17. Results. A total of 461 articles were identified; 13 clinical trials were included, encompassing a total cohort of 1209 patients. Our study determined that a single PD-1/PD-L1 checkpoint blockade provides durable clinical response in mCRC patients with high microsatellite instability (MSI-H). The combinatorial therapy of CTLA-4 + PD-1 inhibitors also showed high response rates in pre-treated MSI-H patients. The single-arm REGONIVO trial reported durable clinical response in patients with microsatellite stable (MSS) status. Conclusions. Our study surmises that PD-1/PD-L1 inhibitors as well as combination therapy with CTLA-4 and PD-1 inhibitors show encouraging response rates in mCRC patients, albeit exclusively in patients with cancer that are of MSI-H status. A single study suggests that nivolumab + regorafenib can reach a durable response rate in MSS patients; however, further studies in larger randomized settings are required.

<h3>Background</h3> Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (³²P) microparticles, combined with standard-of-care chemotherapy. <h3>Patients and methods</h3> In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received ³²P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. <h3>Results</h3> Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received ³²P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to ³²P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively. <h3>Conclusions</h3> Endoscopic ultrasound-guided ³²P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining ³²P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC.

The treatment of advanced pancreatic cancer has not moved much beyond single agent gemcitabine until recently when protocols such as FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) and nab-paclitaxel-gemcitabine have demonstrated some improved outcomes. Advances in technology especially in massively parallel genome sequencing has progressed our understanding of the biology of pancreatic cancer especially the candidate signalling pathways that are involved in tumourogenesis and disease course. This has allowed identification of potentially actionable mutations that may be targeted by new biological agents. The heterogeneity of pancreatic cancer makes tumour tissue collection important with the aim of being able to personalise therapies for the individual as opposed to a one size fits all approach to treatment of the condition. This paper reviews the developments in this area of translational research and the ongoing clinical studies that will attempt to move this into the everyday oncology practice.

Non-coding RNAs (ncRNAs) are an abundant component of the human transcriptome. Their biological role, however, remains incompletely understood. Nevertheless, ncRNAs are highly associated with cancer development and progression due to their ability to modulate gene expression, protein translation and growth pathways. Immune-checkpoint inhibitors (ICIs) are considered one of the most promising and highly effective therapeutic approaches for cancer treatment. ICIs are monoclonal antibodies targeting immune checkpoints such as CTLA-4, PD-1 and PD-L1 signalling pathways that stimulate T cell cytotoxicity and can result in tumor growth suppression. This Review will summarize existing knowledge regarding ncRNAs and their role in cancer and ICI therapy. In addition, we will discuss potential mechanisms by which ncRNAs may influence ICI treatment outcomes.

2630 Background: AK117 is a novel humanized IgG4 monoclonal antibody (mAb) targeting CD47, a macrophage immune checkpoint that allows tumor cells to evade immune destruction by phagocytic cells. CD47 is a target expressed in many cancers. However, the initial dose of anti-CD47 therapy may be limited by severe anemia due to ubiquitous CD47 expression on senescent red blood cells (RBCs). Here, we present encouraging preliminary AK117 safety and receptor occupancy (RO) data from an ongoing dose-escalation study in patients (pts) with advanced or metastatic solid tumors. Methods: This is a first-in-human, phase 1a/1b, multicenter, open label, single arm, dose escalation and dose expansion study of AK117 administered intravenously to adult pts with resistant/refractory advanced or metastatic solid tumors or lymphomas. In the dose escalation phase (phase 1a), an accelerated titration followed by a 3+3+3 design was used to assess the safety and tolerability of AK117 monotherapy (dose range 0.3 mg/kg to 45 mg/kg); and determine the maximum tolerated dose (MTD). AK117 was administered QW on a 28-day treatment cycle and dose limiting toxicity (DLT) observation period. Tumor assessments per RECIST v1.1 were performed once every 8 weeks (2 cycles). Results: As of 15 Feb 2021, 15 pts were enrolled in phase 1a with DLT evaluation of the 30 mg/kg cohort currently in progress. There were no DLTs up to 20 mg/kg QW AK117, inclusive. Five treatment-related adverse events (TRAEs) occurred in 4 subjects as shown in the table below. All pts with TRAEs continue to receive AK117, except the pt on 1 mg/kg AK117 who discontinued due to disease progression. G2 anemia and G1 thrombocytopenia occurred after Cycle 1 in a pt (liposarcoma, 10 mg/kg cohort), who had a medical history of anemia (hemoglobin 119 g/L at screening). No hematological TRAEs were seen in other pts, including those who received 20 mg/kg AK117 QW. There were no infusion-related reactions (IRRs) or grade ≥ 3 TRAEs. Target engagement in the periphery was confirmed by measuring CD47 RO of AK117 on RBCs and T lymphocytes. 100% RO on RBCs and T lymphocytes was achieved after the first dose and continued to Day 8 (prior to second dose) in the 10 mg/kg and 20 mg/kg cohorts. Conclusions: AK117 is safe and well-tolerated up to 20 mg/kg QW, inclusive, with no IRRs or severe TRAEs observed. There were no hematological TRAEs, except in a pt with baseline G1 anemia receiving 10 mg/kg AK117. Unlike other anti-CD47 therapies, AK117 does not require a lower ‘priming’ dose to prevent anemia. Safety evaluation of the 30 mg/kg dose level is in progress. Full and durable RO in the periphery was seen at 10 mg/kg and above. Further evaluation of AK117 in combination with AK104, an anti-PD-1/CTLA-4 bispecific antibody, shall commence imminently. Clinical trial information: NCT04349969. [Table: see text]

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<h2>Abstract</h2><h3>Introduction</h3> Consolidation durvalumab following platinum-based chemoradiotherapy (CRT) significantly improved overall survival for patients with unresectable stage III non-small cell lung cancer (NSCLC) in the PACIFIC trial. However, older patients were underrepresented in PACIFIC, and subsequent analyses suggested trends toward poorer survival and increased toxicity in patients aged ≥70 years old. We assessed the effectiveness and safety of consolidation durvalumab following CRT in older Australian patients with unresectable stage III NSCLC. <h3>Materials and Methods</h3> This retrospective observational study was conducted across seven sites in Sydney, Australia between January 2018 and September 2021. All adult patients with unresectable stage III NSCLC who received platinum-based chemoradiotherapy followed by at least one cycle of consolidation durvalumab were included. Older patients were defined as being ≥70 years old. <h3>Results</h3> Of 152 patients included in the analysis, 42.8% (<i>n</i> = 67) patients were 70 years or older. Median follow-up was 26.1 months. The two-year overall survival and median PFS was similar between older and younger patients. At two years, 74.8% (95% confidence interval [CI]: 65.4–84.2%) of patients <70 years old and 65.2% (95% CI: 53.4–77.0%) of older patients were alive (<i>p</i> = 0.07; hazard ratio [HR] 1.64, 95% CI: 0.95–2.81). Median progression-free survival (PFS) in patients <70 years was 30.3 months (95% CI: 22.2–38.4 months) compared with 26.7 months (95% CI: 12.8–40.6 months) in older patients (<i>p</i> = 0.22; HR 1.46, 95% CI: 0.80–2.65). Toxicity was also similar, with 11.5% of patients <70 years old and 18.5% of older patients experiencing grade 3–4 adverse events (AEs; <i>p</i> = 0.23); 16.1% and 24.6% of the patients, respectively, discontinued treatment due to toxicity (<i>p</i> = 0.19). Grade 3–4 AEs and treatment discontinuation were associated with Charlson Comorbidity Index >5 (<i>p</i> = 0.011) and chronic obstructive pulmonary disease diagnosis at presentation (<i>p</i> = 0.002), respectively. <h3>Discussion</h3> Older Australian patients receiving consolidation durvalumab following CRT experienced comparable outcomes to their younger peers. Comorbidity burden may be more important determinants of treatment tolerance than chronological age.

Introduction Brain metastases commonly occur in patients with non-small cell lung cancer (NSCLC). Standard first-line treatment for NSCLC, without an EGFR, ALK or ROS1 mutation, is either chemoimmunotherapy or anti-PD-1 monotherapy. Traditionally, patients with symptomatic or untreated brain metastases were excluded from the pivotal clinical trials that established first-line treatment recommendations. The intracranial effectiveness of these treatment protocols has only recently been elucidated in small-scale prospective trials. Methods Patients with NSCLC and brain metastases, treated with first-line chemoimmunotherapy or anti-PD-1 monotherapy were selected from the Australian Registry and biObank of thoracic cancers (AURORA) clinical database covering seven institutions. The primary outcome was a composite time-to-event (TTE) outcome, including extracranial and intracranial progression, death, or need for local intracranial therapy, which served as a surrogate for disease progression. The secondary outcome included overall survival (OS), intracranial objective response rate (iORR) and objective response rate (ORR). Results 116 patients were included. 63% received combination chemoimmunotherapy and 37% received anti-PD-1 monotherapy. 69% of patients received upfront local therapy either with surgery, radiotherapy or both. The median TTE was 7.1 months (95% CI 5 - 9) with extracranial progression being the most common progression event. Neither type of systemic therapy or upfront local therapy were predictive of TTE in a multivariate analysis. The median OS was 17 months (95% CI 13-27). Treatment with chemoimmunotherapy was predictive of longer OS in multivariate analysis (HR 0.35; 95% CI 0.14 – 0.86; p=0.01). The iORR was 46.6%. The iORR was higher in patients treated with chemoimmunotherapy compared to immunotherapy (58% versus 31%, p=0.01). The use of chemoimmunotherapy being predictive of iORR in a multivariate analysis (OR 2.88; 95% CI 1.68 - 9.98; p=0.04). Conclusion The results of this study of real-world data demonstrate the promising intracranial efficacy of chemoimmunotherapy in the first-line setting, potentially surpassing that of immunotherapy alone. No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.

Perihilar cholangiocarcinoma (pCCA) is an uncommon malignancy with generally poor prognosis. Surgery is the primary curative treatment; however, the perioperative mortality and morbidity rates are high, with a low 5-year survival rate. Use of preoperative prognostic biomarkers to predict survival outcomes after surgery for pCCA are not well-established currently. This systematic review aimed to identify and summarise preoperative biomarkers associated with survival in pCCA, thereby potentially improving treatment decision-making. The Embase, Medline, and Cochrane databases were searched, and a systematic review was performed using the PRISMA guidelines. English-language studies examining the association between serum and/or tissue-derived biomarkers in pCCA and overall and/or disease-free survival were included. Our systematic review identified 64 biomarkers across 48 relevant studies. Raised serum CA19-9, bilirubin, CEA, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and tumour MMP9, and low serum albumin were most associated with poorer survival; however, the cutoff values used widely varied. Several promising molecular markers with prognostic significance were also identified, including tumour HMGA2, MUC5AC/6, IDH1, PIWIL2, and DNA index. In conclusion, several biomarkers have been identified in serum and tumour specimens that prognosticate overall and disease-free survival after pCCA resection. These, however, require external validation in large cohort studies and/or in preoperatively obtained specimens, especially tissue biopsy, to recommend their use.

<h3>Background</h3> This study explores the potential benefits of neoadjuvant chemotherapy in borderline resectable (BR) pancreatic adenocarcinoma. Despite neoadjuvant treatment (NAT) increasingly being utilised, uncertainty remains as to the optimal approach. <h3>Patients and methods</h3> This study assessed clinical outcomes for 218 consecutive BR patients from the PURPLE registry. We compared initial surgery (IS) to NAT overall, and between different chemotherapy regimens. <h3>Results</h3> Of 1314 non-metastatic patients enrolled, 218 (17%) were considered BR. Of 28 planned for IS, 11/28 (39%) had their tumour excised compared to 68/152 (45%) with NAT (<i>P</i> = 0.59). Among those who received NAT and were resected, 52/100 (52%) received FOLFIRINOX (<i>P</i> = 0.234) and 8/28 (29%) received nab-paclitaxel with gemcitabine (nabPGem). There was no difference in median overall survival (OS) [hazard ratio (HR) 0.72, <i>P</i> = 0.199] between pooled NAT versus IS. Neoadjuvant FOLFIRINOX was associated with improved R0 resection rates (26% versus 7%, <i>P</i> = 0.07) and lower perineural invasion (51% versus 82%, <i>P</i> = 0.02) compared to IS in resected specimens. Neoadjuvant FOLFIRINOX improved OS (HR 0.53, <i>P</i> = 0.02), with a 23% improvement in 2-year OS. There was no difference in survival outcomes between IS and nabPGem. <h3>Conclusions</h3> The results of our study suggest that neoadjuvant FOLFIRINOX could improve R0 resection rate and OS compared to IS.

Abstract Background: The clinical efficacy of immune-checkpoint inhibitors is complicated by the risk for immune-related adverse events (irAEs) that can involve any organ systems. To date, (1) we cannot predict irAE risk reliably at patient level and (2) irAEs remain a diagnosis of exclusion as there are no specific clinical or biological markers. The goal of this study was to elucidate intricate transcriptomic and proteomic signatures of immune cells in patients evolving irAEs. Methods: This pilot trial was conducted as part of a prospective multicenter cohort study (NCT04631731). The study cohort consisted of n=71 patients who were treated with ICIs across Blacktown and Westmead Hospitals, NSW, Australia. Peripheral blood mononuclear cells (PBMCs) were collected from both pre-treatment and after 6-8 weeks post-ICI commencement. Samples were further utilized for RNA sequencing, flow cytometry and Chromium 3’ gene expression analysis (10x Genomics). Results: The median age was 67 years old with the 78% (n=56) of Caucasian origin. The predominant number of patients were treated with dual ICIs. N=21 patients experienced irAEs. Firstly, a differential analysis established a set of genes which were significantly (FDR&amp;lt;0.01) dysregulated between patients with (group A) and without irAEs (group B) and were mostly related to cell cycle and regulation. Notably, phospholipase D signaling pathway was exclusively upregulated in group A and is known to be linked to B cell expansion. Secondly, a cell enrichment analysis within the group A revealed a significant increase of CD4+ and CD8+ T central memory (Tcm) cells upon the toxicity onset as compared to baseline stage. Thirdly, the flow cytometry data established that group A had (1) higher expression of CD27 on CD4+ T cells, a member of Traf-linked tumor necrosis factor receptor family essential for T cells’ maturation and (2) lower expression of inhibitory receptor LAG3 (CD223) which is crucial for maintaining homeostasis of immune system through suppression of T cell proliferation. Finally, we sequenced CD45+ cells from n=4 patients from group A and n=4 from group B at both pre- and post-treatment stages. The unsupervised clustering established 17 different clusters in our single cell dataset with cluster 11 was unique only to patients from group A. The differential analysis established that a set of n=62 genes was significantly upregulated (p&amp;lt;0.05) in cluster 11. Functional annotation established that B cell activation and proliferation pathways were enriched by those genes further stressing B cells’ role in irAEs development. Conclusions: Our real-world cohort study established significant molecular and cellular differences between patients with and without irAEs. Further research in larger cohorts is imperative to validate the established findings and to elucidate the precise mechanisms contributing to the development of irAEs. Citation Format: Dmitrii Shek, Bo Gao, Joey Lai, Brian Gloss, Adnan Nagrial, Ines Pires da Silva, Matteo S. Carlino, Scott A. Read, Golo Ahlenstiel. In-depth multi-omic profiling of immune cells in cancer patients developing immune-related adverse events [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2533.

Abstract Background: Narmafotinib (AMP945) is a selective and orally bioavailable inhibitor of Focal Adhesion Kinase (FAK). FAK plays a key role in tumour growth, particularly in immunosuppression, cancer cell invasion and metastasis, and contributes to multiple mechanisms underlying fibrosis. In the Phase 1 study (healthy volunteers) narmafotinib was safe and well tolerated across single ascending dose (15 to 125 mg) and multiple ascending doses for 7 days (25 to 100 mg), with PK/PD data demonstrating wide tissue distribution and target engagement. Methods: ACCENT trial (NCT05355298) is a Phase 1b/2a, open label study of the pharmacokinetics, safety and efficacy of narmafotinib in combination with gemcitabine and nab-paclitaxel (Abraxane) standard of care as first-line therapy in patients with advanced pancreatic cancer. The trial is a single-arm open label study conducted in two stages. In Part A, patients were enrolled in a 3+3 design to determine the narmafotinib recommended Phase 2 dose (RP2D), with narmafotinib dose-escalation (100, 200 and 400 mg). Part B is a Simon’s two stage design, with the primary objectives of assessing safety, tolerability, and efficacy of the combination using RECIST v1.1 (centrally by independent reviewers). Narmafotinib plasma PK samples were collected on Days -8, -7, 1, 3, 8, and 10 of Run-In/Cycle 1. Safety and tolerability were assessed according to incidence and severity of adverse events. Imaging was conducted every 2 months. Results: Preliminary analysis across all doses (14 patients) showed narmafotinib to be generally safe and well-tolerated and showed promising signs of efficacy. At first on study imaging (Day 56), 86% of patients had stable disease and 12% had a partial response (PR). Subsequent RECIST assessments conducted locally at sites showed PR in 47% of patients. A single DLT was reported: uncontrolled grade 3 nausea (400 mg cohort). Fatigue, grade 3 or below was related to narmafotinib occurred in more than one participant. All patients who completed their first 28-day cycle of treatment elected to stay on narmafotinib, with 7 patients receiving narmafotinib in combination with chemotherapy for 5 months or more. The PK for narmafotinib is dose-proportional across the dose range tested, and the half-life supports once a day dosing. The chemotherapy regimen used in this study did not impact narmafotinib PK. Conclusions: Based on this promising Phase 1b data, 400 mg of narmafotinib has been selected for RP2D and the trial will proceed through Simon’s Two Stage design and enrol up to 50 patients as part of the Phase 2 expansion cohort. Citation Format: Terrie-Anne Cock, Anthony Bishop, Nicole Kruger, Sarah McCormack, Marion Harris, Sumitra Ananda, Lara Lipton, Adnan Nagrial, Nick Pavlakis, Warren Joubert, Laura Donato, Jason Lickliter, Christopher Burns. Phase 1b/2a of narmafotinib (AMP945) in combination with gemcitabine and nab-paclitaxel (Abraxane) standard of care as first-line therapy in patients with advanced pancreatic cancer (ACCENT trial): interim analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT220.

<h2>Abstract</h2><h3>Background</h3> Seminal trials with first-line pembrolizumab for metastatic non-small cell lung cancer (NSCLC) mandated a maximum two-years treatment. We describe real-world outcomes of a multi-site Australian cohort of patients who completed two-years of pembrolizumab. <h3>Methods</h3> Retrospective data were collected from the national AUstralian Registry and biObank of thoRacic cAncers (AURORA). Primary endpoints were progression rate post pembrolizumab discontinuation; and progression free survival (PFS). Local treatment of oligoprogressive disease during pembrolizumab was allowed. <h3>Results</h3> 71 patients from six centres, median age 66.0years, 49% male and 90% ECOG≤1 were identified. Patients were Caucasian(82%) or Asian(16%); past(66%) or current(24%) smokers with mean 37 pack-years. Histology comprised 73% adenocarcinoma and 16% squamous. 18 patients(25%) had brain metastases at diagnosis. Median PD-L1 tumour proportion score (TPS) was 68%; 12 patients(17%) TPS<1% and 43(61%) TPS≥50%. No patients had <i>EGFR/ALK/ROS1</i> alterations; 29/49 tested(60%) had <i>KRAS</i> mutations. Median follow up was 38.7 months. Objective response rate 78.6%. Median PFS 46.1 months (95%CI 39.5-NR), not reached (46.1-NR) in PD-L1 TPS≥1% versus 28.1 months (16.3-NR) in TPS<1% (p=0.013). 17 patients(24%) received additional local therapy for oligoprogression. Post pembrolizumab discontinuation, 20 patients(28%) had disease progression. Higher rates of progression occurred with TPS<1% (OR3.46, p=0.06), without complete response (OR5.06, p=0.04), and with treated oligoprogression (OR3.11, p=0.05). 36-month landmark survival was 98.2%. <h3>Conclusion</h3> Patients completing two-years of pembrolizumab for NSCLC in an Australian cohort had high rates of <i>KRAS</i> mutation and PD-L1 expression; a proportion had brain metastases and treated oligoprogression. Progression post pembrolizumab was higher in PD-L1 TPS<1% and in those without complete response. <h3>Micro Abstract</h3> • Seminal trials with first-line pembrolizumab for metastatic non-small cell lung cancer (NSCLC) mandated a maximum two years treatment. We present real world outcomes of a multi-site Australian cohort of patients who completed two years of treatment. • Retrospective data were collected from the AURORA (AUstralian Registry and biObank of thoRacic cAncers) national database. Primary endpoints were progression rate post pembrolizumab discontinuation and progression free survival (PFS). • 71 patients were identified. Many past (66%) or current (24%) smokers with mean 37 pack-years. Median PD-L1 tumour proportion score (TPS) was 68% with high rates of <i>KRAS</i> mutation (60%). • Post pembrolizumab discontinuation 20 patients (28%) had disease progression. Median PFS was 46.1 months (95%CI 39.5-NR). A significant proportion of patients had brain metastases at diagnosis and treated oligoprogression during pembrolizumab and still completed two years of therapy. • Progression rate after pembrolizumab cessation was higher in PD-L1 negative patients and in those without complete response.

Background Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors. Methods Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1. Results Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer. Conclusions Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted. Trial registration number NCT04047290 .

Abstract Background Consolidation durvalumab after concurrent chemoradiation is the standard of care for unresectable stage III non‐small cell lung cancer (NSCLC) based on the PACIFIC trial. However, there have been reports in the literature suggesting the efficacy of the treatment differs in patients whose tumors harbor epidermal growth factor receptor ( EGFR ) mutations and in those with low programed death ligand‐1 (PD‐L1) expression. This study describes the survival outcomes for patients with unresectable stage III NSCLC treated with chemoradiation followed by durvalumab with a specific focus on EGFR mutation status and PD‐L1 expression. Methods This retrospective observational study was conducted across six sites in Greater Sydney, Australia. It included all patients diagnosed with unresectable stage III NSCLC treated with chemoradiation and who received at least one cycle of durvalumab between January 2018 and September 2021. Patients were stratified according to EGFR mutation status and PD‐L1 tumor proportion score (TPS) of 1%. Results Of the 145 patients included in the analysis, 15/145 (10%) patients harbored an EGFR mutation and 61/145 (42%) patients had PD‐L1 TPS of &lt;1%. At a median follow‐up of 15.1 months from the start of durvalumab, median progression‐free survival (PFS) in EGFR mutant versus wild‐type patients was 7.5 and 33.9 months, respectively (hazard ratio [HR]: 2.7; 95% confidence intervals [95% CI] 1.2–5.7; p = .01). Overall survival (OS) was not different between EGFR mutant and wild‐type patients. There was no statistically significant difference in PFS (HR .7, 95% CI .4–1.7, p = .43) or OS (HR .5, 95% CI .4–4.7, p = .16) between patients with PD‐L1 TPS of &lt;1% versus PD‐L1 TPS of ≥1%. Conclusions Our data adds to the growing evidence that suggests consolidation durvalumab after definitive chemoradiation may not be as efficacious in patients with EGFR ‐mutant tumors compared with EGFR wild‐type NSCLC.

To systematically review all studies comparing multi-agent to single-agent chemotherapy in the first and second-line setting for unresectable pancreatic adenocarcinoma, so as to compare the outcomes of young and elderly patients.This review searched three databases for relevant studies. The inclusion criteria were diagnosis of locally advanced or metastatic pancreatic adenocarcinoma, comparison of an elderly versus young population, comparison of single-agent versus multi-agent chemotherapy, data on survival outcomes, and randomised controlled trials. The exclusion criteria were phase I trials, incomplete studies, retrospective analyses, systematic reviews, and case reports. A meta-analysis was performed on second-line chemotherapy in elderly patients.Six articles were included in this systematic review. Three of these studies explored first-line treatment and three explored second-line treatment. In the subgroup analysis, the meta-analysis showed statistically improved overall survival for elderly patients receiving single-agent second-line treatment.This systematic review confirmed that combination chemotherapy improved survival in the first-line treatment of advanced pancreatic adenocarcinoma, regardless of age. The benefit of combination chemotherapy in second-line studies for elderly patients with advanced pancreas cancer was less clear.

Small-cell lung cancer (SCLC) is an aggressive disease with distinct biological and clinical features. The clinical course of SCLC is generally characterised by initial sensitivity to DNA-damaging therapies, followed by early relapse and broad cross resistance to second line agents. Whilst there has been an enormous expansion of effective targeted and immune-based therapeutic options for non-small cell lung cancer (NSCLC) in the last decade, little improvement has been achieved in SCLC treatment and survival due, at least in part, to underappreciated inter- and intra-tumoral heterogeneity. Here we review the current treatment paradigm of SCLC including recent advances made in utilizing immunotherapy and the challenges of identifying a predictive biomarker for immunotherapy response. We examine emerging new targeted therapies, combination immunotherapy and future directions of SCLC treatment research.

4136 Background: In a phase 1 study, the anti-CD73 monoclonal antibody (mAb) O plus the anti-PD-L1 mAb D showed antitumor activity and manageable safety in previously treated pts with advanced PDAC (Overman et al, J Clin Oncol 2018;36[suppl 15]:abs 4123). Here we report a multicenter, open-label study of O ± D + CT in pts with mPDAC. Methods: Pts were ≥18 years old with ECOG PS 0–1. Part 1 was a dose escalation phase: in Cohort A, previously untreated (1L) pts received O 1500 or 3000 mg IV Q2W for 4 doses then Q4W + D 1500 mg IV Q4W, with Q4W gemcitabine and nab-paclitaxel (GnP). In Cohort B, pts with previous G-based CT (2L) received O 1500 or 3000 mg Q2W for 4 doses then Q4W + D 1500 mg Q4W, with Q4W mFOLFOX. The primary objective for Part 1 was safety and tolerability; secondary objectives included antitumor activity and pharmacokinetics (PK). Part 2 was an expansion phase in which pts were stratified by high/low tumoral CD73 expression by IHC. In Cohort A, 1L pts were randomized 1:1:1 to GnP alone (Arm A1), O + GnP (Arm A2) or O + D + GnP (Arm A3). O was given at the recommended phase 2 dose, 3000 mg. Cohort B did not proceed to dose expansion due to emerging therapies in 2L PDAC pts. The primary endpoint for Part 2 was investigator-assessed objective response rate (ORR) by RECIST v1.1; secondary included PFS, OS, safety, PK and antidrug antibody data. Results: As of November 11, 2022, 25 pts were treated in Part 1 (Cohort A, n=14; Cohort B, n=11), and 170 pts were treated in Part 2 (Arm A1, n=62; Arm A2, n=38; Arm A3, n=70). In Part 1, dose-limiting toxicities occurred in 1 pt (Cohort B, O 3000 mg: Gr 3 nausea and Gr 3 localized edema). Safety was generally similar in Parts 1 and 2. In Part 2, Gr ≥3 treatment-emergent adverse events (TEAEs) occurred in 85.5%, 89.5% and 90.0% of pts in Arms A1, A2 and A3 respectively, most commonly neutropenia (22.6%, 34.2% and 17.1%). In Part 2, TEAEs led to discontinuation in 11.3%, 23.7% and 24.3% of pts respectively. In Part 2, ORR was similar across Arms with a trend toward longer PFS and OS in Arm 3 vs Arm 1. There was a trend toward greater clinical benefit in pts with high CD73 expression when comparing Arm A3 vs Arm A1. Conclusions: O + D + GnP had similar safety and a trend toward improved outcomes compared to GnP. Clinical trial information: NCT03611556 . [Table: see text]

•Primary endpoint of OS with nivolumab plus chemotherapy versus chemotherapy in nonsquamous metastatic NSCLC was not met.•Descriptive analyses showed improved OS with nivolumab plus chemotherapy in all-randomized and squamous NSCLC populations.•PFS and DOR favored nivolumab plus chemotherapy versus chemotherapy in all-randomized and squamous NSCLC populations.•No firm associations were found between select somatic mutations, TMB, or LIPI score and OS with nivolumab plus chemotherapy.•Safety was consistent with previous reports, and no new safety signals were identified. BackgroundIn CheckMate 227 Part 1, first-line nivolumab plus ipilimumab prolonged overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% versus chemotherapy. We report results from CheckMate 227 Part 2, which evaluated nivolumab plus chemotherapy versus chemotherapy in patients with metastatic NSCLC regardless of tumor PD-L1 expression.Patients and methodsSeven hundred and fifty-five patients with systemic therapy-naive, stage IV/recurrent NSCLC without EGFR mutations or ALK alterations were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus chemotherapy or chemotherapy. Primary endpoint was OS with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC. OS in all randomized patients was a hierarchically tested secondary endpoint.ResultsAt 19.5 months’ minimum follow-up, no significant improvement in OS was seen with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC [median OS 18.8 versus 15.6 months, hazard ratio (HR) 0.86, 95.62% confidence interval (CI) 0.69-1.08, P = 0.1859]. Descriptive analyses showed OS improvement with nivolumab plus chemotherapy versus chemotherapy in all randomized patients (median OS 18.3 versus 14.7 months, HR 0.81, 95.62% CI 0.67-0.97) and in an exploratory analysis in squamous NSCLC (median OS 18.3 versus 12.0 months, HR 0.69, 95% CI 0.50-0.97). A trend toward improved OS was seen with nivolumab plus chemotherapy versus chemotherapy, regardless of the tumor mutation status of STK11 or TP53, regardless of tumor mutational burden, and in patients with intermediate/poor Lung Immune Prognostic Index scores. Safety with nivolumab plus chemotherapy was consistent with previous reports of first-line settings.ConclusionsCheckMate 227 Part 2 did not meet the primary endpoint of OS with nivolumab plus chemotherapy versus chemotherapy in patients with metastatic nonsquamous NSCLC. Descriptive analyses showed prolonged OS with nivolumab plus chemotherapy in all-randomized and squamous NSCLC populations, suggesting that this combination may benefit patients with untreated metastatic NSCLC. In CheckMate 227 Part 1, first-line nivolumab plus ipilimumab prolonged overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% versus chemotherapy. We report results from CheckMate 227 Part 2, which evaluated nivolumab plus chemotherapy versus chemotherapy in patients with metastatic NSCLC regardless of tumor PD-L1 expression. Seven hundred and fifty-five patients with systemic therapy-naive, stage IV/recurrent NSCLC without EGFR mutations or ALK alterations were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus chemotherapy or chemotherapy. Primary endpoint was OS with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC. OS in all randomized patients was a hierarchically tested secondary endpoint. At 19.5 months’ minimum follow-up, no significant improvement in OS was seen with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC [median OS 18.8 versus 15.6 months, hazard ratio (HR) 0.86, 95.62% confidence interval (CI) 0.69-1.08, P = 0.1859]. Descriptive analyses showed OS improvement with nivolumab plus chemotherapy versus chemotherapy in all randomized patients (median OS 18.3 versus 14.7 months, HR 0.81, 95.62% CI 0.67-0.97) and in an exploratory analysis in squamous NSCLC (median OS 18.3 versus 12.0 months, HR 0.69, 95% CI 0.50-0.97). A trend toward improved OS was seen with nivolumab plus chemotherapy versus chemotherapy, regardless of the tumor mutation status of STK11 or TP53, regardless of tumor mutational burden, and in patients with intermediate/poor Lung Immune Prognostic Index scores. Safety with nivolumab plus chemotherapy was consistent with previous reports of first-line settings. CheckMate 227 Part 2 did not meet the primary endpoint of OS with nivolumab plus chemotherapy versus chemotherapy in patients with metastatic nonsquamous NSCLC. Descriptive analyses showed prolonged OS with nivolumab plus chemotherapy in all-randomized and squamous NSCLC populations, suggesting that this combination may benefit patients with untreated metastatic NSCLC.

Sustained elevation in neutrophil-to-lymphocyte ratio (NLR) after initial chemoradiotherapy (CRT) has been shown to correlate with worse prognosis in a number of solid organ malignancies. Here, we conducted a retrospective observational cohort study involving six sites across Sydney, Australia, including all patients with unresectable stage III NSCLC treated with CRT and consolidation durvalumab between January 2018 and September 2021. Patients had NLR collected prior to CRT and prior to cycle one of durvalumab. We used an NLR value of 3 to stratify patients into high and low groups. Patients with sustained NLR were defined as those with values ≥3 at both timepoints. A total of 145 patients were included in the study. The median age of patients was 66 years with median follow-up of 15.1 months. The median PFS was 17.6 months in the pre-CRT NLR high cohort and not reached (NR) in the pre-CRT NLR low cohort (HR 1.99; p = 0.01). The median OS was 35.5 months in the high pre-CRT NLR cohort compared with 42.0 months in the low pre-CRT NLR cohort (HR 2.62; 95% CI: 1.23-5.56, p < 0.01). Median PFS for sustained NLR elevation was 17.1 months versus NR (HR 1.5; p < 0.01). Pre-CRT NLR and sustained NLR remained independently prognostic for PFS on multivariate analysis (p = 0.04, p = 0.01) respectively. Pre-CRT NLR and sustained NLR is associated with worse PFS outcomes in unresectable stage III NSCLC treated with CRT and durvalumab. Pre-CRT NLR is also associated with worse OS.

Australians access anticancer drugs predominantly through the Pharmaceutical Benefits Scheme (PBS).To determine why the Pharmaceutical Benefits Advisory Committee (PBAC) rejects submissions to list anticancer drugs on the PBS.We reviewed publicly available information about submissions made to the PBAC for PBS listing of anticancer drugs from 2005 to 2014. Submission characteristics, including clinical and economic evidence, PBAC recommendations, and the reasons offered for rejection were recorded. Two reviewers independently categorised the reason for rejection offered by the PBAC. Logistic regression was used to determine submission characteristics associated with rejection.We identified 213 submissions for 110 unique indications of 60 anticancer drugs. The overall rejection rate was 56% (119/213). Of the 110 indications assessed, 69% (76/110) were rejected at least once. The annual rejection rate ranged from 50 to 73% with little evidence of a trend over time (P = 0.2). Submission characteristics strongly associated with rejection in multivariable analysis included: PBAC judged the clinical evidence to be problematic or uncertain (P < 0.001); PBAC judged the economic evidence to be problematic or uncertain (P < 0.001); and, inactive comparator used (P < 0.001). The most frequent reasons for rejection offered by the PBAC was 'inadequate cost-effectiveness or drug price too high' (75/109, 69%).Inadequate cost-effectiveness and PBAC uncertainty about the clinical and economic evidence were the most frequent reasons for rejection. Clarity of information about PBAC deliberations and their reasons for rejection are important for patients and doctors grappling with decisions about the use of expensive unfunded anticancer drugs.

We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab.Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples.A total of 98 patients were included with a median age of 70 years (range, 46-91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6-6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6-13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate.Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment.

2515 Background: AK112 is a tetrameric bispecific antibody targeting PD-1 and VEGF-A. Published data suggests that the combination of anti-VEGF-A with immune checkpoint inhibitor (ICI) therapy produces complementary and synergistic antitumor effects. Given the strong correlation between VEGF-A and PD-1 expression in the tumor microenvironment, it is postulated that the simultaneous blockade of these 2 targets by AK112 as a single agent might achieve higher target binding specificity and produce enhanced antitumor activity, with an improved safety profile, compared to the co-administration of anti-PD-(L)1 and anti-VEGF therapies. Here, we present preliminary safety and efficacy data from a dose escalation study of AK112. Methods: A multicenter, phase I, open-label dose escalation and expansion study in advanced solid tumors that are resistant/refractory to standard therapies, began in December 2019 to determine the safety and efficacy of AK112 (0.3 mg/kg to 30 mg/kg) administered IV every 2 weeks (Q2W) using an accelerated titration followed by 3+3+3 dose escalation design. Selected dose escalation cohorts were expanded to a maximum of 18 subjects with selected solid tumor types for further evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and anti-tumor activity. Pts with prior exposure to ICI were eligible. PD studies examined serum VEGF levels and PD-1 receptor occupancy (RO) on circulating T-cells as an indication of target engagement. Results: As of 13 Jan 2021, 29 pts, median age 60 years [30-76], have received AK112 at doses of 0.3 mg/kg (n = 1), 1.0 mg/kg (n = 3), 3.0 mg/kg (n = 3), 10.0 mg/kg (n = 13), 20.0 mg/kg (n = 8), and 30.0 mg/kg (n = 1) Q2W. Treatment-related adverse events (TRAEs) occurred in 55.2% of pts. G3 TRAEs occurred in 10.3% [3/29] and treatment-related SAEs occurred in 3.4% [1/29] of pts. There was no G4 TRAE. No DLT occurred. TRAEs leading to treatment discontinuation occurred in 6.9% of pts [2/29]. Most frequent TRAEs were arthralgia (17%), diarrhea (14%), rash (10%), and fatigue (10.3%). Of the 17 evaluable pts treated at doses ≥ 3 mg/kg Q2W, the ORR was 23.5% (4/17) and disease control rate (DCR) was 64.7% (11/17). Among the 4 responders, a responder (endometrial ca) had not received prior ICI or bevacizumab, 2 responders (ovarian ca, mesothelioma) had received prior ICI therapy; and a responder (microsatellite stable colorectal ca) was previously treated with bevacizumab. Conclusions: AK112, up to 20 mg/kg Q2W (inclusive), can be given safely to pts and demonstrated encouraging anti-tumor activity with an ORR of 23.5% when dosed ≥ 3 mg/kg Q2W in a pt population with various solid tumors resistant/relapsed to standard therapies. Enrolment is currently ongoing at 30.0 mg/kg Q2W and in dose escalation cohorts selected for expansion. Updated data, including PK, serum VEGF, and RO will be presented. Clinical trial information: NCT04047290.

ObjectivesThis first-in-human phase I study (NCT03179436) investigated anti–cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti–programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab + pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥ 3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non–small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy.Materials and MethodsPatients with stage III/IV SCLC received quavonlimab 75 mg Q6W plus pembrolizumab 200 mg Q3W for ≤ 2 years. Primary endpoints were safety and tolerability; ORRs as assessed by blinded independent central review per Response Evaluation Criteria In Solid Tumors v1.1 was a secondary endpoint. Progression-free survival (PFS), overall survival (OS), and the correlation of response with PD-L1 expression were exploratory endpoints.ResultsForty patients with extensive-stage SCLC received treatment; median follow-up was 13 months. Dose-limiting toxicity occurred in 4 patients (10%). TRAEs occurred in 80% of patients; grade 3 events occurred in 33% of patients and no grade 4/5 events were reported. Confirmed ORRs (95% CI) were 18% (7–33) among all patients, 7% (<1–34) for PD-L1–positive tumors (n = 14), and 19% (5–42) for PD-L1–negative tumors (n = 21). Response duration ranged from 2.9 to 19.1+ months. Median PFS was 2.0 months; 6-month PFS rate was 26%. Median OS was 11.0 months; 6-month OS rate was 66%.ConclusionsEncouraging antitumor activity was observed with quavonlimab + pembrolizumab in patients with extensive-stage SCLC; responses were observed in PD-L1–positive and PD-L1–negative tumors. The combination was tolerable with manageable toxicities.

This corrects the article DOI: 10.1038/nature21063.

The identification of clinically viable strategies for overcoming resistance to platinum chemotherapy in lung adenocarcinoma has previously been hampered by inappropriately tailored in vitro assays of drug response. Therefore, using a pulse model that closely mimics the in vivo pharmacokinetics of platinum therapy, we profiled cisplatin-induced signalling, DNA-damage and apoptotic responses across a panel of human lung adenocarcinoma cell lines. By coupling this data to real-time, single-cell imaging of cell cycle and apoptosis we provide a fine-grained stratification of response, where a P70S6K-mediated signalling axis promotes resistance on a TP53 wildtype or null background, but not a mutant TP53 background. This finding highlights the value of in vitro models that match the physiological pharmacokinetics of drug exposure. Furthermore, it also demonstrates the importance of a mechanistic understanding of the interplay between somatic mutations and the signalling networks that govern drug response for the implementation of any consistently effective, patient-specific therapy.

4101 Background: Pancreatic cancer remains a devastating disease, with the diagnosis typically being made late. ctDNA has shown promise as a screening test for various tumor types. The detection of ctDNA post curative intent surgery has been associated with a high risk of recurrence in multiple solid tumors. We explored the potential of ctDNA to improve pancreatic cancer outcomes. Methods: Data from separate US and Australian series were combined. Plasma samples were collected prior to surgery in both studies and post-operative samples were collected in Australia from cases undergoing curative intent surgery. Clinicians were blinded to ctDNA results and adjuvant therapy was at clinician discretion. Tissue samples from both series were analyzed at Johns Hopkins University. Next generation sequencing was used to search for somatic KRAS mutations in the primary tumors and in cell-free DNA in the plasma. Clinico-pathologic, treatment and outcome data were collected. Results: 119 pts had a ctDNA sample at diagnosis (median age 67 years, 56.3% male). Sixty six pts (55.5 %) had detectable ctDNA, including 3/7 (42.9%) with stage I disease, 54/99 (54.5%) with stage II disease, 4/8 (50%) with stage III disease and 5/5 (100%) with metastases. Specific codon 12 KRAS (G12D, G12V or G12R) mutations were identified in the tumor tissue of 12/16 (75%) patients who had a ctDNA sample collected post-surgery. At a median follow-up of 15.2 months, 7/12 (58.3%) pts had recurred, including 3/8 (37.5%) with no detectable ctDNA and 4/4 (100%) with detectable ctDNA post-surgery (HR 4.9, p = 0.04). Detectable ctDNA post-surgery was significantly associated with poor overall survival (HR 6.93, p = 0.006), with a median of 8 months for pts with detectable ctDNA. Conclusions: ctDNA shows promise as a pancreatic cancer screening test, being detectable in a high proportion of pts with early stage disease. The detection of ctDNA post operatively predicts a very high risk of recurrence. The clinical utility of ctDNA to guide adjuvant therapy decision making, and its potential as a real-time marker of treatment effect, are being explored in further studies. Clinical trial information: ACTRN12612000763842.

Pancreatic cancer is the third leading cause of cancer-related deaths, characterised by poor survival, marked molecular heterogeneity and high intrinsic and acquired chemoresistance. Only 10⁻20% of pancreatic cancer patients present with surgically resectable disease and even then, 80% die within 5 years. Our increasing understanding of the genomic heterogeneity of cancer suggests that the failure of definitive clinical trials to demonstrate efficacy in the majority of cases is likely due to the low proportion of responsive molecular subtypes. As a consequence, novel treatment strategies to approach this disease are urgently needed. Significant developments in the field of precision oncology have led to increasing molecular stratification of cancers into subtypes, where individual cancers are selected for optimal therapy depending on their molecular or genomic fingerprint. This review provides an overview of the current status of clinically used and emerging treatment strategies, and discusses the advances in and the potential for the implementation of precision medicine in this highly lethal malignancy, for which there are currently no curative systemic therapies.

Chimeric antigen receptor T (CAR-T) cell therapy has dramatically revolutionised cancer treatment. The FDA approval of two CAR-T cell products for otherwise incurable refractory B-cell acute lymphoblastic leukaemia (B-ALL) and aggressive B-cell non-Hodgkin lymphoma has established this treatment as an effective immunotherapy option. The race for extending CAR-T therapy for various tumours is well and truly underway. However, response rates in solid organ cancers have been inadequate thus far, partly due to challenges posed by the tumour microenvironment (TME). The TME is a complex structure whose role is to subserve the persistence and proliferation of tumours as well as support their escape from immune surveillance. It presents several obstacles like inhibitory immune checkpoint proteins, immunosuppressive cells, cytokines, chemokines, stromal factors and adverse metabolic pathways. CAR structure and CAR-T therapies have evolved to overcome these obstacles, and we now have several novel CARs with improved anti-tumour activity demonstrated in xenograft models and in some clinical trials. This chapter provides a discussion of the evolution of CAR-T therapies to enable targeting specific aspects of the TME.

Abstract Background: The anti-TIGIT antibody vibo in combination with pembro was well tolerated across all doses in the dose-escalation phase of the ongoing phase 1 study in pts with advanced solid tumors (NCT02964013); promising antitumor activity of vibo + pembro was observed in anti-PD-1/PD-L1-naive NSCLC. We present initial results of the dose-expansion phase in pts with advanced cervical cancer naive to PD-1/PD-L1 inhibitors. Methods: Pts with histologically confirmed, locally advanced, or metastatic cervical cancer who failed prior standard-of-care chemotherapy or who experienced early progression on definitive chemoradiation and were naive to PD-1/PD-L1 inhibitors were randomly assigned 1:1 to receive 1 of 2 doses of vibo (200 or 700 mg) + pembro (200 mg) Q3W for ≤35 cycles (~2 y) or until PD, toxicity, or pt withdrawal. Primary end points were safety and tolerability. Secondary and exploratory end points included ORR, DOR, and PFS by investigator review per RECIST v1.1. Results: Median age of the 80 pts with cervical cancer was 49 y; 58% had an ECOG PS of 1; 53% received ≥2 prior lines of therapy; and 61% had PD-L1-positive tumors. 41 pts received vibo 200 mg, and 39 received vibo 700 mg. Median follow-up was 12 mo (range, 5-26). Treatment-related AEs (TRAEs) occurred in 27 pts in each treatment group (66%, vibo 200 mg; 69%, vibo 700 mg). The most frequent TRAEs (≥15%) were rash (22%), increased lipase (17%), and pruritus (17%) with vibo 200 mg + pembro and pruritus (28%), pyrexia (21%), rash (15%), and fatigue (15%) with vibo 700 mg + pembro. Grade 3 or 4 TRAEs occurred in 29% (vibo 200 mg + pembro) and 18% (vibo 700 mg + pembro). No deaths due to TRAEs were reported. Efficacy is reported in the Table. Conclusions: Vibo + pembro was safe in pts with advanced cervical cancer. Antitumor activity was comparable between the 2 doses of vibo studied and responses were observed irrespective of PD-L1 status. Based on these data, the RP2D for vibo remains 200 mg Q3W. Efficacy By Treatment Group By PD-L1 Statusa Vibo 200 mg + Pembro n = 41 Vibo 700 mg + Pembro n = 39 PD-L1-positive n = 49 PD-L1-negative n = 21 Confirmed ORR, % (95% CI) 15 (6-29) 23 (11-39) 20 (10-34) 14 (3-36) CR, n (%) 2 (5) 5 (13) 6 (12) 1 (5) PR, n (%) 4 (10) 4 (10) 4 (8) 2 (10) SD, n (%) 12 (29) 7 (18) 14 (29) 3 (14) PD, n (%) 18 (44) 19 (49) 20 (41) 12 (57) Median DOR, months (range)b Not reached (10 to 31+) Not reached (4+ to 35+) Not reached (4+ to 35+) Not reached (21 to 27+) Median PFS, months (95% CI) 2 (2-4) 2 (2-4) 4 (2-4) 2 (1-4) CR, complete response; DOR, duration of response; PD, progressive disease; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease. aPD-L1 status was unknown in 10 patients; data were pooled across treatment groups. PD-L1 positivity was defined as combined positive score (CPS) ≥1 or when CPS was missing, as tumor proportion score ≥1% or mononuclear immune cell density score ≥2. b“+” indicates no PD present at the time of the last disease assessment. Citation Format: Ronnie Shapira-Frommer, Ruth Perets, Mark Voskoboynik, Kathryn Mileham, Adnan Nagrial, Brian Stein, Vincent Chung, Martin Gutierrez, Diana Chen, Tanya Keenan, Mohini Rajasagi, Jane Healy, Sun Young Rha. Safety and efficacy of vibostolimab (vibo) plus pembrolizumab (pembro) in patients (pts) with cervical cancer naive to PD-1/PD-L1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT508.

There is robust trial evidence for improved overall survival (OS) with immunotherapy in advanced solid organ malignancies. The real-world long-term survival data and the predictive variables are not yet known. Our aim was to evaluate factors associated with 3-year and 5-year OS for patients treated with immune checkpoint inhibitors (ICIs).We performed a retrospective study of patients who received ICIs as management of advanced solid organ malignancies in two tertiary Australian oncology centres from 2012-2017. Data pertaining to clinical characteristics, metastatic disease burden, immune-related adverse events (IRAEs) and tumour responses were collected and their relationship to survival examined.In this analysis of 264 patients, 202 (76.5%) had melanoma, 46 (17.4%) had non-small cell lung cancer (NSCLC), 12 (4.5%) had renal cell carcinoma (RCC) and 4 (1.5%) had mesothelioma. The 5-year OS rates were 42.1% in patients with melanoma, 19.6% with NSCLC, 75% with RCC, and none of the mesothelioma patients were alive at 5 years. In multivariate analysis, an ECOG score of 0 (Hazard ratio [HR] 0.39; 95% confidence interval [CI] 0.23-0.66; p < 0.001) and the occurrence of IRAE's of any grade (HR 0.61; 95% CI 0.37-0.95; p = 0.05) were associated with better 5-year survival. The presence of bone metastases (HR 1.62; 95% CI 1.03-2.82; p = 0.05) and liver metastases (HR 1.76; 95% CI 1.07-2.89; p = 0.03) were associated with worse 5-year survival.These results support the long-term benefits of immunotherapy that in some patients, extend to at least 5 years. ECOG performance status of 0 and the occurrence of irAEs are associated with better long-term survival. Survival is significantly influenced by metastatic site and cancer type. These predictive clinical correlates aid discussions and planning in the delivery of ICIs to patients.

8548 Background: Drugs selectively targeting oncogenic mutant (mut) BRAF show activity against metastatic melanoma (MM) carrying these mutations. Distinguishing clinico-pathologic features of mut BRAF MM may influence patient (pt) selection and stratification in trials of these drugs, but no large studies have comprehensively examined this possibility. Our aim was to identify clinico-pathologic correlates of the BRAF mutation status in pts with MM. Methods: Consecutive BRAF tested pts with MM were followed prospectively. Tumor sections were screened by high resolution melt curve analysis of BRAF exon 15 and abnormal results confirmed by DNA sequencing. Data were collected on demographics, details of the primary melanoma (PM) and diagnostic, prognostic and treatment details from date of first distant metastasis (DM). Chi-square and Mann Whitney U tests were used to assess the association of clinico-pathologic features with BRAF status. Multivariate analysis was performed using a logistic regression model. Results: 97/207 pts (47%) had a mutation in exon 15 of the BRAF gene. Of these 72 (74%) were V600E, 19 (20%) V600K, and 6(6%) another mutation or combination. Pt age at diagnosis of DM was significantly different for mut (median age 56, n = 73) and wt (median age 62, n = 81: p < 0.005) tumours. There was no difference between mut/wt in disease free interval from diagnosis of PM to date of DM, sex, site of metastases at diagnosis of DM, regional lymph node involvement ever, resection of DM with intent to cure, response to chemotherapy (CT) or length of response to CT. ECOG status was not significantly different between mut/wt when adjusted for age. Features of the PM significantly associated (p < 0.05) with BRAF mut were: age at PM ≤ 50 yrs (OR = 3.16, 95%CI: 1.28-7.80); superficial spreading or nodular histopathologic subtype (OR = 3.96, 95%CI: 1.32-11.86); and truncal location (OR = 2.66, 95%CI: 1.09-6.47). Conclusions: The BRAF mutation rate in an Australian MM cohort was 47% and non-V600E activating mutations were more common than previously reported. Characteristics of the preceding PM and age at diagnosis differed in BRAF mut and wt MM pts. Clinical features of metastatic disease were essentially indistinguishable. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Roche

Improving patient care for individuals with lung cancer is a priority due to the increasing burden of the disease globally. One way this can be done is by improving patient self-management capabilities through increasing their self-efficacy. This can improve positive outcomes for patients with chronic conditions and increase their ability to manage the challenges of such illnesses. Unfortunately, patients with chronic conditions often struggle to travel far from home to engage with patient education events, a common means of improving self-efficacy. The development of more accessible tools for improving patient self-efficacy is required to increase quality of life for patients with chronic conditions.To evaluate the feasibility of delivering symptom identification and management information to patients with advanced lung cancer using an online program.This article describes a pre-post test study to evaluate a Qstream online learning platform to improve patient self-efficacy for managing advanced lung cancer symptoms. Undertaking this program should increase participant knowledge about the side-effects they may experience as a result of their treatment and in turn increase help-seeking behavior and self-efficacy for the participant cohort. Quantitative data collected by the Qstream platform on the completion rates of participants will be used as a tool to evaluate the intervention. Additionally, validated scales will be used to collect data on patient self-efficacy. Qualitative data will also be collected via an exit survey and thematic content analysis of semi-structured interviews.The research is in the preliminary stages but thus far a protocol has been approved in support of the project. Additionally, advisory committee members have been identified and initial meetings have been undertaken.Development of new approaches for increasing patient understanding of their care is important to ensure high quality care continues to be delivered in the clinical setting.

Anti-PD-1 antibodies (pembrolizumab and nivolumab) have shown improved overall survival in second-line treatment for metastatic non-small cell lung cancer (NSCLC) with durable responses. We aimed to assess the pattern of disease progression amongst patients who initially responded to anti-PD-1 agents and their subsequent management. We retrospectively assessed all patients who commenced single-agent anti-PD-1 antibodies between June 2012 and February 2016 at a single centre. Radiological responses were assessed by the investigator using RECIST 1.1 and irRC. Progressive disease (PD) patterns were defined as solitary, oligometastatic (2-3 lesions), generalized (>3 lesions), enlargement of existing or new lesions, visceral or non-visceral. Management and survival after progression were examined. A total of 81 patients received single-agent pembrolizumab (n=43) or nivolumab (n=38). Of the seventeen (21.3%) patients achieving partial response, three were treatment-naïve, fifteen (88.2%) were former or current smokers, none had EGFR mutation or ALK translocation. The median number of disease sites at baseline was three, and two patients had stable brain metastases after radiotherapy at the commencement of anti-PD1 treatment. Ten (58.8%) responders developed acquired resistance, with a median time to progression of 20.2 months. Nine (90%) had solitary (n=4) or oligometastatic (n=5) progression. Five (50%) progressed only at existing sites, three (30%) developed new lesions only, and two (20%) progressed at both existing and new sites. Four (40%) progressed at non-visceral sites only, and one progressed in the brain at a previously treated site. Five (50%) patients underwent local treatment to solitary (n=2) or oligoprogressive disease (n=3) with all five achieving local control with radiotherapy. Seven(70%) continued anti-PD-1 agents beyond progression, while the three (30%) remaining patients did not receive any further therapy. With a median follow-up of 24.8 months, five (50%) of the patients had died, one from an infective exacerbation of COPD, one from type 1 respiratory failure, and three from disease progression. The median duration of treatment was 4.35 months (1.96 to 11.46) and the median overall survival after progression was 11.44 months. This study suggested that acquired resistance to anti-PD1 agents could often result in solitary or oligometastatic progression, and that CNS progression was uncommon. In a subset of patients, treatment beyond progression with or without local therapy to oligometastatic disease may provide ongoing and durable clinical benefit.

e16206 Background: While adjuvant therapy provides a survival benefit for patients (pts) with early-stage pancreatic cancer there are currently no biomarkers that define pts that are more or less likely to benefit from such treatment. This prospective study investigated the use of circulating tumour DNA (ctDNA) as a marker of residual disease, where detection could predict recurrence. Methods: Patients newly diagnosed with operable pancreatic adenocarcinoma were enrolled. PCR-based-SafeSeqS assays were used to identify mutations at codons 12, 13 and 61 of KRAS in the primary tumor and to detect ctDNA in plasma samples. Patient management was as per standard of care, blinded to ctDNA data. Results: From January 2015 to June 2017, 42 pts with matched plasma samples, collected pre- and post-operatively, and tumor tissue available were evaluated. The median time between surgery and post-op blood collection was 6.3 (range:4-8) weeks. RAS mutations were identified in 38 (90.5%) tumor samples. ctDNA was detected in 23/37 (62.2%) pre-op and 13/35 (37.1%) post-op plasma samples. In multivariate analysis including stage, and resection margin, ctDNA status was the only statistically significant variable. Pre-op ctDNA detection was associated with worse median recurrence free survival (RFS), 10.3 months versus not reached, (Hazard Ratio (HR),3.4; 95% confidence interval (CI), 1.5-7.6; P = 0.005) and 5.4 months versus 17.1 months, (HR, 5.4; 95% CI, 4.7-37.3; P < 0.0001) post-operatively. Similarly, the presence of ctDNA was associated with worse median overall survival (OS), 13.8 months versus not reached pre-operatively, (HR,3.4; 95% CI 1.1 to 8.3; P = 0.04) and 10.6 months versus not reached (HR,4.5; 95% CI 2.4-28.6; P = 0.001) post-operatively. Notably, recurrence occurred in 13 of 13 pts with detectable post-op ctDNA, despite more than half receiving standard adjuvant chemotherapy. Conclusions: ctDNA analysis is a promising prognostic marker in early-stage pancreatic cancer that could be used to stratify recurrence risk and guide risk-adaptive treatment strategies. ctDNA detection post-operatively may also define a pt subset destined to progress despite standard adjuvant chemotherapy, where novel approaches need to be explored Clinical trial information: ACTRN12612000763842.

4588 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with first and second line chemotherapy resulting in modest survival benefits. Immunotherapy using single agent anti-PD-1 therapy has also shown low activity with an objective response rate (ORR) of less than 10%. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell carcinoma. To date, no trials in BTC pts with ipi/nivo therapy have been reported. Methods: 39 pts with metastatic BTCs were enrolled into the CA 209-538 clinical trial for rare cancers. Patients received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for 4 doses, followed by nivo 3mg/kg q 2 weekly. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers including PD-L1 expression and tumour mutation burden. Results: 39 pts with BTC were enrolled and 33 pts (85%) had received at least one prior line of systemic treatment (0-2 lines). The ORR was 24% and the CBR 45% with the median duration of response not been reached (range 2-26+months). Responses were observed in 3/14 intrahepatic, 1/10 extrahepatic, 0/2 unspecified cholangiocarcinoma and 5/13 gallbladder ca pts. None of the responding pts had a microsatellite instable tumour. 2 pts with durable partial responses were subsequently rendered surgically free of disease. Median OS and PFS were 6.1 and 3.1 months respectively. 22 (56%) pts experienced an immune –related adverse event (irAE) with grade3/4 irAEs being observed in 8 (20%) pts. Conclusions: Combination immunotherapy with ipi/nivo demonstrates significant clinical activity in a subset of patients with advanced microsatellite stable BTC. The response rate compares favourably to clinical trials investigating single agent anti-PD-1 therapy. Clinical trial information: NCT02923934 .

Due to difficulties in identifying sufficient-sized cohorts there remains uncertainty about prognostic and clinical differences that may be unique to asbestos-related lung cancer (ARLC). In this study, we use the Helsinki Criteria to define a group of ex-workers with lung cancer attributable to asbestos exposure and investigate differences that may exist.A total of 529 patients seeking workers' compensation for their lung cancer were assigned to either ARLC or the non-ARLC based on parameters defined in the Helsinki Criteria. Clinical and survival details were collected and analyzed.In our study population, ARLC patients were on average older (72.1 ± 7.8) than non-ARLC patients (66.5 ± 10.2, P < 0.001) and were more likely to be diagnosed as a result of incidental findings or screening program (P < 0.001). The groups were similar in terms of clinical characteristics with the only difference being that plaques were more prevalent among ARLC patients (P < 0.001). Differences were observed for median overall survival (OS), ARLC (9 months) and non-ARLC (13 months, P = 0.005), as well for treatment (P = 0.01). After adjusting for age, however, these differences disappeared.Age at diagnosis, pleural plaques, and asymptomatic presentation were the attributes that we identified as significantly different between asbestos-related cancer and other lung cancers. In this cohort, ARLC patients were older diagnosis and with worse overall survival.

Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs.

Abstract Background: Safe, effective treatment options for advanced melanoma that progressed on a PD-1/PD-L1 inhibitor is an unmet medical need. Results of the phase 1b KEYNOTE-029 trial showed promising antitumor activity in advanced melanoma with pembro combined with a CTLA-4 inhibitor. This ongoing, open-label, multiarm phase 1/2 study (NCT03179436) evaluating the CTLA-4 inhibitor Qmab + pembro showed antitumor activity as first-line treatment for advanced NSCLC and for previously treated extensive-stage SCLC. Data from the efficacy expansion phase in pts with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor are presented. Methods: Pts with unresectable stage III-IV melanoma and confirmed progressive disease (PD) per iRECIST within 12 wk of the last dose of a PD-1/PD-L1 inhibitor given alone or in combination for ≥2 doses (combinations with CTLA-4 inhibitors were not allowed) were randomly assigned (1:1) to receive Qmab 25 mg IV Q6W with or without pembro 400 mg IV Q6W; 100 pts in the Qmab + pembro arm and 40 pts in the Qmab monotherapy arm were planned for enrollment. Treatment in both arms was given for up to 18 cycles (~2 y) or until PD, toxicity, or pt withdrawal. Pts who had PD after ≥2 Qmab monotherapy cycles could crossover to Qmab + pembro. Tumor imaging was assessed Q9W to wk 54 and Q12W thereafter. Primary end points were safety and ORR by BICR per RECIST v1.1. Secondary and exploratory end points included DOR and PFS by BICR per RECIST v1.1 and OS. Results: 151 pts were enrolled (n = 111, Qmab + pembro; n = 40, Qmab monotherapy); median time from first dose to database cutoff was 7.7 mo. In all pts, median age was 64 y; 66% of pts were male, 33% had BRAF-mutant tumors, and 50% had elevated LDH. Treatment-related adverse events (TRAEs) were reported in 87 pts (78%) in the Qmab + pembro arm and 24 pts (60%) in the Qmab monotherapy arm; grade 3/4 TRAEs were reported in 16 pts (14%) and 3 pts (8%), respectively. The most common TRAEs were pruritus (26%), fatigue (14%), diarrhea (14%), and rash (13%). No treatment-related deaths occurred in either arm; 5% of pts discontinued because of TRAEs. Confirmed ORR was 9% (95% CI, 4.4-15.9) with Qmab + pembro (1 CR, 9 PRs) and 3% (95% CI, 0.1-13.2) with Qmab monotherapy (1 PR). Median DOR was not reached (NR; range, 2.0+ to 13.8+ mo) with Qmab + pembro. DOR was 1.9+ with Qmab monotherapy. Median PFS was 2.1 mo (95% CI, 2.1-3.2) with Qmab + pembro and 2.1 mo (95% CI, 2.1-2.5) with Qmab monotherapy; 6-mo PFS rates were 21% and 13%, respectively. Median OS was NR (95% CI, 11.2 mo to NR) with Qmab + pembro and 7.8 mo (95% CI, 6.3 to NR) with Qmab monotherapy; 6-mo OS rates were 74% and 73%, respectively. Conclusions: Qmab + pembro was generally well tolerated and provided modest antitumor activity in pts with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor. This combination and a coformulation of Qmab + pembro will be further investigated in the KEYMAKER-U02 study. Citation Format: Sanjeev Deva, Jacek Mackiewicz, Stephane Dalle, Helen Gogas, Iwona Lugowska, Alfonso Berrocal, Alexander M. Menzies, Michele Maio, Adnan Nagrial, Karmele Mujika Eizmendi, Jean-Jacques Grob, Christian Caglevic, Megan Lyle, Juan Martin-Liberal, Rachel Altura, Yixin Ren, Anuradha Khilnani, Jobin Cyrus, Shabana Siddiqi, Michal Lotem. Phase 1/2 study of quavonlimab (Qmab) + pembrolizumab (pembro) in patients (pts) with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT557.

Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a lethal disease with a poor 5-year survival. Systemic treatments can be used to control symptoms and prolong life. Cytotoxic chemotherapies are commonly administered, with combination treatments, such as fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine showing the largest clinical benefits. Newer genomic classifications of PDAC may provide a rationale for targeted therapies or immunotherapies, although at present these remain largely experimental. This review discusses the evidence behind the currently used regimens, while introducing the potential future of pancreatic cancer care.

4125 Background: LAPC is associated with a poor prognosis. Current standard treatment is limited to chemotherapy or chemo-radiotherapy. P-32 Microparticles is a brachytherapy device that implants a predetermined dose of P-32 into pancreatic tumours via endoscopic ultrasound (EUS) guidance. This reports the initial results of a pilot study in combination with chemotherapy. Methods: Eligible patients were permitted to receive either GNP or FOLFIRINOX. P-32 was implanted at week 4 or 5. The dose of P-32 was calculated from tumour volume to deliver an absorbed dose of 100 Gy. Diffusion pattern of the P-32 suspension was assessed by EUS and bremsstrahlung SPECT/CT imaging. Safety data was graded using CTCAE v4.0 criteria. Response was assessed according to RECIST 1.1 with CT scans every 8 weeks and FDG-PET scans at baseline and week 12. Results: 50 patients were enrolled (Intent-to-Treat population (ITT)) of which 42 were implanted with the device (Per Protocol population (PP)). 10 received FOLFIRINOX and 40 GNP. Median age was 65, 28 were male and all had a PS 0/1. 1070 adverse events (ITT) were reported; 153 (80% of patients) were ≥ Grade 3. The most common AEs of ≥ Grade 3 were haematological (39, 46%) and gastrointestinal disorders (30, 34%). No serious device- or radiation-related toxicities have been reported. PP Local Disease Control Rate at Week 16 was 90%; 95% CI: 77-97% and at Week 24 was 71%; 95% CI: 55-84%. Overall Response Rate (ORR) was 31%; 95% CI: 18-47%. Median change in tumour volume from Baseline to Week 16 and to Week 24 was -38% (range +89% to -90%) and -27.5% (range +139% to -79%). Ten (24%) patients underwent surgical resection following repeat staging. Eight patients had R0 margin. Conclusions: The use of EUS-guided implantation of P-32 is feasible, with an acceptable safety profile in combination with first-line chemotherapy for LAPC patients. Encouraging OR and DCR are observed. Further follow-up to inform results of local progression free survival and progression free survival is warranted. Acknowledgement: Nab-paclitaxel was supported by Specialised Therapeutics Australia Pty Ltd. Clinical trial information: NCT03003078.

Abstract Background An ongoing open-label, multiarm, multicenter, phase I study of the anti–CTLA-4 antibody MK-1308 in combination with pembrolizumab in advanced solid tumors (NCT03179436) revealed manageable safety and promising efficacy in patients (pts) with advanced non-small cell lung cancer receiving first-line therapy [Perets et al. J Clin Oncol. 2019;37(suppl):2558]. Here we report data from the small cell lung cancer (SCLC) cohort of this study. Methods In the dose confirmation phase, pts with advanced SCLC received MK-1308 at 75 mg Q6W + pembrolizumab 200 mg Q3W (up to 35 cycles). The primary end point was safety, and the secondary end point was ORR based on blinded independent central review (BICR) per RECIST v1.1. PFS based on BICR per RECIST v1.1 and OS were exploratory end points. The database cutoff date for this analysis was June 3, 2019. Results Forty pts with previously treated advanced SCLC (second-line or beyond) were enrolled and dosed; median duration of follow-up was 11 mo. At data cutoff, 32 pts (80%) discontinued study treatment—23 (58%) due to progressive disease, 4 (10%) due to AE, 2 (5.0%) due to clinical progression—and 3 (7.5%) withdrew consent. Median age was 66 years; 60% of pts were male and 65% had ECOG PS 1 at baseline. Seven pts achieved partial response according to BICR assessment, for an ORR of 18% (95% CI, 7.3-33). Eight pts (20%) had a best overall response of stable disease and 21 (53%) had progressive disease. Response duration ranged from 2.9 to 8.4+ mo. At the time of the data cutoff, 5 of 7 responses (71%) were ongoing. Median time to response was 2.1 mo (range, 1.1-12). Median PFS was 2.0 mo (95% CI, 1.9-3.9), and the 6-mo PFS rate was 26%. Median OS was 11 mo (95% CI, 5.9-not reached), and the 6-mo OS rate was 66%. Treatment-related adverse events (TRAEs) as determined by the investigator occurred in 32 pts (80%). Grade 3 TRAEs were reported in 11 pts (28%); no grade 4-5 events were reported. Three pts (7.5%) discontinued treatment due to TRAEs. Conclusion In heavily pretreated pts with SCLC, MK-1308 + pembrolizumab was generally well tolerated with encouraging antitumor activity. Clinical trial identification NCT03179436. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure B.C. Cho: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): MOGAM Institute; Honoraria (self), Research grant / Funding (self): Dong-A ST; Honoraria (self), Research grant / Funding (self), Licensing / Royalties: Champions Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Yuhan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono; Honoraria (self), Research grant / Funding (self): Dizal Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Shareholder / Stockholder / Stock options: Bridgebio Therapeutics; Shareholder / Stockholder / Stock options: Gencurix Inc. K. Yoh: Research grant / Funding (institution): MSD. J. Bar: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy: OncoHost; Advisory / Consultancy: VBL; Research grant / Funding (institution): Pfizer. A. Nagrial: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AZ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Incyte. D.R. Spigel: Leadership role: Centennial Medical Center; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Boehringer-Ingelheim; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Genentech; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Intuitive Surgical; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Purdue Pharma; Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Travel / Accommodation / Expenses: Sysmex. M. Gutierrez: Shareholder / Stockholder / Stock options: COTA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Esanex; Advisory / Consultancy: Guardant 360; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Foundation Medicine. D-W. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. D. Rasco: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Regeneron. M. Satouchi: Honoraria (self), Research grant / Funding (institution): MSD. M-J. Ahn: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: ONO; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda; Advisory / Consultancy: Lilly; Advisory / Consultancy: Alpha Pharm. D.H. Lee: Honoraria (self): AbbVie; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): ChongKunDang; Honoraria (self): CJ Healthcare; Honoraria (self): Eli Lilly; Honoraria (self): Janssen; Honoraria (self): Menarini; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Mundipharma; Honoraria (self): Novartis; Honoraria (self): Ono; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Samyang Biopharm; Honoraria (self), Advisory / Consultancy: ST Cube; Honoraria (self): Takeda. C. Maurice-Dror: Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche. S. Siddiqi: Full / Part-time employment: Merck & Co., Inc.. X. Li: Full / Part-time employment: Merck & Co., Inc.. J. Cyrus: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R.A. Altura: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R. Perets: Advisory / Consultancy: Karyopharm; Advisory / Consultancy: BiolineRx. All other authors have declared no conflicts of interest.

4127 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (&gt; 2 prior regimens) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the PK, safety and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m 2 ) and A (125 mg/m 2 ) were administered intravenously on Days 1, 8, and 15 of each cycle. PK was evaluated on day 1 of cycle 1 in cohorts 1-3. Safety was evaluated by clinical and laboratory assessments. Efficacy was assessed by CA19-9 levels, objective response using RECIST criteria, progression-free survival (PFS) and overall survival (OS). A fourth cohort using a modified dosing schedule of 0.4 mg/kg SBP-101 days 1-5 for cycles 1-2 and days 1, 8, and 15 every cycle thereafter was added to mitigate hepatic toxicity, and that dose and schedule were recommended for phase 1b expansion. Interim Results: Fifty patients were enrolled (N=25, phase 1a and N=25, phase 1b) and have received up to 12 treatment cycles. SBP-101 plasma C max and AUC 0-t increased in a slightly more than dose proportional manner and were unchanged by the addition of G and A. PK parameters of G and A were unaltered by increasing doses of SBP-101. The most common nonserious adverse events related to SBP-101 (&gt;10%) are fatigue (N=15), LFT/transaminase abnormalities (N=15), vision abnormalities (N=6), injection site pain (N=13), dehydration (N=7), diarrhea (N=7) and nausea (N=6). Serious adverse events related to SBP-101 observed in some subjects include hepatic toxicity (N= 6) and retinal toxicity (N=6) both occurring after prolonged treatment and requiring dose reduction or discontinuation. There is no evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. At the recommended dose and schedule (N=30), CA19-9 levels decreased 60-99% in 19 of 29 evaluable patients, with 12/28 evaluable patients achieving partial responses (43%) and 11/28 achieving stable disease at 8 weeks (39%). Nine subjects are ongoing. PFS was confounded by SBP-101 dosing holds implemented to investigate potential toxicity. Median OS has not been reached. Conclusions: Interim results suggest SBP-101 may enhance first-line treatment with G and A in patients with metastatic PDA. Hepatic toxicity can be mitigated with dose reduction or discontinuation. Retinal toxicity that occurred in some subjects is under investigation. Clinical trial information: NCT03412799.

Abstract Background: BGB-283 is a novel inhibitor of the RAF dimer with potent and reversible inhibitory activities against RAF family kinases including wild type A-RAF, B-RAF, C-RAF and B-RAF V600E, as well as EGFR. BGB-283 demonstrated acceptable safety and early clinical activity in its Phase 1A study. In this Phase IB dose expansion study, we further evaluated safety and tolerability of BGB-283 and investigated efficacy in pre-selected patients (pts) with B-RAF or K-RAS/N-RAS-mutated solid tumors. Methods: This Phase 1B study was a multicenter, open-label, multiple-arm, dose expansion study. Pts were treated at the RP2D of BGB-283 at 30 mg/day. There were 10 different expansion arms for: B-RAF V600-mutated melanoma (not previously treated with a B-RAF or MEK inhibitor, and B-RAF and/or MEK inhibitor-resistant pts), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), papillary thyroid cancer (PTC) and other solid tumors with B-RAF mutations; K-RAS/N-RAS-mutated endometrial cancer, NSCLC, CRC, and other solid tumors with K-RAS/N-RAS or NF-1 mutations. The primary end point was the response rate based on RECIST Version 1.1. Adverse events (AEs) are reported per CTCAE V4.03. Results: As of 19th Sep 2016, 96 pts were enrolled: median age was 63 years (range: 20 to 82 years) with all pts having baseline ECOG PS of 0 or 1. Forty-seven (49.0%) subjects had received ≥3 prior lines of treatment, 22 (22.9%) had received 2 prior lines of treatment, and 18 (18.8%) had received 1 prior line of treatment. BGB-283 was generally well-tolerated. Drug-related AEs were mostly Grade 1/2 in severity; the most common were fatigue in 37 (38.5%) subjects, nausea in 16 (16.7%), decreased appetite in 21 (21.9%), and diarrhea in 17 (17.7%). A total of 34 (35.4%) subjects experienced study drug-related Grade 3/4 AEs, notably drug-related thrombocytopenia (6.3%), palmar-plantar erythrodysesthesia syndrome (1.0%) and hypertension (8.3%). In the cohorts with previously-untreated B-RAF V600-mutated melanoma (n=7), PTC with B-RAF mutation (n=3) and NSCLC with K-RAS mutation (n=6), the response rates were 42.9% (95% confidence interval [CI], 9.9, 81.6), 33.3% (95% CI, 0.8, 90.6) and 16.7% (95% [0.4, 64.1]), respectively. Confirmed PR was seen in the single case of ovarian cancer with B-RAF mutation enrolled and also in one of 4 melanoma subjects with a confirmed B-RAF V600 mutation, who had not responded to B-RAF and/or MEK inhibitor(s). One unconfirmed PR was found in two NSCLC subjects with a B-RAF mutation. Conclusions: BGB-283 was generally well-tolerated during the Phase 1B stage of the study. Antitumor activity was not only observed in subjects with B-RAF V600-mutated solid tumors including melanoma, PTC, and ovarian cancer, but also in subjects with K-RAS-mutated NSCLC. When added to the efficacy data in the Phase IA portion of this study, with objective responses noted in these tumor subtypes as well as in K-RAS-mutated endometrial carcinoma, BGB-283 demonstrated a desirable risk-benefit profile for further efficacy and safety investigation. Citation Format: Jayesh Desai, Hui Gan, Catherine Barrow, Michael B. Jameson, Ben Solomon, Victoria Atkinson, Andrew Haydon, Michael Millward, Stephen Begbie, Michael Brown, Benjamin Markman, William Patterson, Andrew Hill, Lisa Horvath, Adnan Nagrial, Gary Richardson, Christopher Jackson, Michael Friedlander, David Gibbs, Phillip Parente, Jason Yang, Lai Wang, Yunxin Chen, Lusong Luo. A Phase IB study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT002. doi:10.1158/1538-7445.AM2017-CT002

Abstract Background: BGB-283 is a novel inhibitor of the RAF dimer with potent and reversible inhibitory activities against RAF family kinases including wild type ARAF, BRAF, CRAF and BRAF V600E, as well as EGFR. We report here the initial findings of the dose escalation component of an ongoing phase I first-in-human, dose escalation and expansion trial of BGB-283. Methods: Safety, tolerability, pharmacokinetics, recommended phase 2 dose and antitumor activity of BGB-283 were evaluated in patients (pts) with advanced BRAF, N- or KRAS mutant solid tumors. The phase Ia dose escalation study utilized a modified 3+3 dose escalation design. Adverse events (AEs) are reported per CTCAE V4.03 and responses per RECIST V1.1. Results: As of 31st Oct 2015, 31 pts (mutations: 18 KRAS; 3 NRAS; 7 BRAF V600E; 2 BRAF non-V600 and 1 NRAS/BRAF non-V600) enrolled in 7 cohorts received BGB-283 from 5 mg QD to 60 mg QD. BGB-283 was well tolerated. MTD was determined to be 40 mg/QD and dose-limiting toxicity (DLT) was thrombocytopenia. Most frequent treatment-related AEs were fatigue (68%), anorexia (48%), constipation (42%), thrombocytopenia (39%), nausea (39%), vomiting (39%), dermatitis acneiform (39%), hand-foot syndrome (35%), hypertension (35%) and dysphonia (32%). Frequent treatment-related Grade 3/4 AEs included thrombocytopenia (13%), fatigue (10%) and ALT increase (10%). Cutaneous malignancies associated with the approved first-generation BRAF inhibitors have not been observed in pts treated with BGB-283, with a mean follow-up of 6 months. The plasma concentrations of BGB-283 increased proportionally from 5 mg QD through 50 mg QD. The mean t½ of BGB-283 was around 110 hours. Among 29 evaluable pts, one of the only two melanoma pts with a BRAF V600E mutation had a partial response (PR) (on treatment over 249 days). In addition, there were two confirmed PRs including 1 pt with KRAS mutated endometrial cancer (on treatment over 456 days) and 1 thyroid cancer pt with BRAF V600E mutation (on treatment over 481 days); and one unconfirmed PR for 1 pt with KRAS mutated NSCLC (stable disease with transient PR and on treatment for over 572 days). Except for the K-RAS mutated endometrial cancer patient, all other three responders are still on study treatment at the cutoff date. Furthermore, 14 of the 29 evaluable pts achieved prolonged stable disease (3 pts have been on treatment for over 300 days), with the disease control rate at 62%. Finally, 18F-FDG uptake was measured at baseline and at the end of cycle 1 to evaluate BGB-283 pharmacodynamic activity. Partial metabolic responses were observed in 13/30 (43%) pts. Conclusions: BGB-283 was well tolerated and the MTD on a continuous once daily dosing was determined at 40 mg/day. Promising clinical activity was observed at multiple dose levels in pts with BRAF or KRAS mutated tumors. BGB-283 activity and safety are being further investigated in a number of molecularly-defined tumors in an ongoing phase Ib expansion study. Citation Format: Jayesh Desai, Hui Gan, Catherine Barrow, Michael B. Jameson, Grant Mcarthur, Ben Tran, Michael Lam, Laird Cameron, Andrew Weickhardt, Jason Yang, Lai Wang, Zhen Qin, Lusong Luo, Ben Solomon. Phase I study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT005.

Abstract Background: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial is designed to exploit results from whole genome sequencing of pancreatic cancer collected under the auspices of the ICGC in Australia. Results showed that small subsets of patients had actionable changes in their tumor genome that could be druggable with currently available therapies. Only 7% of cases were found to be KRAS wildtype, and this phenotype may enrich for susceptibility to EGFR inhibition. Her2 positivity occurs in 2% and may confer sensitivity to Her inhibition. Tumors displaying defects in the DNA damage repair pathway (∼5%) respond to DNA damaging chemotherapy. Trial Design: The IMPaCT trial has recently been amended to a single arm pilot study of first line molecularly guided therapy for advanced pancreas cancer. Patients are permitted to begin their first cycle of chemotherapy with gemcitabine with or without nab-paclitaxel while awaiting molecular results. We screen potential patients for the three molecular targets: Her2 amplification: trastuzumab + gemcitabine; KRAS wildtype: erlotinib + gemcitabine; and DNA damage: platinum-based chemotherapy. In our initial cohort of patients who underwent resection with curative intent, 70% recurred. Recurrence occurred 16m after initial surgery. Collection of tissue commenced in 2009. The first site to open was in April 2013 by which time, only 8 patients for whom we had complete sequence data and actionable mutations were still alive, so we changed the trial to screen de novo metastatic patients. Using the WGS data, we constructed a custom sequencing panel to use DNA extracted from FFPE core biopsies to screen in real time for mutations in KRAS, BRCA2, BRCA1, PALB2 and ATM. Her2 screening is undertaken with IHC and FISH. We have screened 89 cases in 18m, 8 have relevant molecular targets. The average time from biopsy to delivery of results is 21d. 2 of the 8 eligible cases have commenced precision therapy on trial. Citation Format: Lorraine Chantrill, Skye Simpson, Amber Johns, Mona Martyn-Smith, Angela Chou, Clare Watson, Adnan Nagrial, Venessa Chin, Lucille Sebastian, Sonia Yip, John Simes, Nick Pavlakis, Peter Grimison, Ray Asghari, Sandra Harvey, Andrew Biankin. Precision medicine for advanced pancreas cancer: the individualized molecular pancreatic cancer therapy (IMPaCT) trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT210. doi:10.1158/1538-7445.AM2015-CT210

296 Background: There is currently no standard of care for the second-line treatment of advanced pancreatic cancer. Very few randomised studies have been performed in this setting. The aim of this analysis was to compare the different therapeutic approaches in this setting, and the rate of second line treatment delivery and its influence on reported overall survival. Methods: We carried out a systematic analysis of studies in advanced pancreatic cancer. 1 st and 2 nd line chemotherapy trials were identified from MEDLINE, EMBASE &amp; CENTRAL using the COCHRANE sensitive search strategy. Objective response rates (ORR) and survival (PFS &amp; OS) were extracted and compared amongst groups using the Mann-Whitney U test. For 1 st line studies, the percentage of patients who received 2 nd line chemotherapy was also extracted and plotted against reported median overall survival (OS) and post-progression survival (PPS), defined as arithmetic difference between median OS and progression-free survival. Linear regression was used to explore the relationship between overall survival and second-line chemotherapy. Results: 20 first line clinical trials with 42 treatment arms met the inclusion criteria treating an aggregate total of 5,768 patients. Overall survival was positively correlated with use of second-line chemotherapy (r=0.65; p=0.012). 61 second-line studies were identified treating an aggregate total of 2,562 patients in 66 treatment arms. Combination treatment was associated with an improved response rate (p=0.045) and PFS (p=0.024) when compared to single agent therapy. Conclusions: In this exploratory analysis, these data suggest that there is a small benefit of second-line chemotherapy in pancreatic cancer. In first-line chemotherapy studies, the use of subsequent treatment correlates with improved overall survival. In second line studies, combination chemotherapy is associated with higher response rates and survival.

CancerVolume 129, Issue 7 p. 1129-1130 LETTER TO THE EDITOR Is there a role for combined anti–PD-1/CTLA-4 checkpoint blockade in the management of advanced biliary tract cancers? Oliver Klein MD, Oliver Klein MD orcid.org/0000-0003-0022-9553 Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, AustraliaSearch for more papers by this authorDamien Kee MD, Damien Kee MD Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorAdnan Nagrial MD, Adnan Nagrial MD Blacktown Hospital, Blacktown, New South Wales, Australia University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorBen Markman MD, Ben Markman MD Department of Medical Oncology, Alfred Health, Prahran, Victoria, Australia Monash University, Melbourne, Victoria, AustraliaSearch for more papers by this authorCraig Underhill MD, Craig Underhill MD Albury-Wodonga Regional Cancer Centre, Albury-Wodonga, New South Wales, AustraliaSearch for more papers by this authorMichael Michael MD, Michael Michael MD Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorAndreas Behren PhD, Andreas Behren PhD Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia School of Cancer Medicine, La Trobe University, Melbourne, Victoria, AustraliaSearch for more papers by this authorJodie Palmer PhD, Jodie Palmer PhD Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia School of Cancer Medicine, La Trobe University, Melbourne, Victoria, AustraliaSearch for more papers by this authorNiall C. Tebbutt MD, PhD, Niall C. Tebbutt MD, PhD Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia University of Melbourne, Melbourne, Victoria, AustraliaSearch for more papers by this authorMatteo S. Carlino MD, PhD, Matteo S. Carlino MD, PhD Blacktown Hospital, Blacktown, New South Wales, Australia University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorJonathan Cebon MD, PhD, Jonathan Cebon MD, PhD Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia School of Cancer Medicine, La Trobe University, Melbourne, Victoria, AustraliaSearch for more papers by this author Oliver Klein MD, Oliver Klein MD orcid.org/0000-0003-0022-9553 Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, AustraliaSearch for more papers by this authorDamien Kee MD, Damien Kee MD Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorAdnan Nagrial MD, Adnan Nagrial MD Blacktown Hospital, Blacktown, New South Wales, Australia University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorBen Markman MD, Ben Markman MD Department of Medical Oncology, Alfred Health, Prahran, Victoria, Australia Monash University, Melbourne, Victoria, AustraliaSearch for more papers by this authorCraig Underhill MD, Craig Underhill MD Albury-Wodonga Regional Cancer Centre, Albury-Wodonga, New South Wales, AustraliaSearch for more papers by this authorMichael Michael MD, Michael Michael MD Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorAndreas Behren PhD, Andreas Behren PhD Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia School of Cancer Medicine, La Trobe University, Melbourne, Victoria, AustraliaSearch for more papers by this authorJodie Palmer PhD, Jodie Palmer PhD Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia School of Cancer Medicine, La Trobe University, Melbourne, Victoria, AustraliaSearch for more papers by this authorNiall C. Tebbutt MD, PhD, Niall C. Tebbutt MD, PhD Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia University of Melbourne, Melbourne, Victoria, AustraliaSearch for more papers by this authorMatteo S. Carlino MD, PhD, Matteo S. Carlino MD, PhD Blacktown Hospital, Blacktown, New South Wales, Australia University of Sydney, Sydney, New South Wales, AustraliaSearch for more papers by this authorJonathan Cebon MD, PhD, Jonathan Cebon MD, PhD Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia School of Cancer Medicine, La Trobe University, Melbourne, Victoria, AustraliaSearch for more papers by this author First published: 24 January 2023 https://doi.org/10.1002/cncr.34660 See correspondence on pages 1131–2, this issue. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume129, Issue71 April 2023Pages 1129-1130 RelatedInformation

&lt;p&gt;Histological diagnoses&lt;/p&gt;

&lt;div&gt;AbstractPurpose:&lt;p&gt;Combination immunotherapy with anti–CTLA-4 and anti–PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs.&lt;/p&gt;Patients and Methods:&lt;p&gt;CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease).&lt;/p&gt;Results:&lt;p&gt;Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7–10.5] and overall survival was 14.8 months (95% CI: 4.1–21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events.&lt;/p&gt;Conclusions:&lt;p&gt;Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.&lt;/p&gt;&lt;/div&gt;

&lt;p&gt;Histological diagnoses&lt;/p&gt;

&lt;div&gt;AbstractPurpose:&lt;p&gt;Combination immunotherapy with anti–CTLA-4 and anti–PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs.&lt;/p&gt;Patients and Methods:&lt;p&gt;CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease).&lt;/p&gt;Results:&lt;p&gt;Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7–10.5] and overall survival was 14.8 months (95% CI: 4.1–21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events.&lt;/p&gt;Conclusions:&lt;p&gt;Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.&lt;/p&gt;&lt;/div&gt;

&lt;p&gt;Best response according to histological grade&lt;/p&gt;

&lt;p&gt;Authorship change form&lt;/p&gt;

&lt;p&gt;Best response according to histological grade&lt;/p&gt;

&lt;p&gt;Authorship change form&lt;/p&gt;