M. Catherine Pietanza

First-line therapy for advanced non–small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.

In the randomized, open-label, phase III KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non-small-cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations. We report an updated OS and tolerability analysis, including analyses adjusting for potential bias introduced by crossover from chemotherapy to pembrolizumab.Patients were randomly assigned to pembrolizumab 200 mg every 3 weeks (for up to 2 years) or investigator's choice of platinum-based chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross over to pembrolizumab upon meeting eligibility criteria. The primary end point was progression-free survival; OS was an important key secondary end point. Crossover adjustment analysis was done using the following three methods: simplified two-stage method, rank-preserving structural failure time, and inverse probability of censoring weighting.Three hundred five patients were randomly assigned (pembrolizumab, n = 154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up, 25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to chemotherapy crossed over on study to receive pembrolizumab. When adjusted for crossover using the two-stage method, the hazard ratio for OS for pembrolizumab versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using rank-preserving structural failure time and inverse probability of censoring weighting were similar. Treatment-related grade 3 to 5 adverse events were less frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%, respectively).With prolonged follow-up, first-line pembrolizumab monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to pembrolizumab as subsequent therapy.

Background Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. Methods The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394. Findings Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0–464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0–470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0–288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. Interpretation Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. Funding Bristol-Myers Squibb.

PURPOSE In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680 ). METHODS Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. RESULTS As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. CONCLUSION First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS).Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point.Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti-PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure.Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.

Targeting DLL3 with an antibody-drug conjugate eliminates tumor-initiating cells in high-grade pulmonary neuroendocrine cancers.

PURPOSE Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC. METHODS Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS. RESULTS Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%. CONCLUSION Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.

Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.

Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen.We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer.Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells).Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted.Stemcentrx Inc.

Abstract Purpose: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types. Experimental Design: LCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242). Results: Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation. Conclusions: LCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. Clin Cancer Res; 22(14); 3618–29. ©2016 AACR.

Development of acquired resistance limits the utility of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for the treatment of EGFR-mutant lung cancers. There are no accepted targeted therapies for use after acquired resistance develops. Metastasectomy is used in other cancers to manage oligometastatic disease. We hypothesized that local therapy is associated with improved outcomes in patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI.Patients who received non-central nervous system local therapy were identified by a review of data from a prospective biopsy protocol for patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy and other institutional biospecimen registry protocols.Eighteen patients were identified, who received elective local therapy (surgical resection, radiofrequency ablation, or radiation). Local therapy was well tolerated, with 85% of patients restarting TKI therapy within 1 month of local therapy. The median time to progression after local therapy was 10 months (95% confidence interval [CI]: 2-27 months). The median time until a subsequent change in systemic therapy was 22 months (95% CI: 6-30 months). The median overall survival from local therapy was 41 months (95% CI: 26-not reached).EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy are amenable to local therapy to treat oligometastatic disease when used in conjunction with continued EGFR inhibition. Local therapy followed by continued treatment with an EGFR TKI is well tolerated and associated with long PFS and OS. Further study in selected individuals in the context of other systemic options is required.

Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m 2 /day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. Response was determined by imaging at weeks 4 and 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of veliparib with TMZ. Exploratory objectives included PARP-1 and SLFN11 immunohistochemical expression, MGMT promoter methylation, and circulating tumor cell quantification. Results No significant difference in 4-month PFS was noted between TMZ/veliparib (36%) and TMZ/placebo (27%; P = .19); median OS was also not improved significantly with TMZ/veliparib (8.2 months; 95% CI, 6.4 to 12.2 months; v 7.0 months; 95% CI, 5.3 to 9.5 months; P = .50). However, ORR was significantly higher in patients receiving TMZ/veliparib compared with TMZ/placebo (39% v 14%; P = .016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred with TMZ/veliparib: 50% versus 9% and 31% versus 7%, respectively. Significantly prolonged PFS (5.7 v 3.6 months; P = .009) and OS (12.2 v 7.5 months; P = .014) were observed in patients with SLFN11-positive tumors treated with TMZ/veliparib. Conclusion Four-month PFS and median OS did not differ between the two arms, whereas a significant improvement in ORR was observed with TMZ/veliparib. SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in SCLC.

The American College of Chest Physicians (ACCP) produced an evidence-based guideline on treatment of patients with small-cell lung cancer (SCLC). Because of the relevance of this guideline to American Society of Clinical Oncology (ASCO) membership, ASCO reviewed the guideline, applying a set of procedures and policies used to critically examine guidelines developed by other organizations.The ACCP guideline on the treatment of SCLC was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel updated the literature search, reviewed the content, and considered additional recommendations.The ASCO Endorsement Panel determined that the recommendations from the ACCP guideline, published in 2013, are clear, thorough, and based on current scientific evidence. ASCO endorses the ACCP guideline on the treatment of SCLC, with the addition of qualifying statements.Surgery is indicated for selected stage I SCLC. Limited-stage disease should be treated with concurrent chemoradiotherapy in patients with good performance status. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle one or two of chemotherapy. Chemotherapy should consist of four cycles of a platinum agent and etoposide. Extensive-stage disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. Prophylactic cranial irradiation prolongs survival in patients with limited-stage disease who achieve a complete or partial response to initial therapy and may do so in similarly responding patients with extensive-stage disease as well. Additional information is available at http://www.asco.org/endorsements/sclc and http://www.asco.org/guidelineswiki.

EGFR mutations underlie the sensitivity of lung cancers to erlotinib and gefitinib and can occur in any patient with this illness. Here we examine the frequency of EGFR mutations in smokers and men.We determined the frequency of EGFR mutations and characterized their association with cigarette smoking status and male sex.We tested 2,142 lung adenocarcinoma specimens for the presence of EGFR exon 19 deletions and L858R. EGFR mutations were found in 15% of tumors from former smokers (181 of 1,218; 95% CI, 13% to 17%), 6% from current smokers (20 of 344; 95% CI, 4% to 9%), and 52% from never smokers (302 of 580; 95% CI, 48% to 56%; P < .001 for ever v never smokers). EGFR mutations in former or current smokers represented 40% of all those detected (201 of 503; 95% CI, 36% to 44%). EGFR mutations were found in 19% (157 of 827; 95% CI, 16% to 22%) of tumors from men and 26% (346 of 1,315; 95% CI, 24% to 29%) of tumors from women (P < .001). EGFR mutations in men represented 31% (157 of 503; 95% CI, 27% to 35%) of all those detected.A large number of EGFR mutations are found in adenocarcinoma tumor specimens from men and people who smoked cigarettes. If only women who were never smokers were tested, 57% of all EGFR mutations would be missed. Testing for EGFR mutations should be considered for all patients with adenocarcinoma of the lung at diagnosis, regardless of clinical characteristics. This strategy can extend the use of EGFR tyrosine kinase inhibitors to the greatest number individuals with the potential for substantial benefit.

In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab.Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS.After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off.Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.

Phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA) encodes the p110α subunit of the mitogenic signaling protein phosphoinositide 3-kinase (PI3K). PIK3CA mutations in the helical binding domain and the catalytic subunit of the protein have been associated with tumorigenesis and treatment resistance in various malignancies. Characteristics of patients with PIK3CA-mutant lung adenocarcinomas have not been reported. We examined epidermal growth factor receptor (EGFR), Kirsten rate sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), human epidermal growth factor receptor 2 (HER2), PIK3CA, v-akt murine thymoma vial oncogene homolog 1 (AKT1), v-ras neuroblastoma viral oncogene homolog (NRAS), dual specificity mitogen-activated protein kinase kinase 1 (MEK1), and anaplastic lymphoma kinase (ALK) in patients with adenocarcinoma of the lung to identify driver mutations. Clinical data were obtained from the medical records of individuals with mutations in PIK3CA. Twenty-three of 1,125 (2%, 95% CI: 1-3) patients had a mutation in PIK3CA, 12 in exon 9 (10 E545K and 2 E542K), and 11 in exon 20 (3 H1047L and 8 H1047R). The patients (57% women) had a median age of 66 at diagnosis (range: 34-78). Eight patients (35%) were never smokers. Sixteen of 23 (70%, 95% CI: 49-86) had coexisting mutations in other oncogenes-10 KRAS, 1 MEK1, 1 BRAF, 1 ALK rearrangement, and 3 EGFR exon 19 deletions. We conclude that PIK3CA mutations occur in lung adenocarcinomas, usually concurrently with EGFR, KRAS, and ALK. The impact of PIK3CA mutations on the efficacy of targeted therapies such as erlotinib and crizotinib is unknown. Given the high frequency of overlapping mutations, comprehensive genotyping should be carried out on tumor specimens from patients enrolling in clinical trials of PI3K and other targeted therapies.

Abstract Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with a unique natural history characterized by a short doubling time, high growth fraction, and early development of widespread metastases. Although a chemotherapy- and radiation-sensitive disease, SCLC typically recurs rapidly after primary treatment, with only 6% of patients surviving 5 years from diagnosis. This disease has been notable for the absence of major improvements in its treatment: Nearly four decades after the introduction of a platinum–etoposide doublet, therapeutic options have remained virtually unchanged, with correspondingly little improvement in survival rates. Here, we summarize specific barriers and challenges inherent to SCLC research and care that have limited progress in novel therapeutic development to date. We discuss recent progress in basic and translational research, especially in the development of mouse models, which will provide insights into the patterns of metastasis and resistance in SCLC. Opportunities in clinical research aimed at exploiting SCLC biology are reviewed, with an emphasis on ongoing trials. SCLC has been described as a recalcitrant cancer, for which there is an urgent need for accelerated progress. The NCI convened a panel of laboratory and clinical investigators interested in SCLC with a goal of defining consensus recommendations to accelerate progress in the treatment of SCLC, which we summarize here. Clin Cancer Res; 21(10); 2244–55. ©2015 AACR. See all articles in this CCR Focus section, “Progress in Lung Cancer.”

Despite the paucity of therapeutic advances in SCLC, considerable progress in understanding its biology, molecular biology, model systems, and potential therapeutic targets has been made (Fig. 4 and Table 1). Studies of early lung and neuroendocrine cell development models have provided insights into the cell of origin for SCLC. New GEMMs have illustrated the universal importance of TP53 and RB1 gene mutations in the pathogenesis of SCLC and the potential role of additional genetic changes as well as changes in transcription factor expression. PDXs and CDXs provide new means for preclinical testing of new therapies. Molecular studies have identified the high mutation burden found in SCLC and have identified differences between SCLC, carcinoids, and large cell neuroendocrine tumors. Potential therapeutic targets include EZH2, PARP, cyclin-dependent kinase 1 (CDK1), MCL1, Bcl-2, BIM, sonic Hh, WNT, NOTCH1, Aurora kinase, FGFR, PIK3CA, RET, THZ1, JAK-STAT, FAK, CXCR4, PD-L1, Fuc-GM1, CD56, and CD47. Ongoing and future clinical trials have to show which of these candidates can be translated into an effective targeted therapy. Thus, the future of improving outcomes for patients with SCLC appears promising, but there are still a number of unanswered questions that need to be addressed in the future and these are outlined below.Figure 4Some of the many areas of current therapeutic interest in small cell lung cancer. Cell surface targets include a number of receptor tyrosine kinases implicated in proliferative signaling, invasion, and angiogenesis; factors regulating neuroendocrine differentiation that are being explored as targets for antibody drug conjugates; immunologic regulators; and targets for tumor-specific vaccine strategies. Intracellular pathways of particular interest include metabolic and apoptotic regulators, cell cycle checkpoint controls, developmental signaling pathways, the MYC family of transcriptional regulators, and epigenetic modifiers of histones that affect chromosomal accessibility and gene expression. FAK, focal adhesion kinase; RET, ret proto-oncogene; FGFR1, fibroblast growth factor receptor 1; VEGFR, vascular endothelial growth factor receptor; DLL3, delta-like 3 (Drosophila); CXCR4, chemokine (C-X-C motif) receptor 4; PD-L1, programmed death ligand-1; Fuc-GM1, fucosyl-monosialotetrahexosylganglioside; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; mTOR, mammalian target of rapamycin; BCL2, B-cell lymphoma 2; ASCL1, achaete-scute family bHLH transcription factor 1; NEUROD1, neuronal differntiation 1; DLL4, delta-like 4 (Drosophila); WNT, wingless-type MMTV integration site family member; WEE1, WEE1 G2 checkpoint kinase; CHK1, checkpoint kinase 1; PARP1, poly-ADP ribose polymerase 1; MYCL1, v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog; NMYC, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived; MYC, v-myc avian myelocytomatosis viral oncogene homolog; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; LSD1, lysine (K)-specific demethylase 1A; MLL2, myeloid/lymphoid or mixed-lineage leukemia.View Large Image Figure ViewerDownload (PPT)Table 1Therapeutic Agents and Targets in Small Cell Lung CancerAgentTargetTrial PhaseReferencesErismodegib, sonidegib (LDE225)Smoothened (hedgehog antagonist)Preclinical, I57Belani C.P. 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Cron K. et al.CD47 blockade triggers T cell-mediated destruction of immunogenic tumors.Nat Med. 2015; 21: 1209-1215Crossref PubMed Scopus (5) Google ScholarBcl, B-cell lymphoma; EIF4E, eukaryotic translation initiation factor 4E; DLL4, delta-like 4 (Drosophila); FGFR, fibroblast growth factor receptor; PDGFR, platelet derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor; mTOR, mammalian target of rapamycin; RET, ret proto-oncogene; CDK7, cyclin-dependent kinase 7; JAK, Janus kinase; FAK, focal adhesion kinase; CXCR4, chemokine receptor 4; PARP, poly-ADP ribose polymerase; CD56, neural cell adhesion molecule; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; RAF1, Raf-1 proto-oncogene, serine/threonine kinase; BRAF, B-Raf proto-oncogene, serine/threonine kinase; VEGF, vascular endothelial growth factor; FLT, fms-related tyrosine kinase; HGF, hepatocyte growth factor (hepapoietin A; scatter factor); IGF-1R, insulin-like growth factor 1 receptor; WEE1, WEE1 G2 checkpoint kinase; CTLA-4, cytotoxic T-lymphocyte–associated antigen-4; PD-1, programmed death-1; GM1, monosialotetrahexosylganglioside; CD47, integrin-associated protein.a Clinical development halted at the time. 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Background Pembrolizumab plus pemetrexed–platinum led to superior overall survival and progression-free survival, and a higher proportion of patients with a confirmed complete or partial response over placebo plus pemetrexed–platinum in the KEYNOTE-189 study. We aimed to evaluate prespecified exploratory patient-reported outcomes (PROs) in patients in KEYNOTE-189. Methods In the multicentre, double-blind, randomised, placebo-controlled, phase 3 KEYNOTE-189 study done at 126 cancer centres in 16 countries, eligible patients aged 18 years or older with histologically or cytologically confirmed metastatic non-squamous non-small-cell lung cancer without sensitising EGFR or ALK alterations, measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive intravenous pembrolizumab (200 mg) or saline placebo every 3 weeks for up to 2 years (35 cycles); all patients received four cycles of intravenous pemetrexed (500 mg/m2) with carboplatin (5 mg/mL per min) or cisplatin (75 mg/m2; investigator's choice) every 3 weeks for four cycles, followed by pemetrexed maintenance therapy every 3 weeks. Permuted block randomisation (block size six) was done with an interactive voice-response system and stratified by PD-L1 expression, choice of platinum, and smoking status. Patients, investigators, and other study personnel were unaware of treatment assignment. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13) were administered at cycles 1–5, every three cycles thereafter during year 1, and every four cycles during years 2–3. The primary endpoints (overall survival and progression-free survival) have been published previously. Key PRO endpoints were change from baseline to week 12 (during chemotherapy) and week 21 (following chemotherapy) in QLQ-C30 global health status/quality of life (GHS/QOL) score, and time to deterioration in cough, chest pain, or dyspnoea. PROs were analysed in all randomly assigned patients who received at least one dose of study medication and who completed at least one PRO assessment, and the results are provided with two-sided, nominal p values. This ongoing study is registered with ClinicalTrials.gov, number NCT02578680. Findings Between Feb 26, 2016, and March 6, 2017, 616 patients were enrolled; median follow-up was 10·5 months (range 0·2–20·4) as of data cutoff on Nov 8, 2017. 402 (99%) of 405 patients in the pembrolizumab plus pemetrexed–platinum group and 200 (99%) of 202 patients in the placebo plus pemetrexed–platinum-treated group completed at least one PRO assessment. At baseline, 359 (89%) of 402 patients in the pembrolizumab plus pemetrexed–platinum group and 180 (90%) of 200 in the placebo plus pemetrexed–platinum group were compliant with QLQ-C30; at week 12, 319 (90%) of 354 and 149 (89%) of 167 patients were compliant, respectively; and at week 21, 249 (76%) of 326 and 91 (64%) of 143 patients were compliant, respectively. From baseline to week 12, GHS/QOL scores were maintained with both pembrolizumab plus pemetrexed–platinum (least-squares mean change: 1·0 point [95% CI −1·3 to 3·2] increase) and placebo plus pemetrexed–platinum (−2·6 points [−5·8 to 0·5] decrease; between-group difference: 3·6 points [−0·1 to 7·2]; p=0·053). From baseline to week 21, GHS/QOL scores were better maintained with pembrolizumab plus pemetrexed–platinum (least-squares mean change: 1·3 points [95% CI −1·2 to 3·6] increase) than with placebo plus pemetrexed–platinum (−4·0 points [−7·7 to −0·3] decrease; between-group difference: 5·3 points [1·1 to 9·5]; p=0·014). Median time to deterioration in cough, chest pain, or dyspnoea was not reached (95% CI 10·2 months to not reached) with pembrolizumab plus pemetrexed–platinum, and was 7·0 months (4·8 months to not reached) with placebo plus pemetrexed–platinum (hazard ratio 0·81 [95% CI 0·60–1·09], p=0·16). Interpretation The addition of pembrolizumab to standard chemotherapy maintained GHS/QOL, with improved GHS/QOL scores at week 21 in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group. These data further support use of pembrolizumab plus pemetrexed–platinum as first-line therapy for patients with metastatic non-squamous non-small-cell lung cancer. Funding Merck Sharp & Dohme.

IntroductionThis exploratory analysis retrospectively evaluated outcomes in patients with advanced NSCLC to determine whether baseline brain metastases influenced the efficacy of first-line pembrolizumab plus chemotherapy versus chemotherapy alone.MethodsWe pooled data for patients with advanced NSCLC in KEYNOTE-021 cohort G (nonsquamous), KEYNOTE-189 (nonsquamous), and KEYNOTE-407 (squamous). Patients were assigned to platinum-doublet chemotherapy with or without the addition of 35 cycles of pembrolizumab 200 mg every 3 weeks. All studies permitted enrollment of patients with previously treated or untreated (KEYNOTE-189 and KEYNOTE-407 only) stable brain metastases. Patients with previously treated brain metastases were clinically stable for 2 or more weeks (≥4 wk in KEYNOTE-021 cohort G), had no evidence of new or enlarging brain metastases, and had no steroid use at least 3 days before dosing. Patients with known untreated asymptomatic brain metastases required regular imaging of the brain.ResultsA total of 1298 patients were included, 171 with and 1127 without baseline brain metastases. Median (range) durations of follow-up at data cutoff were 10.9 (0.1‒35.1) and 11.0 (0.1‒34.9) months, respectively. Hazard ratios (pembrolizumab + chemotherapy/chemotherapy) were similar for patients with and without brain metastases for overall survival (0.48 [95% confidence interval (CI): 0.32‒0.70] and 0.63 [95% CI: 0.53‒0.75], respectively) and progression-free survival (0.44 [95% CI: 0.31‒0.62] and 0.55 [95% CI: 0.48‒0.63], respectively). In patients with brain metastases, median overall survival was 18.8 months with pembrolizumab plus chemotherapy and 7.6 months with chemotherapy, and median progression-free survival was 6.9 months and 4.1 months, respectively. Objective response rates were higher and duration of response longer with pembrolizumab plus chemotherapy versus chemotherapy regardless of brain metastasis status. Incidences of treatment-related adverse events with pembrolizumab plus chemotherapy versus chemotherapy were 88.2% versus 82.8% among patients with brain metastases and 94.5% versus 90.6% in those without.ConclusionsWith or without brain metastasis, pembrolizumab plus platinum-based histology-specific chemotherapy improved clinical outcomes versus chemotherapy alone across all programmed death ligand 1 subgroups, including patients with programmed death ligand 1 tumor proportion score less than 1% and had a manageable safety profile in patients with advanced NSCLC. This regimen is a standard-of-care treatment option for treatment-naive patients with advanced NSCLC, including patients with stable brain metastases.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 5-year efficacy and safety outcomes from the phase III KEYNOTE-407 study (ClinicalTrials.gov identifier: NCT02775435). Eligible patients with previously untreated, metastatic squamous non-small-cell lung cancer (NSCLC) were randomly assigned 1:1 to pembrolizumab 200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3 weeks for four cycles, followed by pembrolizumab or placebo for up to 35 cycles. Primary end points were overall survival (OS) and progression-free survival (PFS) per RECIST version 1.1 by blinded independent central review (BICR). Five hundred fifty-nine patients were randomly assigned in the intention-to-treat population (pembrolizumab plus chemotherapy, n = 278; placebo plus chemotherapy, n = 281). The median time from random assignment to data cutoff was 56.9 (range, 49.9-66.2) months. OS and PFS were improved with pembrolizumab plus chemotherapy versus placebo plus chemotherapy (hazard ratio [95% CI], 0.71 [0.59 to 0.85] and 0.62 [0.52 to 0.74]), with 5-year OS rates of 18.4% versus 9.7%, respectively. Toxicity was manageable. Among 55 patients who completed 35 cycles of pembrolizumab, the objective response rate was 90.9% and the 3-year OS rate after completion of 35 cycles (approximately 5 years after random assignment) was 69.5%. Pembrolizumab plus chemotherapy maintained an OS and PFS benefit versus placebo plus chemotherapy in previously untreated, metastatic squamous NSCLC and is a standard-of-care first-line treatment option for metastatic squamous NSCLC regardless of programmed death ligand 1 expression.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680 ). Eligible patients with previously untreated metastatic nonsquamous non–small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non–small-cell lung cancer without EGFR/ALK alterations.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines. Furthermore, there are no prospective trial data to inform the management of the distinct presentations of irAEs. Recognizing a need for uniform terminology for the natural history, response to treatment, and patterns of irAEs, the Society for Immunotherapy of Cancer (SITC) convened a consensus panel composed of leading international experts from academic medicine, industry, and regulatory agencies. Using a modified Delphi consensus process, the expert panel developed clinical definitions for irAE terminology used in the literature, encompassing terms related to irAE natural history (ie, re-emergent, chronic active, chronic inactive, delayed/late onset), response to treatment (ie, steroid unresponsive, steroid dependent), and patterns (ie, multisystem irAEs). SITC developed these definitions to support the adoption of a standardized vocabulary for irAEs, which will have implications for the uniform application of irAE clinical practice guidelines and to enable future irAE clinical trials.

We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial.This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome.Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status.tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.

Abstract Purpose: This phase II study was conducted to assess the efficacy of temozolomide in patients with relapsed small cell lung cancer (SCLC). Experimental Design: Patients with disease progression after one or two prior chemotherapy regimens received temozolomide at 75 mg/m2/d for 21 days of a 28-day cycle. The primary endpoint was the overall response rate [ORR; complete response (CR) plus partial response (PR)], which was evaluated separately in sensitive and refractory cohorts. In the available tissue, we assessed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status by PCR and MGMT expression by immunohistochemistry. Results: Sixty-four patients were accrued: 48 patients in the sensitive cohort and 16 in the refractory group. One CR and 10 PRs were noted in sensitive patients [ORR, 23%; 95% confidence interval (CI), 12%–37%]. Two PRs were seen in the refractory cohort (ORR, 13%; 95% CI, 2%–38%). As second- and third-line treatment, the ORR was 22% (95% CI, 9%–40%) and 19% (95% CI, 7%–36%), respectively. Among patients with target brain lesions, 38% had a CR or PR (95% CI, 14%–68%). Grade ≥3 thrombocytopenia and neutropenia were observed in nine patients (14%). A greater number of cases with methylated MGMT had a response compared to those with unmethylated MGMT (38% vs. 7%; P = 0.08). Conclusion: Temozolomide has activity in relapsed SCLC, particularly for brain metastases. Response to temozolomide may correlate with MGMT methylation in SCLC. Clin Cancer Res; 18(4); 1138–45. ©2012 AACR.

Abstract BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-X L or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-X L inhibitor, prevented BCL-X L from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-X L -addicted cells with low activator BH3s and BCL-X L overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL-1 . As doxorubicin and dinaciclib also reduced BCL-X L , the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells.

KRAS mutations are present in 30% of lung adenocarcinomas. Salirasib prevents Ras membrane binding thereby blocking the function of all Ras isoforms. This phase II study determined the activity of salirasib in patients with advanced lung adenocarcinomas with KRAS mutations.Two cohorts of patients with stage IIIB/IV lung adenocarcinoma were eligible: patients with tumors with KRAS mutations who were previously treated with chemotherapy and patients receiving initial therapy who had ≥15 pack-year smoking history. Salirasib was given orally from days 1 to 28 of a 35-day cycle. The primary end point was the rate of nonprogression at 10 weeks.Thirty-three patients were enrolled. Thirty patients had KRAS mutations (23 patients who were previously treated and 7/10 patients who had no prior therapy). Of the previously treated patients, 7 of 23 (30%) had stable disease at 10 weeks, and 4 of 10 (40%) previously untreated patients had stable disease at 10 weeks. No patient had a radiographic partial response (0% observed rate, 95% confidence interval 0-12%). The median overall survival was not reached (>9 months) for previously untreated patients and it was 15 months for patients who received prior chemotherapy. Diarrhea, nausea, and fatigue were the most common toxicities.Salirasib at the current dose and schedule has insufficient activity in the treatment of KRAS mutant lung adenocarcinoma to warrant further evaluation. The successful enrollment of 30 patients with tumors with KRAS mutant lung adenocarcinoma over 15 months at a single site demonstrates that drug trials directed at a KRAS-specific genotype in lung cancer are feasible.

BackgroundPhysicians are often asked about complementary therapies by patients with cancer, and data show that the interest in and use of these therapies among patients with cancer is common. Therefore, it is important to assess the current evidence base on the benefits and risks of complementary therapies (modalities not historically used in modern Western medicine).MethodsA systematic literature review was carried out and recommendations were made according to the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines development methodology.ResultsA large number of randomized controlled trials, systematic reviews, and meta-analyses, as well as a number of prospective cohort studies, met the predetermined inclusion criteria. These trials addressed many different issues pertaining to patients with lung cancer, such as symptoms of anxiety, mood disturbance, pain, quality of life, and treatment-related side effects. The available data cover a variety of interventions, including acupuncture, nutrition, mind-body therapies, exercise, and massage. The body of evidence supports a series of recommendations. An evidenced-based approach to modern cancer care should integrate complementary therapies with standard cancer therapies such as surgery, radiation, chemotherapy, and best supportive care measures.ConclusionsSeveral complementary therapy modalities can be helpful in improving the overall care of patients with lung cancer. Physicians are often asked about complementary therapies by patients with cancer, and data show that the interest in and use of these therapies among patients with cancer is common. Therefore, it is important to assess the current evidence base on the benefits and risks of complementary therapies (modalities not historically used in modern Western medicine). A systematic literature review was carried out and recommendations were made according to the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines development methodology. A large number of randomized controlled trials, systematic reviews, and meta-analyses, as well as a number of prospective cohort studies, met the predetermined inclusion criteria. These trials addressed many different issues pertaining to patients with lung cancer, such as symptoms of anxiety, mood disturbance, pain, quality of life, and treatment-related side effects. The available data cover a variety of interventions, including acupuncture, nutrition, mind-body therapies, exercise, and massage. The body of evidence supports a series of recommendations. An evidenced-based approach to modern cancer care should integrate complementary therapies with standard cancer therapies such as surgery, radiation, chemotherapy, and best supportive care measures. Several complementary therapy modalities can be helpful in improving the overall care of patients with lung cancer.

<h2>Abstract</h2><h3>Background</h3> Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC. <h3>Materials and Methods</h3> Cases of pathologically-confirmed stage IV LCNEC evaluated at Memorial Sloan Kettering Cancer Center from 2006 to 2013 were identified. We collected demographic, treatment, and survival data. Available radiology was evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. <h3>Results</h3> Forty-nine patients with stage IV LCNEC were identified. The median age was 64 years, 63% of patients were male, and 88% were smokers. Twenty-three patients (n = 23/49; 47%) had brain metastases, 17 at diagnosis and 6 during the disease course. Seventeen LCNEC patients (35%) had molecular testing, of which 24% had <i>KRAS</i> mutations (n = 4/17). Treatment data for first-line metastatic disease was available on 37 patients: 70% (n = 26) received platinum/etoposide and 30% (n = 11) received other regimens. RECIST was completed on 23 patients with available imaging; objective response rate was 37% (95% confidence interval, 16%-62%) with platinum/etoposide, while those treated with other first-line regimens did not achieve a response. Median overall survival was 10.2 months (95% confidence interval, 8.6-16.4 months) for the entire cohort. <h3>Conclusion</h3> Patients with stage IV LCNEC have a high incidence of brain metastases. <i>KRAS</i> mutations are common. Patients with stage IV LCNEC do not respond as well to platinum/etoposide compared with historic data for extensive stage small-cell lung cancer; however, the prognosis is similar. Prospective studies are needed to define optimum therapy for stage IV LCNEC.

Abstract Purpose: In patients with epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma, treatment with erlotinib or gefitinib is associated with a 75% radiographic response rate and progression-free survival of approximately 12 months. The most common mechanism of acquired resistance to erlotinib is development of a secondary mutation in EGFR, suggesting that these tumors continue to depend on EGFR signaling. We hypothesized that combined EGFR blockade would overcome acquired resistance to erlotinib in patients with lung adenocarcinoma. To evaluate the toxicity and efficacy of cetuximab and erlotinib in patients with acquired resistance to erlotinib, we conducted this phase I/II clinical trial. Experimental Design: Patients with lung adenocarcinoma and clinically defined acquired resistance to erlotinib were treated with erlotinib 100 mg daily, along with cetuximab every 2 weeks in three escalating dose cohorts (250 mg/m2, 375 mg/m2, and 500 mg/m2). The recommended phase II dose was then evaluated in a two-stage trial, with a primary end point of objective response rate. Results: A total of 19 patients were enrolled. The most common toxicities for the combination of cetuximab and erlotinib were rash, fatigue, and hypomagnesemia. The recommended phase II dose identified was cetuximab 500 mg/m2 every 2 weeks and erlotinib 100 mg daily. At this dose and schedule, no radiographic responses were seen (0 of 13, 0%, 95% CI, 0–25). Conclusions: Combined EGFR inhibition, with cetuximab 500 mg/m2 every 2 weeks and erlotinib 100 mg daily, had no significant activity in patients with acquired resistance to erlotinib. Clin Cancer Res; 17(8); 2521–7. ©2011 AACR.

We describe clinical, pathologic, and molecular characteristics of never-smoker patients with small-cell lung cancers (SCLCs).We identified cases of SCLCs evaluated at our institution from 2005 to 2012. We collected smoking history, demographic, treatment, and survival data. EGFR, KRAS, PIK3CA, ALK testing, RB protein expression, and next generation sequencing were performed on available samples.Two percent (23 of 1040) of patients with SCLCs were never-smokers. Eighty-three percent (19 of 23) had de novo SCLCs, whereas 17% had SCLC transformation as acquired resistance to erlotinib after treatment for EGFR-mutant lung carcinomas. Median survival from SCLC diagnosis was 23 months. Of de novo SCLCs, ALK rearrangement, KRAS mutations, EGFR mutations, and RB loss were identified in zero of five, zero of eight, two of eight, and six of seven, respectively. Two de novo samples underwent next generation sequencing. One had mutations in p53 and RB1 with amplification in TERT, and a second had mutations in CBL and GNAS with amplification in MYCL1.Two percent of patients with SCLCs are never-smokers. Although transformation to SCLC can rarely occur in acquired resistance to erlotinib, 83% of never-smokers with SCLCs had de novo SCLC. RB loss was noted in 86% of cases. Multiplexed genotyping can be performed on tissues to identify potentially actionable oncogenic drivers.

Abundant research has now demonstrated that patient and clinician reports of symptoms—and particularly symptomatic toxicities (ie, adverse events) during cancer treatment—provide discrepant yet complementary data (1–3). How can this be? Can’t only the patient or the clinician be “right”? The more patient-centered among us might state that the patient is always right by definition because nobody (not even the most sensitive clinician) can truly know another person’s subjective experience. But the more traditional among us might assert that clinicians should be considered right because they have an “objective” perspective based on experience and training, which prevents them from exaggerating or understating what they observe. In fact, it appears that both the patient and clinician provide information of value, which when combined provides a more accurate understanding of the patient’s symptoms. This finding is good news for those of us who are interested in improving the measurement of symptoms in clinical trials and practice. The optimistic among us might state that all we need to do now is figure out how to operationalize this approach.

Background: Pembro þ chemo improves efficacy as 1L therapy for metastatic squamous and nonsquamous NSCLC, regardless of PD-L1 TPS.We explored the

First-line pembrolizumab plus chemotherapy with pemetrexed and platinum significantly improved OS (HR 0.49, P <.001), PFS (HR 0.52, P <.001) and ORR (47.6% vs 18.9%, P <.001) vs placebo plus chemotherapy with pemetrexed and platinum for metastatic nonsquamous NSCLC in the double-blind phase 3 KEYNOTE-189 study (NCT02578680); benefit was observed in all analyzed subgroups, including PD-L1 TPS <1%, 1-49%, and ≥50%. We explored the association of TMB with efficacy in KEYNOTE-189.

Background Pembrolizumab plus platinum‐based chemotherapy has demonstrated improved clinical outcomes over chemotherapy alone in patients with previously untreated advanced/metastatic non–small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD‐L1) expression. This study pooled data from 3 randomized controlled trials to evaluate outcomes with pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced/metastatic NSCLC negative for PD‐L1 (ie, a tumor proportion score &lt; 1%). Methods Individual patient data were pooled from KEYNOTE‐021 cohort G (nonsquamous; NCT02039674), KEYNOTE‐189 (nonsquamous; NCT02578680 and NCT03950674), and KEYNOTE‐407 (squamous; NCT02775435). Treatment comprised pembrolizumab plus chemotherapy (pemetrexed and platinum for nonsquamous histology and carboplatin and paclitaxel/nab‐paclitaxel for squamous histology) or chemotherapy alone. Responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent, central review. No α was assigned to this descriptive, exploratory analysis. Results Four hundred forty‐four of the 1328 patients (33.4%) who were enrolled across the 3 trials had PD‐L1‒negative tumors (256 on pembrolizumab plus chemotherapy [nonsquamous, n = 155; squamous, n = 94; other, n = 7] and 188 on chemotherapy alone [nonsquamous, n = 83; squamous, n = 99; other, n = 6]). The median time from randomization to the data cutoff was 28.0 months (range, 14.7‐55.4 months). Pembrolizumab plus chemotherapy improved overall survival (OS; hazard ratio [HR], 0.63; 95% CI, 0.50‐0.79) and progression‐free survival (HR, 0.68; 95% CI, 0.56‐0.83) over chemotherapy. Sixteen patients in the pembrolizumab plus chemotherapy arm completed 2 years of treatment; the objective response rate was 87.5% (95% CI, 61.7%‐98.4%), and the 3‐year OS rate was 100%. Adverse events (AEs) were experienced by 99.2% of the patients who received pembrolizumab plus chemotherapy and by 98.9% of the patients who received chemotherapy alone, with grade 3 or higher AEs occurring in 71.4% and 72.0%, respectively; immune‐mediated AEs and infusion reactions were experienced by 29.0% and 12.4%, respectively. Conclusions Pembrolizumab plus chemotherapy demonstrated response and survival improvements with manageable safety in comparison with chemotherapy alone in PD‐L1‒negative advanced/metastatic NSCLC, and it is a standard‐of‐care first‐line therapy for patients with advanced NSCLC, regardless of PD‐L1 expression. Lay Summary Some tumors produce a protein called programmed death ligand 1 (PD‐L1), which interacts with the body's immune system and prevents an immune response against cancer. Antibody therapies such as pembrolizumab block interactions between tumor PD‐L1 and the immune system and enable an immune response. Used alone, pembrolizumab provides benefit for patients with non–small cell lung cancer (NSCLC) tumors that produce PD‐L1. However, when it is combined with chemotherapy, which can stimulate anticancer immune responses, pembrolizumab provides a benefit, regardless of tumor PD‐L1 production. This article shows that among patients with NSCLC whose tumors produce no PD‐L1, outcomes are better with pembrolizumab plus chemotherapy in comparison with chemotherapy alone.

Abstract Background Somatic KRAS mutations are detected in approximately 15%-30% of lung adenocarcinomas, with regional variation, and are associated with poor prognosis. We explored the prevalence of KRAS mutations and their association with efficacy in participants (pts) with non-squamous NSCLC enrolled in the KEYNOTE-042 study of pembrolizumab monotherapy vs platinum-based chemotherapy as first-line therapy for advanced PD-L1-positive (TPS ≥1%) NSCLC (NCT02220894). Methods KRAS mutational status and tumor mutational burden (TMB) were assessed by whole-exome sequencing (WES) in pts with who had available tumor and matched-normal tissue. This exploratory analysis included descriptive analyses of the correlation between KRAS mutational status and shifts in distributions of TMB and PD-L1 expression and the association of KRAS and KRAS G12C status with efficacy. Results Of the 782 pts with non-squamous histology, 301 (38%) were evaluable by WES and had matched tumor and normal DNA. KRAS mutations were identified in 69 (23%) pts, including 29 (10%) G12C carriers. Pts with vs without KRAS mutation tended to have higher PD-L1 TPS (median [IQR] 60% [10-95] vs 35% [10-80]) and TMB (median [IQR] 191 [129-288] vs 105 [56-226] mut/exome). Outcomes of pembrolizumab and of chemotherapy for pts with and without KRAS mutation and for KRAS G12C carriers are in the table. Of note, CIs were wide given the modest frequency of KRAS mutation and low frequency of KRAS G12C.TableLBA4TableWith Any KRAS MutationWith KRAS G12C MutationWithout Any KRAS MutationPembro Mono-therapy (N = 30)Chemo-therapy (N = 39)Pembro Mono-therapy (N = 12)Chemo-therapy (N = 17)Pembro Mono-therapy (N = 127)Chemo-therapy (N = 105)ORR, % (95% CI)56.7 (37.4-74.5)18.0 (7.5-33.5)66.7 (34.9-90.1)23.5 (6.8-49.9)29.1 (21.4-37.9)21.0 (13.6-30.0)PFS, median, mo (95% CI)12 (8-NR)6 (4-9)15 (10-NR)6 (4-8)6 (4-7)6 (6-8)PFS, HR (95% CI)0.51 (0.29-0.87)0.27 (0.10-0.71)1.00 (0.75-1.34)OS, median, mo (95% CI)28 (23-NR)11 (7-25)NR (23-NR)8 (5-NR)15 (12-24)12 (11-18)OS, HR (95% CI)0.42 (0.22-0.81)0.28 (0.09-0.86)0.86 (0.63-1.18) Conclusion Findings of this descriptive exploratory analysis suggest that pembrolizumab monotherapy should be considered as a standard first-line treatment option for PD-L1-positive advanced non-squamous NSCLC regardless of KRAS mutational status. These findings also suggest that a pembrolizumab-containing regimen is a clinically relevant comparator for studies of KRAS -targeted therapy given as first-line treatment of NSCLC. Clinical trial identification KEYNOTE-042; NCT02220894. Editorial acknowledgement Joanne Tomassini and Melanie Leiby, both of Merck & Co., Inc., Kenilworth, NJ, for writing support. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure R.S. Herbst: Advisory / Consultancy: Abbvie Pharmaceuticals; Advisory / Consultancy: ARMO Biosciences; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly and Company; Advisory / Consultancy: EMD Serrano; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Genmab; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Heat Biologics; Advisory / Consultancy: Infinity Pharmaceuticals; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy, Research grant / Funding (self): Merck & Co., Inc., Kenilworth, NJ, USA; Advisory / Consultancy: Nektar; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: NextCure; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Shire PLC; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Tocagen; Officer / Board of Directors: Junshi Pharmaceuticals. G. Lopes: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Merck & Co., Inc.. D.M. Kowalski: Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: BMS. K. Kasahara: Research grant / Funding (institution): MSD. Y-L. Wu: Advisory / Consultancy, Research grant / Funding (institution): Boehringer-Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Sanofi. G. De Castro Jr.: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer-Ingelheim; Honoraria (self), Honoraria (institution): Novartis; Honoraria (institution): Amgen; Honoraria (institution): Astellas. B.C. Cho: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Bristol Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Yuhan. H.Z. Turna: Research grant / Funding (institution): MSD. R. Cristescu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. D. Aurora-Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. J. Lunceford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. J. Kobie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M. Ayers: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M.C. Pietanza: Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: Merck Sharp & Dohme. B. Piperdi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. T.S.K. Mok: Honoraria (self), Advisory / Consultancy, Leadership role, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): SFJ Pharmaceuticals; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Xcovery; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options: Hutchinson MedPharma; Honoraria (self): Janssen; Honoraria (self): Takeda; Honoraria (self): Fishawack Facilitate Ltd; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: ACEA Biosciences Inc.; Advisory / Consultancy: Celgene, Vertex, geneDecode, OncoGenex, Ignyta; Leadership role, Shareholder / Stockholder / Stock options: Sanomics Ltd; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Cirina; Non-remunerated activity/ies, ASCO board of directors: ASCO; Non-remunerated activity/ies, track chair for ESMO 2019: ESMO.

Superiority of 1L pembro monotherapy vs chemo in pts with metastatic NSCLC with PD-L1 TPS ≥50% and no sensitizing EGFR/ALK alterations was demonstrated in KEYNOTE-024 (NCT02142738). We report updated efficacy and safety from KEYNOTE-024 with 5 years follow-up. Eligible pts were randomized to pembro (200 mg Q3W for up to 35 cycles [∼2 years]) or chemo. Randomization was stratified by ECOG PS (0/1), histology (squamous/nonsquamous), and region (East Asia/other). Pts randomized to chemo who had PD and met eligibility criteria could cross over to pembro monotherapy. Pts randomized to pembro who completed 2 years of therapy or who stopped pembro after achieving CR and then had PD were eligible for a second course of pembro monotherapy. Endpoints included PFS (primary); OS, ORR, and safety (secondary); and duration of response (exploratory). For this analysis, response/PD was assessed by investigators per RECIST v1.1. 305 pts were randomized (pembro, 154; chemo, 151). As of June 1, 2020, median (range) time from randomization to data cutoff was 59.9 (55.1–68.4) mo. 83 (55.0%) pts randomized to chemo crossed over to pembro. Efficacy in the ITT population and in 39/154 (25.3%) pts in the pembro arm who completed 35 cycles of pembro are shown in the Table. 12/154 pts started second course pembro; outcomes in these pts will be presented. Among all treated pts, incidence of treatment-related grade 3–5 AEs was 31.2% with pembro vs 53.3% with chemo.Table: LBA51EfficacyPembro (N = 154)Chemo (N = 151)Median OS, mo (95% CI)26.3 (18.3–40.4)13.4 (9.4–18.3)- HR (95% CI)0.62 (0.48–0.81)Kaplan-Meier estimate of 5-year OS rate, %31.916.3Pts who completed35 cycles (N = 39)ORR, n (%)a32 (82.1)- CR4 (10.3)- PR28 (71.8)- SD6 (15.4)Pts alive at data cutoff, n/N (%)32/39 (82.1)bKaplan-Meier estimate of 3-year OS rate after completing pembro, %81.4aAt data cutoff, 18/39 pts were alive and had not experienced PD per investigator assessment. b7 patients died due to PD; 2 did not receive any additional treatment. Open table in a new tab aAt data cutoff, 18/39 pts were alive and had not experienced PD per investigator assessment. b7 patients died due to PD; 2 did not receive any additional treatment. Pembro continues to show improvements in OS vs chemo as 1L treatment for metastatic NSCLC with PD-L1 TPS ≥50%. Despite the high crossover rate, 5-year OS was approximately doubled among pts who received pembro (31.9% vs 16.3%). Fewer pts who received pembro experienced grade 3−5 AEs vs those who received chemo. Long-term OS and durable responses were observed with pembro monotherapy.

The spectrum and evolution of proliferation rates in stage IV lung carcinoids is poorly defined. In particular, there are limited data on the prevalence and characteristics of tumors exceeding the standard upper proliferative criteria-as defined largely based on early-stage carcinoids-in metastatic setting. Sixty-six patients with stage IV lung carcinoids were identified, and all evaluable samples (n = 132; mean 2 samples per patient) were analyzed for mitotic counts and Ki-67 rate. Clinicopathologic and genomic features associated with elevated proliferation rates (>10 mitoses per 2 mm2 and/or >20% hot-spot Ki-67), and evolution of proliferation rates in serial specimens were analyzed. We found that mitoses and/or Ki-67 exceeded the standard criteria in 35 of 132 (27%) samples, primarily (31/35 cases) at metastatic sites. Although neuroendocrine neoplasms with >10 mitoses per 2 mm2 are currently regarded as de facto neuroendocrine carcinomas, the notion that these cases are part of the spectrum of carcinoids was supported by (1) well-differentiated morphology, (2) conventional proliferation rates in other samples from same patient, (3) genetic characteristics, including the lack of RB1/TP53 alterations in all tested samples (n = 19), and (4) median overall survival of 2.7 years, compared to <1 year survival of stage IV neuroendocrine carcinomas in the historic cohorts. In patients with matched primary/metastatic specimens (48 pairs), escalation of mitoses or Ki-67 by ≥10 points was observed in 35% of metastatic samples; clonal relationship in one pair with marked proliferative progression was confirmed by next-generation sequencing. Notably, escalation of proliferation rate was documented in a subset of metastases arising from resected typical carcinoids, emphasizing that the diagnosis of typical carcinoid in primary tumor does not assure low proliferation rate at metastatic sites. In conclusion, stage IV lung carcinoids frequently exceed the standard proliferative criteria established for primary tumors, and commonly exhibit proliferative escalation at metastatic sites. Despite the overlap of proliferation rates, these tumors show fundamental morphologic, genomic and clinical differences from neuroendocrine carcinomas, and should be classified separately from those tumors. Awareness of the increased proliferative spectrum in metastatic carcinoids is critical for their accurate diagnosis. Further studies are warranted to explore the impact of proliferation indices on prognosis and therapeutic responses of patients with metastatic carcinoids.

We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials.This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1, and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11, KEAP1, and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome.Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n = 293; KEYNOTE-407, n = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1, STK11, or KRAS mutation status.These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen.

Bevacizumab is effective for the treatment of non-small cell lung cancer (NSCLC). Ongoing trials are exploring the safety of bevacizumab in patients with inactive, previously treated brain metastases. However, bevacizumab safety and efficacy in the treatment of active brain metastases is unknown. Bevacizumab received accelerated FDA approval for progressive glioblastoma, a primary brain tumor, because of high response rates and low incidence of intracranial hemorrhage. We retrospectively identified patients treated with bevacizumab for active (treatment naïve or progressive) central nervous system (CNS) metastases from NSCLC. MRI scans performed at least 6 weeks after initiating bevacizumab were assessed for response. There were six patients, four women and two men with a median age of 60 years (range 59–77) at initiation of bevacizumab. Five patients had progressive CNS metastases despite prior treatment including surgery, radiotherapy, and/or chemotherapy; one patient had treatment-naïve brain metastases. Two patients had leptomeningeal metastases, isolated or coexistent with parenchymal brain metastases in one patient each. Bevacizumab was administered alone to one patient and in combination with various cytotoxic chemotherapies in the others. Toxicity included an asymptomatic (Grade 1) intra-tumoral hemorrhage which occurred in one of three patients receiving concurrent anticoagulation with bevacizumab. There was no recurrent CNS bleeding in two patients with a prior history of such hemorrhage. Best CNS response (RECIST) was partial in two, stable disease in three, and progression in one. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 14.1 months following initiation of bevacizumab. Clinical benefit was also observed in the form of improved symptoms and reduced corticosteroid requirements. Bevacizumab should be used with caution in patients with active CNS metastases pending additional safety data. This series suggests bevacizumab may be safe and effective for progressive brain metastases from NSCLC and deserves further study.

BackgroundPulmonary large cell neuroendocrine carcinomas (LCNEC) are aggressive neoplasms with poor prognosis. The role of neoadjuvant and adjuvant therapies in these tumors remains uncertain.MethodsWe performed a retrospective review of a prospective database. Kaplan-Meier estimates of overall survival (OS) were determined and compared across prognostic factors using log-rank analysis and the Cox proportional hazards model.ResultsOne hundred patients with resected LCNEC were identified from 1992 to 2008. Of these, 54% were male and 98% current or former smokers (mean 60.3 pack-years). Twenty-two patients received neoadjuvant platinum chemotherapy with a response rate of 68% (15 of 22). Eighty percent (80 of 100) underwent lobectomy and 11% (11 of 100) pneumonectomy with a 90% (90 of 100) complete resection (R0) rate. Seventy-one percent (71 of 100) were stage I-II, and 20 of 71 received platinum adjuvant chemotherapy. Mean OS was 40 months. Univariate factors associated with decreased OS included male gender (p = 0.007), increasing tumor (T) stage (p = 0.004), and stage III–IV disease (p = 0.04). Stage IB patients fared significantly worse than IA (p = 0.006). Multivariate analyses identified male gender (hazard ratio [HR] 2.3, p = 0.007), comorbid pulmonary disease (HR 2.3, p = 0.012), and pathologic stage (HR = 2.2, p = 0.011) as associated with risk of death. Univariate analysis in stage IB-IIIA completely resected (R0) patients receiving combination platinum-based induction and (or) adjuvant chemotherapy showed a trend toward improved OS (median survival 7.4 vs 2 years, p = 0.052).ConclusionsThe LCNEC has a high response rate to platinum-based neoadjuvant chemotherapy. Resected advanced-stage patients receiving combination neoadjuvant and (or) adjuvant chemotherapy may have a survival advantage. These therapies should be considered in resectable patients with LCNEC. Pulmonary large cell neuroendocrine carcinomas (LCNEC) are aggressive neoplasms with poor prognosis. The role of neoadjuvant and adjuvant therapies in these tumors remains uncertain. We performed a retrospective review of a prospective database. Kaplan-Meier estimates of overall survival (OS) were determined and compared across prognostic factors using log-rank analysis and the Cox proportional hazards model. One hundred patients with resected LCNEC were identified from 1992 to 2008. Of these, 54% were male and 98% current or former smokers (mean 60.3 pack-years). Twenty-two patients received neoadjuvant platinum chemotherapy with a response rate of 68% (15 of 22). Eighty percent (80 of 100) underwent lobectomy and 11% (11 of 100) pneumonectomy with a 90% (90 of 100) complete resection (R0) rate. Seventy-one percent (71 of 100) were stage I-II, and 20 of 71 received platinum adjuvant chemotherapy. Mean OS was 40 months. Univariate factors associated with decreased OS included male gender (p = 0.007), increasing tumor (T) stage (p = 0.004), and stage III–IV disease (p = 0.04). Stage IB patients fared significantly worse than IA (p = 0.006). Multivariate analyses identified male gender (hazard ratio [HR] 2.3, p = 0.007), comorbid pulmonary disease (HR 2.3, p = 0.012), and pathologic stage (HR = 2.2, p = 0.011) as associated with risk of death. Univariate analysis in stage IB-IIIA completely resected (R0) patients receiving combination platinum-based induction and (or) adjuvant chemotherapy showed a trend toward improved OS (median survival 7.4 vs 2 years, p = 0.052). The LCNEC has a high response rate to platinum-based neoadjuvant chemotherapy. Resected advanced-stage patients receiving combination neoadjuvant and (or) adjuvant chemotherapy may have a survival advantage. These therapies should be considered in resectable patients with LCNEC.

Germline mutations in the BRCA2 cancer susceptibility gene are associated with an increased risk of pancreatic cancer (PC). Breast-pancreas cancer families with BRCA1 mutations have also been observed. The influence of a family history (FH) of PC on BRCA mutation prevalence in patients with breast cancer (BC) is unknown.A clinical database review (2000-2009) identified 211 Ashkenazi Jewish (AJ) BC probands who 1) underwent BRCA1/2 mutation analysis by full gene sequencing or directed testing for Ashkenazi founder mutations (BRCA1: 185delAG and 5382insC; BRCA2: 6174delT) and 2) had a FH of PC in a first-, second-, or third-degree relative. For each proband, the pretest probability of identifying a BRCA1/2 mutation was estimated using the Myriad II model. The observed-to-expected (O:E) mutation prevalence was calculated for the entire group.Of the 211 AJ BC probands with a FH of PC, 30 (14.2%) harbored a BRCA mutation. Fourteen (47%) of the mutations were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnosed with BC at age ≤ 50 years were found to have a higher BRCA1/2 mutation prevalence than probands with BC who were diagnosed at age > 50 years (21.1% vs 6.9%; P = .003). In patients with a first-, second-, or third-degree relative with PC, mutation prevalences were 15.4%, 15.3%, and 8.6%, respectively (P = .58). In the overall group, the observed BRCA1/2 mutation prevalence was 14.2% versus an expected prevalence of 11.8% (O:E ratio, 1.21; P = .15).BRCA1 and BRCA2 mutations are observed with nearly equal distribution in AJ breast-pancreas cancer families, suggesting that both genes are associated with PC risk. In this population, a FH of PC was found to have a limited effect on mutation prevalence.

Introduction:Concurrent signal transduction inhibition with the epidermal growth factor receptor (EGFR) inhibitor gefitinib and the mammalian target-of-rapamycin inhibitor everolimus has been hypothesized to result in enhanced antitumor activity in patients with non-small cell lung cancer (NSCLC). This phase II trial assessed the efficacy of the combination of gefitinib and everolimus in patients with advanced NSCLC.Methods:Two cohorts of 31 patients with measurable stage IIIB/IV NSCLC were enrolled: (1) no prior chemotherapy and (2) previously treated with cisplatin or carboplatin and docetaxel or pemetrexed. All patients received daily everolimus 5 mg and gefitinib 250 mg. Response was assessed after 1 month and then every 2 months. Pretreatment tumor specimens were collected for mutation testing.Results:Sixty-two patients were enrolled (median age: 66 years, 50% women, 98% stage IV, all current/former smokers, and 85% adenocarcinoma). Partial responses were seen in 8 of 62 patients (response rate: 13%; 95% confidence interval: 5–21%); five responders had received no prior chemotherapy. Three partial responders had an EGFR mutation. Both patients with a KRAS (G12F) mutation responded. The median time to progression was 4 months. Median overall survival was 12 months, 27 months for no prior chemotherapy patients, and 11 months for patients previously treated with chemotherapy.Conclusions:The 13% partial response rate observed did not meet the prespecified response threshold to pursue further study of the combination of gefitinib and everolimus. The response rate in patients with non-EGFR mutant tumors was 8%, likely reflecting activity of everolimus. Further investigation of mammalian target-of-rapamycin inhibitors in patients with NSCLC with KRAS G12F-mutated tumors is warranted.

We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy.This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14mg/m(2) on days 1 and 3 with IV topotecan at 1.25mg/m(2) on days 1-5 of an every 3-week cycle. The primary end-point of this study was overall response rate.Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%).Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy.

KEYNOTE-024 (ClinicalTrials.gov, NCT02142738) is a multicenter, international, phase 3, randomized, open-label, controlled trial of treatment with the anti‒PD-1 antibody pembrolizumab vs platinum-based chemotherapy as first-line therapy for patients with advanced NSCLC of any histology with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR mutations or ALK translocations. Results from the primary analysis of KEYNOTE-024 demonstrated that after a median follow-up of 11.2 months, pembrolizumab significantly improved PFS (HR=0.50; P<0.001) and OS (HR=0.60; P=0.005) and was associated with a lower rate of treatment-related AEs compared with chemotherapy. Patients were randomly assigned to receive either 35 cycles of pembrolizumab 200 mg every 3 weeks or 4–6 cycles of investigator's choice of carboplatin/cisplatin + gemcitabine, carboplatin + paclitaxel, or carboplatin/cisplatin + pemetrexed with optional pemetrexed maintenance (for those with non-squamous histology). Randomization was stratified by ECOG performance status (0 vs 1), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Treatment continued until disease progression per RECIST version 1.1, intolerable toxicity, or withdrawal of consent. Patients in the chemotherapy arm who experienced disease progression could cross over to receive pembrolizumab monotherapy. Response was assessed every 9 weeks by blinded independent central review per RECIST version 1.1. The primary endpoint was PFS; secondary endpoints were OS, ORR, and safety. 305 patients were enrolled (pembrolizumab, n=154; chemotherapy, n=151). At the time of data cutoff (July 10, 2017) after a median follow-up of 25.2 months, 73 patients (47.4%) in the pembrolizumab arm and 96 patients (63.6%) in the chemotherapy arm had died. The hazard ratio for OS was 0.63 (95% CI, 0.47–0.86; nominal P=0.002). Median (95% CI) OS was 30.0 (18.3–not reached) months in the pembrolizumab arm and 14.2 (9.8–19.0) months in the chemotherapy arm. The Kaplan-Meier estimate of OS at 12 months was 70.3% (95% CI, 62.3%–76.9%) for the pembrolizumab group and 54.8% (95% CI, 46.4%–62.4%) for the chemotherapy group. 82 patients allocated to the chemotherapy arm crossed over to receive pembrolizumab upon meeting eligibility criteria. Treatment-related adverse events were less frequent in the pembrolizumab arm than in the chemotherapy arm (76.6% versus 90.0%, respectively) as were treatment-related grade 3-5 adverse events (31.2% versus 53.3%). With more than half of patients having OS events and prolonged follow‒up, first-line pembrolizumab monotherapy remains superior to platinum-based chemotherapy despite the crossover from the control arm to an anti-PD1 inhibitor as subsequent therapy.

Objectives The Hedgehog pathway has been implicated in small cell lung cancer (SCLC) tumor initiation and progression. Pharmacologic blockade of the key Hedgehog regulator, Smoothened, may inhibit these processes. We performed a phase I study to determine the maximum tolerated dose (MTD) of sonidegib (LDE225), a selective, oral Smoothened antagonist, in combination with etoposide/cisplatin in newly diagnosed patients with extensive stage SCLC. Materials and methods Patients received 4–6 21-day cycles of etoposide/cisplatin with daily sonidegib. Patients with response or stable disease were continued on sonidegib until disease progression or unacceptable toxicity. Two dose levels of sonidegib were planned: 400 mg and 800 mg daily, with 200 mg daily de-escalation if necessary. Next generation sequencing was performed on available specimens. Circulating tumor cells (CTCs) were quantified at baseline and with disease evaluation. Results Fifteen patients were enrolled. 800 mg was established as the recommended phase II dose of sonidegib in combination with etoposide/cisplatin. Grade 3 or greater toxicities included: anemia (n = 5), neutropenia (n = 8), CPK elevation (n = 2), fatigue (n = 2), and nausea (n = 2). Toxicity led to removal of one patient from study. Partial responses were confirmed in 79% (11/14; 95% CI: 49–95%). One patient with SOX2 amplification remains progression-free on maintenance sonidegib after 27 months. CTC count, at baseline, was associated with the presence of liver metastases and after 1 cycle of therapy, with overall survival. Conclusions Sonidegib 800 mg daily was the MTD when administered with EP. Further genomic characterization of exceptional responders may reveal clinically relevant predictive biomarkers that could tailor use in patients most likely to benefit.

9013 Background: Pembro + chemo significantly improved OS and PFS over chemo alone and had manageable safety as 1L therapy for metastatic nonsquamous NSCLC in the KEYNOTE-189 study (NCT02578680). The benefit was observed irrespective of PD-L1 TPS. We present updated OS based on longer follow-up and, for the first time, PFS2. Methods: Eligible pts were randomized 2:1 to pembro (n = 410) or placebo (n = 206) + pemetrexed and carboplatin or cisplatin for 4 cycles followed by pembro or placebo for up to 35 cycles + maintenance pemetrexed. Pts in the chemo arm could crossover to pembro alone upon PD. Poststudy anticancer therapy and outcomes were collected. PFS2 was defined as time from randomization to PD per investigator after start of 2L therapy or death, whichever occurred first. There was no multiplicity adjustment, and all P values are nominal. Data cutoff was 21 Sep 2018. Results: With 18.7-mo median follow-up, pembro + chemo continued to provide longer OS (HR 0.56 [95% CI 0.45-0.70], P &lt; .00001; median 22.0 mo vs 10.7 mo) and PFS (HR 0.48 [95% CI 0.40-0.58], P &lt; .00001). Benefit was seen in all PD-L1 TPS groups (Table). 2L+ therapy was received by 45% in the pembro + chemo arm and 59% (54% 2L+ immunotherapy) in the placebo + chemo arm. PFS2 was longer for 1L pembro + chemo (HR 0.49 [95% CI 0.40-0.59], P &lt; .00001; median 17.0 mo vs 9.0 mo), with no difference by TPS (Table). Conclusions: 1L pembro + pemetrexed/platinum continued to show substantial OS benefit in metastatic nonsquamous NSCLC, regardless of PD-L1 TPS and despite 54% of pts in the placebo + chemo arm receiving subsequent immunotherapy. Median OS, PFS and PFS2 were approximately doubled with pembro + chemo. These data confirm that pembro should be given as part of 1L therapy to maximize outcomes in both PD-L1–expressing and PD-L1–non-expressing NSCLC. Clinical trial information: NCT02578680. [Table: see text]

Abstract Background KRAS mutations are observed in ∼25% of lung adenocarcinomas, with some studies suggesting it is a prognostic factor in NSCLC. We assessed the prevalence of KRAS mutations and their association with efficacy in an exploratory analysis of the KEYNOTE-189 study of pembrolizumab plus pemetrexed and platinum chemotherapy vs placebo plus chemotherapy as first-line therapy for metastatic non-squamous NSCLC (NCT02578680). Methods Whole-exome sequencing (WES) was used to assess KRAS status and tumor mutational burden (TMB) in participants (pts) who had available tumor and matched-normal tissue. Descriptive analyses of the association of KRAS and KRAS G12C status with efficacy were included as part of this exploratory analysis, as was correlation between KRAS mutational status and shifts in TMB and PD-L1 expression distributions. Results 289 (47%) of 616 pts had evaluable WES data from both tumor and normal DNA. 89 (31%) of 289 pts had KRAS mutation, including 37 (13%) G12C carriers. Pts with vs without KRAS mutations tended to have higher PD-L1 TPS (median [IQR] 30% [1-71] vs 5% [0-60]) and higher TMB (median [IQR] 204 [137-276] vs 141 [85-252] mut/exome). Outcomes of pembrolizumab plus chemotherapy and of placebo plus chemotherapy in pts with and without KRAS mutation and in KRAS G12C carriers are summarized in the table. 95% CIs were wide given the modest frequency of KRAS mutation, particularly KRAS G12C, and the 2:1 randomization that resulted in small populations for placebo plus chemotherapy.TableLBA5TableWith Any KRAS MutationWith KRAS G12C MutationWithout Any KRAS MutationPembro + Chemo (N = 59)Placebo + Chemo (N = 30)Pembro + Chemo (N = 26)Placebo + Chemo (N = 11)Pembro + Chemo (N = 145)Placebo + Chemo (N = 55)ORR, % (95% CI)40.726.750.018.247.610.9(28.1-54.3)(12.3-45.9)(29.9-70.1)(2.3-51.8)(39.2-56.0)(4.1-22.3)PFS, median, mo (95% CI)9 (7-14)5 (5-9)11 (6-18)5 (5-NR)9 (7-14)5 (4-5)PFS, HR (95% CI)0.47 (0.29-0.77)0.48 (0.22-1.06)0.40 (0.29-0.57)OS, median, mo (95% CI)21 (16-NR)14 (8-NR)18 (11-NR)25 (8-NR)23 (19-NR)9 (7-17)OS, HR (95% CI)0.79 (0.45-1.38)1.14 (0.45-2.92)0.55 (0.37-0.81) Conclusion Based on this descriptive exploratory analysis, pembrolizumab plus pemetrexed and a platinum should be a standard first-line treatment for pts with metastatic non-squamous NSCLC regardless of KRAS mutation status. Clinical trial identification KEYNOTE-189, NCT02578680. Editorial acknowledgement Joanne Tomassini and Melanie Leiby, both of Merck & Co., Inc., Kenilworth, NJ, USA, for writing support. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure S. Gadgeel: Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Xcovery; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novocure; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy: Pharmamar. D. Rodriguez-Abreu: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis. E. Felip: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy: Abbvie; Honoraria (self), lecture fees: AstraZeneca; Honoraria (self), lecture fees: Bristol Myers Squibb; Honoraria (self), lecture fees: Novartis. E. Esteban: Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): MSD. G. Speranza: Research grant / Funding (institution): MSD. M. Reck: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Merck ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: Eli LIlly; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Abbvie; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis. R. Hui: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Eli Lilly. M. Boyer: Honoraria (self), Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): MSD; Honoraria (institution): Roche; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Ascentage Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Janssen. E.B. Garon: Honoraria (self): Dracen; Honoraria (self), Research grant / Funding (institution): EMD Serono; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): Iovance; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Neon; Research grant / Funding (institution): MSD. H. Horinouchi: Honoraria (self), Advisory / Consultancy: Eli LIlly; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): ONO; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self): Kyowa-Kirin; Honoraria (self): Taiho; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Chugai/Roche; Research grant / Funding (institution): Genomic Health. R. Cristescu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. D. Aurora-Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. J. Lunceford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. J. Kobie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M. Ayers: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. B. Piperdi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M.C. Pietanza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M.C. Garassino: Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Otsuka Pharma; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Celgene; Advisory / Consultancy: Incyte; Advisory / Consultancy: Takeda; Advisory / Consultancy: Inivata; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Tiziana Sciences; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy: Sanofi-Aventis; Research grant / Funding (institution): Spectrum Pharmaceuticals.

KEYNOTE-021 cohort C was the first study to show antitumor activity for pembrolizumab plus platinum-based chemotherapy in previously untreated advanced nonsquamous NSCLC; the combination significantly improved efficacy vs platinum-based chemotherapy alone in cohort G. We explored the relationship between TMB and outcomes in KEYNOTE-021 cohorts C and G.

Abstract BACKGROUND: Neuroendocrine tumor (NET) cell lines frequently express both insulin‐like growth factor (IGF) ligand and the cognate IGF‐1 receptor (IGF‐1R) and, as such, potentially depend on the activation of IGF‐1R and its downstream effectors for growth and survival. Preclinical studies suggest that somatostatin analogs and mammalian target of rapamycin (mTOR) inhibitors exhibit antitumor activity against NETs through inhibition of IGF‐1‐dependent signaling, suggesting that IGF‐1R inhibition may be a promising therapeutic approach to NETs. Therefore, the authors of this report evaluated the safety and efficacy of MK‐0646, a fully human monoclonal antibody (MoAb) that binds to the IGF‐1R, as monotherapy in patients with metastatic, well‐differentiated NETs. METHODS: A phase 2 study was performed in which patients received intravenous MK‐0646 10 mg/kg once weekly over 1 hour. Archived pretreatment tumor tissue was obtained and genotyped for v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ), phosphatidylinositol‐3‐kinase, catalytic, alpha polypeptide ( PIK3CA ); and v‐raf murine sarcoma viral oncogene homolog B1 ( BRAF ) mutations, and immunohistochemistry was performed to measure the expression IGF‐1R. RESULTS: Twenty‐five patients received treatment (40% women; median age, 61 years; age range, 37‐83 years), including 15 patients with carcinoid tumors and 10 patients with pancreatic NETs. No partial or complete responses were observed. The median progression‐free survival was 4.2 months in the pancreatic NET cohort (range, 0.7‐6.7 months) and 2.7 months in the carcinoid cohort (range, 2‐3 months). Serious adverse events that were potentially related to MK‐0646 included grade 3/4 hyperglycemia in 8 of 25 patients (32%), grade 2 hypersensitivity reaction in 1 of 24 patients (4%), and grade 3 lipase elevation in 1 of 25 patients (4%). CONCLUSIONS: Despite a compelling preclinical rationale, MK‐0646 was inactive as a single agent in well‐differentiated NETs. Further studies of MK‐0646 as a monotherapy in unselected NETs are unwarranted. Cancer 2012. © 2012 American Cancer Society.

Pemetrexed is an antifolate agent approved for the treatment of advanced lung cancer. Major side effects include myelosuppression and neutropenia. Three patients developed kidney disease while being treated with maintenance pemetrexed. Kidney biopsy specimens showed tubulointerstitial injury with tubular simplification, shrinkage, loss of brush border, and tubular atrophy in a more advanced case. Kidney function remained impaired, but stable, after discontinuation of pemetrexed therapy in all cases.

Purpose To examine the correlations between uni-dimensional RECIST and volumetric measurements in patients with lung adenocarcinoma and to assess their association with overall survival (OS) and progression-free survival (PFS). Materials and methods In this study of patients receiving chemotherapy for lung cancer in the setting of a clinical trial, response was prospectively evaluated using RECIST 1.0. Retrospectively, volumetric measurements were recorded and response was assessed by two different volumetric methods at each followup CT scan using a semi-automated segmentation algorithm. We subsequently evaluated the correlation between the uni-dimensional RECIST measurements and the volumetric measurements and performed landmark analyses for OS and PFS at the completion of the first and second follow-ups. Kaplan–Meier curves together with log-rank tests were used to evaluate the association between the different response criteria and patient outcome. Results Forty-two patients had CT scans at baseline, after the first follow up scan and second followup scan, and then every 8 weeks. The uni-dimensional RECIST measurements and volumetric measurements were strongly correlated, with a Spearman correlation coefficient (ρ) of 0.853 at baseline, ρ = 0.861 at the first followup, ρ = 0.843 at the 2nd followup, and ρ = 0.887 overall between-subject. On first follow-up CT, partial responders and non responders as assessed by an “ellipsoid” volumetric criteria showed a significant difference in OS (p = 0.008, 1-year OS of 70% for partial responders and 46% for non responders). There was no difference between the groups when assessed by RECIST criteria on first follow-up CT (p = 0.841, 1-year OS rate of 64% for partial responders and 64% for non responders). Conclusion Volumetric response on first follow-up CT may better predict OS than RECIST response. Clinical relevance statement Assessment of tumor size and response is of utmost importance in clinical trials. Volumetric measurements may help to better predict OS than uni-dimensional RECIST criteria.

Small cell lung cancers (SCLCs) are characterized by aberrantly methylated O(6)-methyl-guanine-DNA methyltransferase (MGMT). Epigenetic silencing of MGMT is associated with loss of MGMT activity and improved sensitivity to alkylating agents in glioblastomas. We have reported the activity of temozolomide, a non-classical alkylating agent, in patients with relapsed sensitive or refractory SCLCs, given at 75 mg/m2/day for 21 of 28 days. However, prolonged myelosuppression was noted. We therefore evaluated a 5-day dosing schedule of temozolomide and examined MGMT as a predictive biomarker for temozolomide treatment in SCLC.Patients with sensitive or refractory SCLCs and progression after one or two prior chemotherapy regimens received temozolomide 200 mg/m2/day for 5 consecutive days in 28-day cycles. The primary endpoint was tolerability. We also assessed MGMT promoter methylation status by PCR and MGMT expression by immunohistochemistry in tumor specimens.Of 25 patients enrolled, 5 experienced grade 3 or 4 toxicity (anemia, thrombocytopenia, neutropenia, and constipation). The partial response rate was 12% [95% CI: 3-31%], with partial responses in 2 refractory patients. We were able to obtain tumor samples for more than half of patients for MGMT testing.Temozolomide 200 mg/m2/day for 5 days in 28-day cycles is tolerable and active in patients with relapsed SCLCs. No treatment-limiting prolonged cytopenias were observed, making this our preferred schedule for further studies. Acquisition of archived biospecimens is feasible and necessary in order to continue evaluating the role of MGMT as a predictive biomarker in SCLCs.

Abstract Background: STK11 (also known as LKB1) and KEAP1 mutations have been associated with chemoresistance and poor outcomes and shown to be more frequent in PD-L1-negative tumors with high tumor mutational burden (TMB). We performed an exploratory analysis of KEYNOTE-042 (NCT02220894) to assess the prevalence of STK11 and KEAP1 mutations and their association with efficacy. Methods: STK11 and KEAP1 status and TMB were assessed by whole-exome sequencing (WES) in tumor tissue and matched-normal DNA. PD-L1 was assessed with the PD-L1 IHC 22C3 pharmDx assay. Descriptive analyses were performed to assess the correlation of STK11 and KEAP1 status with TMB and PD-L1 expression distributions and the association between STK11 and KEAP1 status and efficacy. Results: 429/1274 pts (34%) had evaluable WES data from tumor and normal DNA. STK11 and KEAP1 mutations were seen in 33 (8%) and 64 (15%) pts, respectively; 12 pts (3%) had both mutations. Pts with STK11 mutation tended to have a lower PD-L1 TPS than pts without (median [IQR] 15% [3-50] vs 40% [10-80]); TPS tended to be similar in pts with vs without KEAP1 mutation (40% [10-81] vs 40% [10-80]). TMB score tended to be higher in pts with vs without STK11 (median [IQR] 191 [104-272] vs 146 [72-253]) or KEAP1 (183 [114-283] vs 142 [68-252]) mutation. ORR, PFS, and OS with pembrolizumab were similar in pts with vs without STK11 or KEAP1 mutation; chemotherapy efficacy was lower in pts with vs without STK11 mutation (Table). Pembrolizumab was associated with better outcomes than chemotherapy regardless of STK11 or KEAP1 status (Table). 95% CIs were wide given the modest frequency of STK11 and KEAP1 mutations. Conclusions: The findings of this exploratory analysis suggest pembrolizumab monotherapy should be considered a standard first-line treatment option for advanced PD-L1-positive NSCLC regardless of STK11 or KEAP1 status. STK11KEAP1With MutationWithout MutationWith MutationWith MutationPembroChemoPembroChemoPembroChemoPembroChemo(n = 16)(n = 17)(n = 214)(n = 182)(n = 31)(n = 33)(n = 199)(n = 166)ORR, % (95% CI)31 (11-59)6 (&amp;lt;1-29)29 (23-36)24 (18-30)35 (19-55)18 (7-35)29 (22-35)23 (17-30)PFS, median, mo (95% CI)5 (2-NR)5 (4-11)6 (4-7)6 (6-7)6 (4-24)6 (4-7)6 (4-6)6 (6-8)PFS, HR (95% CI)0.75 (0.36-1.57)0.91 (0.74-1.13)0.67 (0.38-1.17)0.96 (0.77-1.20)OS, median, mo (95% CI)18 (10-NR)8 (6-13)17 (13-23)12 (11-15)17 (7-NR)9 (7-26)17 (13-23)12 (11-15)OS, HR (95% CI)0.37 (0.16-0.86)0.83 (0.65-1.05)0.75 (0.42-1.35)0.78 (0.61-0.99) Citation Format: Byoung Chul Cho, Gilberto Lopes, Dariusz M. Kowalski, Kazuo Kasahara, Yi-Long Wu, Gilberto Castro, Hande Z. Turna, Razvan Cristescu, Deepti Aurora-Garg, Andrey Loboda, Jared Lunceford, Julie Kobie, Mark Ayers, M. Catherine Pietanza, Bilal Piperdi, Tony S. Mok. Relationship between STK11 and KEAP1 mutational status and efficacy in KEYNOTE-042: pembrolizumab monotherapy versus platinum-based chemotherapy as first-line therapy for PD-L1-positive advanced NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT084.

Immune checkpoint inhibitors (ICIs) of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) have been rapidly adopted in US clinical practice for first-line therapy of metastatic non-small cell lung cancer (NSCLC) since regulatory approval in October 2016, and a better understanding is needed of long-term outcomes of ICI therapy administered in real-world settings outside of clinical trials. Our aim was to describe long-term outcomes of first-line pembrolizumab monotherapy at US oncology practices for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status.This retrospective two-cohort study used technology-enabled abstraction of deidentified electronic health records (EHR cohort) plus enhanced manual chart review (spotlight cohort) to study adult patients with stage IV NSCLC, PD-L1 expression ≥50%, no documented EGFR/ALK/ROS1 genomic aberration, and ECOG performance status 0-1 who initiated first-line pembrolizumab monotherapy from 1-November-2016 to 31-March-2020 (EHR cohort, with data cutoff 31-March-2021) or from 1-December-2016 to 30-November-2017 (spotlight cohort, with data cutoff 31-August-2020). Kaplan-Meier analysis was used to determine overall survival (OS; both cohorts) and, for the spotlight cohort, real-world progression-free survival (rwPFS) and real-world tumor response (rwTR).The EHR cohort included 566 patients (298 [53%] men); the spotlight cohort included 228 (105 [46%] men); median age in both cohorts was 71. Median follow-up from pembrolizumab initiation to data cutoff was 35.1 months (range, 12.0-52.7) and 38.4 months (range, 33.1-44.9) in EHR and spotlight cohorts, respectively. Median OS was 19.6 months (95% CI, 16.6-24.3) and 21.1 months (95% CI, 16.2-28.9), respectively; 3-year OS rates were 36.2% and 38.2% in EHR and spotlight cohorts, respectively. In the spotlight cohort, median rwPFS was 7.3 months (95% CI, 5.7-9.2); 88 patients (38.6%; 95% CI, 32.2-45.2) experienced rwTR of complete or partial response. For 151/228 patients (66%) who discontinued pembrolizumab, the most common reasons were disease progression (70 [46%]) and therapy-related adverse effects (35 [23%]).Real-world outcomes remain consistent with outcomes observed in clinical trials, supporting long-term benefits of first-line pembrolizumab monotherapy for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status.

This study evaluated the quality of life and neuropsychologic functioning among patients enrolled between 1989 and 1993 in the First International CNS Germ-Cell Tumor Study. Quality-of-life questionnaires (Short Form-36 or Child Health Questionnaire) were completed on 43 patients at median follow-up of 6.1 years after diagnosis (range, 4.5-8.8 years), and intellectual and academic testing was performed on 22 patients. Psychosocial and physical functioning of patients aged 19 years and older at follow-up was within the average range, whereas the same functioning for patients aged 18 years and younger, as reported by their parents at follow-up, was low average and borderline, respectively. Overall psychosocial and physical health summary scores were positively correlated with age at diagnosis for both groups combined. Those who received CNS radiation therapy (n = 29) reported significantly worse physical health, but similar psychosocial health, compared with those treated without radiation. Neuropsychologic testing indicated full-scale and verbal IQ, reading, spelling, and math skills in the average range, and performance IQ in the low average range. Intelligence and math skills were positively correlated with age at diagnosis. Those with germinomas significantly outperformed those with nongerminomatous/ mixed tumors on all neuropsychological measures administered. Younger patients diagnosed with CNS germ-cell tumors are at increased risk for psychosocial and physical problems as well as neuropsychologic deficits. Exposure to irradiation adversely affects overall physical functioning, whereas tumor pathology appears to be a salient neurocognitive risk factor. Collaborative and randomized studies are required to further elucidate the late effects arising from factors such as age at diagnosis, tumor histology, level of irradiation therapy, and chemotherapy toxicity among these young and potentially curable patients.

IntroductionAlthough patients with non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib, they uniformly develop resistance to these agents. The secondary EGFR T790M mutation is found in 50% of patients with acquired resistance. Herein, we studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, HER2, and EphB4, in NSCLC patients known or suspected of having tumors harboring T790M.MethodsEligible patients included those with relapsed or recurrent advanced NSCLC who progressed after ≥12 weeks of stable disease or response to erlotinib or gefitinib and/or those patients with a documented EGFR T790M. XL647 300 mg was administered once daily. The primary end point was objective response rate. Pretreatment plasma samples were collected for mutation testing of circulating tumor DNA.ResultsForty-one patients were enrolled; 33 were evaluable for efficacy. One partial response was observed (response rate 3% and 90% confidence interval, 0% to 14%). Of patients whose tumors harbored T790M, 67% (8/12) had progression of disease as best response compared with 14% (3/21) of those without this mutation. Plasma samples from 40 patients were available for mutation testing, 14 (35%) of which were found to have EGFR mutations.ConclusionsThe 3% response rate observed did not meet the prespecified threshold to recommend further study of XL647 in patients who develop acquired resistance to erlotinib or gefitinib. Patients with T790M had a significantly worse progression-free survival.

Small cell lung cancer (SCLC) represents 13% of all lung cancer cases diagnosed in the United States. Although a chemotherapy and radiation-sensitive disease, SCLC recurs rapidly with only 5% of patients surviving five years. This dismal prognosis likely is secondary to few improvements in its treatment, without significant changes in its standard of care over the last three decades. SCLC has a unique biology with specific molecular and cellular changes, which are the subject of active investigation. Here, we summarize the alterations leading to the pathogenesis of SCLC: chromosomal changes; dysregulation of tumor suppressor genes, oncogenes, and signaling pathways; upregulation of receptor tyrosine kinases, growth factors and cellular markers; and the persistence of developmental pathways. Each of these represents potential targets for therapy and many biologic agents are being studied.

Background: Clinicians can miss up to half of patients’ symptomatic toxicities in cancer clinical trials and routine practice. Although patient-reported outcome questionnaires have been developed to capture this information, it is unclear whether clinicians will make use of patient-reported outcomes to inform their own toxicity documentation, or to prompt symptom management activities. Methods: 44 lung cancer patients that participated in a phase 2 treatment trial self-reported 13 symptomatic toxicities derived from the National Cancer Institute’s Common Terminology Criteria for Adverse Events and Karnofsky Performance Status via tablet computers in waiting areas immediately preceding scheduled visits. During visits, clinicians viewed patients’ self-reported toxicity and performance status ratings on a computer interface and could agree or disagree/reassign grades (“shared” reporting). Agreement of clinicians with patient-reported grades was tabulated, and compared using weighted kappa statistics. Clinical actions in response to patient-reported severe (grade 3/4) toxicities were measured (e.g. treatment discontinuation, dose reduction, supportive medications). For comparison, 45 non-trial patients with lung cancer being treated in the same clinic by the same physicians were simultaneously enrolled in a parallel cohort study in which patients also self-reported toxicity grades but reports were not shared with clinicians (“non-shared” reporting). Results: Toxicities and performance status were reported by patients and reviewed by clinicians at (780/782) 99.7% of study visits in the phase 2 trial which used “shared” reporting. Clinicians agreed with patients 93% of the time with kappas 0.82–0.92. Clinical actions were taken in response to 67% of severe patient-reported toxicities. In the “non-shared” reporting comparison group, clinicians agreed with patients 56% of the time with kappas 0.04–0.48 (significantly worse than shared reporting for all symptoms), and clinical actions were taken in response to 44% of severe patient-reported toxicities. Conclusion: Clinicians will frequently agree with patient-reported symptoms and performance status, and will use this information to guide documentation and symptom management. (ClinicalTrials.gov: NCT00807573).

7503 Background: Patients (pts) with SCLC respond to initial platinum (PLT) based chemotherapy (CT), but rapidly progress. Combined blockade of PD-1 and CTLA-4 immune checkpoint pathways has anti-tumor activity with a manageable safety profile. Nivolumab (NIVO) is a fully human IgG4 PD-1 immune checkpoint inhibitor approved in the US & Japan. Interim safety and efficacy of NIVO +\- ipilimumab (IPI), a CTLA-4 checkpoint inhibitor, in pretreated SCLC pts are reported. Methods: Pts who were PLT sensitive or refractory and had progressive disease were enrolled regardless of tumor PD-L1 status or number of prior CT regimens. This open-label study randomized pts to NIVO 3 mg/kg IV Q2W or NIVO+IPI (1 + 1 mg/kg, 1 + 3 mg/kg or 3 + 1 mg/kg) IV Q3W for 4 cycles followed by NIVO 3 mg/kg Q2W. Primary objective was overall response rate (ORR). Other objectives were safety, PFS, OS and biomarker analysis. Results: Seventy-five pts were enrolled (NIVO, n = 40; NIVO+IPI, n = 35); 59% had ≥ 2 prior regimens. Drug-related adverse events (DrAEs) in ≥ 10% were fatigue (18%), diarrhea (13%), nausea (10%), and decreased appetite (10%) with NIVO; and fatigue (29%), diarrhea (17%), pruritus (14%), nausea, endocrine disorders and rash (11% each) with NIVO+IPI. Gr 3/4 DrAE in ≥ 5% included diarrhea and rash (6% each; NIVO+IPI). Drug-related pneumonitis occurred in 2 pts (1 per arm). One pt experienced a drug-related SAE of myasthenia gravis on study which was fatal. Of 40 evaluable NIVO pts, partial response (PR) was seen in 6, 15% (duration of ongoing responses [DOR] 80-251+ days); stable disease (SD) in 9, 22.5%; and progressive disease (PD) in 25, 62.5%. In 20 evaluable NIVO+IPI pts, 1 had complete response (CR), 5% (DOR 322+ days); 4 had a PR, 20% (DOR 41-83+ days); 6 had SD, 30%, and 9 had PD, 45%. In the NIVO+IPI arm, 12 pts had not reached first tumor assessment and 3 were not evaluable. Nine pts (23%) continue treatment with NIVO and 19 (54%) with NIVO+IPI. Conclusions: In this PD-L1 unselected SCLC population with progression post-PLT, NIVO alone or combined with IPI was tolerable. ORR was 15% (NIVO) and 25% (NIVO+IPI) for evaluable pts; durable responses were noted. Updated safety, clinical activity and biomarker analysis will be presented. Clinical trial information: NCT1928394.

In clinical trials, traditional monitoring methods, paper documentation, and outdated collection systems lead to inaccuracies of study information and inefficiencies in the process. Integrated electronic systems offer an opportunity to collect data in real time.We created a computer software system to collect 13 patient-reported symptomatic adverse events and patient-reported Karnofsky performance status, semi-automated RECIST measurements, and laboratory data, and we made this information available to investigators in real time at the point of care during a phase II lung cancer trial. We assessed data completeness within 48 hours of each visit. Clinician satisfaction was measured.Forty-four patients were enrolled, for 721 total visits. At each visit, patient-reported outcomes (PROs) reflecting toxicity and disease-related symptoms were completed using a dedicated wireless laptop. All PROs were distributed in batch throughout the system within 24 hours of the visit, and abnormal laboratory data were available for review within a median of 6 hours from the time of sample collection. Manual attribution of laboratory toxicities took a median of 1 day from the time they were accessible online. Semi-automated RECIST measurements were available to clinicians online within a median of 2 days from the time of imaging. All clinicians and 88% of data managers felt there was greater accuracy using this system.Existing data management systems can be harnessed to enable real-time collection and review of clinical information during trials. This approach facilitates reporting of information closer to the time of events, and improves efficiency, and the ability to make earlier clinical decisions.

The relationship between tumor-node-metastasis (TNM) stage and patterns of failure in limited-stage small cell lung cancer (LS-SCLC) remains unclear. We hypothesized that TNM stage predicts brain metastasis risk, and could inform the use of prophylactic cranial irradiation.We reviewed 283 patients with stage I-IIIB SCLC. Competing-risks regression was used to analyze local, distant, and brain failure. Multivariate analysis was used to evaluate the effect of treatment and clinical factors on failure and OS.Patients with stage I or II SCLC (35% of cohort) had significantly better survival and lower risk of distant and brain metastasis, compared with stage III patients. The 5-year cumulative incidence of brain metastasis for stage I/II and III were 12% and 26%, respectively. Stage had no correlation with local failure. On multivariate analysis, stage was independently prognostic for survival, distant metastasis risk, and brain metastasis risk.TNM staging predicts likelihood of distant metastasis, brain metastasis, and survival in LS-SCLC. This supports the routine use of TNM staging in clinical practice. The lower risk of brain metastasis in stage I and II SCLC suggests that prophylactic cranial irradiation could play a more limited role in treatment of early-stage disease.

Aim: To determine real-world outcomes with first-line pembrolizumab monotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor expression ≥50%. Methods: This retrospective study included adults with ECOG 0-1 initiating first-line pembrolizumab monotherapy on/after 24 October 2016 (EHR cohort) or from 1 December 2016 through 30 November 2017 (spotlight cohort) with ≥6-month follow-up. We estimated Kaplan-Meier overall survival (OS, both cohorts), and, for spotlight, real-world progression-free survival (rwPFS) by Kaplan-Meier and real-world tumor response (rwTR). Results: For 423 patients in the EHR cohort and 188 in spotlight, median OS was 18.9 months (95% CI: 14.9-25.5) and 19.1 months (12.6-not reached), respectively. For spotlight, median rwPFS was 6.8 months (5.3-8.1); rwTR of complete/partial response was 48% (41-56%). Conclusion: Observed OS, rwPFS and rwTR were consistent with clinical trial findings.

Thymic carcinoma (TC) is a rare cancer and patients failing initial chemotherapy (relapse/refractory) face limited therapeutic options given no approved options or consensus standard of care. This study aimed to identify and summarize clinical outcomes of all regimens evaluated in clinical trials of relapsed or refractory patients. Interventional trials enrolling advanced TC patients who failed first-line chemotherapy and reported outcomes in this group were eligible for inclusion in our systemic literature review (SLR). Between-study heterogeneity was assessed to determine the feasibility of pooling specific studies and treatments. Objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and duration of response (DOR) endpoints were of interest for meta-analysis. Nineteen trials were identified in the SLR. Three trials with one or two TC patients were removed from our assessment to reduce publication bias. Response rates among studies with at least ten TC patients varied from 9 % to 38 %. Pooled ORRs in patients receiving S-1 (46 patients), sunitinib (46 patients), or pembrolizumab (66 patients) were 28 %, 24 %, and 21 %, respectively. Prolonged duration of response with pembrolizumab was observed with a pooled median of 23.8 months (95 % confidence interval [CI]: 12, not reached). Median PFS of five months or greater was reported in patients treated with sunitinib, lenvatinib, pembrolizumab, capecitabine + gemcitabine, everolimus, or S-1. Median OS of 20 months or greater was reported in trials evaluating S-1 or pembrolizumab; this endpoint was not reached in trials evaluating lenvatinib, regorafenib, or sunitinib. Generalizability of treatment effects is challenging in the research of rare diseases and meta-analysis of clinical outcomes may help to increase precision and relevance of results to the larger TC population. Our study found limited treatment options upon relapse, demonstrating a need for further investigations into novel therapeutics and well-powered clinical trials to better inform on optimal treatments.

Purpose:XL647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (EGFR), vascular endothelial growth factor receptor 2, HER2 and Ephrin type-B receptor 4 (EphB4). We undertook an open-label, multi-institutional Phase II study to investigate the efficacy and safety of XL647 in treatment-naive non–small-cell lung cancer patients clinically enriched for the presence of EGFR mutations.Methods:Eligibility included patients with advanced-stage treatment-naive lung adenocarcinoma with a known sensitizing mutation of EGFR or patients with at least one of the following criteria: being Asian, female, or having minimal or no smoking history. Two dosing schedules were evaluated; in the “intermittent 5 & 9 dosing” cohort, XL647 350 mg for 5 days every 14 days was given; and in the “daily dosing” cohort, XL647 300 mg daily for 28 days was administered. Tumor EGFR mutation status was determined on available tissue. The primary end point was confirmed objective response rate.Results:Forty-one patients were treated on the intermittent 5 & 9 dosing- and 14 on the daily-dosing schedule. The majority of patients were eligible on the basis of smoking history. The response rate and progression-free survival for the two schedules combined were 20% and 5.3 months (90% confidence interval, 3.7–6.7), respectively. Thirty-eight patients (69%) had material available for mutation testing and 14 EGFR-sensitizing mutations were detected. The response rate and progression-free survival for EGFR-mutation–positive patients were 57% (8/14) and 9.3 months (90% confidence interval, 5.5–11.7). The toxicities were comparable between the two schedules; the most common adverse effects being diarrhea, nausea, and fatigue.Conclusions:XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. The adverse-event profile was similar for the two dosing schedules. XL647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (EGFR), vascular endothelial growth factor receptor 2, HER2 and Ephrin type-B receptor 4 (EphB4). We undertook an open-label, multi-institutional Phase II study to investigate the efficacy and safety of XL647 in treatment-naive non–small-cell lung cancer patients clinically enriched for the presence of EGFR mutations. Eligibility included patients with advanced-stage treatment-naive lung adenocarcinoma with a known sensitizing mutation of EGFR or patients with at least one of the following criteria: being Asian, female, or having minimal or no smoking history. Two dosing schedules were evaluated; in the “intermittent 5 & 9 dosing” cohort, XL647 350 mg for 5 days every 14 days was given; and in the “daily dosing” cohort, XL647 300 mg daily for 28 days was administered. Tumor EGFR mutation status was determined on available tissue. The primary end point was confirmed objective response rate. Forty-one patients were treated on the intermittent 5 & 9 dosing- and 14 on the daily-dosing schedule. The majority of patients were eligible on the basis of smoking history. The response rate and progression-free survival for the two schedules combined were 20% and 5.3 months (90% confidence interval, 3.7–6.7), respectively. Thirty-eight patients (69%) had material available for mutation testing and 14 EGFR-sensitizing mutations were detected. The response rate and progression-free survival for EGFR-mutation–positive patients were 57% (8/14) and 9.3 months (90% confidence interval, 5.5–11.7). The toxicities were comparable between the two schedules; the most common adverse effects being diarrhea, nausea, and fatigue. XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. The adverse-event profile was similar for the two dosing schedules.

Abstract Background Historically, pts with NSCLC and brain metastases have had poor prognosis. Randomized studies have shown OS and PFS benefit and manageable safety with pembro plus chemo vs chemo alone in pts with advanced NSCLC. We present a pooled analysis of outcomes in pts with NSCLC and stable brain metastases at baseline who were enrolled in randomized clinical trials evaluating pembro plus platinum-based chemo as first-line therapy for advanced/metastatic NSCLC. Methods This post hoc analysis pooled data for pts with stable, treated or untreated brain metastases from KEYNOTE-021 cohort G (nonsquamous; NCT02039674), 189 (nonsquamous; NCT02578680), and 407 (squamous; NCT02775435). Pts were randomly assigned to platinum-doublet chemo (pemetrexed-carboplatin/cisplatin for nonsquamous NSCLC and carboplatin-paclitaxel/nab-paclitaxel for squamous NSCLC) with/without pembro; KEYNOTE-189 and 407 were placebo-controlled. Response (systemic, including in brain) was assessed per RECIST v1.1 by blinded, independent central review. Results Of 1298 pts included, 171 (13%) had baseline brain metastases. Median (range) follow-up was 10.9 (0.1–35.1) mo and 11.0 (0.1–34.9) mo in pts with and without brain metastases, respectively. HRs for OS and PFS were improved with pembro plus chemo vs chemo irrespective of baseline brain metastasis status (Table). ORR was higher and duration of response (DOR) was longer with pembro plus chemo vs chemo alone. All-cause grade 3–5 AEs with pembro plus chemo vs chemo alone occurred in 81.4% vs 70.3% of pts with brain metastases and 68.3% vs 65.6% without brain metastases.Table1483PDTableNOS HR (95% CI)PFS HR (95% CI)ORR, %Median DOR, mo (range)Brain metastasesPembro plus chemo1050.48 (0.32–0.70)0.44 (0.31–0.62)39.011.3 (1.1+ to 27.9+)Chemo6619.76.8 (1.3+ to 9.4)No brain metastasesPembro plus chemo6430.63 (0.53–0.75)0.55 (0.48–0.63)54.612.2 (1.1+ to 29.3+)Chemo48431.86.0 (1.4+ to 30.1+)+, response ongoing at data cutoff. Conclusions Pembro plus chemo provided clinical benefit for pts with NSCLC pts, regardless of presence/absence of stable brain metastases. The toxicity profile was manageable. Pembro plus chemo is standard of care therapy for pts with advanced NSCLC, including those with baseline brain metastases. Clinical trial identification NCT02039674; NCT02578680; NCT02775435. Editorial acknowledgement Rozena Varghese, PharmD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, 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., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure S.F. Powell: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Vyriad; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Novartis. D. Rodriguez Abreu: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Roche. C.J. Langer: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): OSI (Astellas); Research grant / Funding (institution): Merck; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Advantage; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Inovio; Research grant / Funding (institution): Ariad; Research grant / Funding (institution): StemCentrx; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Guardant Health; Advisory / Consultancy: Merck; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Bayer/Onyx; Advisory / Consultancy: Abbott; Advisory / Consultancy: Morphotek; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Clarient; Advisory / Consultancy: Caris Diagnostics; Advisory / Consultancy: Vertex; Advisory / Consultancy: Synta Pharmaceuticals; Advisory / Consultancy: Celgene; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Hospira; Advisory / Consultancy: Helsinn; Advisory / Consultancy: Synta Pharmaceuticals; Advisory / Consultancy: Clovis; Advisory / Consultancy: Ariad (Takeda); Advisory / Consultancy: Takai; Advisory / Consultancy: Regeneron;Officer / Board of Directors (data and safety monitoring committee member): Eli Lilly; Officer / Board of Directors (data and safety monitoring committee member): Amgen; Officer / Board of Directors (data and safety monitoring committee member): Synta Pharmaceuticals; Officer / Board of Directors (data and safety monitoring committee member): Agennix; Officer / Board of Directors (data and safety monitoring committee member): SWOG; Officer / Board of Directors (data and safety monitoring committee member): Peregrine Pharmaceuticals; Officer / Board of Directors (data and safety monitoring committee member): Incyte; Speaker Bureau / Expert testimony (CME presenter): PIK; Speaker Bureau / Expert testimony (CME presenter): PER; Speaker Bureau / Expert testimony (CME presenter): NOCR; Speaker Bureau / Expert testimony (CME presenter): Imedex; Speaker Bureau / Expert testimony (CME presenter): CCO; Speaker Bureau / Expert testimony (CME presenter): RTP; Speaker Bureau / Expert testimony (CME presenter): MLG; Speaker Bureau / Expert testimony (CME presenter): TRM; Speaker Bureau / Expert testimony (CME presenter): Web-MD. L. Paz-Ares: Honoraria (self), Spouse / Financial dependant: Roche; Honoraria (self), Spouse / Financial dependant: Lilly; Honoraria (self), Spouse / Financial dependant: Boehringer Ingelheim; Honoraria (self), Spouse / Financial dependant: AstraZeneca; Honoraria (self), Spouse / Financial dependant: Novartis; Honoraria (self), Spouse / Financial dependant: Pfizer; Honoraria (self), Spouse / Financial dependant: Amgen; Honoraria (self), Spouse / Financial dependant: BMS; Honoraria (self), Spouse / Financial dependant: MSD; Honoraria (self), Spouse / Financial dependant: Merck; Honoraria (self), Spouse / Financial dependant: Sanofi; Honoraria (self), Spouse / Financial dependant: PharmaMar; Honoraria (self), Spouse / Financial dependant: Servier; Honoraria (self), Spouse / Financial dependant: Sysmex; Honoraria (self), Spouse / Financial dependant: Incyte; Honoraria (self), Spouse / Financial dependant: Ipsen; Honoraria (self), Spouse / Financial dependant: Adacap; Honoraria (self), Spouse / Financial dependant: Bayer; Honoraria (self), Spouse / Financial dependant: Blueprint Medicines; Honoraria (self), Spouse / Financial dependant: Celgene; Officer / Board of Directors: Genomica; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer. H. Kopp: Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Sanofi; Honoraria (self): Roche; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Amgen. J. Rodriguez-Cid: Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Celgene. D. Kowalski: Research grant / Funding (institution): MSD. Y. Cheng: Research grant / Funding (institution): MSD. T. Kurata: Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Eli Lilly; Honoraria (self): Chugai; Honoraria (self): Ono; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim. M.M. Awad: Advisory / Consultancy: Merck. J. Lin: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. B. Zhao: Full / Part-time employment: Merck Sharp & Dohme Corp. M.C. Pietanza: Full / Part-time employment: Merck Sharp & Dohme Corp. B. Piperdi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme Corp. M.C. Garassino: Honoraria (self), Research grant / Funding (institution): Merck; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Celgene; Honoraria (self), Research grant / Funding (institution): MedImmune; Honoraria (self): Incyte; Honoraria (self): Ignyta. All other authors have declared no conflicts of interest.

Aim: To determine real-world time on treatment (rwToT) with first-line pembrolizumab monotherapy for metastatic non-small-cell lung cancer (NSCLC) with programmed death ligand-1 (PD-L1) tumor proportion score (TPS) ≥50%. Methods: The Kaplan–Meier rwToT was estimated from electronic health record data for adults who initiated first-line pembrolizumab monotherapy for stage IV, PD-L1 TPS ≥50% NSCLC, with negative/unknown EGFR/ALK aberrations, and ≥6 months’ follow-up until database cutoff. Results: A total of 386 patients with ECOG 0–1 had a median rwToT of 6.9 months (95% CI: 5.6–8.3) and 12-month on-treatment rate of 36.4% (31.2–41.6) versus 40.3% (32.5–47.9) and 37.6% (31.9–43.4) in KEYNOTE-024 (KN024) and KN042 (stage IV/TPS ≥50% subpopulation), respectively. The 24-month restricted-mean rwTOT (extrapolated) was 10.5 months (9.4–11.7), versus 11.0 (9.5–12.5) and 10.4 (9.3–11.5) in KN024 and KN042, respectively. Conclusion: First-line pembrolizumab monotherapy rwToT in metastatic PD-L1 TPS ≥50% NSCLC for trial-matched patients is similar to treatment duration in KN024 and KN042.

9521 Background: In a previous analysis of KEYNOTE-189 (NCT02578680), we showed that tissue TMB (tTMB) assessed by whole-exome sequencing was not significantly associated with efficacy in either arm and that pembro + chemo improved outcomes vs placebo + chemo in both the tTMB ≥175 and tTMB &lt; 175 mut/exome subgroups. Here, we explored the association of bTMB with efficacy in KEYNOTE-189. Methods: 616 patients (pts) were randomized 2:1 to pembro + chemo or placebo + chemo. bTMB was assessed in cfDNA using the Guardant Health Omni assay. Association of bTMB (continuous square root transformed) with outcomes in each arm was assessed using Cox proportional hazards models (OS, PFS) and logistic regression (ORR) adjusted for ECOG PS; statistical significance was determined at the 0.05 level without multiplicity adjustment. The clinical utility of bTMB on outcomes was assessed using the cutoff that most closely approximated the 175 mut/exome tTMB cutoff as determined by AUROC analysis. Data cutoff was 21 Sep 2018. Results: 235 (38%) treated pts had evaluable tTMB and bTMB: 160 in the pembro + chemo arm and 75 in the placebo + chemo arm. bTMB as a continuous variable was not significantly associated with OS or ORR for pembro + chemo (one-sided P = .229 and .051) or placebo + chemo (two-sided P = .641 and .069); bTMB was significantly associated with PFS in the pembro + chemo arm (one-sided P = .015) but not the placebo + chemo arm (two-sided P = .058). bTMB and tTMB scores were moderately correlated (r = .61). The bTMB cutoff that most closely approximated tTMB 175 mut/exome was 15 mut/Mb (AUROC 0.81, 95% CI 0.75-0.86). 178 (76%) pts had concordant bTMB and tTMB results—101 low and 77 high by both—whereas 57 (24%) had discordant results—21 high bTMB but low tTMB, 36 low bTMB but high tTMB. Pembro + chemo improved OS, PFS, and ORR vs placebo + chemo for bTMB ≥15 and &lt; 15 mut/exome (Table). Conclusions: Similar to previous findings based on tTMB, bTMB has limited clinical utility in the setting of pembro with pemetrexed and platinum given as first-line therapy for metastatic nonsquamous NSCLC. Clinical trial information: NCT02578680 . [Table: see text]

9001 Background: Pembro monotherapy showed durable antitumor activity as third-line or later therapy for metastatic SCLC, leading to FDA approval in that setting. KEYNOTE-604 was a double-blind, phase 3 study of pembro + EP vs placebo + EP as first-line therapy for ES-SCLC (NCT03066778). Methods: Eligible patients (pts) with previously untreated ES-SCLC and no untreated CNS metastases were randomized 1:1 to pembro 200 mg Q3W or saline placebo for up to 35 cycles plus 4 cycles of standard-dose EP. Pts with CR or PR after cycle 4 could receive PCI at investigator discretion. Randomization was stratified by platinum choice (carboplatin vs cisplatin), ECOG PS (0 vs 1), and LDH (≤ULN vs &gt; ULN). Primary endpoints were OS and PFS (RECIST v1.1, blinded central review) in the ITT population. ORR, DOR, and safety were secondary endpoints. OS and PFS treatment differences were assessed by the stratified log-rank test. The protocol specified 2 interim analyses (IAs) and a final analysis (FA). Prespecified efficacy boundaries were one-sided P = 0.0048 for PFS at IA2 (prespecified final PFS analysis) and 0.0128 for OS at FA. Results: 453 pts were randomized. 223/228 pts assigned to pembro + EP and 222/225 assigned to placebo + EP received ≥1 dose of assigned treatment; 1 pt assigned to pembro + EP received placebo + EP in error. Median age was 65 y, 74% had ECOG PS 1, and 57% had LDH &gt; ULN; more pts in the pembro + EP arm had baseline brain metastases (14% vs 10%). At FA (median follow-up, 21.6 mo), 9% of pts in the pembro + EP arm and 1% in the placebo + EP arm remained on study treatment; 12% and 14% received PCI. At IA2 (median follow-up, 13.5 mo), pembro + EP significantly improved PFS in the ITT population (HR 0.75 [95% CI 0.61-0.91], P = 0.0023; median 4.5 vs 4.3 mo). At FA, pembro + EP prolonged OS in the ITT population, but the significance threshold was not met (HR 0.80 [95% CI 0.64-0.98], P = 0.0164; median 10.8 vs 9.7 mo). In a post hoc analysis of OS in the as-treated population, the nominal P value was smaller than the significance threshold (HR 0.78 [95% CI 0.63-0.97], P = 0.0124). ORR at FA was 71% for pembro + EP vs 62% for placebo + EP; median DOR was 4.2 vs 3.7 mo. Observed AEs were as expected; any-cause AEs were grade 3-4 in 77% vs 75%, grade 5 in 6% vs 5%, and led to discontinuation in 15% vs 6%. Conclusions: Pembro + EP significantly improved PFS and prolonged OS compared with placebo + EP as first-line therapy for pts with ES-SCLC. No unexpected toxicities were seen with pembro + EP. These data support the benefit of pembro-containing regimens for ES-SCLC. Clinical trial information: NCT03066778.

Our aim was to evaluate real-world time on treatment (rwToT), overall and by KRAS mutation status, with first-line pembrolizumab monotherapy for advanced non-small cell lung cancer (NSCLC) in real-world oncology practice in the US. rwToT is a readily available, intermediate-range endpoint that is moderately to highly correlated with overall survival in clinical trials and real-world data. Using deidentified electronic medical record data, we studied patients with ECOG performance status (PS) of 0-2 who initiated pembrolizumab (1 November 2016 to 31 March 2020) for advanced NSCLC with programmed death-ligand 1 (PD-L1) expression ≥ 50% and without EGFR/ALK/ROS1 genomic alterations. The data cutoff was 31 March 2021, and the median study follow-up was 34 months. The Kaplan-Meier median rwToT with first-line pembrolizumab monotherapy was 7.4 months (95% CI, 6.3-8.1) for 807 patients with PS 0-1, which was consistent with the median treatment duration in the KEYNOTE-024 trial (7.9 months). The median rwToT for 237 patients with PS 2 was 2.1 months (95% CI, 1.4-2.8). For those with KRAS-mutated and KRAS wild-type nonsquamous NSCLC and PS 0-1, the median rwToT was 7.6 months and 7.0 months, respectively. Our findings suggest long-term benefit of first-line pembrolizumab monotherapy for advanced NSCLC with PD-L1 expression ≥ 50% in real-world settings in the US, particularly for patients with good performance status at the start of therapy, irrespective of KRAS status.

Pembrolizumab (pembro) + platinum-based chemotherapy (chemo) significantly prolonged OS and PFS compared with placebo + chemo in patients (pts) with previously untreated, metastatic squamous NSCLC in the phase III KEYNOTE-407 study (NCT02775435). We report the 5-y outcomes in the ITT population and in pts who completed 35 cycles of pembro (∼2 y). Eligible pts were randomized 1:1 to receive pembro 200 mg or placebo + carboplatin and paclitaxel/nab-paclitaxel Q3W for 4 cycles, followed by pembro or placebo up to 35 cycles. Eligible pts in the placebo + chemo group were allowed to crossover on-study to up to 35 cycles of open-label pembro monotherapy upon unblinding after verification of PD by BICR. Primary endpoints were OS and PFS per RECIST v1.1 by BICR. Pts were randomized to pembro + chemo (n = 278) or placebo + chemo (n = 281). As of Feb 23, 2022, median time from randomization to data cutoff was 56.9 (range, 49.9–66.2) mo; 117 pts crossed over from the placebo + chemo group to receive pembro monotherapy, and an additional 26 pts received subsequent anti–PD-(L)1 therapy; the effective crossover rate was 51.1%. Median OS in the ITT population was 17.2 mo for the pembro + chemo group and 11.6 mo for the placebo + chemo group; HR, 0.71 (95% CI, 0.59–0.85). Respective 5-y OS rates were 18.4% and 9.7%. Additional efficacy outcomes are described in the table. Grade 3‒5 AEs occurred in 74.8% and 70.0% of pts in the pembro + chemo and placebo + chemo groups, respectively. Among 55 pts who completed 35 cycles of pembro, ORR was 90.9%, and 3-y OS rate after completion of 35 cycles (⁓5 y after randomization) was 69.5%.Table: 974MOITT populationPembrolizumab + chemotherapy n = 278Placebo + chemotherapy n = 281Median OS (95% CI), mo17.2 (14.4‒19.7)11.6 (10.1‒13.7)OS HR (95% CI)0.71 (0.59‒0.85)5-year OS rate, %18.49.7Median PFS (95% CI), mo8.0 (6.3‒8.5)5.1 (4.3‒6.0)PFS HR (95% CI)0.62 (0.52‒0.74)5-year PFS rate, %10.83.5ORR (95% CI), %62.2 (56.2‒68.0)38.8 (33.1‒44.8)Median DOR (range), mo9.0 (1.3+ to 61.5+)4.9 (1.3+ to 58.6+)–DOR ≥4 y; %21.616.0+ indicates no PD by time of last assessment. Open table in a new tab + indicates no PD by time of last assessment. After 5 y of follow-up, pembro + chemo continued to demonstrate prolonged OS and PFS vs chemo alone without increased toxicity. Most pts who completed 35 cycles had objective responses and were alive at data cutoff. These long-term data support use of pembro + chemo as a standard first-line treatment option for metastatic squamous NSCLC.

Bronchial and thymic carcinoids are rare. We present epidemiologic data and potential risk factors. The approach to bronchial and thymic carcinoid patients is discussed, from the initial diagnosis and evaluations to treatment. These malignancies follow staging systems of their site of origin. Because bronchial and thymic carcinoids are rare, we use many treatment strategies that have been demonstrated in gastrointestinal and pancreatic neuroendocrine tumors . The lack of information regarding efficacy in bronchial and thymic carcinoids, as well as the scarcity of therapeutic options available, demands the importance of clinical trials that include these patients.

Prevalence of tumor PD-L1 expression in extensive-stage small-cell lung cancer (ES-SCLC) is variable, and data on PD-L2 expression are limited. The prognostic values of these biomarkers are not well understood. The current study was conducted to address these data gaps.A retrospective cohort study of Danish patients with histologically confirmed ES-SCLC and evaluable tumor samples who were receiving usual care before the introduction of immunotherapy was conducted. Protein expression of PD-L1 and PD-L2 was determined by immunohistochemistry (IHC) using the PD-L1 IHC 22C3 pharmDx assay and a PD-L2 IHC assay using a propriety mouse monoclonal antibody. A combined positive score (CPS) of ≥1 was used to define biomarker positivity. Kaplan-Meier plots and Cox proportional hazard models were employed to assess the relationship between PD-L1 and PD-L2 protein expression and OS.Among 80 patients, 31% (n=25) and 36% (n=29) had disease positive for PD-L1 and PD-L2, respectively. Overall, 85% (n=68) of patients had concordant PD-L1/PD-L2 status; 26% (n=21) had double positive disease (both PD-L1 and PD-L2 CPS ≥1) and 59% (n=47) had double negative disease (both PD-L1 and PD-L2 CPS <1). PD-L1 and PD-L2 positivity were each associated with longer OS (unadjusted hazard ratios [HRs], 0.35 [95% CI, 0.21-0.61] and 0.50 [95% CI, 0.31-0.82]); the associations persisted after adjustment for several known prognostic factors (HRs, 0.41 [95% CI, 0.22-0.75] and 0.44 [95% CI, 0.25-0.79] for PD-L1 and PD-L2 positivity, respectively). When evaluating OS in patients with double positive disease, unadjusted and adjusted HRs for double positive compared with double negative were similar to those with only PD-L1 or PD-L2 positivity (unadjusted HR, 0.36 [95% CI, 0.20-0.64]; adjusted HR, 0.36 [0.18-0.73]).PD-L1 and PD-L2 positivity were observed in approximately one-third of assessed ES-SCLC tumor samples and were highly congruent. Patients with PD-L1 and PD-L2 positivity, alone or combined, were associated with longer OS, independent of other prognostic factors.

8512 Background: Preclinical data indicate that the combination of veliparib, an oral PARP-1/2 inhibitor, and TMZ result in synergistic tumor growth delay or regression. We hypothesized that adding veliparib to TMZ will improve outcomes in pts with relapsed sensitive and refractory SCLCs. Methods: Relapsed SCLC pts treated with 1 or 2 prior regimens were randomized 1:1 to receive oral TMZ 150-200mg/m2/day on days 1-5 of a 28-day cycle along with either veliparib or placebo 40mg twice daily, orally, on days 1-7. Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in pts with sensitive disease (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Correlative studies included immunohistochemistry to evaluate MGMT and PARP and circulating tumor cell enumeration. Results: Between Aug 2012 and Feb 2015, 104 pts were enrolled and 100 pts were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. The proportions of pts alive and progression-free at 4-months were similar between the two arms, 36% vs. 27% (p=0.39). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. In the 93 evaluable pts, response rate was significantly higher with veliparib/TMZ compared to TMZ alone (39% vs 14%, p=0.016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Correlative evaluations are ongoing and will be available at the time of presentation. Conclusions: Response rate was significantly higher with veliparib/TMZ compared to TMZ alone, although an improvement in PFS was not noted. Hematologic toxicity of the combination may have impacted PFS by limiting dosing. Characterizing MGMT and PARP expression in responders may allow for better patient selection and the potential to improve outcomes of this combination in SCLCs. Clinical trial information: NCT01638546.

Data on utilization and clinical outcomes of programmed cell death protein or programmed death-ligand 1 (PD-[L]1) inhibitors in NSCLC with uncommon oncogenic alterations is limited.This retrospective study used a deidentified U.S. nationwide clinicogenomic database to select patients with advanced nonsquamous NSCLC without EGFR, ALK, or ROS1 alterations, diagnosed from January 1, 2016 to September 30, 2020, who initiated first-line therapy. Our objectives were to summarize characteristics and treatment patterns for patients with four little-studied genomic alterations or driver-negative NSCLC. We estimated Kaplan-Meier real-world time on treatment (rwTOT) and time to next treatment for patients receiving PD-(L)1 inhibitors. The data cutoff was September 30, 2021.Of the 3971 eligible patients, 84 (2%) had NSCLC with BRAF V600E mutation, 117 (3%) had MET exon 14 skipping mutation, 130 (3%) had MET amplification, 91 (2%) had ERBB2 activation mutation, and 691 patients (17%) had driver-negative NSCLC. Patient characteristics differed among cohorts as expected. The most common first-line regimen in each cohort was a PD-(L)1 inhibitor as monotherapy or in combination with chemotherapy. The median rwTOT with anti-PD-(L)1 monotherapy was 4.6 months in the driver-negative cohort and ranged from 2.9 months (ERBB2 mutation) to 7.6 months (BRAF V600E mutation). The median rwTOT with anti-PD-(L)1-chemotherapy combination was 5.2 months in the driver-negative cohort and 6 months in all but the BRAF V600E cohort (17.5 mo). The patterns of real-world time to next treatment results were similar.Substantial use of anti-PD-(L)1 therapy and associated clinical outcomes are consistent with previous real-world findings and suggest no detriment from PD-(L)1 inhibitors for advanced nonsquamous NSCLC harboring one of these four genomic alterations relative to driver-negative NSCLC.

Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types.Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated.Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses.This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

Introduction:In the phase I and II trials, the dose-limiting toxicities of pemetrexed included neutropenia, thrombocytopenia, and fatigue. Grade 3 bilateral peripheral edema that resembled cellulitis was not commonly described.Methods:Since 2009, the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center has identified 14 patients who developed bilateral peripheral edema and erythema of the lower extremities while receiving pemetrexed chemotherapy. During this time, 489 patients with thoracic malignancy have been treated with pemetrexed.Results:There were seven men and seven women. Average age was 72 years. All patients had stage IV adenocarcinoma of the lung. The edema presented at a median of eight doses (range, 3–23 doses.) Other causative factors such as deep vein thrombosis, renal insufficiency, and congestive heart failure were excluded. Thirteen of the 14 patients required the drug to be stopped or dose lowered.Conclusion:We have collected 14 cases with lung adenocarcinoma treated with pemetrexed who developed bilateral lower extremity edema and erythema, a condition rarely described. In all cases, symptoms resolved with discontinuation or dose reduction of the drug. Patients who received corticosteroids showed improvement in their symptoms.

<h3>Introduction:</h3> <i>EGFR-</i>mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, they develop resistance, often due to acquisition of a second-site mutation (T790M). Current EGFR TKIs select for T790M in preclinical models of acquired resistance. We explored whether all EGFR TKIs similarly select for the T790M mutation using data from early clinical trials and established in vitro models of acquired resistance. <h3>Methods:</h3> We analyzed the clinical characteristics of eight patients with metastatic EGFR-mutant lung adenocarcinoma who were treated first-line with XL647 and then progressed. XL647 is an ATP-competitive inhibitor of EGFR, HER2, KDR, and EPHB4. Additional molecular preclinical studies were performed to characterize resistance. <h3>Results:</h3> Four patients displayed confirmed partial responses (PRs), three patients had unconfirmed PRs, and one patient displayed stable disease. Only one of five patients' tumor samples available for analysis after disease progression harbored the T790M mutation. Eight patients subsequently received erlotinib, with (<i>n</i> = 3) or without (<i>n</i> = 5) chemotherapy. Three of five patients treated with single-agent erlotinib derived additional benefit, staying on drug up to 9 months. EGFR-mutant PC-9 cells with acquired resistance to XL647 did not harbor the T790M mutation, displayed a distinct mRNA profile from PC-9 cells with T790M-mediated resistance, and were moderately sensitive to erlotinib in growth inhibition assays. Crystal structure analyses of XL647/EGFR T790M did not reveal a different binding mode from that of erlotinib. <h3>Conclusions:</h3> The findings of this exploratory study suggest that different EGFR TKIs may select for distinct mechanisms of resistance. These results raise the possibility that different EGFR TKIs could be sequentially used to improve outcomes in patients with <i>EGFR</i>-mutant lung cancer. Further work investigating this hypothesis is warranted.

7508 Background: Notch signaling is implicated in cancer stem cell self-renewal and proliferation; thus being an appealing target in the treatment of SCLC. Tarextumab (TRXT), a fully human IgG2 antibody targeting Notch2 and 3 receptors, has shown preclinical efficacy in SCLC models with cisplatin. This Phase Ib study explores the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of TRXT with EP in chemo-naive ED-SCLC. Methods: Notch signaling is implicated in cancer stem cell self-renewal and proliferation; thus being an appealing target in the treatment of SCLC. Tarextumab (TRXT), a fully human IgG2 antibody targeting Notch2 and 3 receptors, has shown preclinical efficacy in SCLC models with cisplatin. This Phase Ib study explores the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of TRXT with EP in chemo-naive ED-SCLC. Results: By November 18, 2014, 27 pts were treated with TRXT at dose range from 5 mg/kg to 15 mg/kg. The MTD was not reached and TRXT 15 mg/kg was determined to be the Phase 2 dose. One DLT of Grade 3 nausea and vomiting was reported in the 10 mg/kg dose cohort. Frequently reported ( ≥ 15%) TRXT-related adverse events were: diarrhea (59.3%), fatigue (44.4%), nausea (40.7%), anemia (25.9%), decreased appetite (25.9%) and vomiting (25.9%); most were Grade 1 or 2 and managed with supportive care. The overall response rate was 84%. The median duration of treatment was 128 days (6 cycles) with mPFS and mOS of 124 and 228 days, respectively. The median follow-up for PFS and OS was of 86 and 107 days respectively. Conclusions: TRXT with EP is well tolerated. Encouraging anti-tumor activity has been observed. Final safety, efficacy, PK, immunogenicity and predictive biomarker results will be presented. TRXT at a dose of 15 mg/kg has been selected for the phase 2 randomized, placebo-controlled portion of the study, which is ongoing. Clinical trial information: NCT01859741.

9021 Background: In the double-blind, phase 3 KEYNOTE-189 study (NCT02578680), pembro + pem + plt significantly improved OS and PFS over pbo + pem + plt as first-line therapy for nonsquamous NSCLC. Grade 3-5 drug-related AE rates were higher with pembro. We report the prespecified patient-reported outcome (PRO) analyses from KEYNOTE-189. Methods: 616 patients (pts) were randomized to pembro 200 mg Q3W or pbo for 2 y; all pts received pem + 4 cycles of carboplatin or cisplatin. The EORTC QLQ-C30 and QLQ-LC13 were administered at cycles 1-5, then every 3 cycles during yr 1 and every 4 cycles during yrs 2 and 3. Key PRO outcomes were change from baseline to wks 12 and 21 in the QLQ-C30 global health status/QoL score and time to deterioration in the composite of cough, chest pain, or dyspnea. PROs were analyzed in all treated pts who completed ≥1 PRO instrument (n = 602). P values are nominal and 2-sided. Results: QLQ-C30 and QLQ-LC13 compliance was ~90% at baseline and wk 12 in both arms and was ~75% with pembro and ~63% with pbo at wk 21. Mean baseline scores were 61.98 and 60.56 in the pembro and pbo arms. At wks 12 and 21, global health status/QoL scores were stable with pembro and decreased with pbo, with significantly greater decrement with pbo at wk 21 (Table). The proportion of improved global health status/QoL was similar at wk 12 (28.9% with pembro vs 26.5% with pbo; P = .5450) but was greater with pembro at wk 21 (30.1% vs 22.5%; P = .0496). Median time to deterioration in the composite of cough, chest pain, or dyspnea was NR with pembro (95% CI 10.2 mo-NR) vs 7.0 mo (95% CI, 4.8-NR) with pbo (HR 0.81; 95% CI 0.60-1.09; nominal 2-sided P = .081). Conclusions: In this double-blind trial, pembro + pem + plt maintained or improved HRQoL over pem + plt alone despite a higher grade 3-5 treatment-related AE rate. Along with superior efficacy, these data support the use of pembro + pem + plt as first-line therapy for metastatic nonsquamous NSCLC. Clinical trial information: NCT02578680.

LBA8505 Background: SCLC remains among the most deadly of malignancies. Rovalpituzumab tesirine is a first-in-class ADC comprised of a humanized monoclonal antibody against DLL3, a dipeptide linker, and a pyrrolobenzodiazepine (PBD) dimer toxin. DLL3 is highly expressed in neuroendocrine tumors, including approximately 80% of SCLC. The emerging results of the SCLC patients (pts) in a first-in-human study (NCT01901653) are reported here. Methods: Pts with progressive SCLC after at least 1 previous systemic therapy were eligible. Efficacy was assessed by the investigator via RECIST v1.1, and toxicity graded per CTCAE v4.03. When available, archived tumor tissue was assessed retrospectively for DLL3 expression by immunohistochemistry. Results: Seventy-four (74) pts were enrolled at dose levels ranging from 0.05 to 0.8 mg/kg at either q3w or q6w. Among evaluable pts treated at doses of 0.2-0.4 mg/kg, 15/61 (25%; 95% CI 15-37%) achieved a best response of PR or CR, and 44/61 (72%; 95% CI 59-83%) achieved clinical benefit (best response of at least SD). Among pts with available archive tissue specimens and ≥ 50% of cells expressing DLL3 (DLL3 hi , an intended companion diagnostic cutoff), 12/22 (55%; 95% CI 32-76%) achieved a best response of PR or CR, and 20/22 (91%; 95% CI 71-99%) achieved clinical benefit, with a median overall survival of 8 (range 1-18+) months. In 3 rd line DLL3 hi pts (n = 10), where no approved therapy currently exists, the ORR and CBR were 70% and 90%, respectively, with at least 4 evaluable pts achieving OS of &gt; 6 (8, 15, 18 and 18) months. Among responders treated at the phase 2 dose of 0.3 mg/kg, the median duration of response was 6 (range 1-8+) months. Among all SCLC pts, the most common grade 3+ toxicities considered study drug-related have included serosal effusions (14%), thrombocytopenia (12%) and skin reactions (8%). Conclusions: With manageable toxicity, rovalpituzumab tesirine demonstrates encouraging single-agent anti-tumor activity and durability in recurrent or refractory SCLC. A single-arm pivotal study in 3 rd line DLL3-expressing SCLC has been initiated. Clinical trial information: NCT01901653.

Pembrolizumab monotherapy showed significantly longer overall survival and fewer treatment-related adverse events compared to chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with programmed death ligand-1 (PD-L1)-positive tumors in the first-line setting in KEYNOTE (KN)-024 and in those previously treated in KN010. The objective of this analysis was to assess the benefit-risk of pembrolizumab in terms of quality-adjusted survival amongst patients in these trials.The Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis was used to compare treatments. Survival time was partitioned into three health states: with toxicity before disease progression, without toxicity before disease progression, and disease progression until death. Health state utilities were estimated using EuroQol-5 Dimensions, 3 Levels (EQ-5D-3L) data collected in the trials. Q-TWiST was calculated as the utility-weighted sum of the mean health state durations. Trial data analyzed included the primary analysis and subsequent data cutoffs. The base-case analysis was based on the most recent analysis of the trials.Patients randomized to pembrolizumab had 2.49 months greater Q-TWiST (P value < 0.001) compared to those randomized to platinum-based chemotherapy at a follow-up of 24 months in KN024, and 2.29 months greater Q-TWiST (P value < 0.001) compared to docetaxel over 30 months follow-up in KN010. Results across the trial analyses showed an increase in trend for the Q-TWiST improvement of pembrolizumab over time.Pembrolizumab showed significant improvement in Q-TWiST compared to chemotherapy in advanced or metastatic NSCLC in both previously untreated and treated patients. The benefits of pembrolizumab continued to accrue with longer follow-ups.

Abstract Background: KEYNOTE-189 is a randomized, placebo-controlled, Phase III study of pembro plus pemetrexed-platinum versus placebo plus pemetrexed-platinum among pts with metastatic nonsquamous NSCLC. At median follow-up of 10.5 months, pts in the pembro-combination arm had improved OS (HR, 0.49; 95% CI, 0.38-0.64; P&amp;lt;0.001) and PFS (HR, 0.52; 95% CI, 0.43-0.64; P&amp;lt;0.001) compared with pts in the placebo-combination arm. We present a retrospective, exploratory evaluation of outcomes among pts with liver and brain metastases at baseline from an updated analysis. Methods: Pts with untreated metastatic nonsquamous NSCLC, ECOG PS 0/1, and without EGFR/ALK alteration were randomized 2:1 to receive up to 35 Q3W cycles of pembro 200 mg or placebo plus 4 cycles of pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 followed by maintenance pemetrexed. Randomization was stratified by PD-L1 TPS (&amp;lt;1% vs ≥1%), platinum (carboplatin vs cisplatin), and smoking status (current/former vs never). Response was assessed by RECIST v1.1 per blinded, independent central review. OS and PFS were primary endpoints. Results: 616 pts were randomized (pembro-combination, n=410; placebo-combination, n=206). At data cutoff, median follow-up was 18.7 months. At baseline, 19% of pts had liver metastases and 18% had brain metastases. HRs for OS and PFS favored the pembro-combination vs placebo-combination across all groups, and were similar for pts with/without liver or brain metastases (Table). Conclusion: Pembro plus pemetrexed-platinum provided superior outcomes vs chemotherapy alone irrespective of liver or brain metastases in pts with untreated metastatic nonsquamous NSCLC. Benefit was observed in pts with brain or liver metastases, for whom prognosis is historically poor. PFSOSN*Median, mo (95% CI)HR(95% CI)Median, mo (95% CI)HR(95% CI)Pts With Liver MetastasesPembro-combination666.1 (4.7-8.5)0.52 (0.34-0.81)12.6 (8.1-19.1)0.62 (0.39-0.98)Placebo-combination493.4 (2.8-4.7)6.6 (4.6-7.6)Pts Without Liver MetastasesPembro-combination3449.2 (8.8-11.0)0.48 (0.39-0.59)23.7 (20.1-25.9)0.58 (0.45-0.74)Placebo-combination1575.4 (4.9-6.7)13.2 (10.0-16.4)Pts With Brain MetastasesPembro-combination736.9 (5.4-11.0)0.42 (0.27-0.67)19.2 (15.0-25.9)0.41 (0.24-0.67)Placebo-combination354.7 (2.2-5.5)7.5 (4.6-10.0)Pts Without Brain MetastasesPembro-combination3379.2 (8.3-10.9)0.48 (0.39-0.59)22.4 (19.7-25.4)0.59 (0.46-0.75)Placebo-combination1714.9 (4.7-5.9)12.1 (9.1-15.0)*25 patients had both brain and liver metastases. 1 of 2 Citation Format: Marina C. Garassino, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Giovanna Speranza, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J. Hochmair, Steven F. Powell, Susanna Y.-S. Cheng, Helge G. Bischoff, Nir Peled, Francesco Grossi, Ross R. Jennens, Martin Reck, Rina Hui, Edward B. Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E. Gray, Anna Cardellino, Jing Yang, M. Catherine Pietanza, Delvys Rodríguez-Abreu. Outcomes among patients (pts) with metastatic nonsquamous NSCLC with liver metastases or brain metastases treated with pembrolizumab (pembro) plus pemetrexed-platinum: Results from the KEYNOTE-189 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT043.

Meeting abstracts Treatment options for SCLC after failing platinum-based (PLT) chemotherapy (CT) are limited. Combined blockade of programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) immune checkpoint pathways has anti-tumor activity with a manageable safety profile. Nivolumab

e19002 Background: KRAS mutations are the most common oncogenic drivers in lung cancers without any approved targeted therapy. Preclinical evidence suggests that KRAS mutations are highly dependent on the NF-kB pathway. Bortezomib, a proteasome inhibitor, has been shown to downregulate the NF-kB pathway and lead to objective responses in patients with KRAS G12D in early phase clinical trials. In this single-institution, phase II study we assessed the efficacy and safety of subcutaneous bortezomib in KRAS mutant lung cancers. Methods: Patients with advanced KRAS G12D mutant lung cancers were eligible. Bortezomib was administered at 1.3mg/m2/dose subcutaneously on days 1, 4, 8, and 11 of a 21 day cycle until disease progression or unacceptable toxicity. The primary objective was radiographic response rate (RECIST version 1.1). The secondary endpoints were progression free survival (PFS) and overall survival (OS) determined from the date of first bortezomib treatment. Simon two-stage minimax design was used (H0= 10%, H1= 30%, power = 90%). Results: Sixteen patients with KRAS G12D mutant lung adenocarcinomas were treated on study: 38% never smokers, 31% former smokers ≤ 15 pack years, and 69% with invasive mucinous adenocarcinomas. Patients received treatment for a median of 2 months (range 1-12). One patient had a partial response with a 66% reduction in disease burden (6% observed rate, 95% CI 0.2 to 30.2%). Of the 6 patients (40%) with stable disease, 2 remained on study for over 5 months. The median PFS was 1 month (95% CI 1-6). The median OS was 13 months (95% CI 6-NA). The median OS from date of diagnosis of metastatic disease was 39 months (95% CI 35-NA). The most common treatment-related toxicities of any grade were fatigue (50%), diarrhea (38%), nausea (31%), and rash (31%). Treatment-related peripheral neuropathy occurred in 25% of patients (3 patients with grade 1, 1 patient with grade 2). Conclusions: In patients with KRAS G12D mutant lung cancers, bortezomib was associated with modest anti-tumor activity and durable disease control in a small subset of patients. Further investigation into predictive biomarkers for the efficacy of bortezomib should be pursued. Without a clear biomarker, no further study of bortezomib in KRAS- mutant lung cancers is warranted. Clinical trial information: NCT01833143.

PARP1 is overexpressed in small cell lung cancer (SCLC) and represents a novel therapeutic target for this disease. Preclinical data indicates that combining veliparib (an oral PARP-1/2 inhibitor) and temozolomide (TMZ) results in synergistic tumor growth delay or regression. In this study, we investigated whether adding veliparib to TMZ would improve outcomes in patients with relapsed sensitive and refractory SCLCs. Candidate predictive biomarkers, including SLFN11, were then explored. SCLC patients previously treated with 1 or 2 prior regimens were enrolled in the trial and randomized 1:1 to receive oral TMZ 150-200mg/m2/day (D1-5) with either veliparib or placebo 40mg twice daily, orally (D1-7) (NCT01638546). Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in patients with platinum sensitive (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Archived tissue was available for 53 patients for biomarker analysis. 104 patients were enrolled and 100 patients were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. Progression free survival at 4-months was similar between the two arms, 36% vs. 27% (p=0.39). However, in 93 evaluable pts, response rate was significantly higher in pts treated with veliparib/TMZ compared to TMZ alone (39% vs 14%, p =0.016). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Levels of SLFN11, a marker of SCLC response to PARP inhibition in preclinical models, were assessed by immunohistochemistry. High SLFN11 in patient tumors (obtained at original diagnosis) was associated with a trend towards better overall survival in the veliparib/TMZ arm, but no difference in outcome in the TMZ alone arm. Additional correlative studies are ongoing, including assessment of MGMT promoter methylation, and will be available at the time of presentation. The combination of veliparib/TMZ increased response rates significantly, compared to TMZ alone. Hematologic toxicities of the combination may have impacted PFS (which was not significantly different between the arms) by limiting dosing. Biomarkers such as SLFN11, ATM, or MGMT promoter methylation could potentially help guide patient selection in the SCLC population.

Abstract Background: Mutations in the tumor suppressor genes STK11 (also known as LKB1) and KEAP1 have been associated with poorer clinical outcomes in patients (pts) with NSCLC. In an exploratory analysis, we assessed the prevalence of STK11 and KEAP1 mutations and their association with efficacy in KEYNOTE-189 (NCT02578680). Methods: STK11 and KEAP1 status and tumor mutational burden (TMB) were assessed by whole-exome sequencing (WES) in pts who had available tumor and matched-normal tissue. PD-L1 was assessed by the PD-L1 IHC 22C3 pharmDx assay. The association of STK11 and KEAP1 status with efficacy and their correlation with TMB and PD-L1 expression distributions were evaluated descriptively. Results: WES data from both tumor and normal DNA were evaluable for 289 (47%) of 616 pts, of whom 54 (19%) had an STK11 mutation and 68 (24%) had a KEAP1 mutation; 29 (10%) had both STK11 and KEAP1 mutations. PD-L1 TPS tended to be lower in pts with vs without STK11 mutation (median [IQR] 0% [0-16] vs 15% [0-75]), whereas TMB score tended to be higher in pts with mutation (209 [132-265] vs 146 [89-264]). Similar patterns were seen for pts with vs without KEAP1 mutation (PD-L1 TPS: 1% [0-13] vs 20% [0-75]; TMB: 173 [124-267] vs 147 [89-263]). Although ORR of pembrolizumab plus chemotherapy was lower and PFS and OS shorter in pts with vs without STK11 and KEAP1 mutation, pembrolizumab plus chemotherapy was associated with numerically better outcomes than placebo plus chemotherapy regardless of mutation status (Table). 95% CIs were wide given the modest mutation frequency and the 2:1 randomization in favor of pembrolizumab plus chemotherapy. Conclusions: Data from this exploratory analysis support use of pembrolizumab plus pemetrexed and platinum as standard first-line therapy for pts with metastatic nonsquamous NSCLC regardless of STK11 or KEAP1 status. STK11KEAP1With MutationWithout MutationWith MutationWithout MutationPembro + ChemoPlacebo + ChemoPembro + ChemoPlacebo + ChemoPembro + ChemoPlacebo + ChemoPembro + ChemoPlacebo + Chemo(n = 36)(n = 18)(n = 168)(n = 67)(n = 45)(n = 23)(n = 159)(n = 62)ORR, % (95% CI)31 (16-48)17 (4-41)49 (41-57)16 (8-27)36 (22-51)17 (5-39)48 (40-56)16 (8-28)PFS, median, mo (95% CI)6 (4-9)5 (5-9)10 (8-14)5 (5-5)5 (4-11)5 (5-9)10 (8-14)5 (5-5)PFS, HR (95% CI)0.81 (0.44-1.47)0.38 (0.27-0.52)0.65 (0.38-1.12)0.38 (0.28-0.53)OS, median, mo (95% CI)17 (5-NR)8 (7-NR)23 (20-NR)12 (8-25)13 (7-NR)9 (7-NR)24 (20-NR)12 (8-NR)OS, HR (95% CI)0.75 (0.37-1.50)0.59 (0.41-0.85)0.81 (0.44-1.49)0.57 (0.39-0.84) Citation Format: Shirish M. Gadgeel, Delvys Rodriguez-Abreu, Enriqueta Felip, Emilio Esteban, Giovanna Speranza, Martin Reck, Rina Hui, Michael Boyer, Edward B. Garon, Hidehito Horinouchi, Razvan Cristescu, Deepti Aurora-Garg, Andrey Loboda, Jared Lunceford, Julie Kobie, Mark Ayers, Bilal Piperdi, M. Catherine Pietanza, Marina C. Garassino. Pembrolizumab plus pemetrexed and platinum vs placebo plus pemetrexed and platinum as first-line therapy for metastatic nonsquamous NSCLC: analysis of KEYNOTE-189 by STK11 and KEAP1 status [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-397.

8064 Background: Patients with ALK + non-small cell lung cancer (NSCLC) initially respond to crizotinib, but eventually develop resistance. Treatment of patients with ALK positive lung cancer with HSP90 inhibitors leads to clinical and radiographic response. We hypothesized that treatment of patients with ALK rearranged NSCLC with crizotinib and ganetespib, an HSP90 inhibitor, would be safe. Methods: All patients had ALK rearranged metastatic non-small cell lung cancer not previously treated with crizotinib. Prior chemotherapy was allowed. Patients were treated with crizotinib 250 mg bid continuously; ganetespib was administered intravenously on days 1 and 8 of a 21-day cycle. In a standard 3+ 3 design, ganetespib was explored at 3 different dose levels. The primary objective was to determine the maximum tolerated dose of the combination of crizotinib and ganetespib. Secondary objectives included establishing the safety profile (CTCAE v4) of the combination in patients with ALK+ lung cancer, exploring the efficacy (RR by RECIST 1.1, PFS, and OS). Results: 12 patients were treated with combined crizotinib and ganetespib: 100 mg/m2(n=3), 150 mg/m2(n=3), and 200 mg/m2 (n=6). Women: 8/12, Median Age: 56 (range 41-70), Prior therapy: none (7 pts), 1 line (4 pts), or 2 lines (1 pt). Median duration of treatment: 100 mg/m2=30 weeks, 150 mg/m2=54 weeks, and 200 mg/m2= 6 weeks. There were no first-cycle DLTs. The maximum tolerated dose was crizotinib 250 mg bid/ganetespib 200 mg/m2. The most common toxicities were fatigue, diarrhea, nausea, vomiting, and dizziness. Grade 4 elevation in ALT (n=1) and Grade 3 elevations in lipase (n=2), AST (n=1), and amylase (n=1) were observed. 5 patients stopped therapy due to toxicity. 4 discontinued due to progressive disease. 3 patients continue on treatment. PR = 67% (8/12), SD= 16% (2/12), PD =8% (1/12), Not Evaluable =8% (1/12). Median OS has not been reached (median f/u = 15 months, with 10 patients still alive). Conclusions: In patients with ALK+ lung cancers, crizotinib and ganetespib can be combined, with an MTD of crizotinib 250 mg bid continuously and ganetespib 200 mg/m2 on days 1 and 8 of a 21 day cycle. Further evaluation of this combination in patients not previously treated with crizotinib is warranted. Clinical trial information: (NCT01579994).

Aim: We pooled patient-level data from three randomized controlled studies to evaluate the combination of pembrolizumab plus chemotherapy in patients with untreated advanced/metastatic non-small-cell lung cancer (NSCLC) and programmed cell death ligand 1 (PD-L1) tumor proportion score <1% in East Asia. Methods: The analysis included 107 patients from China, Japan, Korea, Thailand and Taiwan (pembrolizumab plus chemotherapy, n = 56; chemotherapy alone, n = 51). Results: For pembrolizumab plus chemotherapy versus chemotherapy alone, median overall survival was 21.3 versus 12.6 months (HR, 0.55 [95% CI: 0.35-0.87]) and median progression-free survival was 8.4 versus 6.0 months (HR, 0.64 [95% CI: 0.43-0.96]). Conclusion: The analysis supports the use of pembrolizumab in combination with platinum-based chemotherapy for East Asian patients with PD-L1-negative, advanced NSCLC.This analysis evaluated outcomes for East Asian patients with a type of advanced lung cancer which does not express a protein called programmed cell death ligand 1 (PD-L1). The patients received either an immunotherapy, called pembrolizumab, in combination with chemotherapy or chemotherapy alone. Overall survival (how long people live) and progression-free survival (how long people live without their disease getting worse) were longer for patients who received treatment with pembrolizumab plus chemotherapy versus those who received chemotherapy alone. Side effects among East Asian patients were similar to those previously described for a global patient population. These results support the use of pembrolizumab in combination with chemotherapy for East Asian patients with lung cancer that does not express PD-L1. Clinical Trial Registration: NCT02039674; NCT02578680; NCT03950674; NCT02775435; NCT03875092 (ClinicalTrials.gov).

In the phase 3 KEYNOTE-604 study (NCT03066778), pembrolizumab plus etoposide and platinum chemotherapy (EP) significantly (p = 0.0023) improved progression-free survival versus placebo plus EP in previously untreated extensive-stage SCLC (ES-SCLC). We present health-related quality of life (HRQoL) results from KEYNOTE-604.Patients with stage IV SCLC were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles plus four cycles of EP. Secondary end points included mean change from baseline to week 18 in the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) global health status/quality of life (GHS/QoL) scale and time to deterioration in the composite outcome of cough, chest pain, or dyspnea from QLQ-C30 and QLQ-Lung Cancer Module 13. Two-sided, nominal p values are reported.A total of 439 patients completed at least one QLQ-C30 and QLQ-Lung Cancer Module 13 assessment (pembrolizumab + EP, n = 221; placebo + EP, n = 218). GHS/QoL scores improved from baseline to week 18: least squares mean (95% confidence interval [CI]) changes were 8.7 (5.3-12.1) for pembrolizumab plus EP and 4.2 (0.9-7.5) for placebo plus EP. Between-group differences in least squares mean scores were improved for pembrolizumab plus EP (4.4 [95% CI: 0.2-8.7], p = 0.040]). Median time to deterioration for the composite end point was not reached and 8.7 (95% CI: 5.9-not reached) months, respectively (hazard ratio = 0.80 [95% CI: 0.56-1.14], p = 0.208).First-line pembrolizumab plus EP therapy maintained HRQoL in patients with ES-SCLC and may be associated with greater improvement than placebo plus EP. Together with the efficacy and safety findings in KEYNOTE-604, HRQoL data support the benefit of pembrolizumab in ES-SCLC.

Therapeutic options for small-cell lung cancer (SCLC) remain limited, with etoposide/platinum (EP) as the standard first-line chemotherapy regimen. However, patients with extensive-stage (ES)-SCLC experience high relapse rates within months after initial therapy. Pembrolizumab, a humanized monoclonal antibody against PD-1, has shown antitumor activity as monotherapy in heavily pretreated patients with PD-L1–positive SCLC in the phase 1b KEYNOTE-028 study. KEYNOTE-604 (ClinicalTrials.gov, NCT03066778) evaluates EP plus either pembrolizumab or placebo as first-line therapy for ES-SCLC.

LBA8505 The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Sunday, June 5, 2016, and in the Annual Meeting Proceedings online supplement to the June 20, 2016, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

Several factors play a role in job selection after completion of a hematology/oncology training program, such as a fellows’ overall career goals, expected income potential, and limitations imposed by visa status, among many others. Training programs play an integral role in mentoring trainees in career selection. For many, the first job is often not career-long. In addition to considerations for a fellow considering a first job out of fellowship, physicians will consider a change because of dissatisfaction at one’s current position, desire for advancement opportunities, or a desire to work in a different sector. Other factors include non-occupational issues such as career opportunities for a spouse or desire for a different geographic location. Frequent employment changes are common with crossover between academia, clinical practice, industry, or government service. Possessing the skills needed to recognize one’s strengths, weaknesses, and goal prioritization can allow for more optimal job selection should a career transition into a different discipline occur. Recognizing opportunities that present themselves and potentially taking advantage of them can lead to professional and personal growth.

Small cell lung cancer (SCLC) accounts for 15% of lung cancer cases and is associated with a dismal prognosis. Standard therapeutic regimens have been improved over the past decades, but without a major impact on patient survival. The development of targeted therapies based on a better understanding of the molecular basis of the disease is urgently needed. At the genetic level, SCLC appears very heterogenous, although somatic mutations targeting classical oncogenes and tumor suppressors have been reported. SCLC also possesses somatic mutations in many other cancer genes, including transcription factors, enzymes involved in chromatin modification, receptor tyrosine kinases and their downstream signaling components. Several avenues have been explored to develop targeted therapies for SCLC. So far, however, there has been limited success with these targeted approaches in clinical trials. Further progress in the optimization of targeted therapies for SCLC will require the development of more personalized approaches for the patients.

Background: Patients (pts) with SCLC respond to initial platinum (PLT) based chemotherapy (CT), but rapidly progress. Combined blockade of PD-1 and CTLA-4 immune checkpoint pathways has anti-tumor activity with a manageable safety profile. Nivolumab (NIVO) is a fully human IgG4 PD-1 immune checkpoint inhibitor approved in the US & Japan. Interim safety and efficacy of NIVO ± ipilimumab (IPI), a CTLA-4 checkpoint inhibitor, in pretreated SCLC pts are reported. Material and methods: Pts who were PLT sensitive or refractory and had progressive disease were enrolled regardless of tumor PD-L1 status or number of prior CT regimens. This open-label study randomized pts to NIVO 3 mg/kg IV Q2W or NIVO + IPI (1 + 1 mg/kg, 1 + 3 mg/kg, or 3 + 1 mg/kg) IV Q3W for 4 cycles followed by NIVO 3 mg/kg Q2W. Primary objective was overall response rate (ORR). Other objectives were safety, PFS, OS and biomarker analysis. Results: Seventy-five pts were enrolled (NIVO, n = 40; NIVO + IPI, n = 35); 59% had ≥2 prior regimens. Drug-related adverse events (DrAEs) in ≥10% were fatigue (18%), diarrhea (13%), nausea (10%), and decreased appetite (10%) with NIVO; and fatigue (29%), diarrhea (17%), pruritus (14%), nausea, endocrine disorders, and rash (11% each) with NIVO + IPI. Gr 3–4 DrAEs in ≥5% included diarrhea and rash (6% each; NIVO + IPI). Drug-related pneumonitis occurred in 2 pts (1 per arm). One pt experienced a drug-related SAE of myasthenia gravis on study which was fatal. Of 40 evaluable NIVO pts, partial response (PR) was seen in 6 (15%; duration of ongoing responses [DOR] 80–251+ days); stable disease (SD) in 9 (22.5%); and progressive disease (PD) in 25 (62.5%). In 20 evaluable NIVO + IPI pts, 1 had complete response (CR) (5%; DOR 322+ days); 4 had PR (20%; DOR 41–83+ days); 6 had SD (30%), and 9 had PD (45%). In the NIVO + IPI arm, 12 pts had not reached first tumor assessment and 3 were not evaluable. Nine pts (23%) continue treatment with NIVO and 19 (54%) with NIVO + IPI. Conclusions: In this PD-L1 unselected SCLC population with progression post-PLT, NIVO alone or combined with IPI was tolerable. ORR was 15% (NIVO) and 25% (NIVO + IPI) for evaluable pts; durable responses were noted. Updated safety, clinical activity and biomarker analysis will be presented. Clinical Trial Number: NCT1928394.

Background: Therapeutic options for SCLC remain limited, with EP as the standard first-line chemotherapy regimen. However, patients (pts) with ES-SCLC experience high relapse rates within months after initial therapy. Pembrolizumab, a humanized monoclonal antibody against PD-1, has shown antitumor activity as monotherapy in heavily pretreated pts with PD-L1–positive SCLC in the phase 1b KEYNOTE-028 study. KEYNOTE-604 (ClinicalTrials.gov, NCT03066778) evaluates EP plus either pembrolizumab or placebo (pbo) as first-line therapy for ES-SCLC. Trial design: In this international, double-blind, phase 3 trial, adults with newly diagnosed ES-SCLC, ECOG PS ≤ 1, and no previous systemic therapy for SCLC are randomized 1:1 to receive either EP plus a 200-mg fixed dose of pembrolizumab intravenously (IV) once every 3 weeks (Q3W) or EP plus pbo IV Q3W. Randomization is stratified by the chosen platinum therapy (carboplatin vs cisplatin), ECOG PS (0 vs 1), and baseline lactate dehydrogenase concentration (≤ upper limit of normal [ULN] vs > ULN). Study treatment includes a total of 4 cycles of EP and 2 y of pembrolizumab/pbo and continues until documented PD, intolerable toxicity, or withdrawal of consent. Pts with a response after 4 cycles of EP plus pbo or pembrolizumab may receive prophylactic cranial irradiation. Pts who complete 2 y of pembrolizumab treatment or stop pembrolizumab for reasons other than PD/intolerability, but subsequently have documented PD, may receive an additional 1 y of pembrolizumab. Tumor response is assessed every 6 wk for 48 wk, and every 9 wk thereafter by RECIST version 1.1 by blinded independent central review. AEs occurring during treatment and 30 d thereafter (90 d for serious AEs) are graded per Common Terminology Criteria for Adverse Events, version 4.0. Primary endpoints are PFS and OS. Secondary endpoints are ORR, duration of response, safety, and patient-reported outcomes. Enrollment is ongoing with a planned enrollment of approximately 430 pts. Clinical trial identification: NCT03066778; EudraCT Number: 2016-004309-15 Legal entity responsible for the study: Merck & Co., Inc., Kenilworth, NJ, USA Funding: This research was supported by Merck & Co., Inc., Kenilworth, NJ, USA Disclosure: C.M. Rudin: Advisory board member: Abbvie, Araxes, BMS, Celgene, G1 Therapeutics, Harpoon, Novartis. L. Shen, M.C. Pietanza: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA. Keywords: pembrolizumab, PD-L1, small-cell lung cancer, KEYNOTE-604

Background: KEYNOTE-189 is a randomized, placebo-controlled, Phase III study of pembro plus pemetrexed-platinum versus placebo plus pemetrexed-platinum among pts with metastatic nonsquamous NSCLC. At median follow-up of 10.5 months, pts in the pembro-combination arm had improved OS (HR, 0.49; 95% CI, 0.38-0.64; P<0.001) and PFS (HR, 0.52; 95% CI, 0.43-0.64; P<0.001) compared with pts in the placebo-combination arm. We present a retrospective, exploratory evaluation of outcomes among pts with liver and brain metastases at baseline from an updated analysis.Methods: Pts with untreated metastatic nonsquamous NSCLC, ECOG PS 0/1, and without EGFR/ALK alteration were randomized 2:1 to receive up to 35 Q3W cycles of pembro 200 mg or placebo plus 4 cycles of pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 followed by maintenance pemetrexed. Randomization was stratified by PD-L1 TPS (<1% vs ≥1%), platinum (carboplatin vs cisplatin), and smoking status (current/former vs never). Response was assessed by RECIST v1.1 per blinded, independent central review. OS and PFS were primary endpoints.Results: 616 pts were randomized (pembro-combination, n=410; placebo-combination, n=206). At data cutoff, median follow-up was 18.7 months. At baseline, 19% of pts had liver metastases and 18% had brain metastases. HRs for OS and PFS favored the pembro-combination vs placebo-combination across all groups, and were similar for pts with/without liver or brain metastases (Table).Conclusion: Pembro plus pemetrexed-platinum provided superior outcomes vs chemotherapy alone irrespective of liver or brain metastases in pts with untreated metastatic nonsquamous NSCLC. Benefit was observed in pts with brain or liver metastases, for whom prognosis is historically poor.PFSOSN*Median, mo (95% CI)HR(95% CI)Median, mo (95% CI)HR(95% CI)Pts With Liver MetastasesPembro-combination666.1 (4.7-8.5)0.52 (0.34-0.81)12.6 (8.1-19.1)0.62 (0.39-0.98)Placebo-combination493.4 (2.8-4.7)6.6 (4.6-7.6)Pts Without Liver MetastasesPembro-combination3449.2 (8.8-11.0)0.48 (0.39-0.59)23.7 (20.1-25.9)0.58 (0.45-0.74)Placebo-combination1575.4 (4.9-6.7)13.2 (10.0-16.4)Pts With Brain MetastasesPembro-combination736.9 (5.4-11.0)0.42 (0.27-0.67)19.2 (15.0-25.9)0.41 (0.24-0.67)Placebo-combination354.7 (2.2-5.5)7.5 (4.6-10.0)Pts Without Brain MetastasesPembro-combination3379.2 (8.3-10.9)0.48 (0.39-0.59)22.4 (19.7-25.4)0.59 (0.46-0.75)Placebo-combination1714.9 (4.7-5.9)12.1 (9.1-15.0)*25 patients had both brain and liver metastases.1 of 2Citation Format: Marina C. Garassino, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Giovanna Speranza, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J. Hochmair, Steven F. Powell, Susanna Y.-S. Cheng, Helge G. Bischoff, Nir Peled, Francesco Grossi, Ross R. Jennens, Martin Reck, Rina Hui, Edward B. Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E. Gray, Anna Cardellino, Jing Yang, M. Catherine Pietanza, Delvys Rodríguez-Abreu. Outcomes among patients (pts) with metastatic nonsquamous NSCLC with liver metastases or brain metastases treated with pembrolizumab (pembro) plus pemetrexed-platinum: Results from the KEYNOTE-189 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT043.