Jose Lutzky

An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.

Background Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma. Methods We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0·3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640. Findings The best overall response rate was 11·1% (95% CI 4·9–20·7) for 10 mg/kg, 4·2% (0·9–11·7) for 3 mg/kg, and 0% (0·0–4·9) for 0·3 mg/kg (p=0·0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0·3 mg/kg, respectively; the most common grade 3–4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0·3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0·3 mg/kg group). Interpretation Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. Funding Bristol-Myers Squibb.

Abstract Background Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax ® -L) to standard therapy for newly diagnosed glioblastoma. Methods After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002

Bortezomib, as a single agent and in combination with dexamethasone, was examined as first-line treatment in 32 consecutive patients with untreated symptomatic multiple myeloma. Patients received bortezomib 1.3 mg/m(2) for a maximum of six 3-week cycles; oral dexamethasone 40 mg was added if a less than partial response (PR) was achieved after two cycles or a less than complete response (CR) was achieved after four cycles. The response rate (CR + PR) was 88%, with undetectable paraprotein (CR) in 6%, and detectable by immunofixation only in 19% [near (n)CR]. All 32 patients completed the first two cycles of bortezomib alone, of whom 3% achieved CR, 9% nCR, and 28% PR. Ten patients received single-agent bortezomib on study, and dexamethasone was added in 22, leading to 15 improved responses. The most common adverse events >/=grade 2 included sensory neuropathy (31%), constipation (28%), myalgia (28%) and fatigue (25%). Sensory neuropathy grade 2 or 3 was reversible within a median of 3 months in five of 10 patients. Bortezomib treatment did not affect stem cell mobilization in eight or transplantation in six patients. Bortezomib alone or in combination with dexamethasone is an effective induction therapy with a high CR and nCR rate and manageable toxicities in previously untreated patients with myeloma.

<h3>Importance</h3> Uveal melanoma is characterized by mutations in<i>GNAQ</i>and<i>GNA11</i>, resulting in mitogen-activated protein kinase pathway activation. <h3>Objective</h3> To assess the efficacy of selumetinib, a selective, non–adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. <h3>Design, Setting, and Participants</h3> Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. <h3>Interventions</h3> One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m²orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m²intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. <h3>Main Outcomes and Measures</h3> Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. <h3>Results</h3> Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71;<i>P</i> &lt; .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06;<i>P</i> = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. <h3>Conclusions and Relevance</h3> In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01143402

Dendritic cell targeting safely leads to integrated humoral and cellular immunity when combined with TLR agonists in cancer patients.

Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA).KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual.Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5-10·9). Median progression-free survival was 5·6 months (95% CI 3·7-7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05-2·22; p=0·98). Median overall survival was not reached (95% CI 12·9-not reached) versus 15·2 months (12·7-not reached; HR 1·61; 95% CI 0·91-2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group.The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma.Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).

Immunotherapy is associated with durable clinical benefit in patients with melanoma, and this consensus statement outlines recommendations for its use. The panel has based their guidance on the available evidence and outlines a treatment paradigm using drugs that are FDA approved. Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts—including physicians, nurses, and patient advocates—to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

PURPOSE Combination of antiprogrammed cell death protein-1 (PD-1) plus anti–cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy. METHODS Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non–anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR. RESULTS Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody–based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1–negative, non-T-cell–inflamed, and intermediate tumor phenotypes. CONCLUSION To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.

In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB-C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings.Patients with resected stage IIIB-C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS.At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60-0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value.Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253.

To assess the antitumor activity of vitespen (autologous, tumor- derived heat shock protein gp96 peptide complexes) by determining whether patients with stage IV melanoma treated with vitespen experienced longer overall survival than patients treated with physician's choice.Patients (N = 322) were randomly assigned 2:1 to receive vitespen or physician's choice (PC) of a treatment containing one or more of the following: dacarbazine, temozolomide, interleukin-2, or complete tumor resection. This open-label trial was conducted at 71 centers worldwide. Patients were monitored for safety and overall survival.Therapy with vitespen is devoid of significant toxicity. Patients randomly assigned to the vitespen arm received variable number of injections (range, 0 to 87; median, 6) in part because of the autologous nature of vitespen therapy. Intention-to-treat analysis showed that overall survival in the vitespen arm is statistically indistinguishable from that in the PC arm. Exploratory landmark analyses show that patients in the M1a and M1b substages receiving a larger number of vitespen immunizations survived longer than those receiving fewer such treatments. Such difference was not detected for substage M1c patients.These results are consistent with the immunologic mechanism of action of vitespen, indicating delayed onset of clinical activity after exposure to the vaccine. The results suggest patients with M1a and M1b disease who are able to receive 10 or more doses of vitespen as the candidate population for a confirmatory study.

Pigment Cell & Melanoma ResearchVolume 21, Issue 4 p. 492-493 Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation Jose Lutzky, Jose Lutzky Division of Hematology/Oncology, Melanoma Program, Mount Sinai Medical Center, Miami Beach, FL, USASearch for more papers by this authorJuergen Bauer, Juergen Bauer Deparments of Dermatology and Pathology, and UCSF Comprehensive Cancer Center, University of California, San Francisco, CA, USASearch for more papers by this authorBoris C. Bastian, Corresponding Author Boris C. Bastian Deparments of Dermatology and Pathology, and UCSF Comprehensive Cancer Center, University of California, San Francisco, CA, USA *Address correspondence to Boris C. Bastian, e-mail: bastian@cc.ucsf.eduSearch for more papers by this author Jose Lutzky, Jose Lutzky Division of Hematology/Oncology, Melanoma Program, Mount Sinai Medical Center, Miami Beach, FL, USASearch for more papers by this authorJuergen Bauer, Juergen Bauer Deparments of Dermatology and Pathology, and UCSF Comprehensive Cancer Center, University of California, San Francisco, CA, USASearch for more papers by this authorBoris C. Bastian, Corresponding Author Boris C. Bastian Deparments of Dermatology and Pathology, and UCSF Comprehensive Cancer Center, University of California, San Francisco, CA, USA *Address correspondence to Boris C. Bastian, e-mail: bastian@cc.ucsf.eduSearch for more papers by this author First published: 11 July 2008 https://doi.org/10.1111/j.1755-148X.2008.00475.xCitations: 176Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume21, Issue4August 2008Pages 492-493 RelatedInformation

Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown.We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively.Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients.Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.

This multicenter, open-label, phase II study evaluated the safety and clinical activity of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2, and 3, in patients with metastatic melanoma.Thirty-two patients with a maximum of one prior systemic therapy received axitinib at a starting dose of 5 mg twice daily. The primary endpoint was objective response rate.Objective response rate was 18.8% [95% confidence interval (CI), 7.2-36.4], comprising one complete and five partial responses with a median response duration of 5.9 months (95% CI, 5.0-17.0). Stable disease at 16 weeks was noted in six patients (18.8%), with an overall clinical benefit rate of 37.5%. Six-month progression-free survival rate was 33.9%, 1-year overall survival rate was 28.1%, and median overall survival was 6.6 months (95% CI, 5.2-9.0). The most frequently (>15%) reported nonhematologic, treatment-related adverse events were fatigue, hypertension, hoarseness, and diarrhea. Treatment-related fatal bowel perforation, a known class effect, occurred in one patient. Axitinib selectively decreased plasma concentrations of soluble VEGFR (sVEGFR)-2 and sVEGFR-3 compared with soluble stem cell factor receptor (sKIT). No significant association was noted between plasma levels of axitinib and response. However, post hoc analyses indicated potential relationships between efficacy endpoints and diastolic blood pressure of 90 mm Hg or higher as well as baseline serum lactate dehydrogenase levels.Axitinib was well tolerated, showed a selective VEGFR-inhibitory profile, and showed single-agent activity in metastatic melanoma. Further evaluations of axitinib, alone and combined with chemotherapy, are ongoing.

Durvalumab is a selective, high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 (PD-L1) binding to programmed death 1. Here we report safety and clinical activity in the NSCLC cohort of a phase I/II trial that included multiple tumor types (Study 1108; NCT01693562).Patients with stage IIIB-IV NSCLC (squamous or nonsquamous) received durvalumab 10 mg/kg every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. Primary objectives were safety and antitumor activity. Tumoral PD-L1 expression was assessed using the VENTANA SP263 Assay. Responses were assessed by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1). Adverse events were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events (v4.03).Of 304 patients, 79.0% were previously treated. Confirmed objective response rate was 21.8% in patients with greater than or equal to 25% PD-L1 expression and 6.4% in those with less than 25%; 25.9% in first-line patients and 12.7% in previously treated patients; and 14.0% in squamous and 16.7% in nonsquamous disease. Median overall survival was 12.4 months and median progression-free survival was 1.7 months; both were numerically longer in the PD-L1 greater than or equal to 25% group than in the PD-L1 less than 25% group (overall survival 16.4 versus 7.6 months, respectively; progression-free survival 2.6 versus 1.4 months, respectively). Treatment-related adverse events occurred in 57.2%, were grade 3/4 in 10.2%, and led to discontinuation in 5.6%. One patient (0.3%) died of treatment-related pneumonia with underlying pneumonitis.Durvalumab was clinically active irrespective of histology in this mostly pretreated population, with a manageable safety profile. Response rates and survival appeared to be enhanced in patients with greater tumoral PD-L1 expression.

Background: Epacadostat is a potent inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) enzyme.We present phase 1 results from a phase 1/2 clinical study of epacadostat in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, in advanced melanoma (NCT01604889).Methods: Only the phase 1, open-label portion of the study was conducted, per the sponsor's decision to terminate the study early based on the changing melanoma treatment landscape favoring exploration of programmed cell death protein 1 (PD-1)/PD-ligand 1 inhibitor-based combination strategies.Such decision was not related to the safety of epacadostat plus ipilimumab.Patients received oral epacadostat (25, 50, 100, or 300 mg twice daily [BID]; 75 mg daily [50 mg AM, 25 mg PM]; or 50 mg BID intermittent [2 weeks on/1 week off]) plus intravenous ipilimumab 3 mg/kg every 3 weeks.Results: Fifty patients received ≥1 dose of epacadostat.As of January 20, 2017, 2 patients completed treatment and 48 discontinued, primarily because of adverse events (AEs) and disease progression (n = 20 each).Dose-limiting toxicities occurred in 11 patients (n = 1 each with epacadostat 25 mg BID, 50 mg BID intermittent, 75 mg daily; n = 4 each with epacadostat 50 mg BID, 300 mg BID).The most common immune-related treatment-emergent AEs included rash (50%), alanine aminotransferase elevation (28%), pruritus (28%), aspartate aminotransferase elevation (24%), and hypothyroidism (10%).Among immunotherapy-naive patients (n = 39), the objective response rate was 26% by immune-related response criteria and 23% by Response Evaluation Criteria in Solid Tumors version 1.1.No objective response was seen in the 11 patients who received prior immunotherapy.Epacadostat exposure was dose proportional, with clinically significant IDO1 inhibition at doses ≥25 mg BID.Conclusions: When combined with ipilimumab, epacadostat ≤50 mg BID demonstrated clinical and pharmacologic activity and was generally well tolerated in patients with advanced melanoma.Trial registration: ClinicalTrials.gov

Abstract Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti–PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF -wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti–PD-L1 therapy may provide treatment options for patients with advanced melanoma.

We evaluated the activity of intratumoral Coxsackievirus A21 (V937) in 57 patients with unresectable stage IIIC or IV melanoma.In this multicenter, open-label, phase II study, patients received up to a total V937 dose of 3 × 108 TCID50 (50% tissue culture infectious dose) in a maximum 4.0-mL volume by intratumoral injection. Ten sets of V937 injections were administered between days 1 and 127 (NCT01227551). Patients who had stable disease or were responding could continue treatment in an extension study (NCT01636882). Response and progression status were based on contrast-enhanced computed tomography, magnetic resonance imaging, or caliper measurement and were categorized using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Other evaluations included monitoring of adverse events and serum levels of V937 and anti-V937 antibody titers. The primary efficacy end point was 6-month progression-free survival (PFS) rate per irRECIST.The primary efficacy end point, 6-month PFS rate per irRECIST, was 38.6% (95% CI, 26.0 to 52.4). Durable response rate (partial or complete response for ≥ 6 months) was 21.1% per irRECIST. Best overall response rate (complete plus partial response) was 38.6% (unconfirmed) and 28.1% (confirmed) per irRECIST. Regression of melanoma was observed in noninjected lesions. Based on Kaplan-Meier estimation, 12-month PFS was 32.9% (95% CI, 19.5 to 46.9) per irRECIST and 12-month overall survival was 75.4% (95% CI, 62.1 to 84.7). No treatment-related grade ≥ 3 adverse events occurred. Viral RNA was detected in serum within 30 minutes of administration. Neutralizing antibody titers increased to > 1:16 in all patients after day 22, without effect on clinical or immunologic response.V937 was well tolerated and warrants further investigation for treatment of patients with unresectable melanoma. Studies of combination approaches with V937 and immune checkpoint inhibitors are ongoing.

Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors.Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures.175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%).Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes.NCT02335918.

PURPOSE: To determine immune responses and toxicity to the anti-idiotype vaccine, as well as clinical responses and survival, we initiated a clinical trial for patients with advanced melanoma treated with an anti-idiotype antibody (TriGem) that mimics the disialoganglioside GD2. PATIENTS AND METHODS: Forty-seven patients with advanced melanoma received either 1-, 2-, 4-, or 8-mg doses of TriGem (Titan Pharmaceuticals Inc, South San Francisco, CA) mixed with QS-21 adjuvant (Aquila Biopharmaceuticals, Inc, Worcester, MA) 100 μg subcutaneously weekly for 4 weeks and then monthly until disease progression. Median age was 57 years, there were 32 men and 15 women, 43% of patients had undergone prior therapy for metastatic disease, 55% had disease confined to soft tissue, and 45% had visceral metastasis. RESULTS: Hyperimmune sera from 40 of 47 patients showed an anti–anti-idiotype (Ab3) response. Patient Ab3 was truly Ab1′ because it specifically bound purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody consisted of predominantly immunoglobulin (Ig)G, and all IgG subclasses were represented. One patient had a complete response that persisted at 24 months, and 12 patients were stable from 14+ to 37+ months (median, 18+ months). Disease progression occurred in 32 patients on study from 1 to 17 months (median, 5.5 months), and 21 have died at 1 to 16 months (median, 6 months). The Kaplan-Meier–derived overall median survival has not been reached. Median survival has not been reached for the 26 patients with soft tissue disease only and was 13 months for 21 patients with visceral metastasis. Toxicity consisted of local reaction at the site of injection and mild fever and chills. CONCLUSION: TriGem has minimal toxicity and generates robust and specific IgG immune responses against GD2. Objective responses were minimal, but there may be a favorable impact on disease progression and survival that will require prospective randomized trials.

Abstract Background In the phase III ALSYMPCA trial, metastatic castration-resistant prostate cancer (mCRPC) patients had few prior life-prolonging therapies. Following ALSYMPCA, which demonstrated radium-223 survival benefit, and before radium-223 U.S. commercial availability, an expanded access program (EAP) providing early-access radium-223 allowed life-prolonging therapies in current use. Subjects, Materials, and Methods This phase II, open-label, single-arm, multicenter U.S. EAP (NCT01516762) enrolled patients with symptomatic mCRPC, ≥2 bone metastases, and no lung, liver, or brain metastases. Patients received radium-223 55 kBq/kg intravenously every 4 weeks × 6. Primary outcomes were acute and long-term safety. Additional analyses were done by number of radium-223 injections, and prior or concomitant abiraterone or enzalutamide use. Results Of 252 patients, 184 received radium-223: 165/184 (90%) had Eastern Cooperative Oncology Group (ECOG) performance status 0–1; 183 (99%) had prior systemic anticancer therapy. Treatment-related adverse events occurred in 93/184 (51%) patients during treatment and 11 (6%) during follow-up. Median overall survival was 17 months, with 134/184 (73%) patients censored because of short follow-up due to radium-223 approval. In post hoc analyses, patients with ≥3 prior anticancer medications, baseline ECOG performance status ≥2, and lower baseline hemoglobin were less likely to receive 5–6 radium-223 injections and unlikely to benefit from radium-223. Radium-223 was well tolerated regardless of concurrent or prior abiraterone or enzalutamide. Conclusion Radium-223 was well tolerated, with no new safety concerns; safety was maintained with abiraterone or enzalutamide. Patients with more advanced disease were less likely to benefit from radium-223. Clinicians should consider baseline characteristics and therapy sequence for greatest clinical value. Implications for Practice In this phase II U.S. expanded access program, radium-223 was well tolerated, with a median overall survival of 17 months in metastatic castration-resistant prostate cancer patients. In post hoc analyses, radium-223 was safe regardless of concurrent abiraterone or enzalutamide, and median overall survival appeared longer when radium-223 was used earlier in patients with less prior treatment. Patients with more advanced disease were less likely to benefit from radium-223. Clinicians should consider baseline clinical characteristics and therapy sequence to provide the greatest clinical value to patients.

Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available.To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants.The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma.These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.

Glembatumumab vedotin is an antibody-drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma.This single-arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry.In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6-5.5 months), and the median OS was 9.0 months (95% CI, 6.1-11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB-positive epithelial cells.Glembatumumab vedotin had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Treatment-related rash may be associated with response.

Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited.A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates (according to the modified Response Evaluation Criteria in Solid Tumors, version 1.1); the clinical benefit rate; the time to response; the duration of response; and safety.A total of 24 patients with stage IV BRAF-mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases.Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF-mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing.

We assessed the safety and efficacy of melphalan, arsenic trioxide (ATO) and ascorbic acid (AA) (MAC) combination therapy for patients with multiple myeloma (MM) who failed more than two different prior regimens. Patients received melphalan (0.1 mg/kg p.o.), ATO (0.25 mg/kg i.v.) and AA (1 g i.v) on days 1-4 of week 1, ATO and AA twice weekly during weeks 2-5 and no treatment during week 6 of cycle 1; during cycles 2-6, the schedule remained the same except ATO and AA were given twice weekly in week 1. Objective responses occurred in 31 of 65 (48%) patients, including two complete, 15 partial and 14 minor responses. Median progression-free survival and overall survival were 7 and 19 months respectively. Twenty-two patients had elevated serum creatinine levels (SCr) at baseline, and 18 of 22 (82%) showed decreased SCr levels during treatment. Specific grade 3/4 haematological (3%) or cardiac adverse events occurred infrequently. Frequent grade 3/4 non-haematological adverse events included fever/chills (15%), pain (8%) and fatigue (6%). This steroid-free regimen was effective and well tolerated in this heavily pretreated group. These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM.

<h3>Background</h3> Immune checkpoint inhibitors have become the first line therapy in melanoma treatment and their use is extending to other malignancies. However, we are still learning about immune side effects produced by these drugs and their severity especially in patients with history of inflammatory diseases. <h3>Case presentation</h3> We present two cases of metastatic melanoma treated with nivolumab and pembrolizumab (anti PD-1). Both patients developed acute interstitial nephritis during immune checkpoint therapy. We emphasize the causal association between immune checkpoint inhibitors and the nephritis. The timing of drug administration and appearance of nephritis is suggestive of a causal relation between the checkpoint inhibitor therapy and this adverse event. <h3>Conclusions</h3> Although uncommon, some side effects from checkpoint inhibitors can be severe and may need to be addressed with immunosuppression. Given the increasing frequency of immunotherapy use, awareness should be raised in regards to immune side effects and their appropriate management.

<h3>Background</h3> CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) was the first immune checkpoint receptor clinically targeted for use in cancer treatment. It is expressed exclusively on T-cells where its primary role is to regulate the amplitude of the early stages of T-cell activation.1 Ipilimumab, a CTLA-4 blocking antibody, has been widely used for the treatment of patients with high risk and metastatic melanoma. Given its mechanism of action and consequent immune activation, the side effect profile of this drug greatly differs from that of standard cytotoxic chemotherapy. Adverse events are from the most part immune-mediated, ranging from the more common, such as rash and fatigue, to the less common, such as immune endocrinopathy and colitis. <h3>Case presentation</h3> We describe a case of immune-mediated thrombotic thrombocytopenic purpura (TTP) in a 68&nbsp;year-old woman with high risk, stage III melanoma occurring after 3&nbsp;cycles of adjuvant treatment with ipilimumab as part of a clinical trial. <h3>Conclusion</h3> The range of immune-mediated adverse events during treatment with ipilimumab is wide and varied and clinicians should have a high degree of suspicion when managing these patients.

High-quality response to multiple myeloma (MM) therapy can be predictive for improved outcomes. Novel agents may improve the depth of responses and therefore prolong survival. We report on the extended follow-up of a phase II study in frontline MM of bortezomib alone and in combination with dexamethasone. Forty-nine previously untreated, symptomatic MM patients received bortezomib 1.3 mg/m(2), days 1, 4, 8, 11, for up to six 3-week cycles. High-dose dexamethasone was added for patients not reaching either a partial response after cycle 2 or a complete response (CR) after cycle 4. The overall response rate in 48 evaluable patients was 90%, with 42% achieving at least a very good partial response, of which 19% were CR/near CR. Thirty-six patients received high-dose dexamethasone with 28 (77%) showing improved response. Twenty-seven patients have undergone successful stem-cell transplantation (SCT). After median follow-up of 49 months, 15 patients have died; median overall survival has still not been reached, with an estimated survival at 4 years of 67%. Overall survival with and without SCT was not different (P = 0.54). Grade 3/4 adverse events included neutropenia (10%), sensory neuropathy (6% grade 3), neuropathic pain (4% grade 3), and diarrhoea (4% grade 3). Bortezomib +/- dexamethasone is an effective and well-tolerated induction regimen for the frontline treatment of MM.

9001 Background: Three prior phase II studies of Imatinib mesylate (IM) in 62 pts with advanced melanoma reported only 1 response in a pt with acral melanoma. A proportion of melanomas arising from acral, mucosal, and chronic sun damaged (CSD) sites are characterized by KIT mutations (mut) or amplifications (amp) and we hypothesized that this subset of tumors would be sensitive to IM. We thus designed this phase II study of IM restricted to pts with melanoma harboring such alterations in KIT. Methods: Pts with unresectable melanoma arising from acral, mucosal, and CSD sites whose tumor harbored a 4q12 amp by FISH or mut in KIT and who had measureable disease by RECIST were eligible. Pts received IM 400 mg BID continually. Response was assessed every cycle (6 wks). A Simon 2-stage design was employed where initially 16 pts would be treated; if ≥ 2 responses were observed, a total of 25 pts would be enrolled. If ≥5 responses were seen in 25 pts, the study was to be considered positive. Results: Of 81 pt tumors screened, 17 (21%) had a KITmut or amp: 5/22 (23%) acral, 12/45 (27%) mucosal, 0/13 (0%) CSD, 0/1 (0%) unknown primary. 12 (15%) had a mut only; 4 (5%) had an amplification only; 1 (2%) had both. Thus far, 7 have been treated, with 5 currently evaluable for response. Median age: 64 yrs (range, 61–86); 2 male/5 female; median KPS: 90 (range, 80- 90); median # of prior therapies: 1 (range, 0–4). 3 pts (43%) achieved a PR (18 wks - exon 13 mut; 21 wks, ongoing - exon 11 mut; 18 wks, ongoing - exon 11 mut &amp; amp); 2 pts (28%) achieved SD (12 wks - exon 11 mut; 11 wks - amp). 3 pts required a dose reduction to 400 mg QD for rash, GI toxicity and fatigue. 1 pt required a second dose reduction to 300 mg QD for visual changes. Conclusions: In this pt population, 21% of tumors are characterized by mut or amp of KIT. The 3 responses observed have allowed expansion to the second stage of enrollment which is currently on-going. While IM has limited activity in a non-selected melanoma pt population, a substantial proportion of melanomas harboring KIT mut or amp appear to respond. It may be possible to identify appropriate pts prospectively for treatment with IM. (Supported by R01FD003445–01, ASCO YIA, N01CM62206, and the Live4Life Foundation.) No significant financial relationships to disclose.

High dose interleukin-2 (HD IL-2) can induce durable responses in a subset of patients leading to long-term survival. Immune checkpoint blockade (ICB) has demonstrated similarly durable responses in a larger proportion of patients. However, not all patients respond to immune checkpoint blockade and subsequent therapeutic options need to be explored.The PROCLAIM database was queried for patients with metastatic melanoma who had received HD IL-2 after treatment with ipilimumab or without prior ICB. Patient characteristics, toxicity and efficacy were analyzed.A total of 52 metastatic melanoma patients were treated with high dose IL-2 after ipilimumab and 276 patients were treated with high dose IL-2 without prior ICB. The overall response rate in the prior ipilimumab group was 21 % as compared to 12 % in the group that had not received prior ipilimumab. The median overall survival, measured from the initiation of HD IL-2 therapy, was 19.3 months in the prior ipilimumab group and 19.4 months in the no prior ICB group. Toxicities observed on HD IL-2 were relatively equivalent between the groups although there were cases of CTLA4 antibody-induced colitis reported after HD IL-2 treatment and a CTLA4 antibody-induced colitis related death.In this retrospective analysis HD IL-2 therapy displayed antitumor activity in melanoma patients who progressed following treatment with ipilimumab. Most HD IL-2 toxicity was not worsened by prior ipilimumab therapy except for one treatment related death from colitis. Care should be taken to avoid reactivation of CTLA4 antibody-induced colitis.

9006 Background: No treatment has extended survival in stage IV melanoma. Melanomas are highly angiogenic and metastatic, express high levels of vascular endothelial growth factor receptors (VEGFRs) 2 and 3 and form vascular-like structures in vivo that may be exploited therapeutically. Axitinib is an oral, potent and selective inhibitor of VEGFRs 1, 2, 3 with preliminary evidence of clinical activity as monotherapy against similarly aggressive pro-angiogenic malignancies, such as metastatic renal cell carcinoma. Methods: 32 patients with ≤1 prior treatment for metastatic disease and ECOG PS 0–1 received single-agent axitinib at a starting dose of 5 mg BID. The primary endpoint was objective response rate (ORR) by RECIST criteria. BP was monitored regularly. Blood samples were also collected before and after therapy to explore pharmacodynamic (PD) and potential PK/PD relationships between clinical response and plasma soluble proteins. Results: The most common treatment-related adverse events (AEs) were fatigue (62.5%), hypertension (43.8%), hoarseness (34.4%), and diarrhea (31.3%). One patient experienced grade 5 bowel perforation. ORR was 15.6% (95% CI: 5.3, 32.8%) per investigator assessment with response duration ranging from 2.3 to >10.2 months. Median PFS was 2.3 months (95% CI: 1.8, 5.7). Median OS was 6.8 months (95% CI: 5.2, 10.4; range 0.8->22.6 months). The median OS of patients experiencing dBP ≥ 90 mm Hg on axitinib therapy was 13.0 months (n=13) vs 6.2 months for those with dBP < 90 mm Hg (n= 9). Furthermore, axitinib therapy selectively decreased soluble VEGFR2 and VEGFR3 (vs sKIT), and increased VEGF in the blood, demonstrating PD activity against the targeted VEGF receptors. The study of PK/PD relationships is ongoing. Conclusions: Axitinib has demonstrable single-agent activity in melanoma. Preliminary analyses indicate that patients who achieve elevated dBP ≥ 90 mm Hg on therapy have longer survival associated with potent and selective inhibition of targeted VEGFRs. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology Bayer, Genentech™ BioOncology, Novartis, Pfizer Oncology, Wyeth Pfizer Oncology Novartis, Pfizer Oncology Bayer, Bristol-Myers Squibb, Genentech™ BioOncology, Novartis, Pfizer Oncology, Wyeth

9034 Background: The monoclonal antibody ipilimumab targets cytotoxic T-lymphocyte antigen-4. The most common AEs associated with ipilimumab are irAEs, and both antitumor and irAE responses likely reflect its immune-mediated mechanism of action. In this report, a potential association between disease control (DC) or overall survival (OS) and irAEs in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in 3 Phase II clinical trials was explored. Methods: Across 3 Phase II studies (CA184008, 022, and 007), ipilimumab (10 mg/kg) was given every 3 weeks (Q3W) x 4 (induction); eligible pts could continue to receive ipilimumab Q12W starting at week (wk) 24 (maintenance). In study 022, pts were randomized to 0.3, 3, and 10 mg/kg groups, whereas study 008 was a single-arm trial of ipilimumab 10 mg/kg. In study 007, ipilimumab 10 mg/kg was administered either with placebo or daily prophylactic budesonide. Disease control (CR/PR/SD) was evaluated using modified World Health Organization (mWHO) and immune- related response criteria (Hodi FS, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 3008). Association between DC and grade 0/1 vs. grade ≥2 irAEs was examined (studies 007, 008, and 022). Association between OS and irAEs which developed within 12 wks of ipilimumab treatment was also explored using landmark analyses from Day 81 (studies 008 and 022). Results: Across the 3 phase II studies, the rate of DC by mWHO in pts with grade 0/1 irAEs was 20–24% and in pts with grade ≥2 irAEs was 34–43%. The number of pts with DC was higher among those who experienced an irAE compared with those who did not, but DC was not statistically significantly associated with grade 0/1 vs grade ≥2 irAEs. For pts who lived up to Day 81 in studies 008 and 022, median OS (95% CI) from Day 81 was 14.8 mo (10.0–21.7) for any irAE and 8.21 mo (5.29–13.7) for no irAE within 12 weeks; median OS was 13.6 mo (5.78-NR) for any grade ≥2 irAE and 11.3 mo (7.95–15.8) for no grade ≥2 irAE within 12 weeks. Conclusions: DC and survival benefits with ipilimumab are observed among pts that develop an irAE and among pts that do not develop an irAE. Thus, pts who do not experience an irAE may still demonstrate clinical benefit with ipilimumab. [Table: see text]

<h2>Abstract</h2><h3>Background</h3> This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2). <h3>Patients and Methods</h3> Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin^R Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIM^SM) beginning in 2011. Statistical analyses were performed using datasets as of September 24, 2015. <h3>Results</h3> Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2. <h3>Conclusions</h3> HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients.

Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal tumors in patients with melanoma recurrence following surgery. We aim to describe the safety of talimogene laherparepvec. Intralesional talimogene laherparepvec was administered at less than or equal to 4 ml×10 PFU/ml at protocol day 1, then less than or equal to 4 ml×10 PFU/ml 21 days later, and then every 14 days. Treatment continued until complete response, absence of injectable tumors, progressive disease, intolerance, or US Food and Drug Administration approval. Adverse events were graded during and 30 days after the end of treatment. Lesions suspected to have herpetic origin were tested for talimogene laherparepvec DNA by quantitative PCR (qPCR). Between September 2014 and October 2015, 41 patients were enrolled with stage IIIB (22%), IIIC (37%), IVM1a (34%), IVM1b (5%), and IVM1c (2%) melanoma. The median age was 72 (range: 32-96) years and 54% of the patients were men. Patients had an ECOG performance status of 0 (68%) or 1 (32%). The median treatment duration was 13.1 (3.0-41.1) weeks. Treatment-related adverse events of greater than or equal to grade 3 were reported in three (7.3%) patients and included vomiting, upper abdominal pain, chills, hyperhidrosis, nausea, pyrexia, and wound infection. Suspected herpetic lesions were swabbed in five (12%) patients. One of the five tested positive for talimogene laherparepvec DNA by qPCR, but this lesion had been injected previously with talimogene laherparepvec. During the study, five patients completed treatment because of complete response per investigators. In the clinical practice setting, talimogene laherparepvec has a safety profile comparable to that observed in previous clinical trials. Talimogene laherparepvec (IMLYGIC) is now approved in the US, European Union, and Australia.

Abstract: This is a unique report of two cases of patients with end-stage renal disease on hemodialysis, receiving ipilimumab for treatment of metastatic melanoma, as there is a paucity of safety and efficacy data in this patient subgroup. Keywords: report of cases, hemodialysis, advanced melanoma

Purpose Biochemotherapy improves responses in metastatic melanoma, but not overall survival, in randomized trials. We developed a maintenance biotherapy regimen after induction biochemotherapy in an attempt to improve durability of responses and overall survival. Patients and Methods One hundred thirty-three chemotherapy-naïve patients with metastatic melanoma without CNS metastases were treated at 10 melanoma centers. The biochemotherapy induction regimen included cisplatin, vinblastine, dacarbazine, decrescendo interleukin-2 (IL-2), and interferon alfa-2b with granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine support. Patients not experiencing disease progression were eligible for maintenance biotherapy with low-dose IL-2 and GM-CSF followed by intermittent pulses of decrescendo IL-2 over 12 months. Patients were observed for response, progression-free survival, toxicity, and overall survival. Results The response rate to induction biochemotherapy was 44% (95% CI, 35% to 52%; complete response, 8%; partial response, 36%; stable disease, 29%). The median number of biochemotherapy cycles was four, and the median number of maintenance biotherapy cycles was five. The median progression-free survival was 9 months, and the median survival was 13.5 months. The 12-month and 24-month survival rates were 57% and 23%, respectively. Twenty percent of patients remain alive (12 without disease), with median follow-up of 30 months (95% CI, 25+ to 45+ months). Thirty-nine percent of patients developed CNS metastases. The median times to CNS progression and death were 8 months and 5 months, respectively. Conclusion Maintenance biotherapy after induction biochemotherapy seems to prolong progression-free survival and improve overall survival compared with recent multicenter trials of biochemotherapy or chemotherapy. The regimen should be studied in a randomized clinical trial in patients with advanced metastatic melanoma. CNS progression remains a formidable challenge.

9025 Background: Ipilimumab is a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Data from a phase II study showed that patients with previously treated advanced melanoma had proportionately more complete/partial responses (CR/PR) and stable disease (SD) with ipilimumab induction 10 mg/kg every 3 weeks (Q3W) X 4 compared with lower doses using the same schedule. Methods: In this randomized, double-blind, multicenter, phase II trial, patients with unresectable stage III/IV melanoma who had progressive disease (PD) on or were intolerant to prior therapies received ipilimumab induction dosing at 0.3, 3, or 10 mg/kg Q3W X 4. Eligible patients received maintenance therapy Q12W starting at Week 24 at their assigned blinded dose. Patients with PD could cross over to open-label ipilimumab 10 mg/kg induction plus maintenance in another study. The primary endpoint was the best overall response rate (BORR [CR or PR]). Efficacy was measured with modified World Health Organization (mWHO) criteria. Per protocol, tumor evaluation after PD by mWHO (ie, an overall > 25% increase in measurable tumor burden) before treatment with non-ipilimumab neoplastic therapy was permitted. Results: There were 217 patients treated. There was a statistically significant trend indicating an increase in BORR with increasing dose (p = 0.0015). The difference in BORR between 10 and 0.3 mg/kg was 11.2% [95% CI, 3.9 - 18.5]. Rates of immune-related adverse events (irAEs) increased with increasing dose. Conclusions: These data favor 10 mg/kg as the optimal dose. 0.3 mg/kg appears to be clinically ineffective. Follow-up for patients is ongoing. Ipilimumab dose (mg/kg) 10 (n = 72) 3 (n = 72) 0.3 (n = 73) BORR - % [95% CI] CR - n 11.1 [4.9 - 20.7] 2 4.2 [0.9 - 11.7] 0 0 [0.0 - 4.9] 0 Disease control rate (DCR = PR + CR + SD) - % [95% CI] 29.2 [19.0 - 41.1] 26.4 [16.7 - 38.1] 13.7 [6.8 - 23.8] Any irAE - % 70.4 64.8 26.4 Grade 3/4 irAE - % Any 25.4 7.0 Gastrointestinal 15.5 2.8 0 Hepatobiliary 2.8 0 0 Endocrine 1.4 2.8 0 Skin 4.2 1.4 0 Bowel perforations - % 0 0 0 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb

Journal Article Nodular Bleomycin Toxicity Get access Michael B. Cohen, M.D., Michael B. Cohen, M.D. Departments of Pathology, Radiology, and Medicine, College of Physicians and Surgeons of Columbia University, New York, New York Search for other works by this author on: Oxford Academic Google Scholar John H. M. Austin, M.D., John H. M. Austin, M.D. Departments of Pathology, Radiology, and Medicine, College of Physicians and Surgeons of Columbia University, New York, New York Search for other works by this author on: Oxford Academic Google Scholar Alison Smith-Vaniz, M.D., Alison Smith-Vaniz, M.D. Departments of Pathology, Radiology, and Medicine, College of Physicians and Surgeons of Columbia University, New York, New York Search for other works by this author on: Oxford Academic Google Scholar Jose Lutzky, M.D., Jose Lutzky, M.D. Departments of Pathology, Radiology, and Medicine, College of Physicians and Surgeons of Columbia University, New York, New York Search for other works by this author on: Oxford Academic Google Scholar Margaret M. Grimes, M.D. Margaret M. Grimes, M.D. Departments of Pathology, Radiology, and Medicine, College of Physicians and Surgeons of Columbia University, New York, New York Search for other works by this author on: Oxford Academic Google Scholar American Journal of Clinical Pathology, Volume 92, Issue 1, 1 July 1989, Pages 101–104, https://doi.org/10.1093/ajcp/92.1.101 Published: 01 July 1989 Article history Received: 05 August 1988 Accepted: 29 August 1988 Published: 01 July 1989

In order to determine whether imatinib mesylate (Gleevec), a tyrosine kinase inhibitor that binds the CD-117 (c-kit) receptor, may be of value in the treatment of malignant melanoma, an immunohistochemical analysis of 40 cases of primary and metastatic melanoma was undertaken. Thirty-five of the 40 cases showed 1+ or stronger labelling for CD-117 (up to a maximum of 4+). Three patients with neoplasms showing 4+ staining were selected for imatinib therapy. None responded. c-kit (CD-117) expression in melanoma appears to be common; however, the value of imatinib therapy remains to be proven.

CRA9003 Background: Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012). Methods: We conducted a 16 center randomized phase II study of hyd-sulfate sel 75 mg BID vs TMZ 150 mg/m 2 daily for 5 days in 28-day cycles (or DTIC 1000 mg/m 2 q21 days) for patients (pts) with metastatic UM with a Q209 Gq/11 mut who have not received prior TMZ/DTIC. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall survival (OS) and response rate (RR). Select pts underwent tumor biopsies at baseline and after 14 (+/- 3 days) of sel. Our statistical plan required ≥80 pts randomized and ≥68 events to detect a PFS hazard ratio of 0.6 (p=0.1). Randomization was stratified by mut (Gq vs G11), M stage and number of prior therapies (tx). Tumor assessment occurred every 4 weeks (wks) for 8 wks and then every 8 wks using RECIST 1.1. Pts receiving TMZ who progressed could receive sel (TMZ→sel). Results: 80 pts were randomized. Sel (n=39): median age 66 (range 32-86), 54% male, 54% G11 mut, median ECOG PS 0 (range 0-1), 97% M1c, median prior tx 0 (range 0-2). TMZ (n=41): median age 60 (range 34-81), 63% male, 58% G11 mut, median ECOG PS 0 (range 0-1), 93% M1c, median prior tx 0 (range 0-2). 11/39 (28%) pts on sel experienced grade (gr) 3 toxicity (tox) manageable with dose modification (5 CPK elevation, 3 LFT elevation, 1 rash, 1 lymphopenia, 1 edema). 1/41 (2%) pt on TMZ experienced gr 3 tox (neutropenia). No gr 4/5 tox occurred. 28 pts on sel underwent paired tumor biopsies with inhibition of pERK and cyclinD1 observed by Western blot at day 14. At interim analysis (9/25/12), 55 pts were evaluable with 45 progression events and 16 deaths. Sel (n=27): median PFS 16 wks (95% CI 8-30.9), RR 11%, median OS 11.8 months (95% CI 4.8-not reached). TMZ (n=28): median PFS 4 wks (95% CI 3.7-15), RR 0%, median OS 4.7 months (95% CI 4.3-14.3). TMZ→sel (n=25): median PFS 8.1 wks (95% CI 7-15), RR 0%. Conclusions: Sel is the first drug to ever show improved clinical activity in UM relative to TMZ. Sustained target inhibition is observed with sel. Final results will be presented. Clinical trial information: NCT01143402.

No standard of care therapy exists for patients with metastatic uveal melanoma who are not HLA-A2:01 positive. The phase 1b, open-label CLEVER study (NCT03408587) evaluated V937 in combination with ipilimumab in patients with uveal melanoma.Adults with advanced uveal melanoma and liver metastases received up to 8 cycles of intravenous V937 (1 × 109 TCID50 per infusion; infusions on days 1, 3, 5, and 8 [cycle 1], then every 3 weeks [Q3W] thereafter [cycles 2-8]) and 4 cycles of intravenous ipilimumab 3 mg/kg Q3W (beginning at cycle 1 day 8). The primary endpoint was safety. Secondary endpoints included objective response rate and progression-free survival (PFS) per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).Eleven patients were enrolled (median age, 65.0 years) and received a median of 6 injections of V937 and 3.5 infusions of ipilimumab. The best overall response was stable disease in 3 patients and progressive disease in 8 patients. All patients exhibited progression per irRECIST, with a 9% irPFS rate at week 26. Ten patients had treatment-related AEs, the most frequent of which were diarrhea (55%), fatigue (45%), and myalgia (36%). Two grade 3 AEs (diarrhea, n = 2) were considered related to ipilimumab; neither was related to V937.Although the combination of V937 with ipilimumab had a manageable safety profile, meaningful clinical benefit was not observed in patients with uveal melanoma and liver metastases.ClinicalTrials.gov, NCT03408587 (January 24, 2018).

During the past 3 decades, the incidence, morbidity, and mortality of malignant melanoma have increased dramatically. Advanced melanoma has remained a disease that is for the most part incurable and has challenged all therapeutic efforts to make a dent in its natural history. Recent advances in the understanding of the molecular alterations in melanoma and in the immunologic mechanisms playing a role in this malignancy have brought hope that significant progress can be achieved, as evidenced by early encouraging clinical data. This review will summarize these recent developments and their impact on current clinical practice.

Background: Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation.Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach.We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes.Methods: Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma.Cohort 1 was treatment naïve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2.Cohort 2 received vemurafenib for 7-18 weeks before enrollment.Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1-5 and days 15-19.The primary objective was to assess complete responses (CR) at 10 weeks ±3 (assessment 1) and 26 weeks ±3 (assessment 2) from the start of HD IL-2.Results: Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15).Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3-24) for both cohorts combined, and 27% (95% CI 8-55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively.No unexpected toxicities occurred.A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure.Conclusions: Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent.Lower than expected response rates to vemurafenib were observed.Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.

Background Basal cell carcinoma (BCC) is the most common malignancy worldwide, yet the management of patients with advanced or metastatic disease is challenging, with limited treatment options. Recently, programmed death receptor 1 (PD-1) inhibition has demonstrated activity in BCC after prior Hedgehog inhibitor treatment. Methods We conducted a multicenter, retrospective analysis of BCC patients treated with PD-1 inhibitor therapy. We examined the efficacy and safety of PD-1 therapy, as well as clinical and pathological variables in association with outcomes. Progression-free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated using Kaplan-Meier methodology. Toxicity was graded per Common Terminology Criteria for Adverse Events V.5.0. Results A total of 29 patients with BCC who were treated with PD-1 inhibition were included for analysis, including 20 (69.0%) with locally advanced and 9 (31.0%) with metastatic disease. The objective response rate was 31.0%, with five partial responses (17.2%), and four complete responses (13.8%). Nine patients had stable disease (31.0%), with a disease control rate of 62.1%. The median DOR was not reached. Median PFS was 12.2 months (95% CI 0.0 to 27.4). Median OS was 32.4 months (95% CI 18.1 to 46.7). Two patients (6.9%) developed grade 3 or higher toxicity, while four patients (13.8%) discontinued PD-1 inhibition because of toxicity. Higher platelets (p=0.022) and any grade toxicity (p=0.024) were significantly associated with disease control rate. Conclusions The clinical efficacy of PD-1 inhibition among patients with advanced or metastatic BCC in this real-world cohort were comparable to published trial data. Further investigation of PD-1 inhibition is needed to define its optimal role for patients with this disease.

This phase 1 study evaluated the safety and tolerability of adjuvant treatment with subcutaneous granulocyte macrophage colony-stimulating factor (GM-CSF) administered in combination with escalating doses of thalidomide in patients with surgically resected stage II (T4), III, or IV melanoma at high risk for recurrence. Adjuvant treatment included GM-CSF 125 μg/m2 subcutaneously for 14 days and thalidomide at an initial dose of 50 mg/d, escalated in cohorts of 3 to 6 patients each to a maximum of 400 mg/d followed by 14 days of rest. Treatment was continued for up to 1 year in the absence of disease progression. Of 19 patients treated, the most common toxicities were grade 1/2 constipation (68%), fatigue (58%), neuropathy (42%), bone and joint pain (37%), and dyspnea, dizziness, injection site skin reaction, and somnolence (32% each). Thrombotic events in 3 of 19 patients (16%), including 1 treatment-related death, were the most serious adverse events and were thought to be due to thalidomide. With a median follow-up of 945 days (2.6 y), 8 (42%) patients were alive, including 1 with disease and 7 without evidence of disease. GM-CSF plus thalidomide as adjuvant therapy for patients with resected high-risk melanoma was associated with a high incidence of thrombotic events. Because life-threatening events are unacceptable in the adjuvant setting, up-front antithrombotic prophylaxis will be necessary for further evaluation of GM-CSF plus thalidomide as a viable regimen in this patient group.

Introduction. Despite its low incidence, acquired factor VIII inhibitor is the most common autoantibody affecting the clotting cascade. The exact mechanism of acquisition remains unclear, but postpartum patients, those with autoimmune conditions or malignancies, and those with exposure to particular drugs appear most susceptible. There have been several case reports describing acquired FVIII inhibitors in patients receiving interferon alpha for HCV treatment and in patients being treated for HIV. To our knowledge, this is the first case of a patient with HCV and HIV who was not actively receiving treatment for either condition. Case Presentation. A 57-year-old Caucasian male with a history of HIV and HCV was admitted to our hospital for a several day history of progressively worsening right thigh bruising and generalized weakness. CTA of the abdominal arteries revealed large bilateral retroperitoneal hematomas. Laboratory studies revealed the presence of a high titer FVIII inhibitor. Conclusion. Our case of a very rare condition highlights the importance of recognizing and understanding the diagnosis of acquired FVIII inhibitor. Laboratory research and clinical data on the role of newer agents are needed in order to better characterize disease pathogenesis, disease associations, genetic markers, and optimal disease management.

Malignant melanoma remains a difficult clinical problem. Chemotherapy is not effective and immunotherapy has long been contemplated as the preferred approach to this disease. Extensive passive and active immunotherapy trials have been conducted. Active vaccination with whole cells or defined antigens, administered with a panoply of techniques to increase immunogenicity, has yielded inconsistent results. The development of antibody-based vaccines has allowed vaccination without the need for tumor tissue material or purified antigens. The idiotype network theory originally proposed by Lindemann and by Jerne provided the basis for the development of anti-idiotype (anti-Id) antibody vaccines, which mimic the internal image of the epitope targeted for immunization. Preclinical and phase I clinical data are available for various malignancies. In melanoma, some of the anti-Id vaccines have targeted gangliosides. One of these vaccines, TriGem, has been successful in generating a robust and specific humoral immunity in melanoma patients. Phase II data suggest this anti-Id vaccine has clinical activity. Semin Oncol 29:462-470. Copyright 2002, Elsevier Science (USA). All rights reserved.

In autologous bone marrow transplantation in patients with acute myeloid leukemia (AML), 4-hydroperoxycyclophosphamide (4-HC) is a commonly used ex vivo purging agent for leukemic blasts. In the present report, we demonstrate that exposure to high concentrations of 4-HC for 1 hour, as used in ex vivo bone marrow purging, produces internucleosomal DNA fragmentation characteristic of apoptosis, or programmed cell death (PCD), in human myeloid leukemia HL60 cells. Lower concentrations of 4-HC (10, 20, or 50 microM/L) failed to cause this effect, while higher concentrations (> or = 200 microM/L) produced random DNA fragmentation. 4-HC-mediated internucleosomal DNA fragmentation was associated with a marked induction in c-jun and significant reductions in bcl-2 and c-myc oncogene expressions. A combined treatment with interleukin-3 (IL-3) plus IL-6 for 18 hours before an additional, 1-hour concurrent treatment with 4-HC (100 microM/L) significantly increased 4-HC-induced DNA fragmentation as well as colony growth inhibition of HL60 cells. The effects of cotreatment with IL-3 plus IL-6 were also associated with a further, modest decrease in bcl-2 and c-myc and augmentation of c-jun expression. These findings highlight an alternative mechanism of 4-HC-induced leukemic cell death that can be potentially enhanced by cotreatment with IL-3 plus IL-6.

7543 Background: Allovectin-7, a bicistronic plasmid formulated with a cationic lipid system and encoding HLA-B7 and β-2 microglobulin, is an immunotherapeutic designed to induce a pro-inflammatory response and express allogenic MHC-class I antigen upon intralesional administration. Methods: We have conducted a Phase 2 dose-escalation trial to evaluate the safety and efficacy of Allovectin-7 in patients with metastatic melanoma. Eligible patients had stage III or IV metastatic melanoma recurrent or unresponsive to prior therapy; injectable lesion(s); ECOG PS 0–1 and adequate organ function. Patients with brain or visceral (except lung) metastases, abnormal LDH, or any lesion ≥100 cm2 were excluded. Patients with 2 or more injectable lesions were randomized to receive injections of 2 mg Allovectin-7 divided for injection for up to 5 lesions. Patients received weekly intratumoral injections of a total of 2 mg of Allovectin-7 for 6 weeks followed by 3 weeks of observation and evaluation. Overall Response (OR) was assessed using RECIST guidelines two weeks following the last injection of each cycle. Patients with stable or responding disease received additional cycles of Allovectin-7. Results: Final, audited data are presented for the 133 patients enrolled. All patients were evaluated for safety (6 patients in the dose-escalation stage and 127 patients in the 2 mg efficacy stage), and 127 patients were evaluated for efficacy. Fifteen patients (11.8%, 95% CI: 6.2–17.4) achieved an objective response lasting a median duration of 12.7 months (95% CI: 8.3 - ongoing). The responders include two patients who had lesions resected and found no evidence of melanoma. Median time to progression was 1.6 months and median overall survival was 21.3 months (95% CI: 14.8–33.4). There were no reported Grade 3 or Grade 4 adverse events associated with Allovectin-7. Conclusions: Results indicate that high-dose Allovectin-7 is an active, well-tolerated treatment for Stage III/IV metastatic melanoma patients with injectable cutaneous, subcutaneous, or nodal lesions. The details of the Phase 3, follow-up clinical trial design will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Vical Vical

Advanced malignant melanoma has historically been considered a uniformly lethal disease. Recent scientific strides have led to unprecedented understanding of both the molecular alterations and the mechanisms of immune evasion in this malignancy. The realization that an intense and dynamic interplay of stimulatory and inhibitory signals occurs in the "immune synapses" among T cells, tumor cells and dendritic cells, led to the development and subsequent clinical testing of agonist and antagonist monoclonal antibodies (mAb) that can modulate these signals. The resulting positive outcomes of the clinical trials utilizing CTLA-4, PD-1 and PD-L1 modulating drugs, has catapulted the field of immunotherapy into the realm of standard treatment. In this article we review the most important agents and clinical data feeding the ongoing paradigm change in the treatment of advanced melanoma.

gpNMB is an internalizable transmembrane glycoprotein expressed in multiple tumor types including melanoma. The ADC GV (CDX-011) delivers the potent cytotoxin MMAE to gpNMB+ cells. GV has shown promising activity in advanced melanoma and breast cancer (Ott JCO 2014; Yardley JCO 2015). In this Phase 2 single-arm study (CDX011-05), efficacy and safety of GV (1.9 mg/kg q3w) is assessed in advanced melanoma patients (pts) with disease progression after ≤1 chemotherapy, ≥1 checkpoint inhibitor, and if BRAF mutation ≥1 BRAF or MEK + BRAF inhibitor. gpNMB expression is determined retrospectively by central IHC on archival tumor and/or pre-treatment tumor biopsy. Primary endpoint is objective response rate (ORR) (RECIST 1.1) with ≥6 responders out of 52 evaluable pts as threshold for determining statistical positive outcome. Additional endpoints include progression free survival and overall survival (PFS, OS) (95% CI), duration of response (DOR), safety, pharmacodynamics, pharmacokinetics, and correlation of outcome with gpNMB expression. Enrollment (n = 62) completed in April 2016: median age = 67 years; 55% male; 21% BRAF mutation; 53% >2 lines prior therapy. Preliminary tumor response data (n = 57 evaluable; 5 pts pending 1st response assessment): 1 complete response (CR) and 7 partial response (PR [current confirmed ORR = 14%]); 1 single time-point PR; 26 stable disease (SD) (duration 6-51+ weeks, 11 ongoing). Thus far, 50/51 evaluable pts had gpNMB+ tumors, and 38/51 had 100% of epithelial cells gpNMB+. Toxicities include rash, alopecia, fatigue, neuropathy, nausea, neutropenia, decreased appetite and diarrhea; rash may correlate with efficacy. GV has shown promising activity including induction of partial and complete responses in patients with heavily pre-treated melanoma. The safety profile is manageable and consistent with cytotoxic treatment. DOR, PFS, OS, and correlation of biomarkers with outcome will be analyzed on the mature dataset. An additional cohort will be treated with GV in combination with varlilumab, an activating anti-CD27 monoclonal antibody, in order to evaluate safety and efficacy of the combination.

8002 Background: Vitespen (Oncophage; formerly HSPPC-96) is an autologous, tumor-derived, heat shock protein (gp96)-peptide complex vaccine that has shown signals of clinical activity in patients (pts) with metastatic melanoma, and colon and renal cancers. Methods: This phase 3 trial compares vitespen v. PC in AJCC stage IV melanoma. Pts had ECOG PS 0/1 and ≥7 g tumor tissue for vaccine production. Randomization was 2:1 favoring vitespen, and stratified by ECOG PS and AJCC substage (M1a, -b, -c). Vitespen was administered s.c. weekly for 4 weeks, then biweekly until vaccine depletion or disease progression (DP). PC treatment was any regimen including IL-2 and/or dacarbazine/temozolomide and/or tumor resection. Pts were evaluated every 3 months for 1st year, every 6 months for 2nd year, then annually until DP. Primary endpoint was overall survival (OS). OS data, based on ITT, were analyzed using 1-sided log-rank tests. Results: From Jan 2002-Sept 2004, 322 pts at 76 centers (US, Europe, Russia/Ukraine, Australia) were enrolled. 215 pts were randomized to vitespen, 107 pts to PC. Mean age was 55 y; 59% were male; ECOG was 0 in 71% of pts; 19% of pts were M1a, 24% M1b, 57% M1c. 62% of pts in vaccine arm received vitespen; median number of vaccines was 6 (range, 0–74). As of Sept 2005, 18 pts were in tumor evaluation phase, 53 in survival follow-up, 251 off-study (death, withdrew consent, lost to follow-up). Median follow-up time for vaccine and PC arms was 250 and 289 d, respectively. Estimated median survival for vaccine and PC arms was 281 and 322 d, respectively (P = .078). M1a pts in the vaccine arm survived longer than those in the PC arm (626 v. 383 d, P = .177). Survival was comparable in both arms for M1b pts (297 v. 320 d, P = .478), and longer in the PC arm for M1c pts (299 v. 226 d, P = .015). Impact of number of doses was examined using landmark analyses to correct potential biases. Pts who received ≥10 doses of vaccine survived longer than those who received PC (377 v. 478 d, P = .072). Conclusions: Vitespen confers qualitative survival benefit over PC for M1a melanoma pts. If 10 doses of vaccine can be administered, vitespen also appears to confer survival benefit over PC for M1b pts. A phase 3 trial evaluating vitespen in M1a and M1b pts is planned. [Table: see text]

The intracellular metabolism and cytotoxic effects of Ara-C and 2′-difluorodeoxycytidine (dFdC or Gemcitabine) administered with or without deoxycytidine (dCyd) were examined in cisplatin-resistant (2008/C13) and -sensitive (2008) human ovarian cystadenocarcinoma cells. Compared to 2008 cells, 2008/C13 cells possess 2.1-fold higher glutathione (GSH) levels, enhanced expressions of GSH S-transferase (GST)-π mRNA and protein, and significantly greater activity of GST, GSH peroxidase, and GST reductase. Although 2008/C13 cells were slightly cross-resistant to 4-hydroperoxycyclophosphamide, the drug displayed a steep dose-response (colony growth inhibition) effect toward these cells. 2008/C13 cells expressed greater sensitivity toward Ara-C and Gemcitabine. This was associated with intracellular Ara-CTP and dFdCtriphosphate levels in 2008/C13 significantly higher than those in 2008 cells. Against bone marrow progenitor cells, the cytotoxic effects of submicromolar levels of Ara-C or dFdC, produced in plasma following intraperitoneal administration of the drugs, were significantly reversed by cotreatment with high levels of dCyd achieved in plasma following intravenous administration. In contrast, the metabolism and cytotoxic effects of Ara-C and dFdC in 2008 and 2008/C13 cells were not significantly altered by dCyd concentrations that are reached in the peritoneum following intravenous administration. These in vitro data suggest that systematically administered dCyd might protect bone marrow progenitor cells against Ara-C cytotoxicity without impairing antitumor activity of intraperitoneal Ara-C.

Importance of the field: Immunotherapy for cancer has been investigated for several decades, achieving limited success. The development of effective new immunotherapeutic agents has reignited interest in the filed. Intralesional injection of plasmids in order to transfect genes capable of stimulating or augmenting immune recognition and destruction of tumors is a relatively new approach.Areas covered in this review: Our objective is to discuss the role velimogene aliplasmid (Allovectin-7®, Vical Incorporated), a plasmid–lipid complex containing the DNA sequences encoding HLA-B7 and β2 microglobulin, as an immunotherapeutic agent.What the reader will gain: Intralesional velimogene aliplasmid induces anti-tumor responses in a proportion of melanoma patients with locoregional and limited distant metastases. Preclinical data and the results of Phase I, II and III clinical trials with this drug are reviewed. The limited data in other malignancies is also reviewed. Velimogene aliplasmid in humans appears safe, with minimal drug-related adverse events.Take home message: Velimogene aliplasmid has activity in melanoma with local and limited distant disease associated with an excellent safety profile. The activity of this approach is also being investigated in other malignancies.

18016 Background: Oxaliplatin is a platinum derivative without nephrotoxicity with in vitro activity against human melanoma cell lines. (Mohammed, MQ, 2000; Tashiro, T, 1989). A Phase I trial suggested activity in melanoma (Mathe, G, 1986) but Phase II data is lacking. A non-nephrotoxic platinum compound active in melanoma is of interest in the development of combination chemo-or chemoimmunotherapy. Methods: This was a Phase II prospective study of oxaliplatin in patients with previously treated or refractory advanced melanoma. The primary endpoint was to evaluate the response rate, survival, freedom from progression (FFP) and the tolerability of oxaliplatin in this patient population. Key inclusion criteria were: metastatic (stage IV) or unresectable malignant melanoma progressing following treatment with at least one and at most three chemotherapy regimens. ECOG PS 0–2, measurable disease and adequate organ and marrow function were required. Oxaliplatin 130 mg/m 2 was given IV in 250–500 mL D5W over 120 minutes every 21 days for at least 2 cycles. Patients were evaluated for response every 2 cycles. Gehan’s two-stage design was utilized. Results: Ten patients were treated between March 2004 and March 2005. Three patients were female and 3 male with a median age of 62.5 years. All patients had PS 0–1. The median number of cycles was 2 (1–6). Three patients had disease stabilization (SD) for median of 3 months. No objective responses were seen; therefore, the study did not progress to the second stage.All patients have progressed and all have expired but one. Median survival from registration was 168 days (128–383). Toxicities included grade 2 fatigue (2 pts) and grade 2 neuropathy (3 pts); one patient had grade 3 diarrhea. Conclusions: Treatment with oxaliplatin in previously treated patients with melanoma is well tolerated at the dose and schedule studied but did not result in objective responses and further development in this population cannot be recommended. Incorporation into combination regimens in previously untreated patients may be of interest. No significant financial relationships to disclose.

7503 Background: BCT improves responses in MM but survival benefit remains disappointing. We developed a novel MBT regimen following induction BCT to improve survival. (CCR 8(9):2775, 2002) Methods: In this multi-center trial, MBT was given to non-progressing pts following induction BCT with decrescendo IL-2 (JCO 17(9):2752, 1999). The 12 mo. MBT (28 d cycle) regimen consisted of low dose IL-2 (2 MIU sq d1–5, 8–12, 15–19, 22–26) and GM-CSF (250 mcg sq d1–14) combined with pulses of high dose decrescendo IL-2 (18 MIU/m2 IV over first 6 hrs, 18 MIU/m2 IV over next 12 hrs and 18 MIU/m2 IV over final 24 hrs) mos 1–6, 8, 10, 12. OS and TTP were primary and secondary endpoints respectively. Results: 133 pts were evaluable. 12% of pts were M1a, 20% M1b, and 68% M1c. ECOG 0, 1 were 71% and 24%. 35% failed high dose adjuvant interferon. The median number of BCT cycles and MBT cycles were 4 and 5. Response to BCT was 8% CR, 36% PR, 29% SD and 27% PD. 4 pts had response to MBT (3 PR to CR, 1 SD to PR). 5 pts (3 PR and 2 SD) underwent complete resection of residual disease. The median TTP and OS were 9 (7.8–12.0) and 14 mos (11.5–15.4) respectively. The 12 and 24 mo. survivals were 57% and 23%. 20% of pts remain alive and 12% are NED with median follow-up 30 mos. 52 pts (39%) developed CNS progression. 21 of these (40%), CNS was the only site or first site of progression. The median CNS TTP and subsequent survival was 8 and 5 mos. Conclusions: MBT post induction BCT appears to prolong TTP and improve OS compared to multi-center trials of BCT or chemotherapy. CNS progression remains a formidable challenge. A new trial incorporating CNS consolidation into this BCT, MBT sequential regimen is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Berlex, Chiron, Chiron Biopharma Cefus (Europe) Chiron, Chiron Biopharma, Schering, Schering Oncology Berlex, Chiron, Chiron Biopharma, John Wayne Cancer Center, John Wayne Cancer Institute, Schering Oncology Chiron

&lt;p&gt;Supplemental Table 1. Adverse events observed and adjudicated as possibly, probably or definitely related to therapy (n = 19).&lt;/p&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%–56%] and 1 on cohort B (12.5%; 90% CI, 0.6%–47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%–47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1–3.9 months) and 9.1 months (90% CI, 4.3–14.2 months), respectively, in all treated patients.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited. &lt;i&gt;Clin Cancer Res; 21(10); 2289–96. ©2015 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%–56%] and 1 on cohort B (12.5%; 90% CI, 0.6%–47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%–47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1–3.9 months) and 9.1 months (90% CI, 4.3–14.2 months), respectively, in all treated patients.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited. &lt;i&gt;Clin Cancer Res; 21(10); 2289–96. ©2015 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;p&gt;Supplemental Table 1. Adverse events observed and adjudicated as possibly, probably or definitely related to therapy (n = 19).&lt;/p&gt;

&lt;p&gt;DATA SUPPLEMENT Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238&lt;/p&gt;

&lt;p&gt;DATA SUPPLEMENT Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238&lt;/p&gt;

&lt;div&gt;AbstractPurpose:&lt;p&gt;In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings.&lt;/p&gt;Patients and Methods:&lt;p&gt;Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS.&lt;/p&gt;Results:&lt;p&gt;At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60–0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8&lt;sup&gt;+&lt;/sup&gt; T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value.&lt;/p&gt;Conclusions:&lt;p&gt;Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-1194" target="_blank"&gt;See related commentary by Augustin and Luke, p. 3253&lt;/a&gt;&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;AbstractPurpose:&lt;p&gt;In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings.&lt;/p&gt;Patients and Methods:&lt;p&gt;Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS.&lt;/p&gt;Results:&lt;p&gt;At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60–0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8&lt;sup&gt;+&lt;/sup&gt; T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value.&lt;/p&gt;Conclusions:&lt;p&gt;Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome.&lt;/p&gt;&lt;/div&gt;

9511 Background: Standard MAPK-targeted therapy (tx) for pts with BRAF MT MM involves combined BRAF and MEK inhibition with high efficacy in advanced melanoma, but durability of response is limited by acquired resistance. One combination, dabrafenib and trametinib (DT), was shown to be less effective in the frontline setting than combined immune checkpoint inhibition (ICI) but did achieve a 48% objective response rate (ORR) after ICI. (Atkins et al., JCO 2022) Preclinical data show that targeting mediators of apoptosis improves response and survival with BRAF-targeted tx. Navitoclax (N) is a BH3-mimetic that inhibits BCL-2, BCL-xL, and BCL-W. We previously demonstrated the safety of DTN in patients with BRAF MT solid tumors in a phase I trial. This randomized phase II study compared DTN to DT. (NCT01989585). Methods: Pts with BRAF MT MM were randomized 1:1 to either DT (standard dosing D 150 mg BID and T 2 mg QD) or DTN (standard DT plus N 225 mg QD) and stratified by maximal tumor burden (RECIST 1.1 sum of diameter of target lesions ≥ 100 mm or &lt; 100 mm). The target sample size was 50 evaluable pts (25 per arm). Prior ICI, but not prior BRAF targeted therapy, was permitted. The co-primary endpoints were to estimate complete response (CR) rate for DTN compared to historic controls and to assess maximal tumor shrinkage of pts treated with DTN vs DT. Secondary endpoints included ORR, progression-free survival (PFS) and overall survival (OS). Results: Fifty-six pts were enrolled and 50 treated (25 DTN, 25 DT) from 1/11/19 – 3/25/22 at 13 sites. Seventeen pts (68%) in each arm received prior ICI. The ORR was 84% for DTN and 80% for DT. The CR rate for DTN was 20% and 15% for DT; this met pre-specified criteria for success of the primary CR endpoint. There was no difference in the maximal tumor shrinkage in pts treated with DTN vs DT. With median follow up of 25.9 months (mo), there was a trend for improved OS with DTN vs DT (median 36 vs 25 mo, log-rank p = 0.07). In the stratification cohort of 37 pts (74%) with smaller baseline tumor burden, there was a statistically significant improvement in OS among pts receiving DTN (log-rank p = 0.05), with two-year estimates of OS of 78% (95% CI: 0.46 to 0.93) for DTN and 57% (95% CI: 0.29 to 0.77) for DT. There was no difference in PFS between the two groups. The most common treatment-related toxicities ( &gt; 50% of pts) were nausea (36), diarrhea (31), fatigue (30), fever (28), and vomiting (27), which were not different in pts treated with DTN vs DT. Conclusions: In pts with BRAF MT MM, DTN was associated with a CR rate of 20% and ORR of 84%. There was a trend for improved OS in pts treated with DTN compared to DT; the difference in OS was significant in pts with smaller tumor burden. The DTN regimen may be considered for further exploration in the post-ICI setting. Updated data on survival and translational studies will be presented. Clinical trial information: NCT01989585 .

&lt;div&gt;AbstractPurpose:&lt;p&gt;In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings.&lt;/p&gt;Patients and Methods:&lt;p&gt;Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS.&lt;/p&gt;Results:&lt;p&gt;At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60–0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8&lt;sup&gt;+&lt;/sup&gt; T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value.&lt;/p&gt;Conclusions:&lt;p&gt;Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-1194" target="_blank"&gt;See related commentary by Augustin and Luke, p. 3253&lt;/a&gt;&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;

&lt;p&gt;DATA SUPPLEMENT Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238&lt;/p&gt;

&lt;p&gt;DATA SUPPLEMENT Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238&lt;/p&gt;

8560 Background: GM-CSF is a multifunctional cytokine that augments T-cell proliferation in the presence of antigen presenting cells (APC) and up-regulates the IL-2 receptor on T lymphocytes and monocytes.Studies have suggested that adding GM-CSF to IL-2 is synergistic, but no data is available on the clinical outcomes of a combination of GM-CSF with the standard HD-IL-2 regimen. Methods: Eligibility criteria included stageIII/IV melanoma, ECOG PS 0-1, and adequate organ function. Patients with > 2 chemotherapy regimens or active CNS metastases were excluded. GM-CSF 125 mg/m2 was injected subcutaneously 7 days before day 1 of HD- IL-2 and continued for 4 weeks, encompassing two cycles of HD-IL-2. IL-2 was administered intravenously at the standard 600,000 U/kg, as published. Immunologic assessments including dendritic cells (DC), IL-2 receptor (IL-2R) and regulatory T-cell (Treg) frequencies were performed at predetermined intervals. A two-stage design targeted a response rate (RR) of ≥ 15%. If ≥ 1 response were seen in 19 patients, accrual would proceed to 30 evaluable patients. Study endpoints included one-year survival, RR, progression-free survival (PFS) and safety. Results: Thirty-six patients were accrued. Six patients were not evaluable because they were either not treated or did not complete at least one course of therapy. Treatment toxicity was comparable to the known toxicity of HD-IL-2 alone. One sudden unexpected death occurred in one patient during IL-2 administration. The median follow-up is 16.2 months. In the 30 evaluable patients there were no complete responses, 4 (13%) partial responses, 8 (27%) with stable disease and 18 (60%) with disease progression. The median overall survival was 10.7 months and PFS was 2.4 months. One-year survival and PFS rates were 32.5% and 7.5%, respectively. Treatment increased DC, IL-2R and Treg in most patients tested. Conclusions: While treatment of advanced melanoma with HD-IL-2 with priming and concomitant sargramostim appears safe, the clinical outcomes are similar to what has been reported for HD-IL-2 alone. Further analyses of the immunologic parameters and clinical correlations will be conducted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Genzyme, Novartis Bayer Bayer, Berlex, Genzyme, Novartis

We have examined the effect of recombinant interleukin 3 (rIL-3) on the metabolism of high-dose cytosine arabinoside (Ara-C), an S-phase-specific agent, in normal human bone marrow mononuclear cells (BMMC) and leukemic blasts from patients with acute myeloid leukemia (AML). Exposure to rIL-3 for 24 h significantly increased the percentage of cycling S-phase cells in normal BMMC as well as leukemic cells. A concomitant expansion of intracellular deoxycytidine triphosphate (dCTP) levels occurred to a significantly greater extent in normal BMMC. Compared to treatment with Ara-C (10 mumol/liter) alone, prior and coadministration of rIL-3 with Ara-C increased Ara-CTP levels in leukemic blasts. However, an identical treatment produced significantly higher dCTP levels in normal BMMC, resulting in a significantly lower mean Ara-CTP to dCTP pool ratio in normal BMMC compared to that observed in each of the samples of AML blasts. Following treatment with Ara-C plus rIL-3 versus Ara-C alone, the alteration in Ara-C DNA incorporation corresponded with the change in Ara-CTP to dCTP ratio observed in normal BMMC and AML blasts. The differential effect of rIL-3 on the metabolism of high-dose Ara-C in normal versus leukemic cells may indicate a role for rIL-3 in enhancing the selectivity of Ara-C toward leukemic myeloblasts.

Although novel immunotherapy has shown promise for patients with melanoma, a more activated state of the immune system may lead to adverse systemic effects. Immunotherapy-induced meningoencephalitis is a rare and seldom reported adverse effect of immunotherapy but with the expanding role of immunotherapy in cancer treatments it must be recognised. Patients receiving immunotherapy should receive a proper warning about the potential for this life-threatening condition. Herein, we report a patient in his 70s with neurological changes after his second treatment with dual immunotherapy for a primary metastatic melanoma of the bladder neck.

BACKGROUND The authors conducted a Phase II study to evaluate the activity of the combination of gemcitabine and vinorelbine in patients with advanced nonsmall cell lung carcinoma (NSCLC). METHODS Patients were eligible if they had Stage IIIB (malignant pleural effusion) or Stage IV NSCLC, no prior chemotherapy, and Cancer and Leukemia Group B performance status (PS) 0–2. Patients with brain metastases were eligible if they were neurologically stable after brain irradiation. Thirty-three patients from participating institutions were enrolled. One patient was ineligible due to untreated brain metastases. Patients were treated with gemcitabine 1250 mg/m2 over 30 minutes (1000 mg/m2 for the first 6 patients) and vinorelbine 25 mg/m2 over 6 minutes, both administered intravenously on Days 1 and 8 every 21 days. Treatment was planned for a total of six cycles or more if the patient had persistent benefit. Growth factors were not allowed. RESULTS Among all 32 eligible patients, there were 8 partial responses, for an overall response rate of 25% (95% confidence interval [CI], 11.5–43.4%). The median survival time was 8.3 months and the 1-year survival rate was 38% (95% CI, 24–59%). Patients with PS 0–1 had a median survival of 11.7 months and a 1-year survival rate of 48%. Grade 3 and 4 neutropenia was observed in 13% and 25% of the 148 treatment cycles, respectively. One patient died of neutropenic sepsis. Only 2 episodes of Grade 3 and 4 thrombocytopenia were observed. Nonhematologic toxicity was minimal. CONCLUSIONS Gemcitabine and vinorelbine is an active and well-tolerated regimen in patients with advanced NSCLC, with response and survival rates at least comparable to those achieved with standard platinum-based regimens. This combination may be particularly suitable for the elderly or for patients who cannot tolerate more toxic platinum-based regimens. Cancer 2000;88:557–62. © 2000 American Cancer Society.

Twenty patients with advanced carcinomas of the colorectum, pancreas, stomach, and breast were enrolled in a Phase I study of a sequential administration of 5-fluorouracil-leu- covorin (FU-LV) combination followed by hydroxyurea (HU) with allopurinol protection (HALF regimen). As a weekly regimen for 6 weeks, followed by a rest period of 2 weeks, FU was administered intravenously (i.v.) during infusion of a 2-hour i.v. infusion of LV at a dose of 500 mg/m2. Six hours following the FU-LV combination, HU (1 gm/m,2) was administered orally. Allopurinol (300 mg every 8 hours, orally) was given the day before and on the day of the administration of the FU-LV combination. The starting dose of FU was 300 mg/m2, with escalations to 900 mg/m2. Mucositis, diarrhea, and hematologic toxicities were mild and sporadic with FU doses up to 750 mg/m2 and occurred in patients who had received prior treatment with FU and/or radiotherapy. Dose-limiting neurocerebellar toxicity was observed in 2 out of 6 patients who received a FU dose of 900 mg/m2. Three additional patients experienced moderate neuromotor toxicity at this dose level. Among 17 patients evaluable for response, partial responses were seen in 3 of the 9 patients with colorectal cancer, 1 of the 3 patients each with carcinoma of breast and pancreas. Three of the 5 responses occurred in patients who had received prior treatment with FU and/or radiation therapy. An FU dose of 750 mg/ m2 is recommended for a Phase II trial of the HALF regimen.

7509 Background: A bicistronic plasmid encoding HLA-B7 and β-2 microglobulin genes formulated in cationic lipids, Allovectin-7® (A-7), is an immunotherapeutic designed to induce a pro-inflammatory response and express MHC-class I after tumor injections. Expression of HLA-B7 in tumors may result in increased immunorecognition of tumors that in turn elicits an antitumor response. Methods: We are conducting a phase 2 trial to evaluate the activity of A-7 in patients (pts) with metastatic melanoma (MM). Eligible pts have stage III or IV MM recurrent or unresponsive to prior therapy; injectable (1 to 25 cm2 cutaneous, subcutaneous, or nodal) lesion(s); ECOG PS 0–1 and adequate organ function. Pts with brain or non-lung visceral metastases or any lesion ≥ 100 cm2 are excluded. Pts with 2 or more injectable lesions are randomized to receive injections into 1 or up to 5 lesions. Pts receive weekly intratumoral injections of a total of 2 mg for 6 wks followed by 3 wks of observation and evaluation. Response is assessed using RECIST guidelines two wks following the last injection of each cycle. Pts with stable or responding disease receive additional cycles. Results: Interim unaudited data will be presented for all 133 pts enrolled. All pts were evaluated for safety (6 pts in the dose escalation stage plus 127 pts in the high-dose stage), and 127 pts are evaluated for efficacy. In an interim data analysis 12 of 91 pts (13.2%) achieved an objective response lasting a median duration of 6.4 months. Median overall survival has not yet been reached and durability of response is still accruing. One Grade 3 and no Grade 4 adverse event associated with A-7 have been reported. Conclusions: Interim results indicate that high-dose A-7 is an active, well-tolerated treatment for Stage III/IV MM pts with injectable cutaneous, subcutaneous, or nodal lesions. No significant financial relationships to disclose.

7509 Background: A bicistronic plasmid encoding HLA-B7 and β-2 microglobulin genes formulated in cationic lipids, Allovectin-7® (A-7), is an immunotherapeutic designed to induce a pro-inflammatory response and express MHC-class I after tumor injections. Expression of HLA-B7 in tumors may result in increased immunorecognition of tumors that in turn elicits an antitumor response. Methods: We are conducting a phase 2 trial to evaluate the activity of A-7 in patients (pts) with metastatic melanoma (MM). Eligible pts have stage III or IV MM recurrent or unresponsive to prior therapy; injectable (1 to 25 cm2 cutaneous, subcutaneous, or nodal) lesion(s); ECOG PS 0–1 and adequate organ function. Pts with brain or non-lung visceral metastases or any lesion ≥ 100 cm2 are excluded. Pts with 2 or more injectable lesions are randomized to receive injections into 1 or up to 5 lesions. Pts receive weekly intratumoral injections of a total of 2 mg for 6 wks followed by 3 wks of observation and evaluation. Response is assessed using RECIST guidelines two wks following the last injection of each cycle. Pts with stable or responding disease receive additional cycles. Results: Interim unaudited data will be presented for all 133 pts enrolled. All pts were evaluated for safety (6 pts in the dose escalation stage plus 127 pts in the high-dose stage), and 127 pts are evaluated for efficacy. In an interim data analysis 12 of 91 pts (13.2%) achieved an objective response lasting a median duration of 6.4 months. Median overall survival has not yet been reached and durability of response is still accruing. One Grade 3 and no Grade 4 adverse event associated with A-7 have been reported. Conclusions: Interim results indicate that high-dose A-7 is an active, well-tolerated treatment for Stage III/IV MM pts with injectable cutaneous, subcutaneous, or nodal lesions. No significant financial relationships to disclose.

ABSTRACT Aim: CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21. Following intratumoral injection, CAVATAK preferentially infects ICAM-1 expressing tumor cells, resulting in cell lysis and a systemic anti-tumor immune response. We here report on the key secondary endpoints in the Phase II CALM study. Methods: The CALM study investigated the efficacy and safety of intratumoral CAVATAK in 57 patients with treated or untreated unresectable Stage IIIC-IVM1c melanoma. Patients received up to 3 x 108 TCID50 CAVATAK intratumorally on study days 1,3,5 and 8 and then every three weeks for a further 6 injections. Patients displaying immune-related progression-free survival (irPFS) or better at 6 months were eligible for 9 additional injections. Key eligibility criteria were ECOG 0-1, and at least 1 injectable cutaneous, subcutaneous, or nodal melanoma metastasis >1.0 cm. The primary endpoint was to achieve >9 of 54 evaluable patients with irPFS at 6 months. Secondary endpoints included median irPFS, 1-year survival, median time to response, irRECIST 1.1 best overall response (BORR) and safety. Results: The primary endpoint of the study was achieved with 19 of 51 (37.3%) evaluable patients displaying irPFS at 6 months. Preliminary analysis of secondary endpoints showed: median irPFS of 4.2 months (95% CI 2.8, 8.3), 1-year survival 61.5% (16 of 26 pts), on-going BORR (irRECIST 1.1) 26.3% (15 of 57 pts) with responses seen in both injected and non-injected lesions, median time to response 2.8 months. To date 15 patients have received additional series of CAVATAK injections. The most common patient side effects observed were Grade 1 local injection site reactions, fatigue, chills and fever. There were no Grade 3 or 4 product-related AE's. Conclusions: Intralesional CAVATAK is a promising novel oncolytic immunotherapeutic agent with limited toxicity and robust responses in both injected and non-injected lesions in patients with advanced melanoma. The effectiveness of CAVATAK warrants additional investigation as monotherapy and in combination with other targeted immunotherapies such as immune checkpoint blockade. Disclosure: R.H. Andtbacka: Travel honorarium–Viralytics; K. Zhou: Salary - Viralytics J.I. Weisberg: Salary–Viralytics; D. Shafren: Stock, salary–Viralytics. All other authors have declared no conflicts of interest.

PurposeTo investigate whether the Vemurafenib-induced increased tumor antigen expression, T lymphocyte infiltration and tumor debulking improve the complete response rate induced by HD IL-2 in metastatic melanoma and if there is synergistic toxicity using the drugs in close approximation.

ABSTRACT Background: Targeted treatments have significantly improved outcomes in patients (pts) with metastatic melanoma (MM). The combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, provides high response rates in BRAF mutation-positive melanoma (BRAF V600E/K melanoma). Trametinib has also shown clinical activity in BRAF wild-type (WT) melanoma. The addition of an immunomodulator may further improve clinical outcomes in metastatic melanoma pts. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 and is associated with a low frequency of anti-drug antibodies, showed durable clinical activity in a Phase 1 study of pts with solid tumors including melanoma. MEDI4736 is being evaluated in combination with dabrafenib/trametinib or trametinib alone in BRAF mutation-positive or BRAF mutation-negative melanoma. Trial design: This global multicenter, open-label Phase 1b study (NCT02027961) is enrolling adults with unresectable or MM and ECOG performance status 0–1 into 3 cohorts. In cohort A, BRAF-V600E/K melanoma pts receive dabrafenib orally (PO) twice daily, trametinib PO once daily (QD) and MEDI4736 intravenously (IV) every 2 wks (q2w), given concomitantly followed by continued dabrafenib/trametinib until progressive disease (PD). In cohorts B and C, BRAF mutation-negative (BRAF-WT) pts receive trametinib PO QD and MEDI4736 IV q2w according to 2 different treatment schedules,until PD. Primary objectives are determination of maximum tolerated dose (dose-limiting toxicity) and safety profile (adverse events, laboratory evaluations, physical exams, echocardiograms/electrocardiograms) of MEDI4736 in combination with dabrafenib/trametinib or trametinib alone. Secondary objectives include antitumor activity (objective response based on RECIST, duration of response, PFS, and overall survival), pharmacokinetic profile, and immunogenicity of the combination. Exploratory objectives include biomarkers, patient-reported outcomes, and tumor growth parameters. Recruitment is ongoing (target: 69 pts). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting Chicago, June 2014 (TPS9108). Disclosure: M.S. Gordon and D. Lawrence: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; J. Lutzky: Medimmune/Astra-Zeneca: clinical trial support. Genentech, BMS, Prometheus: both clinical trial support and speaker bureau. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; M. Butler: Financial support from MedImmune to cover the costs of conducting sponsored clinical studies of Medi4736. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; P.A. Ascierto: Consultancy/research funding/honoraria: BMS, Roche-Genentech, Merck Sharp & Dohme, GSK, Ventana, and Novartis. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; B. Hug: Employee of GlaxoSmithKline. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins, A. Di Pietro, X. Li and P.B. Robbins: Employee of MedImmune and owns stock/stock options in AstraZeneca; A. Ribas: Consultant/funding/stock options Amgen Daiichi-Sankyo GSK Genentech-Roche Merck Novartis Pierre-Favre Kite Pharma Flexus. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.

Background and aims: Merkel cell carcinoma (MCC) is a rare skin cancer with a high rate of recurrence. Serum antibodies to Merkel cell polyomavirus oncoprotein (AMERK) are present in 50% of patients and can be used to monitor for recurrence after achieving remission. It is expected that 90% 0f AMERK titers will normalized by one year after successful treatment and continue to fall subsequently. Our aim is to describe the longitudinal clinical course in patients with MCC and elevated AMERK levels despite having no evidence of disease. Methods: We identified 3 patients treated for MCC at our institution, who had no clinical or radiographic evidence of disease, but were found to maintain elevated AMERK levels. All patients were at least 3-years status post-resection. Laboratory studies, pathology, clinical notes, and imaging were reviewed. Results: Patient A: 84-year-old female with history of osteosarcoma and lung adenocarcinoma, diagnosed with upper extremity MCC (T1N0M0) who’s initial AMERK (201) dropped 35.82% at 7-months but remained at 50% (102) at 3.8 years after resection and sentinel node. Patient B: 35-year-old female with left thigh MCC (T2N1aM0) metastatic to inguinal nodes, underwent resection, inguinopelvic lymphadenectomy followed by adjuvant radiation and immunotherapy with avelumab/pembrolizumab. Her initial AMERK (14,400) decreased 73.19% at 1-month and became elevated to 754 at 16-months, slowly decreasing again but remaining at 252 for the last 3.3 years. Patient C: 70-year-old male with metastatic MCC to inguinal/pelvis nodes of unknown primary (TxN3M0) treated with lymphadenectomy followed by radiation. His initial AMERK titers (30,200) dropped 92.98% at 5-months; but have remained at 1,690 at 3.3 years. All three patients have been followed with subsequent AMERK titers every 3 months, demonstrating persistent elevation without clinical and pathological findings of disease. Conclusions: Surveillance guidelines using AMERK need to accommodate for those outliers who never achieve normal serological titers during long term follow up despite disease remission. Additional research is necessary to overcome the clinical challenges of interpreting the data in these patient’s scenarios.

<h3>Background</h3> Investigational autologous TIL cell therapies have shown promise in patients with advanced cutaneous melanoma and persistent disease after checkpoint inhibitor therapy, a population with a high unmet medical need.^1,2 Made from autologous digested and cryopreserved tumor, ITIL-168 is a TIL cell therapy manufactured to offer an unrestricted T-cell receptor repertoire. DELTA-1 (NCT05050006) is a global, multicenter, phase 2 study evaluating efficacy and safety of ITIL-168 in patients with cutaneous melanoma relapsed or refractory to a PD-1i, patients intolerant to a PD-1i, and patients with stable disease on a PD-1i. <h3>Methods</h3> Adult patients with histologically confirmed advanced cutaneous melanoma and ECOG performance status 0-1 will be enrolled in 1 of 3 cohorts. Cohort 1 (n≈80) will include patients who relapsed after or were refractory to ≥1 prior line of systemic therapy, including a PD-1i and, if <i>BRAF</i>-mutated, a BRAFi ± MEKi. Cohorts 2 and 3 (n≈25 each) will include patients intolerant to PD-1i and those with stable disease after ≥4 doses of PD-1i, respectively. After tumor harvest, patients must have ≥1 measurable lesion per RECIST 1.1. Noncutaneous melanoma, certain prior therapies, and patients with symptomatic and/or untreated central nervous system metastases are ineligible. Patients will receive 5 days of lymphodepleting chemotherapy (cyclophosphamide ×2 days overlapping with fludarabine ×5 days) followed by a single ITIL-168 infusion and supportive IL-2. The primary endpoint is objective response rate (ORR) per central review. Secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, TIL persistence, and safety. Hypothesis testing of ORR will be performed for cohort 1. The primary analysis will occur ≥6 months after the first posttreatment disease assessment of patients in the cohort 1 modified intent-to-treat population. Enrollment has expanded into Canada and Europe. <h3>Acknowledgements</h3> Medical writing support was provided by Christopher Waldapfel, PharmD, of Instil Bio, Inc. and Phylicia Aaron, PhD, of Nexus Global Group Science, with funding from Instil Bio, Inc. <h3>References</h3> Schadendorf D, van Akkoi ACJ, Berking C, <i>et al</i>. Melanoma. Lancet. 2018;<b>392</b>(10151):971-984. Borch TH, Anderson R, Ellebaek E, <i>et al</i>. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. <i>J Immunother Cancer</i>. 2020;<b>8</b>(2):e000668. <h3>Ethics Approval</h3> All patients will provide written informed consent. The study will be approved by the Institutional Review Board/Independent Ethics Committee at each site and conducted in accordance with the Good Clinical Practice Guidelines of the International Council for Harmonisation. <h3>Consent</h3> N/A; the abstract does not contain sensitive or identifiable patient information.

Abstract Background Over 60% of patients (pts) with stage IV melanoma may develop brain metastases, resulting in a significantly increased morbidity and poor overall prognosis. Clinical data for melanoma brain metastases (MBM) treatments are limited, as controlled studies often exclude pts with untreated brain metastases. Methods We conducted a multicenter, retrospective case series investigation with consecutive pts with BRAF-mutant MBM who were treated with BRAF inhibitor encorafenib plus MEK inhibitor binimetinib to evaluate the antitumor response with this combination. Assessments included intracranial, extracranial & global objective response rates (ORRs; percentage of complete [CR] + partial [PR] responses) evaluated by modified RECIST version 1.1; clinical benefit rate (CBR; percentage of CR + PR + stable disease [SD] as best response); time to response, duration of response, and safety. Results A total of 17 pts with stage IV BRAF-mutant MBM who received encorafenib plus binimetinib in centers in the United States were included. Pts had received a median of 2 prior lines of treatment over a median of 520 days since their melanoma diagnosis (median of 55 days since diagnosis of MBM). Of the patients included, 82% had prior treatment with BRAF/MEK inhibitors. The intracranial ORR was 35% (with 3 CRs and 3 PRs) and CBR was 76%, with a median duration of response of 17 weeks. Eight pts with either stable disease or a response were still ongoing treatment at the time of this analysis. Among the 14 MBM pts with prior BRAF/MEK inhibitor treatment, the intracranial ORR was 21% and CBR was 71%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in pts with melanoma without brain metastases. Conclusions Combination therapy with encorafenib plus binimetinib elicited intracranial activity in pts with BRAF-mutant MBM, including in pts previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted. *K. Holbrook and J. Lutzky are co-first authors. Editorial acknowledgement Editorial assistance was provided by JD Cox and Mayville Medical Communications, with funding from Array Biopharma. Legal entity responsible for the study Array BioPharma Inc. Funding Array BioPharma. Disclosure J. Lutzky: Advisory / Consultancy, Speaker Bureau / Expert testimony: Array BioPharma; Advisory / Consultancy, Speaker Bureau / Expert testimony: Regeneron; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Bristol-Myers Squibb. A. Amin: Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Merck; Speaker Bureau / Expert testimony: Regeneron. J.M. Davis: Speaker Bureau / Expert testimony: Exelixis Inc; Advisory / Consultancy: Array BioPharma. M.A. Davies: Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: GSK; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Vaccinex; Advisory / Consultancy: Syndax; Non-remunerated activity/ies: Nanostring. A. Diab: Advisory / Consultancy: Array BioPharma. I.C. Glitza: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Array BioPharma. R.N. Amaria: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Iovance. S. Patel: Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Cardinal Health; Advisory / Consultancy: Castle Biosciences; Research grant / Funding (institution): Deciphera; Advisory / Consultancy, DSMB: Immunocore; Advisory / Consultancy: Incyte; Speaker Bureau / Expert testimony: Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Provectus; Advisory / Consultancy, Research grant / Funding (institution), DSMB: Reata. H.A. Tawbi: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Array BioPharma; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): GSK. All other authors have declared no conflicts of interest.

Oxford Radcliffe Hospitals, Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, UK Email: [email protected] Abstracts of the Sixth International Conference on the Adjuvant Therapy of Malignant Melanoma