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Background: Cutaneous metastases (CMs) are a manifestation of advanced cancer and can be treated with oncolytic immunotherapy. Laboratory studies suggest radiotherapy (RT) may facilitate response to immunotherapy. We hypothesized that oncolytic immunotherapy with talimogene lapherparepvec (T-VEC, an oncolytic immunotherapy that expresses granulocyte-macrophage colony stimulating factor) and RT would produce response in non-targeted metastases., Methods: A randomized phase 2 trial of T-VEC+/-RT was conducted. Eligible patients had ≥1 CM from a solid tumor amenable to T-VEC and RT and another measurable metastasis. Tumor and overall response was assessed using modified World Health Organization (mWHO) criteria. Adverse events (AEs) and quality of life (QOL) were characterized using CTCAE v4.0 and Skindex-16, respectively. Correlative analyses of tumor genomics and the immune system were performed., Results: 19 patients were randomized to receive T-VEC (n = 9) or T-VEC+RT (n = 10). One patient in each arm demonstrated complete response in the largest non-targeted metastasis. The trial was closed after the first stage of enrollment because of no overall mWHO responses, slow accrual and the COVID-19 pandemic. AEs were consistent with prior reports of T-VEC. Skin related QOL was poor before and after treatment. Median progression free survival was 1.2 and 2.5 months in the T-VEC and T-VEC+RT arms; median overall survival was 4.9 and 17.3 months in the T-VEC and T-VEC+RT arms. Analyses of peripheral blood cells and cytokines demonstrated responders exhibited several outlying lymphocyte and cytokine parameters., Conclusions: Low overall response rate, slow accrual, and the COVID-19 pandemic led to closure of this trial. Responses in non-injected and non-irradiated metastases were infrequent., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [CAB reports honoraria from Regeneron, his institution receives research funding for clinical trials from Regeneron, EMD Serono, Physical Sciences Incorporated, Amgen, Elekta, Melanoma and Skin Cancer Trials Limited, Merck, Alpha Tau Medical and the University of California San Francisco, and he has received support to attend meetings from the National Comprehensive Cancer Network, University of Washington, and the National Cancer Institute. SPD reports personal fees from Aadi bioscience, Adaptimmune, GI innovation, GSK, Pfizer, and Servier outside the submitted work. MEL has a consultant role with Johnson and Johnson, Novocure, Janssen, Novartis, Deciphera, Kintara, RBC/La Roche Posay, Trifecta, Genentech, Loxo, Seattle Genetics, Lutris, OnQuality, Roche, Oncoderm, Apricity and research funding from Lutris, Paxman, Novocure, OQL, Novartis and AZ, all outside the submitted work. PBC reports honoraria or personal fees from BMS, GlaxoSmithKline, Genentech/Roche, Provectus, Momenta Pharmaceuticals, Daiichi Sankyo, Merck, Pfizer, Genentech, Takeda, Vanium Group, and Scancell. Consulting or Advisory board: BMS, GlaxoSmithKline, Genentech/Roche, Daiichi Sankyo, Provectus, Momenta Pharmaceuticals, LICR Research, Merck, Immunocore, Cell Medica, Takeda Millennium, Rgenix, Scancell, AstraZeneca, Black Diamond Therapeutics, and Pfizer. Presentations for Medscape. Ownership/equity interests in Molecular MD Corp and Rgenix. Research funding from Pfizer, NCI, and Genentech. ANS reports personal fees from BMS, Immunocore, and Novartis; institutional grant support from BMS, Immunocore, Novartis, Pfizer, AstraZeneca, Xcovery, Checkmate Pharmaceuticals, and Polaris. CA reports consulting fees from Iovance.]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported., Patients and Methods: Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate at Week 12. Plasma was assayed for circulating tumor DNA and 10 cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel., Results: Among the treated patients, expansion of proliferating T-cell populations was observed in responders and nonresponders. Baseline IL6 levels were low in patients achieving an objective radiographic response (median 1.30 vs. 2.86 pg/mL; P = 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR = 1.24, 95% confidence interval (CI), 1.01-1.52; P = 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P = 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR = 1.11, 95% CI, 1.01-1.21; P = 0.023). Week 12 overall response rate was 47% (95% CI, 35%-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI, 10-not reached); 76% of responses (95% CI, 64%-91%) persisted at 36 months., Conclusions: Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL6 and circulating tumor DNA changes during treatment warrant further study as biomarkers of nivo-ipi response., (©2024 American Association for Cancer Research.)

Abstract: The widespread adoption of immune checkpoint inhibitors and small molecule inhibitors of the MAP kinase pathway has transformed the management of locally advanced and metastatic melanoma. Here, we provide a broad overview on the use of these agents in the first-line setting, incorporating a review of the clinical literature as well as the practice patterns of our respective melanoma groups. Throughout, we highlight areas of uncertainty that provide opportunities for future clinical investigation and additional improvement in outcomes for patients with melanoma., Competing Interests: Conflicts of Interest and Source of Funding: J.W.S. received research funding from IO Biotech. P.B.C. is a consultant for Pfizer, Immunocore, and Kestrel Therapeutics and has stock options in Rgenix., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Preclinical studies show that activation of AMP kinase by phenformin can augment the cytotoxic effect and RAF inhibitors in BRAF V600-mutated melanoma. We conducted a phase Ib dose-escalation trial of phenformin with standard dose dabrafenib/trametinib in patients with metastatic BRAF V600-mutated melanoma., Experimental Design: We used a 3+3 dose-escalation design which explored phenformin doses between 50 and 200 mg twice daily. Patients also received standard dose dabrafenib/trametinib. We measured phenformin pharmacokinetics and assessed the effect of treatment on circulating myeloid-derived suppressor cells (MDSC)., Results: A total of 18 patients were treated at dose levels ranging from 50 to 200 mg twice daily. The planned dose-escalation phase had to be cancelled because of the COVID 19 pandemic. The most common toxicities were nausea/vomiting; there were two cases of reversible lactic acidosis. Responses were seen in 10 of 18 patients overall (56%) and in 2 of 8 patients who had received prior therapy with RAF inhibitor. Pharmacokinetic data confirmed drug bioavailability. MDSCs were measured in 7 patients treated at the highest dose levels and showed MDSC levels declined on study drug in 6 of 7 patients., Conclusions: We identified the recommended phase II dose of phenformin as 50 mg twice daily when administered with dabrafenib/trametinib, although some patients will require short drug holidays. We observed a decrease in MDSCs, as predicted by preclinical studies, and may enhance immune recognition of melanoma cells., Significance: This is the first trial using phenformin in combination with RAF/MEK inhibition in patients with BRAF V600-mutated melanoma. This is a novel strategy, based on preclinical data, to increase pAMPK while blocking the MAPK pathway in melanoma. Our data provide justification and a recommended dose for a phase II trial., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Little is known about the long-term outcomes of anti-PD-1 treated patients with melanoma beyond 5 years, especially for patients treated off clinical trials. This retrospective cohort study includes patients with unresectable stage III/IV nonuveal melanoma treated with anti-PD-1 off-trial at Memorial Sloan Kettering Cancer Center between 2014 and 2017 who survived at least 5 years following their first anti-PD-1 dose (N = 139). We characterized overall survival (OS), melanoma-specific survival (MSS) estimates, treatment-free survival rates, and subsequent treatment courses. Median follow-up among 5-plus year survivors (N = 125) was 78.4 months (range 60.0-96.3). OS at year 7 (2 years post 5-year landmark) was 90.1% (95% CI: 83.0%-94.3%). Fourteen deaths occurred, seven due to melanoma. MSS at year 7 (2 years post 5-year landmark) was 95.0% (95% CI: 33.5%-95.2%). In patients who completed anti-PD-1 based therapy and did not require subsequent treatment by 5 years (N = 80), the probability of not requiring additional treatment for an additional 2 years was 95.7% (95% CI: 91.0%-100%). Patients treated with anti-PD-1 regimens off clinical trials who survive at least 5 years from initial anti-PD-1 treatment can be reassured of their excellent long-term prognosis, particularly if they did not require additional melanoma treatment during the first 5 years., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Adjuvant anti-PD1 treatment improves relapse-free survival (RFS) but has not been shown to improve overall survival (OS) in melanoma and is associated with risks of immune-related adverse events (irAEs), some permanent. We identified factors patients consider in deciding whether to undergo adjuvant anti-PD1 treatment and assessed prospective health-related quality of life (HRQoL), treatment satisfaction, and decisional regret., Patients and Methods: Patients with stage IIIB-IV cutaneous melanoma and free of disease, were candidates for adjuvant anti-PD1 immunotherapy, and had not yet discussed adjuvant treatment options with their oncologist were eligible. Participants viewed a 4-minute informational video tailored to their disease stage which communicated comprehensive, quantitative information about the risk of relapse both with and without adjuvant treatment, and risks of each irAE before deciding whether or not to opt for adjuvant therapy. We collected data on demographics, HRQoL, and attitudes toward adjuvant treatment over 1 year., Results: 14/34 patients (41%) opted for adjuvant anti-PD1 immunotherapy, 20/34 (59%) opted for observation. Patients choosing adjuvant immunotherapy scored higher on HRQoL social well-being at pre-treatment, were more likely to endorse positive statements about adjuvant immunotherapy, and to perceive that their physician preferred adjuvant therapy. They had lower decisional regret and higher satisfaction, even if they experienced toxicity or recurrence., Conclusions: When provided with comprehensive quantitative information about risks and benefits of adjuvant anti-PD1 immunotherapy, 20/34 (59%) of patients opted for observation. Patients choosing adjuvant immunotherapy had lower decisional regret and higher satisfaction over time even if they had poorer outcomes in treatment., (© The Author(s) 2023. Published by Oxford University Press.)

Purpose: Nivolumab + ipilimumab (nivo + ipi) is highly efficacious but has high toxicity. Standard treatment in advanced melanoma is four doses of nivo + ipi followed by nivo alone. Whether four doses of nivo + ipi are needed is unclear., Methods: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT) study (NCT03122522) is a multicenter, single-arm phase II clinical trial. Patients received two doses of nivo (1 mg/kg) + ipi (3 mg/kg) followed by a computed tomography scan at week 6. Patients without new lesions or index lesion tumor growth of > 4% had protocol-defined early favorable antitumor effect (FATE) and ceased nivo + ipi, transitioning to nivo monotherapy. Patients without FATE at week 6 received the standard third and fourth doses of nivo + ipi followed by nivo monotherapy. The primary end point was response rate by RECIST 1.1 at week 12. Secondary end points included additional efficacy assessments and safety., Results: Sixty patients were enrolled; 41 patients (68%) had FATE at week 6 and met criteria for stopping nivo + ipi. Best overall response rates by RECIST at week 12 or any time afterward were 48% (95% CI, 35 to 62) and 58% (95% CI, 45 to 71), respectively. With a median follow-up of 25 months, the estimated 18-month progression-free survival and overall survival are 52% and 80%, respectively. Fifty seven percent of patients had grade 3-5 treatment-related toxicity., Conclusion: The efficacy and toxicity of standard four dose nivo + ipi induction therapy in melanoma is likely driven by the first two doses. An interim computed tomography scan after two doses guided cessation of combination dosing and identified almost all responders. Longer follow-up and further study are needed to fully understand the implications of a shortened induction course of nivo + ipi., Competing Interests: Michael A. PostowConsulting or Advisory Role: Bristol Myers Squibb, Novartis, Array BioPharma, NewLink Genetics, Incyte, Merck, Eisai, PfizerResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Array BioPharma (Inst), Infinity Pharmaceuticals (Inst), Regenix (Inst), Merck (Inst), AstraZeneca/MedImmune (Inst) Debra A. GoldmanEmployment: RegeneronStock and Other Ownership Interests: Johnson & Johnson Alexander N. ShoushtariConsulting or Advisory Role: Immunocore, Bristol Myers SquibbResearching Funding: Immunocore, Bristol Myers Squibb, Xcovery, Polaris, Novartis (Inst), Pfizer (Inst)Patents, Royalties, Other Intellectual Property: UpToDate Allison Betof WarnerHonoraria: LG ChemConsulting or Advisory Role: Nanbiotix, Iovance Biotherapeutics, Novartis, Shanghai Jo’Ann Medical Technology, BluePath Solutions, PfizerResearch Funding: Leap Therapeutics Margaret K. CallahanEmployment: Bristol-Myers Squibb (I), Celgene (I), Kleo Pharmaceuticals (I), Bristol-Myers Squibb (I)Consulting or Advisory Role: AstraZeneca, Moderna Therapeutics, Merck, ImmunocoreResearching Funding: Bristol Myers Squibb (Inst)Other Relationship: Clinical Care Options, Potomac Center for Medical Education Omar EtonSpeakers’ Bureau: MerckResearching Funding: Bristol Myers Squibb (Inst) Suresh G. NairStock and Other Ownership Interests: Moderna Therapeutics, Novavax, Biotech, Gilead SciencsResearch Funding: Bristol-Myers Squibb, Merck, Nektar (Inst) Katherine S. PanageasStock and Other Ownership Interests: AstraZeneca, Pfizer, Sunesis Pharmaceuticals Jedd D. WolchokStock and Other Ownership Interests: Tizona Therapeutics, Inc, Adaptive Biotechnologies, Imvaq Therapeutics, Beigene, Linnaeus Therapeutics, Arsenal IO, Geogiamune, LLC, Maverick Therapeutics, Apricity Therapeutics, Trieza TherapeuticsConsulting or Advisory Role: Bristol-Myers Squibb, Merck, Sellas Life Sciences, Lilly, Tizona Therapeutics, Inc,, Amgen, Chugai Pharma, Adaptive Biotechnologies, Ascentage Pharma, PsiOxus Therapeutics, F-Start Biotechnology, Surface Biotechnology, Apricity Therapeutics, PsiOxus Therapeutics, F-Star Biotechnology, Surface Oncology, Apricity Therapeutics, PsiOxus Therapeutics, Astellas Pharma, Recepta Biopharma, Arsenal IO, Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo,Inc, Dragonfly Therapeutics, Geogiamune, Kyowa Kirin Pharmaceutical, Maverick Therapeutics, Werewolf Therapeutics, Trishula Therapeutics, Idera, Imvq Therapeutics, Biscara TherapeuticsResearch Funding: Bristol Myers Squibb (Inst), Genentech/Roche (Inst), Merck Sharp & Dohme (Inst)Patents, Royalties, Other Intellectual Property: I am a co-inventor on an issued patent for DNA vaccines for treatment for cancer in companion animals, I am a co-inventor on a patent for use of oncolytic Newcaste Disease virus, I am a co-inventor and receive royalties for a blood test for monitoring myeloid derived suppressor cells. I am co-inventor and receive royalties for a petent for immune modulating antibododies. I am a co-inventor on a patent for CAR+ T cells targeting differentiation antigens as means to treat cancer. I am a co-inventor on a patent for Anti-CD40 agonist mAb fused to Monophosphory Lipid A (MPL) for cancer therapy, Alphavirus Replicon Particles Expressing TRP2, Engineered Vaccinia Viruses for Cancer Immunotherapy, Recombinant Poxviruses for Cancer Immunotherapy Paul B. ChapmanConsulting or Advisory Role: Merck, Pfizer, Black Diamond TherapeuticsResearch Funding: Pfizer, NCI (Inst), GenentechNo other potential conflicts of interest were reported.

Background: In melanoma patients who progress after prior ipilimumab/nivolumab (ipi/nivo) combination immunotherapy, there is no information regarding the risks and benefits of reinduction ipi/nivo., Methods: This was a retrospective review of 26 melanoma patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) since 2012 who received reinduction ipi/nivo at least 6 months following completion of an initial course of ipi/nivo. We collected data on demographics, genetics, immune-related adverse events (irAEs), best overall responses (BORs), time to treatment failure (TTF) and overall survival (OS)., Results: The BOR rate (complete response+partial response) was 74% (95% CI 52% to 90%) after the first course of ipi/nivo but only 23% (95% CI 8% to 45%)) after reinduction. Response to reinduction did not correlate with response to the initial course. Among the 16 patients who had an objective response to the first course, only four (25%) responded to reinduction. Of five patients who did not respond to the first course, one responded to reinduction. For all patients, median TTF was 5.3 months after reinduction; TTF was shorter for reinduction than for the first course in 85% of patients. Median OS from reinduction was 8.4 months; estimated 2-year OS was 18%. Although reinduction was associated with fewer irAEs than the initial course of ipi/nivo (58% of patients vs 85% of patients in the initial course), eight (31%) patients experienced at least one new irAE after the second course., Conclusions: BOR rate and TTF were markedly less favorable after reinduction with ipi/nivo than after the initial course of ipi/nivo. Reinduction ipi/nivo was associated with frequent irAEs although less frequent than for the initial course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint blocking antibodies are a cornerstone in cancer treatment; however, they benefit only a subset of patients and biomarkers to guide immune checkpoint blockade (ICB) treatment choices are lacking. We designed this study to identify blood-based correlates of clinical outcome in ICB-treated patients. We performed immune profiling of 188 ICB-treated patients with melanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. A supervised statistical learning approach was applied to a discovery cohort to classify phenotypes and determine their association with survival and treatment response. We identified three distinct immune phenotypes (immunotypes), defined in part by the presence of a LAG-3 + CD8 + T cell population. Patients with melanoma with a LAG + immunotype had poorer outcomes after ICB with a median survival of 22.2 months compared to 75.8 months for those with the LAG - immunotype ( P = 0.031). An independent cohort of 94 ICB-treated patients with urothelial carcinoma was used for validation where LAG + immunotype was significantly associated with response ( P = 0.007), survival ( P < 0.001), and progression-free survival ( P = 0.004). Multivariate Cox regression and stratified analyses further showed that the LAG + immunotype was an independent marker of outcome when compared to known clinical prognostic markers and previously described markers for the clinical activity of ICB, PD-L1, and tumor mutation burden. The pretreatment peripheral blood LAG + immunotype detects patients who are less likely to benefit from ICB and suggests a strategy for identifying actionable immune targets for further investigation., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence, and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike, prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for patients with melanoma and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome, and offer recommendations for the best path forward., (©2021 American Association for Cancer Research.)

Purpose: Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown., Experimental Design: Patients with melanoma were prospectively offered tumor sequencing of 341-468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables., Results: A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy ( N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab ( N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months., Conclusions: Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor-refractory melanoma., (©2021 American Association for Cancer Research.)

Purpose: Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous ( n = 3), uveal ( n = 2), and acral ( n = 2) melanoma subtypes., Experimental Design: Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression., Results: For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance., Conclusions: In 4 patients who received immunotherapy, we found 1-3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective., (©2020 American Association for Cancer Research.)

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82% [95% confidence interval (CI) 79-84] and 70% (95% CI 66-74), respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Chronic lymphocytic leukemia (CLL) is associated with immune dysfunction and an increased risk of melanoma. For patients with metastatic melanoma, immunotherapy with checkpoint blocking antibodies is a standard of care. In patients with concomitant CLL and metastatic melanoma, it is not known whether CLL might influence the antimelanoma efficacy or immune-related toxicities of immune checkpoint blockade. Fifteen patients with locally advanced or metastatic melanoma and a concomitant diagnosis of CLL who received pembrolizumab or ipilimumab with or without nivolumab for the treatment of their melanoma at Memorial Sloan Kettering Cancer Center between January 1, 2010, and January 1, 2017, were retrospectively identified. Clinical characteristics including absolute lymphocyte counts during therapy were recorded along with a response to treatment (objective radiographic response, progression-free survival, and adverse events) for each patient. Of 9 response-evaluable patients treated with ipilimumab, 3 (33%) had a partial response, 1 (11%) had stable disease, and 5 (56%) developed progressive disease. Objective tumor responses were also observed with single-agent therapy pembrolizumab and with combination therapy of nivolumab and ipilimumab. Grade 3 or 4 toxicity was observed in 6 of 15 patients (40%), including diarrhea, transaminitis, rash, and hemolytic anemia. Although our retrospective assessment was limited, there was no evidence that CLL responded to the checkpoint blockade. This case series demonstrates that ipilimumab, pembrolizumab, and combined ipilimumab and nivolumab therapies show clinical activity in patients with melanoma and concomitant CLL, at rates consistent with those previously reported. This population may warrant closer surveillance for hematologic immune-related toxicities such as autoimmune hemolytic anemia.

Purpose: Preclinical data suggest that radiotherapy (RT) is beneficial in combination with immune checkpoint blockade. Clinical trials have explored RT with single-agent immune checkpoint blockade, but no trials have reported RT with the combination of nivolumab and ipilimumab., Patients and Methods: We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of RT. Patients had at least one melanoma metastasis that would benefit from palliative RT and one metastasis that would not be irradiated. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg and extracranial RT with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety., Results: Twenty patients were treated (10 in each cohort). The rates of treatment-related grade 3-4 adverse events in Cohort A and B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to RT. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T-cell receptor diversity in some responding patients., Conclusions: RT with nivolumab and ipilimumab was safe compared with historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab., (©2020 American Association for Cancer Research.)

Purpose: To analyze long-term outcomes after treatment discontinuation of anti-programmed death-1 (anti-PD-1) therapy in a cohort of patients with melanoma with the longest follow-up yet available to our knowledge, including a majority of patients treated outside of a clinical trial. We also assessed efficacy of retreatment with anti-PD-1 therapy with or without ipilimumab in relapsing patients., Methods: We retrospectively analyzed all patients with nonuveal, unresectable stage III/IV melanoma treated with single-agent anti-PD-1 therapy at Memorial Sloan Kettering from 2009-2018 who had discontinued treatment and had at least 3 months of follow-up after discontinuation (n = 396). Overall survival for patients with complete response (CR) was calculated from time of CR. Time to treatment failure for patients with CR was time from CR to the next melanoma treatment or death., Results: CRs were seen in 102 of 396 patients (25.8%). The median number of months of treatment after CR was zero (range, stopped before CR to 26 months after CR). With a median follow-up of 21.1 months from time of CR in patients who did not relapse, the probability of being alive and not needing additional melanoma therapy at 3 years was 72.1%. There was no significant association between treatment duration and relapse risk. In multivariable analysis, CR was associated with M1b disease and cutaneous versus mucosal or acral primaries. Among the 78 patients (of 396) retreated after disease progression, response was seen in 5 of 34 retreated patients with single-agent anti-PD-1 therapy and 11 of 44 patients escalated to anti-PD-1 plus ipilimumab., Conclusion: In our cohort, most patients discontinued treatment at the time of CR. Most CRs were durable but the probability of treatment failure was 27% at 3 years. Responses to retreatment were infrequent. The optimal duration of treatment after CR is not yet established.

Introduction: Checkpoint inhibitors have improved outcomes in metastatic melanoma, with 4-year overall survival (OS) of 46% for anti-PD-1 alone or 53% in combination with anti-CTLA-4. However, the median progression free survival is 6.9 and 11.5 months, respectively. Many who progress have gone on to alternative treatments, including surgery, yet the outcome of patients selected for surgery after checkpoint blockade remains unclear., Methods: Patients who were treated with checkpoint blockade from 2003 to 2017, followed by metastasectomy, were identified from a prospectively maintained institutional melanoma database. Response to immunotherapy was assessed at the time of surgery. Patients were categorized as having responding, isolated progressing, or multiple progressing lesions., Results: Of the 237 total patients identified, 208 (88%) had stage IV disease, and 29 (12%) had unresectable stage III disease at the start of immunotherapy. Median OS following first resection was 21 months. Median follow-up among survivors was 23 months. Complete resection at the first operation (n = 87, 37%) was associated with improved survival compared with patients with incomplete resection (n = 150, 63%) [median OS not reached (NR) vs. 10.8 months, respectively; 95% CI: 7.3, 14.8; p < 0.0001]. Patients resected for an isolated progressing or responding tumor had a longer median survival compared with those with multiple progressing lesions (NR vs. 7.8 months, 95% CI: 6.2, 11.2; p < 0.0001)., Conclusions: Patients selected for surgical resection following checkpoint blockade have a relatively favorable survival, especially if they had a response to immunotherapy and undergo complete resection of isolated progressing or responding disease.

Background: Previous analyses of BREAK-2 and BREAK-3 showed that durable outcomes lasting ≥3 years are achievable with dabrafenib in some patients with BRAF V600-mutant metastatic melanoma (MM); however, additional follow-up is needed to fully characterise the long-term impact of dabrafenib in these patients., Methods: BREAK-2 was a single-arm phase 2 study evaluating dabrafenib in treatment-naive or previously treated BRAF V600E/K-mutant MM. BREAK-3, a randomised (3:1) phase 3 study, assessed dabrafenib versus dacarbazine in previously untreated unresectable or metastatic BRAF V600E-mutant melanoma. Five-year analyses were performed., Results: All BREAK-2 patients (N = 92 [V600E, n = 76; V600K, n = 16]) discontinued treatment by the data cutoff. Median follow-up was 13.0 months. In BRAF V600E patients, 5-year progression-free survival (PFS) and overall survival (OS) were 11% and 20%, respectively. Subsequent immunotherapy was received by 22% of patients. In BREAK-3, median follow-up was 17.0 and 12.0 months in the dabrafenib (n = 187) and dacarbazine (n = 63) arms, respectively. Thirty-seven patients (59%) receiving dacarbazine crossed over to dabrafenib following disease progression as per protocol. Five-year PFS was 12% in the dabrafenib arm; all dacarbazine-arm patients progressed or were censored by 5 years. Dabrafenib improved PFS versus dacarbazine, regardless of baseline lactate dehydrogenase levels. Five-year OS rates were 24% and 22% in the dabrafenib and dacarbazine arms, respectively. Subsequent therapy in each arm included anti-CTLA-4 (dabrafenib [24%] and dacarbazine [24%]) and/or anti-PD-1 (8% and 2%) treatment. No new safety signals were observed., Conclusions and Relevance: These data, representing extended follow-up for dabrafenib monotherapy, demonstrate that durable benefit lasting ≥5 years is achievable in a subset of patients., Trial Registration: ClinicalTrials.gov (BREAK-2, NCT01153763; BREAK-3, NCT01227889)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics., Methods: A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed., Results: A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype ( P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043)., Conclusion: Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.

Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAF V600 -mutated metastatic melanoma., Patients and Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling., Results: Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response-related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression., Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct., (©2019 American Association for Cancer Research.)

Driver mutations in oncogenes encode proteins with gain-of-function properties that enhance fitness. Heterozygous mutations are thus viewed as sufficient for tumorigenesis. We describe widespread oncogenic mutant allele imbalance in 13,448 prospectively characterized cancers. Imbalance was selected for through modest dosage increases of gain-of-fitness mutations. Negative selection targeted haplo-essential effectors of the spliceosome. Loss of the normal allele comprised a distinct class of imbalance driven by competitive fitness, which correlated with enhanced response to targeted therapies. In many cancers, an antecedent oncogenic mutation drove evolutionarily dependent allele-specific imbalance. In other instances, oncogenic mutations co-opted independent copy-number changes via the evolutionary process of exaptation. Oncogenic allele imbalance is a pervasive evolutionary innovation that enhances fitness and modulates sensitivity to targeted therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: We performed a retrospective exploratory analysis to evaluate the prognostic and predictive effect of two circulating biomarkers, BRAF V600 mutant circulating tumor DNA (ctDNA) and circulating hepatocyte growth factor (cHGF), in metastatic melanoma., Materials and Methods: This study evaluated patients from BRIM-3, a phase III trial comparing vemurafenib and dacarbazine in 675 patients with BRAF V600 mutated advanced melanoma. ctDNA was measured using droplet digital polymerase chain reaction, and cHGF was measured by enzyme-linked immunosorbent assay. Overall survival (OS) was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were estimated using Cox proportional hazards modeling. Partitioning analysis was used to group patients into risk categories., Results: Patients with elevated levels of baseline BRAF V600 ctDNA had significantly shorter median OS than those with undetectable levels of ctDNA (vemurafenib arm, 9.9 v 21.4 months, respectively, and dacarbazine arm: 6.1 v 21.0 months, respectively). Median OS was also shorter in patients with high levels of cHGF compared with those with low cHGF (vemurafenib arm, 11.9 v 17.3 months, respectively, and dacarbazine arm, 6.1 v 14.4 months, respectively). In a multivariable proportional hazards model with adjustment for lactate dehydrogenase, Eastern Cooperative Oncology Group status, disease stage, and treatment, ctDNA and cHGF were both independent prognostic factors for OS, (HR, 1.75; 95% CI, 1.35 to 2.28 for high v undetectable ctDNA; HR, 1.24; 95% CI, 1.00 to 1.53 for high v low cHGF). Using partitioning analysis, we found that patients with elevated ctDNA combined with elevated cHGF constituted the highest risk group with significantly shorter OS., Conclusion: Here, we report that BRIM-3 patients with high levels of ctDNA and cHGF have worse OS regardless of treatment and that these factors are independent prognostic markers for metastatic melanoma.

Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m 2 intravenously on day 1 of every 21-day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results A total of 129 patients were randomly assigned to receive selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two-sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion In patients with metastatic uveal melanoma, the combination of selumetinib plus dacarbazine had a tolerable safety profile but did not significantly improve PFS compared with placebo plus dacarbazine.

Both the combination of nivolumab + ipilimumab and single-agent anti-PD-1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti-PD-1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single-center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial (n = 122) or commercial use (n = 87). Baseline routine laboratory values were correlated with overall survival (OS) and overall response rate (ORR). Kaplan-Meier estimation and Cox regression were performed. Median OS was 44.4 months, 95% CI (32.9, Not Reached). A total of 110 patients (53%) responded (CR/PR). Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH, and a low neutrophil-to-lymphocyte ratio. These newly identified factors, along with those previously reported to be associated with anti-PD-1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti-PD-1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti-PD-1 alone., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy., Methods: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study., Findings: The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66-0·90] for progression-free survival and 0·74 [0·58-0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57-0·91] for progression-free survival and 0·60 [0·45-0·79] for overall survival) and immunotherapy (HR 0·75 [0·56-1·00] and 0·64 [0·47-0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65-1·17, p interaction =0·61] for progression-free survival and 1·03 [0·80-1·34, p interaction =0·01] for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 [0·40-0·70]), but no associations observed in women (HR 0·85 [0·61-1·18, p interaction =0·03])., Interpretation: Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations., Funding: ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aberrant MAPK and PI3K pathway signaling may drive the malignant phenotype in NRAS-mutant and BRAF WT NRAS WT metastatic melanoma. To target these pathways, NRAS-mutant and BRAF WT NRAS WT patients received oral trametinib at 1.5 mg daily and GSK2141795 at 50 mg daily in a two-cohort Simon two-stage design. Participants had adequate end-organ function and no more than two prior treatment regimens. Imaging assessments were performed at 8-week intervals. A total of 10 NRAS-mutant and 10 BRAF WT NRAS WT patients were enrolled. No objective responses were noted in either cohort. The median PFS and OS were 2.3 and 4.0 months in the NRAS-mutant cohort and 2.8 and 3.5 months in the wild-type cohort. Grade 3 and grade 4 adverse events, primarily rash, were observed in 25% of patients. We conclude that the combination of trametinib and GSK2141795 does not have significant clinical activity in NRAS-mutant or BRAF WT NRAS WT melanoma., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Nivolumab plus ipilimumab (nivo + ipi) is a standard treatment of advanced melanoma. Two randomized trials describe high objective response rates by Response Evaluation Criteria in Solid Tumors. The trials assessed toxic effects using the Common Terminology Criteria for Adverse Events (CTCAE), which may underestimate incidence of clinically significant immune-related adverse events (AEs)., Objective: To describe detailed toxic effects and time to treatment failure of patients with melanoma treated with nivo + ipi in a prospective cohort., Design, Setting, and Participants: A cohort of 64 adults with advanced or unresectable melanoma were examined at a single tertiary cancer and enrolled in an expanded access program of nivo + ipi conducted from December 2014 to January 2016., Interventions: Intravenous nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) administered every 3 weeks for up to 4 doses, followed by nivolumab (3 mg/kg) every 2 weeks or pembrolizumab (2 mg/kg) every 3 weeks until unacceptable toxic effects, disease progression, or complete response., Main Outcomes and Measures: Clinically significant immune-related AEs were defined as CTCAE grade 2 or higher or any immune-related AEs requiring systemic steroids. Time to treatment failure was defined as the interval between initiating therapy and the earliest of clinical progression, new locally directed or systemic treatment other than anti-programmed cell death 1 protein (anti-PD-1) monotherapy, or death., Results: Overall 64 adults with advanced or unresectable melanoma were enrolled (male to female ratio, 1:1; median [range] age, 56 [22-82] years); 25 patients (39%) received all 4 doses of nivo + ipi, and 31 patients (48%) received no maintenance anti-PD-1 therapy. Most who discontinued treatment (n = 31 [80%]) stopped because of toxic effects. Among those patients who were progression free at 12 weeks, time to treatment failure was similar between those who did or did not modify therapy for toxic effects. Fifty-eight patients (91%) had a clinically significant immune-related AE (median, 2/patient), and 46 patients (72%) required systemic steroids. Infliximab or mycophenolate was required in 16 patients (25%) for steroid-refractory immune-related AEs. Seven patients (11%) developed hyperglycemia, 32 patients (50%) had an emergency department visit, and 23 patients (36%) required a hospital admission related to an immune-related AE. Four of 31 patients (13%) who stopped combination therapy early for toxic effects developed a new, clinically significant immune-related AE more than 16 weeks after the last treatment., Conclusions and Relevance: We observed a 91% incidence of clinically significant immune-related AEs leading to frequent emergency department visits, hospitalizations, and systemic immunosuppression. Immuno-oncology trials should routinely report these metrics. Most patients do not tolerate 4 doses of nivo + ipi; however, 4 doses may not be required for clinical benefit.

Purpose: To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking mitogen-activated protein kinase kinase (MEK) inhibitors., Participants: A total of 313 fluid foci in 50 eyes of 25 patients receiving MEK inhibitors for treatment of their metastatic cancer, who had evidence of serous retinal detachments confirmed by optical coherence tomography (OCT)., Design: Single-center, retrospective cohort study., Methods: Clinical examination and OCT were used to evaluate MEK inhibitor-associated subretinal fluid. The morphology, distribution, and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation, and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings and compare choroidal thickness and visual acuity at each time point., Main Outcome Measures: Comparison of OCT characteristics of retinal abnormalities at baseline to fluid accumulation., Results: The majority of patients had fluid foci that were bilateral (92%) and multifocal (77%) and at least 1 focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into 4 morphologies, as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy, and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than 2 Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation, and fluid resolution). A strong positive interobserver correlation was obtained for choroidal thickness measurements (r = 0.97, P < 0.0001) and grading of foci morphology (r = 0.97, P < 0.0001)., Conclusion: The subretinal fluid foci associated with MEK inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK inhibitors did not cause irreversible loss of vision or serious eye damage., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Very little is known about the proportion of oncology trials that get published, the time it takes to publish them, or the reasons why oncology trials do not get published., Methods: We analyzed all clinical trials that closed to accrual at our cancer center between 2009-2013. Trials were categorized by study purpose (therapeutic vs. diagnostic), phase (pilot, phase I, II, or III), and sponsor (industrial, cooperative group, institutional, or peer-reviewed). Final publications were identified in MEDLINE and EMBASE by NCT numbers, or by querying the principal investigator. For trials not published, we surveyed the principal investigators to identify the reason for non-publication., Findings: 469 of 809 protocols (58%) had been published by November 2016. The calculated probability of publication 7 years after completing accrual was 70.4%; the calculated median time to publication was 47 months. Only 18.8% of protocols overall were estimated to be published within 2 years from completing accrual. The calculated probability of publication was higher for therapeutic trials than non-therapeutic trials, but there was no difference based on phase or sponsor. Among protocols not published, 45.3% had completed accrual, and among these, a majority had a manuscript in preparation or review, or the trial was still collecting data. Failure to publish due to a pharmaceutical sponsor was rare. 30.6% of unpublished trials had closed for various reasons before completing accrual, usually due to poor accrual or pharmaceutical sponsor issues., Interpretation: Almost 30% of trials were calculated to be unpublished by 7 years after closing to accrual at our institution. Failure to reach accrual goals was an important factor in non-publication. We have devised new institutional policies that identify trials likely not to meet accrual goals and require early closure. We should be able to shorten the time from accrual completion to publication, especially for pilot and phase I trials for which long follow up is not needed.

Background: We tested the hypothesis that a 4-month course of adjuvant dabrafenib in stage IIIC BRAF-mutated melanoma would improve 2 year RFS from 24% to 51%, and that tumor-derived cell free DNA (cfDNA) in plasma would correlate with and predict recurrence., Methods: Patients with stage IIIC BRAF V600E/K mutated melanoma who were free of disease after surgical resection received 4 months of adjuvant dabrafenib. Patients were evaluated with imaging at baseline, at the end of cycles 2, 4, 6, then every 3 months until disease relapse or 2 years, whichever came first. Serial blood samples were collected for evaluation of cfDNA at the same time., Results: 21/23 patients enrolled were evaluable; 2 patients withdrew consent during the first week of treatment. The 2 year RFS was 28.6% (95% CI 12-48%). The estimated overall survival at 2 years was 78% (95% CI 51-91%). cfDNA detection had a 53% sensitivity in relapsing patients but cfDNA detection did not provide lead-time advantage over CT scanning., Conclusion: A 4-month course of adjuvant dabrafenib did not result in a detectable improvement in 2-year RFS. cfDNA was less sensitive than standard CT imaging and did not provide a lead-time advantage in detecting relapse., Competing Interests: CONFLICTS OF INTEREST MA Postow is on the advisory board for Novartis. PB Chapman is on the advisory board for Merck and consults for Daiichi, Roche and Genetech. JD Wolchok is a consultant for BMS, Merck, and Amgen. JJ Harding has consulted for BMS. Other authors with nothing to disclose.

Purpose: The clinical use of BRAF inhibitors in patients with melanoma is limited by intrinsic and acquired resistance. We asked whether next-generation sequencing of pretreatment tumors could identify coaltered genes that predict for intrinsic resistance to BRAF inhibitor therapy in patients with melanoma as a prelude to rational combination strategies., Patients and Methods: We analyzed 66 tumors from patients with metastatic BRAF -mutant melanoma collected before treatment with BRAF inhibitors. Tumors were analyzed for > 250 cancer-associated genes using a capture-based next-generation sequencing platform. Antitumor responses were correlated with clinical features and genomic profiles with the goal of identifying a molecular signature predictive of intrinsic resistance to RAF pathway inhibition., Results: Among the 66 patients analyzed, 11 received a combination of BRAF and MEK inhibitors for the treatment of melanoma. Among the 55 patients treated with BRAF inhibitor monotherapy, objective responses, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST), were observed in 30 patients (55%), with five (9%) achieving a complete response. We identified a significant association between alterations in PTEN that would be predicted to result in loss of function and reduced progression-free survival, overall survival, and response grade, a metric that combines tumor regression and duration of treatment response. Patients with melanoma who achieved an excellent response grade were more likely to have an elevated BRAF -mutant allele fraction., Conclusion: These results provide a rationale for cotargeting BRAF and the PI3K/AKT pathway in patients with BRAF -mutant melanoma when tumors have concurrent loss-of-function mutations in PTEN . Future studies should explore whether gain of the mutant BRAF allele and/or loss of the wild-type allele is a predictive marker of BRAFi sensitivity., Competing Interests: PTEN Loss-of-Function Alterations Are Associated With Intrinsic Resistance to BRAF Inhibitors in Metastatic MelanomaThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc.Federica CatalanottiNo relationship to discloseDonavan T. ChengEmployment: Illumina, Gilead Sciences (I) Stock and Other Ownership Interests: Illumina, Gilead Sciences (I)Alexander N. ShoushtariConsulting or Advisory Role: Vaccinex, Castle Biosciences, Immunocore Research Funding: Bristol-Myers Squibb, Immunocore Travel, Accommodations, Expenses: Bristol-Myers SquibbDouglas B. JohnsonConsulting or Advisory Role: Bristol-Myers Squibb, Genoptix, Merck Research Funding: Incyte Patents, Royalties, Other Intellectual Property: Intellectual property and patents pending surrounding use of MHC-II and response to immune therapyKatherine S. PanageasNo relationship to discloseParisa MomtazNo relationship to discloseCatherine HighamNo relationship to discloseHelen H. WonNo relationship to discloseJames J. HardingNo relationship to discloseTaha MerghoubNo relationship to discloseNeal RosenStock and Other Ownership Interests: Beigene, Wellspring, Kura Honoraria: Novartis, Eli Lilly, Bayer Consulting or Advisory Role: AstraZeneca, Takeda-Millennium, Daiichi Sankyo, Chugai Pharma Research Funding: Wellspring/Araxes, Chugai Pharma Travel, Accommodations, Expenses: PlexxikonJeffrey A. SosmanHonoraria: Amgen, Merck, Array BioPharma Consulting or Advisory Role: Amgen, Merck, Array BioPharmaMichael F. BergerConsulting or Advisory Role: Cancer Genetics, SequenomPaul B. ChapmanHonoraria: Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Provectus, Momenta Pharmaceuticals, Daiichi Sankyo Consulting or Advisory Role: Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Daiichi Sankyo, Provectus, Momenta Pharmaceuticals Research Funding: GlaxoSmithKline, Genentech, Bristol-Myers Squibb, Pfizer Travel, Accommodations, Expenses: Bristol-Myers SquibbDavid B. SolitHonoraria: Loxo, Pfizer Consulting or Advisory Role: Pfizer, Loxo, (© 2017 by American Society of Clinical Oncology.)

Melanoma patients with BRAF V 600E -mutant tumors display striking responses to BRAF inhibitors (BRAFi); however, almost all invariably relapse with drug-resistant disease. Here, we report that microRNA-125a (miR-125a) expression is upregulated in human melanoma cells and patient tissues upon acquisition of BRAFi resistance. We show that miR-125a induction confers resistance to BRAF V 600E melanoma cells to BRAFi by directly suppressing pro-apoptotic components of the intrinsic apoptosis pathway, including BAK1 and MLK3. Apoptotic suppression and prolonged survival favor reactivation of the MAPK and AKT pathways by drug-resistant melanoma cells. We demonstrate that miR-125a inhibition suppresses the emergence of resistance to BRAFi and, in a subset of resistant melanoma cell lines, leads to partial drug resensitization. Finally, we show that miR-125a upregulation is mediated by TGFβ signaling. In conclusion, the identification of this novel role for miR-125a in BRAFi resistance exposes clinically relevant mechanisms of melanoma cell survival that can be exploited therapeutically., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Pathologic stage II melanoma patients have variable outcomes when divided by substage. We hypothesized that an understanding of the patterns of initial relapse by substage will better inform follow-up guidelines., Methods: We performed a retrospective review of 738 adult patients with pathologic stage II cutaneous melanoma treated at Memorial Sloan Kettering Cancer Center between 1993 and 2013. Clinical records were reviewed to determine time, location, and method of detection of initial relapse., Results: At a median follow-up of 52 months, 219 patients relapsed. Relapses were detected more frequently in higher substages. Initial relapses were most commonly local/in-transit for IIA and IIB and systemic for IIC. Lung and brain were the most frequent sites of systemic relapse. Patient-detection was the most common method of relapse detection (59%) in all substages. The 5-year cumulative incidence for patient-detected relapse was 13.6% for IIA, 18.9% for IIB, and 23.3% for IIC and for image-detected relapse was 3.4, 7.9, and 16.6%, respectively. The 5-year cumulative incidence for physician-detected relapse was less than 10% across all substages and leveled off at 3 years for stage IIA and IIB and 2 years for stage IIC., Conclusions: Relapses were most frequently patient-detected in all stage II substages, highlighting the importance of patient education and self-examination. The highest yield for routine imaging is in stage IIC patients during the first 4 years. Physician examination is unlikely to detect relapses beyond 3 years for stage IIA and IIB and beyond 2 years for stage IIC patients.

There are very few data available regarding the pattern of first metastases in resected mucosal melanomas (MMs) as well as the response of advanced MM to cytotoxic therapy. A retrospective, single-institution cohort was assembled of all patients with advanced/unresectable MM between 1995 and 2012 who had received systemic therapy with available imaging (N=81). Responses to first-line and second-line systemic therapy were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The relationship between response, overall survival, and clinical covariates was investigated using Cox proportional hazards regression. Primary sites included anorectal (N=31, 38%), vulvovaginal (N=28, 35%), head and neck (N=21, 26%), and gallbladder (N=1, 1%) mucosa. Seven percent of patients had their first relapse in the brain. Cytotoxic therapy represented 82 and 51% of first-line and second-line regimens. The best response achieved in the first-line setting was similar for single-agent [10%; 95% confidence interval (CI): 1-32%] and combination alkylator therapy (8%; 95% CI: 2-21%). Median overall survival from first-line treatment was 10.3 months (95% CI: 8.7-13.9 months). Patients with elevated lactic dehydrogenase [hazard ratio (HR): 1.87, 95% CI: 1.10-3.19, P=0.020] and Eastern Cooperative Oncology Group performance status 1-2 (HR: 1.69, 95% CI: 1.05-2.72, P=0.030) had a higher risk of death, whereas patients with 12-week objective responses had a lower risk of death (HR: 0.12, 95% CI: 0.04-0.41, P<0.001). Cytotoxic systemic therapy has modest activity in advanced/unresectable MM, belying its adjuvant benefit. Patients whose tumors have an objective response to therapy have a lower probability of death. Brain imaging should be considered in routine surveillance.

The Common Terminology Criteria for Adverse Events (CTCAE) were developed to document the adverse effects of chemotherapy but are now also used to document immune-related adverse events (irAE). Characterization of irAE by the CTCAE has implications for determining dose-limiting toxicity (DLT) and, consequently, the recommended phase II dose (RP2D) of investigational agents. In the phase I trial of nivolumab + ipilimumab, an asymptomatic increase in lipase was the primary DLT that informed the RP2D. We performed a retrospective study of 119 patients with melanoma who were treated at Memorial Sloan Kettering Cancer Center with the combination of nivolumab + ipilimumab to investigate the relationship between asymptomatic grade 3 or higher increases in amylase and/or lipase and pancreatitis, a known irAE. Of the 119 patients, there were only two cases of pancreatitis, representing 20% of patients with grade 3 or higher amylase, 6.3% of patients with grade 3 or higher lipase, and 20% of patients with grade 3 or higher elevations of both enzymes. The application of the CTCAE, especially in grading independent lab values, should be considered carefully in clinical trials of novel immunotherapeutic agents., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Tumor-derived cell free DNA (cfDNA) can be detected in plasma. We hypothesized that mutated BRAF V600 cfDNA could be quantified in the cerebrospinal fluid (CSF) of patients with central nervous system (CNS) metastases. We collected CSF from patients with BRAF V600E or K-mutated melanoma (N=8) or BRAF V600E mutated Erdheim-Chester Disease (ECD) (N=3) with suspected central nervous system (CNS) involvement on the basis of neurological symptoms (10/11), MRI imaging (8/11), or both. Tumor-derived cfDNA was quantified by digital PCR in the CSF of 6/11 patients (range from 0.15-10.56 copies/μL). Conventional cytology was negative in all patients except in the two patients with markedly elevated levels of tumor-derived cfDNA. In 2 patients with serial measurements, CSF tumor-derived cfDNA levels reflected response to treatment or progressive disease. CSF tumor-derived cfDNA has the potential to serve as a diagnostic tool that complements MRI and may be more sensitive than conventional cytology.

False negative result remains an ongoing problem in direct gene sequencing of cancers. It is important to use the appropriate mutation detection method most appropriate to each circumstance and the available tissue. Here, we report a patient with melanoma of unknown primary with metastases to spleen and bone marrow, who was tested negative for Cobas BRAF V600E mutation, whose cancer progressed on antiprogrammed death 1 (PD1) receptor monoclonal antibody therapy. Subsequent VE1 immunohistochemistry was positive for BRAF V600E mutation, and the tumor responded dramatically to v-Raf murine sarcoma viral oncogene homolog B (BRAF)/Mitogen-activated protein kinase inhibitor combination therapy. This demonstrates how alternative BRAF testing methodology could produce results that can influence treatment choice and the outcome.

The aim of this study was to test the hypothesis that inhibiting mammalian target of rapamycin and insulin-like growth factor-1 receptor would be efficacious in metastatic uveal melanoma. This was a phase 2 trial of everolimus 10 mg daily plus pasireotide long-acting release 60 mg every 28 days enrolling patients with progressive, metastatic uveal melanoma to treatment until progression by Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) or unacceptable toxicity. The primary endpoint was clinical benefit rate, defined as any objective response or RECIST 1.1 stable disease at 16 weeks. A subset of patients underwent baseline indium-111-octreotide scans. A total of 14 patients were enrolled, of which 13 were evaluable for the primary endpoint, before the study was terminated due to poor accrual. Three of 13 (26%) patients obtained clinical benefit. Seven of 13 (54%) had stable disease lasting for a median of 8 weeks (range: 8-16 weeks). Grade 3 adverse events deemed at least possibly related to study drugs were hyperglycemia (n=7), oral mucositis (n=2), diarrhea (n=1), hypophosphatemia (n=1), and anemia (n=1). Seven of 14 (50%) patients required at least one dose reduction due to toxicity. Seven of eight (88%) patients with baseline indium-111-octreotide scans had at least one avid lesion, with significant intrapatient heterogeneity. There was a trend toward an association between octreotide avidity and cytostatic response to therapy (P=0.078). The combination of everolimus and pasireotide has limited clinical benefit in this small metastatic uveal melanoma cohort. Dose reductions for side effects were common. Further investigation into the relationship between somatostatin receptor expression and cytostatic activity of somatostatin analogues is warranted.

The relatively low success rate of phase II oncology trials in predicting success of novel drugs in phase III trials and in gaining regulatory approval may be due to reliance on the endpoint of response rate defined by the RECIST. The neoadjuvant treatment paradigm allows the antitumor activity of a novel therapy to be determined on a pathologic basis at the time of surgery instead of by RECIST, which was not developed to guide clinical decision making or correlate with long-term outcomes. Indeed, the FDA endorsed pathologic complete response (pCR) as a surrogate for overall survival (OS) in early-stage breast cancer and granted accelerated approval to pertuzumab based on this endpoint. We propose that pCR is a biologically rational method of determining treatment effect that may be more likely to predict OS. We discuss some advantages of the neoadjuvant trial design, review the use of neoadjuvant therapy as standards of care, and consider the neoadjuvant platform as a method for drug development. Clin Cancer Res; 22(10); 2323-8. ©2016 AACR., (©2016 American Association for Cancer Research.)

An increased interest has been expressed in finding predictive biomarkers that can guide treatment options for both mutation carriers and noncarriers. The statistical assessment of variation in treatment benefit (TB) according to the biomarker carrier status plays an important role in evaluating predictive biomarkers. For time-to-event endpoints, the hazard ratio (HR) for interaction between treatment and a biomarker from a proportional hazards regression model is commonly used as a measure of variation in TB. Although this can be easily obtained using available statistical software packages, the interpretation of HR is not straightforward. In this article, we propose different summary measures of variation in TB on the scale of survival probabilities for evaluating a predictive biomarker. The proposed summary measures can be easily interpreted as quantifying differential in TB in terms of relative risk or excess absolute risk due to treatment in carriers versus noncarriers. We illustrate the use and interpretation of the proposed measures with data from completed clinical trials. We encourage clinical practitioners to interpret variation in TB in terms of measures based on survival probabilities, particularly in terms of excess absolute risk, as opposed to HR. Clin Cancer Res; 22(9); 2114-20. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purpose: Surrogate endpoints are needed that correlate with overall survival (OS). We analyzed individual patient tumor data from a phase III trial of vemurafenib versus dacarbazine (BRIM3) to identify criteria for tumor measures that correlated with OS. Correlates were validated using a separate data set from a phase II trial of vemurafenib (BRIM2)., Experimental Design: Deidentified tumor measurements and OS data from BRIM3 and from BRIM2 were analyzed. Target tumor measurement data and nontarget tumor data were available from pretreatment, weeks 6,12, and every 9 weeks thereafter. In the BRIM3 data set, associations of OS with both early tumor response (first 12 weeks) and time to progression (TTP) were assessed. Different definitions of response and progression were explored. Findings were validated using the BRIM2 data set., Results: Thresholds of early response were explored ranging from any degree of tumor shrinkage to 100% tumor shrinkage. Correlation was weak at all thresholds tested. TTP, however, was more strongly correlated with OS. The strongest correlation was seen when progression was defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors. This was confirmed by similar analyses in the BRIM2 cohort., Conclusions: TTP defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors was more strongly associated with OS than early tumor shrinkage in melanoma patients treated with RAF inhibitor. In future trials, consideration should be given to replacing response rate with TTP or PFS as preferable clinical endpoints in early-phase studies., (©2015 American Association for Cancer Research.)