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Background: Combination immune checkpoint blockade targeting PD-1 and CTLA-4 leads to high response rates and improved survival in advanced cutaneous melanoma (CM). Less is known about the efficacy of this combination in acral lentiginous melanoma (ALM)., Objectives: To determine the efficacy of combination immune checkpoint blockade targeting PD-1 and CTLA-4 in a real-world, diverse population of ALM., Methods: This multi-institutional retrospective study analyzed patients with histologically confirmed ALM treated with the combination of PD-1 and CTLA-4 inhibitors between 2010-2022. The primary objective of the study was objective response rate (ORR) per RECIST criteria. The secondary objectives were progression-free survival (PFS) and overall survival (OS)., Results: In total, 109 patients with advanced ALM treated with combined PD-1 and CTLA-4 blockade in any line of treatment were included. The majority of patients had stage IV disease (n=81, 74.2%). The ORR for the entire cohort was 18.3% (95% CI 11.6-26.9%), with 9 (8.3%) complete responses (CR) and 11 (10.1%) partial responses (PR). An additional 22 patients (20.2%) had stable disease (SD), and the disease control rate (DCR) was 38.5%. The median PFS was 4.2 months [95% CI 3.25-5.62], while the median OS was 17 months [95% CI 12.4%-23.1%]. A total of 95 patients (87.2%) had a treatment-related adverse event, with 40.4% (n=44/109) experiencing at least one grade 3 or 4 toxicity. Elevated LDH (p=.04), 2+ lines of prior therapy (p=.03), and Asian race/ethnicity (p=.04) were associated with worse OS, while Hispanic/Latino race/ethnicity was associated with better OS (p=.02)., Conclusions: Combination of PD-1 and CTLA-4 blockade is less effective for ALM, as compared to CM, despite similar toxicity. Asian patients, in particular, appear to derive lower benefit from this regimen. Novel treatment approaches are needed for this rare melanoma subtype., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Our goal was to compare molecular and immune profiles of vulvovaginal melanoma (VVM) with cutaneous melanoma (CM) and explore the significance of immune checkpoint inhibitor (ICI) agents on survival., Methods: Samples from VVM and CM tumors underwent comprehensive molecular and immune profiling. Treatment and survival data were extracted from insurance claims data and OS was calculated from time of ICI treatment to last contact. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons., Results: Molecular analysis was performed on 142 VVM and 3823 CM tumors. VVM demonstrated significantly (q < 0·01) less frequent BRAF and more frequent KIT, ATRX, and SF3B1 mutations. Alterations in pathways involving DNA damage and mRNA splicing were more common in VVM, while alterations in cell cycle and chromatin remodeling were less common. Immunogenicity of VVM was lower than CM, with an absence of high TMB (0% vs 46.9%) and lower PD-L1 positivity (18·0% vs 29·5%). Median immune checkpoint gene expression was lower in VVM, as were cell fractions for type I macrophages and CD8+ T-cells(q < 0·01). Myeloid dendritic cells were increased in VVM(q < 0·01). Median OS was shorter for VVM than for CM patients treated with ICIs (17·6 versus 37·9 months, HR:1·65 (95% CI 1·02-2·67) p = 0·04)., Conclusions: VVM has a distinct molecular and immune profile compared to CM, which may contribute to the worse survival in VVM compared to CM patients treated with ICI therapy. Though ICIs have been a mainstay of treatment in recent years, our findings suggest that new therapeutic strategies are needed., Competing Interests: Declaration of competing interest SW and JX are employees of Caris Life Sciences. GTG reports grants from Exelixis and Luceno Dynamics; fees for consulting for Bristol Myers Squibb, Merck, Novartis, Regeneron, Immunocore, Iovance, Lyell Immunopharma, Eisai, Incyte, Pfizer, Sapience Therapeutics, Exicure, and Genentech; fees for payment/honoraria from Immunocore; fees for participation on a Data Safety Monitoring Board/Advisory Board for Huyabio. GKI reports fees for consulting for Sanofi and Pfizer; fees for payment/honoraria from Merck, Sanofi, and Regeneron; fees for support for attending meetings from BMS and Sanofi; fees for participation on a Data Safety Monitoring Board/Advisory Board from Replimune, Castle, and Regeneron; institutional research support from BMS, Regeneron, Replimune, Pfizer, InstilBio, Checkmate Pharmaceuticals, and Xencor. TJH reports consulting fees from J & J, Clovis, AstraZeneca, GSK, Roche Genentech, Caris, Genelux, Aravive, Merck, Eisai, and Seagen. BKE reports fees for participation on a Data Safety Monitoring Board/Advisory Board for Merck and GSK. JB reports fees for consulting for Caris, AstraZeneca, Genentech, GSK Tesaro, and Verastem; fees for participation on a Data Safety Monitoring Board/Advisory Board from Caris, AstraZeneca, GSK Tesaro, and Verastem; fees for a leadership/fiduciary role from American Association of Gynecologic Laparoscopy, and Society of Gynecologic Oncology. The remaining authors have nothing to disclose. All of these disclosures mentioned above are unrelated to this study. No author declares a conflict of interest related to the study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma., Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881., Findings: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups., Interpretation: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting., Funding: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA., Competing Interests: Declaration of interests JSW has been a consultant for AstraZeneca, Bristol Myers Squibb, Merck, and Regeneron; has received research grants (to institution) from Merck and Moderna; has received travel support from Moderna; and is named on a PD-1 patent with Biodesix (not related to this trial). MSC has been a consultant for Amgen, Bristol Myers Squibb, Eisai, Ideaya, Merck Sharp & Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck Serono, and Sanofi; and has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Sanofi. AK has received honoraria from Merck Sharp & Dohme. TaM has received research grants (to institution) from Moderna; has been a consultant or served on a data safety monitoring–advisory board for AstraZeneca, Bristol Myers Squibb, Eisai, GlaxoSmithKline, Merck Sharp & Dohme, and Novartis; has received payment or honoraria from AstraZeneca; and has received travel support from AstraZeneca and Bristol Myers Squibb. MHT has received research grants from Bristol Myers Squibb, Exelixis, and Merck; has been a consultant for Cascade Prodrug, Incyte, and Immune-Onc; has received payment or honoraria from Array Biopharma, Bayer, Blueprint Medicines, Bristol Myers Squibb, Eisai, Merck, Novartis, and Sanofi/Regeneron; and has served on a data safety monitoring or advisory board for Oncosec. KBK has received research grants from Merck and Moderna. MMc has received research grants (to institution) from Aadi Biosciences, Alpine Immune Sciences, Arcus Biosciences, Arvinas, Ascentage Pharma Group, ASCO, Astellas, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, Dragonfly Therapeutics, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, G1 Therapeutics, Genentech–Roche, Gilead Sciences, GlaxoSmithKline, IDEAYA Biosciences, Ikena Oncology, ImmVira Pharma, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Merck, Mereo BioPharma, Metabomed, Moderna, NBE Therapeutics, Nektar, Novartis, OncoC4, Oncorus, PACT Pharma, Pfizer, Plexxikon, Poseida, Prelude Therapeutics, Pyramid Biosciences, Regeneron, Sapience Therapeutics, Scholar Rock, Seattle Genetics, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, TopAlliance Biosciences, and Xilio; and has been a consultant (payment to institution) for Castle Biosciences, Eisai, IQVIA, Merck, Moderna, and Pfizer. GVL has been a consultant for Agenus, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal (Sandoz Company), Highlight Therapeutics, Innovent Biologics USA, Merck Sharp & Dohme, Novartis, OncoSec, PHMR, Pierre Fabre, Provectus, Qbiotics, and Regeneron; has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Pierre Fabre; and has served on an advisory board for Bristol Myers Squibb, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, Provectus, Qbiotics, and Regeneron. RJS has received research grants from Merck; has royalties or licences from Up-to-Date; has been a consultant for Marengo, Merck, Novartis, Pfizer, and Replimune; and has served on a data safety monitoring or advisory board for Duke University and Yale University. MF has received research grants from Moderna; and has served on an advisory board for Bristol Myers Squibb, Instil Bio, Merck, Novartis, and Regeneron. CLC has been a consultant for and has served on an advisory board for EMD Serono, Eisai, Iovance, Merck, Regeneron, and Replimune. AP has had a leadership position in Cota Healthcare and OMI; and holds stock options in Celularity and OMI. ThM has received research grants from Agenus, Anaveon, Bioatla, Bristol Myers Squibb, Day One, Genentech, InflaRx, Iovance, Merck, Regeneron, Replimune, Trisalus, and Ultimovacs; has received payment or honoraria from Honor Health; and has served on a data safety monitoring or advisory board for University of Colorado Cancer Center. VA has received speaker fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Pierre Fabre; has received travel support from Bristol Myers Squibb and Pierre Fabre; and has served on an advisory board for Bristol Myers Squibb, Immunocore, Limbic, Merck Sharp & Dohme, Novartis, and QBiotics. GTG has received research grants (to institution) from Exelixis and Lucerno Dynamics; has been a consultant for Bristol Myers Squibb, Eisai, Exicure, Genentech, Immunocore, Incyte, Iovance, Lyell Immunopharma, Merck, Novartis, Regeneron, and Sapience Therapeutics; has received payment or honoraria from Immunocore; and has served on a data safety monitoring or advisory board for Huyabio. JJL has received research support (all to institution for clinical trials) from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck Sharp & Dohme, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; has been a consultant for 7 Hills, AbbVie, Actym, Alnylam, Alphamab Oncology, Arch Oncology, Atomwise, Bayer, Bright Peak, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Duke Street Bio, Eisai, EMD Serono, Endeavor, Exo, Flame, Fstar, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, Kanaph, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, Inzen, IO Biotech, Macrogenics, Mavu, Merck Sharp & Dohme, Mersana, Nektar, NeoTx, Novartis, Onc.AI, OncoNano, Partner, Pfizer, Pioneering Medicines, PsiOxus, Pyxis, RefleXion, Regeneron, Ribon, Roivant, Saros, Servier, STINGthera, Stipe, Synlogic, Synthekine, Tempest, and Xilio; has served on an advisory board for AbbVie, Evaxion, and Immutep; is a board member of the Society for Immunotherapy of Cancer; holds stock options in Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, and Tempest; and has applied for patents (both provisional) for Serial 15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: diagnostic, prognostic and therapeutic uses thereof). ST has received speaker fees from Bristol Myers Squibb and honoraria from Pfizer; and has served as a paid expert witness for malpractice cases. EIB has received research grants (to institution) from Genentech; has been a consultant for Instilbio, Iovance, Merck, Nektar, Novartis, Sanofi, and Xilio; and has served on a data safety monitoring–advisory board for Asher. JAH is an employee of and holds stock options in Merck & Co, Rahway, NJ, USA. MH is an employee of Merck &Co, Rahway, NJ, USA. MaM, LZ, CR-T, PH, and PA are employees of and hold stock options in Moderna. IF is an employee of and holds stock options in Moderna; and was a co-inventor on the individualised neoantigen therapy Moderna patent. VS is an employee of Moderna; and holds stock options in AbbVie and Moderna. MB is an employee of Moderna; and holds stock options in Bristol Myers Squibb, Moderna, and Novartis. RSM is an employee of and holds stock and options in Moderna; and was a co-inventor on the individualised neoantigen therapy patent and other seminal Moderna patents. TZ is an employee of and holds stock options in Moderna; was a co-inventor on some seminal Moderna patents; and has served as a paid board member for Adaptimmune and Teva Pharmaceuticals. GA, TTT, MS, and JS declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor]., Experimental Design: Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks)., Results: A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, n = 49) or parsaclisib (Part 1, n = 83; Part 2, n = 27) plus pembrolizumab. The maximum tolerated/pharmacologically active doses were itacitinib 300 mg once daily and parsaclisib 30 mg once daily. Most common itacitinib treatment-related adverse events (TRAE) were fatigue, nausea, and anemia. Most common parsaclisib TRAEs were fatigue, nausea, diarrhea, and pyrexia in Part 1, and fatigue, maculopapular rash, diarrhea, nausea, and pruritus in Part 2. In patients receiving itacitinib plus pembrolizumab, four (8.2%) achieved a partial response (PR) in Part 1. Among patients receiving parsaclisib plus pembrolizumab, 5 (6.0%) achieved a complete response and 9 (10.8%) a PR in Part 1; 5 of 27 (18.5%) patients in Part 2 achieved a PR., Conclusions: Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors., Significance: PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset., (© 2023. The Author(s).)

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAF V600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others., Competing Interests: Competing interests: CA—Other: Stock Pfizer, Advisory Board: Iovance and Merck, Memorial Sloan Kettering Cancer Center. EIB—Consulting Fees: Nektar, Instilbio, Novartis, Xilio, Sanofi, Merck, and Iovance. DD—IP Rights: US Patent 63/124,231, Compositions and Methods for Treating Cancer, December 11, 2020, US Patent 63/208,719, Compositions and Methods For Determining Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer, June 9, 2021; Consulting Fees: Checkmate Pharmaceuticals, Finch, Shionogi, Vedanta Biosciences; Fees for Non CE Services: Medical Learning Group (MLG), Clinical Care Options (CCO); Contracted Research: Arcus, Checkmate Pharmaceuticals, CellSight Technologies, Immunocore, Merck, Tesaro/GSK. GTG—Consulting Fees: Bristol Myers Squibb, Regeneron, Genentech, Novartis, Merck, Sapience Therapeutics, Exicure, Eisai, Iovance Biotherapeutics, Lyell Immunopharma, and HUYABIO International; Contracted Research: Exelixis (institutional support), Lucerno Dynamics. OH—Researcher: Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, Cytomx, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck Serono, Nextcure, Novartis, Pfizer, Regeneron, Seattle Gen, Torque, Zelluna; Consultant Advisor Speaker: Alkermes, Amgen, Bactonix, Beigene, Bioatla, BMS, Esai, Roche Genentech, Georiamune, GigaGen, Grit Bio, GSK, Idera, Immunocore, Incyte, Instilbio, IO Biotech, Iovance, Janssen, KSQ, Merck, Moderna, Novartis, Obsidian, Pfizer, Regeneron, Sanofi, Seattle Gen, Tempus, Vial Health Tech, Zelluna; Independent Contractor: Alkermes, Amgen, Bactonix, Beigene, Bioatla, BMS, Esai, Roche Genentech, Georiamune, GigaGen, Grit Bio, GSK, Idera, Immunocore, Incyte, Instilbio, IO Biotech, Iovance, Janssen, KSQ, Merck, Moderna, Novartis, Obsidian, Pfizer, Regeneron, Sanofi, Seattle Gen, Tempus, Vial Health Tech, Zelluna; Publically Traded Stocks: Bactonix. TJH—Contracted Research: Genentech, SkylineDX. BI—Consulting Fees: Johnson & Johnson, Volastra Therapeutics, Merck, AstraZeneca, Eisai and Janssen Pharmaceuticals; research funding to Columbia University from Alkermes, Arcus Biosciences, Checkmate Pharmaceuticals, Compugen, Immunocore, and Synthekine. DBJ—IP Rights: MHC-II for use as immunotherapy biomarker, Abatacept as treatment for irAEs; Consulting Fees: BMS, Catalyst, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoIngineering, Novartis, Oncosec, Pfizer, Targovax; Contracted Research: BMS, Incyte. RPK—Consulting Fees: Regeneron. JJL—Researcher: AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; Consultant Advisor Speaker: AbbVie, Agenus, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic, Synthekine 7 Hills, Affivant, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest, AbbVie, Agenus, Amgen, Immutep, Evaxion. TCM—Consulting Fees: Merck, BMS, GigaGen, OncoSec; Pfizer – Scientific Advisory Board. MJM—Consulting Fees: AstraZeneca, Nektar Therapeutics, Istari Oncology, Immunai, Xilio Therapeutics; Fees for Non CE Services: Bristol Myers Squibb (served as a speaker). ACP—Consulting Fees: Regeneron, BMS, Merck; Fees for Non CE Services: BMS; Contracted Research: Merck, BMS, Iovance, Regeneron, Takeda, Ideaya, Replimune: All payments to institution. KMR—Consulting Fees: BMS, Merck, Eisai, Immunocore. AKSS—Consulting Fees: Novartis, Pfizer, Regeneron, Iovance. Contracted Research: Ascentage, Ideaya, Regeneron, Bristol Myers Squibb, Immunocore, Merck, Nektar, Olatec, Replimune, Seagen. KS—Contracted Research: Trials at Norris Cotton Cancer Center, Syndax, Provectus, OmniSeq, BrightPath Biotherapeutics, Ludwig Institute of Cancer Research, Hlsinn, AbbVie, BMS, OncoSec, Ultimovacs, Altellas, AstraZeneca, Xencor, Exicure, Numab, Checkmate Pharmaceuticals, Natera. RJS—Reseracher: Merck (research funding); Consultant Advisor Speaker: BMS, Merck, Novartis, Pfizer; Other: Faculty for SCION Workshop. JT—Consulting Fees: GSK, Genentech, BMS, Akoya Biosciences, Merck, AstraZeneca, Compugen, Lunaphore; Contracted Research: BMS, Akoya Biosciences; Other: Akoya Biosciences; Other Details: Patent pending for multiplexing imaging strategy; Ownership Interest Less Than 5 Per Cent: Akoya Biosciences. HAT—Consulting Fees: Genentech, BMS, Novartis, Merck, Eisai, Karyopharm, Boxer Capital, Iovance, Jazz Pharmaceuticals, Medicenna; Contracted Research: Genentech, BMS, Novartis, Merck, GSK, EMD Serono, Eisai, Dragonfly Therapeutics, RAPT Therapeutics. JKT—Nothing to Disclose. CV—Nothing to Disclose. SAW—Consulting Fees: Lyell; Contracted Research: research funds to institution from BMS and Apexigen. MKW—Consulting Fees: Merck, Pfizer, Bristol Myers Squibb, Regeneron, EMD-Serono, ExiCure, Castle Biosciences, Adagene. SITC Staff—CG, AK, NL, SM-W—Nothing to Disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown., Methods: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated., Results: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group., Conclusions: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies., Methods: Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers., Results: High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127-GARP- T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse., Conclusions: Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation., Trial Registration Number: NCT01176474 and NCT02970981., Competing Interests: Competing interests: Conflicts of Interest Disclosures: NIK: Advisory Board (Bristol Myers Squibb, Regeneron, Merck, Jounce Therapeutics, Iovance Biotherapeutics, Genzyme, Novartis, Castle Biosciences, Nektar, Instill Bio); Steering or Scientific Committee Member (Nektar, Regeneron, Replimmune, Bristol Myers Squibb, National Comprehensive Cancer Network via Pfizer); Data Safety Monitoring Committee (AstraZeneca, Incyte); Research support (all to institution—Bristol Myers Squibb, Merck, Celgene, Regeneron, Replimmune, Novartis, HUYA Bioscience, GlaxoSmithKline); Common stock (Bellicum, Amarin, Asensus Surgical). ZE: Advisory Board (Pfizer, Array, OncoSec, Regeneron, Genentech, Novartis, Eisai, Natera); Research funding (Novartis, Pfizer). YK: No disclosures to report. BC: No disclosures to report. JDG: President, Statistical Science and Technology Associates; Consultant (Tizona); BMS retirement W2 income; Pfizer pension. MV: No disclosures to report. RF: No disclosures to report. KM: No disclosures to report. TK: No disclosures to report. PB: No disclosures to report. AS: No disclosures to report. EM: No disclosures to report. CMA: No disclosures to report. GTG: Consulting fees from Bristol Myers Squibb, Merck, Regeneron, Esai, Genentech, Novartis, Sapience Therapeutics and Exicure; Institutional research support from Exelixis and Lucerno Dynamics. RK: Advisory Board (Bristol Myers Squibb, Regeneron, Merck, InstilBio, Novartis, Pfizer); Research funding from Bristol Myers Squibb, Regeneron, Merck). JM: Support by NIH/NCI K08CA252164; Research support to Moffitt Cancer Center from Microba Life Science, Morphogenesis, Dr Miriam and Sheldon Adelson Medical Research Foundation, and The Jackson Laboratory. ASB: Advisory board (Deciphera, Bayer). AP: Consultant for BMS, Merck and Regeneron. AR: No disclosures to report. DMW: Owns stocks in BMS (less than $1000). JW: Received less than $10,000 dollars per annum from Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, ImCheck, Sellas, Evaxion and EMD Serono and $10,000–$25,000 dollars from BMS for membership on Advisory Boards; Equity in Biond, Evaxion, OncoC4, Instil Bio and Neximmune; on scientific advisory boards for CytoMx, Incyte, ImCheck, Biond, Sellas, Instil Bio OncoC4 and Neximmune and was remunerated between $10,000–$75,000 dollars; NYU, but not me personally, received research support from BMS, Merck, GSK, Moderna, Pfizer, Novartis and AstraZeneca; Moffitt Cancer Center filed a patent on an IPILIMUMAB biomarker and on TIL preparation that I am named on, and Biodesix filed a PD-1 patent that I was named on; I receive less than $6000 yearly in royalties., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors., Patients and Methods: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed., Results: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062)., Conclusions: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633., (©2022 The Authors; Published by the American Association for Cancer Research.)

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., Competing Interests: Competing interests: GKI reports having consulting/advisory board roles with Boehringer-Ingelheim, Novartis, BMS, Castle Biosciences, Regeneron, Sanofi; receiving research support from Regeneron, Array, Idera, Roche/Genentech, Replimune, Xencor, InstilBio, and having speaker roles for Merck. DYR reports having consulting/advisory board roles with Castle Biosciences. JCH reports having consulting/advisory board roles with Regeneron. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Invasive melanoma is the deadliest type of skin cancer, with 101,110 expected cases to be diagnosed in 2021. Recurrent BRAF and NRAS mutations are well documented in melanoma. Biologic implications of gene fusions and the efficacy of therapeutically targeting them remains unknown. Retrospective review of patient samples that underwent next-generation sequencing of the exons of 592 cancer-relevant genes and whole transcriptome sequencing for the detection of gene fusion events and gene expression profiling. Expression of PDL1 and ERK1/2 was assessed by immunohistochemistry (IHC). There were 33 (2.6%) cases with oncogenic fusions (14 novel), involving BRAF , RAF1 , PRKCA , TERT , AXL , and FGFR3 . MAPK pathway-associated genes were over-expressed in BRAF and RAF1 fusion-positive tumors in absence of other driver alterations. Increased expression in tumors with PRKCA and TERT fusions was concurrent with MAPK pathway alterations. For a subset of samples with available tissue, increased phosphorylation of ERK1/2 was observed in BRAF , RAF1 , and PRKCA fusion-positive tumors. Oncogenic gene fusions are associated with transcriptional activation of the MAPK pathway, suggesting they could be therapeutic targets with available inhibitors. Additional analyses to fully characterize the oncogenic effects of these fusions may support biomarker driven clinical trials.

Purpose/objectives: Clinical trials of anti-Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein (CTLA-4) therapies have demonstrated a clinical benefit with low rates of neurologic adverse events in patients with melanoma brain metastases (MBMs). While the combined effect of these immunotherapies (ITs) and stereotactic radiosurgery (SRS) has yielded impressive results with regard to local control (LC) and overall survival (OS), it has also been associated with increased rates of radiation necrosis (RN) compared to historical series of SRS alone. We retrospectively reviewed patients treated with IT in combination with SRS to report on predictors of clinical outcomes., Materials and Methods: Patients were included if they had MBMs treated with SRS within 1 year of receiving anti-PD-1 and/or CTLA-4 therapy. Clinical outcomes including OS, LC, intracranial death (ID), and RN were correlated with type and timing of IT with SRS, radiation dose, total volume, and size and number of lesions treated., Results: Twenty-nine patients with 171 MBMs were treated between May 2012 and May 2018. Patients had a median of 5 lesions treated (median volume of 6.5 cm 3 ) over a median of 2 courses of SRS. The median dose was 21 Gy. Most patients were treated with ipilimumab (n = 13) or nivolumab-ipilimumab (n = 10). Most patients underwent SRS concurrently or within 3 months of receiving immunotherapy (n = 21). Two-year OS and LC were 54.4% and 85.5%, respectively. In addition, 14% of patients developed RN; however, only 4.7% of the total treated lesions developed RN. The median time to development of RN was 9.5 months. Patients with an aggregate tumor volume >6.5 cm 3 were found to be at increased risk of ID (p = 0.05) and RN (p = 0.03). There was no difference in OS, ID, or RN with regard to type of IT, timing of SRS and IT, number of SRS courses, SRS dose, or number of cumulative lesions treated., Conclusions: In our series, patients treated with SRS and IT for MBMs had excellent rates of OS and LC; however, patients with an aggregate tumor volume >6.5 cm 3 were found to be at increased risk of ID and RN. Given the efficacy of combined anti-PD-1/CTLA-4 therapy for MBM management, further study of optimal selection criteria for the addition of SRS is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Burke, Carrasquilla, Jean, Collins, Anaizi, Atkins, Gibney and Collins.)

Background: Limited data exist on safe discontinuation of antiprogrammed cell death protein 1 (PD-1) therapy in responding patients with advanced melanoma. The use of 18fluorodeoxyglucose ( 18 FDG)-PET/CT scan and tumor biopsy for assessment of active disease may be an effective predictive biomarker to guide such treatment decisions., Methods: A retrospective study of 122 patients with advanced melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anticytotoxic T-lymphocyte-associated protein 4 combination therapy at Georgetown Lombardi Comprehensive Cancer Center was conducted. Uveal melanoma patients and those receiving concurrent experimental therapy were excluded. Baseline characteristics, treatment outcomes, and survival were analyzed. Patients who decided to come off treatment typically after 12 months using CT scan radiographic complete response (CR), 18 FDG-PET/CT scan complete metabolic response (CMR) or tumor biopsy of a non-CR/CMR tumor site negative for active disease (possible pathological CR) were identified and compared with patients who discontinued treatment due to toxicity while their disease was in control. Event-free survival (EFS) was assessed from the last dose of anti-PD-1 therapy to progression requiring subsequent treatment (surgery, radiation, and/or systemic therapy) or referral to hospice/death due to melanoma., Results: 24 (20%) patients discontinued treatment by choice with no active disease and 28 (23%) patients discontinued treatment due to toxicity with disease control after 12-month and 4-month median treatment durations, respectively. Similar baseline characteristics were observed between cohorts except higher prior receipt of ipilimumab (29% vs 7%; p=0.036) and fewer BRAF mutant positive disease (17% vs 41%; p=0.064) in patients off treatment by choice. Three-year EFS rates were 95% and 71%, respectively. No significant associations between EFS and sex, disease stage, lactate dehydrogenase elevation, BRAF status, prior systemic therapy, ECOG performance status, presence of brain metastases, or combination versus monotherapy were observed. Tumor biopsies led to alternative management in 3/10 patients due to active metastatic melanoma or second malignancy., Conclusions: Anti-PD-1 therapy discontinuation after 12 months when no active disease is observed on CT scan, PET/CT scan or tumor biopsy may have low rates of disease relapse in patients with advanced melanoma. Biopsy of residual disease may frequently lead to a change in management. These findings are undergoing validation in the EA6192 trial., Competing Interests: Competing interests: GTG has served as a consultant for Novartis, Bristol Myers Squibb, Array Biopharma, Merck, Regeneron, Exicure and Sapience Therapeutics, and has received institutional research support from Exelixis and Lucerno Dynamics. MBA has served as an advisor for Arrowhead, Aveo, Bristol Myers Squibb, Eisai, Elpis, Genetech/Roche, Leads, Merck, Novartis, Pfizer, Pneuma, Pyxis Oncology, Werewolf and as a consultant to Adagene, Agenus, Apexigen, Exelixis, Idera, ImmunoCore, Iovance, and Neoleuken., (© 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.)

Purpose: Standard-dose pembrolizumab plus alternative-dose ipilimumab (1 mg/kg Q3W for 4 doses) were tolerable and had robust antitumor activity in advanced melanoma in cohort B of the phase 1 KEYNOTE-029 study. Cohort C evaluated standard-dose pembrolizumab with two other alternative ipilimumab regimens., Patients and Methods: Patients with treatment-naive unresectable stage III/IV melanoma were randomly assigned 1:1 to pembrolizumab 200 mg Q3W for ≤24 months plus ipilimumab 50 mg Q6W for 4 doses (PEM200+IPI50), or the same pembrolizumab regimen plus ipilimumab 100 mg Q12W for 4 doses (PEM200+IPI100). Primary end points were incidence of grade 3-5 treatment-related adverse events (TRAE) and objective response rate (ORR) per RECIST v1.1 by independent central review. Per protocol-defined thresholds, grade 3-5 TRAE incidence ≤26% indicated meaningful toxicity reduction and ORR ≥48% indicated no decrease in efficacy versus data reported for other PD-1 inhibitor/ipilimumab combinations., Results: Median follow-up on February 18, 2019, was 16.3 months in PEM200+IPI50 (N = 51) and 16.4 months in PEM200+IPI100 (N = 51). Grade 3-5 TRAEs occurred in 12 (24%) patients in PEM200+IPI50 and 20 (39%) in PEM200+IPI100. One patient in PEM200+IPI50 died from treatment-related autoimmune myocarditis. Immune-mediated AEs or infusion reactions occurred in 21 (42%) patients in PEM200+IPI50 and 28 (55%) in PEM200+IPI100. ORR was 55% in PEM200+IPI50; 61% in PEM200+IPI100., Conclusions: Pembrolizumab 200 mg Q3W plus ipilimumab 50 mg Q6W or 100 mg Q12W demonstrated antitumor activity above the predefined threshold; pembrolizumab plus ipilimumab 50 mg Q6W had lower incidence of grade 3-5 TRAEs than the predefined threshold, suggesting a reduction in toxicity. See related commentary by Jameson-Lee and Luke, p. 5153., (©2021 The Authors; Published by the American Association for Cancer Research.)

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.)

Background: The objective of this work was to characterize outcomes of patients with isolated brain metastases managed with local therapy followed by immune checkpoint inhibitor (ICI) therapy., Materials and Methods: Patients from four medical centers were included if they presented with isolated brain metastases treated with local therapy and received adjuvant treatment with ICIs., Results: Eleven patients with median size of largest brain metastasis of 3.9 cm, treated with surgical resection (n = 8) and/or stereotactic radiosurgery (SRS; n = 6), were included. Ipilimumab/nivolumab was the adjuvant ICI used in four patients, of whom one recurred (25%) and none died, compared with three of seven (43%) who recurred and two of seven (29%) who died following adjuvant treatment with ICI monotherapy. All recurrences were intracranial., Conclusion: Patients with isolated brain metastases treated with surgery or SRS appeared to benefit from adjuvant ICI therapy, particularly with combination therapy. Recurrences in this setting appear to largely occur intracranially., (© 2020 AlphaMed Press.)

Background: Patients with chronic viral infections including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) are at increased risk of developing malignancies. The safety and efficacy of ICI therapy in patients with both cancer and chronic viral infections is not well established as most clinical trials of ICIs excluded these patient populations., Methods: We performed a retrospective analysis of patients with advanced-stage cancers and HIV, HBV, or HCV infection treated with ICI therapy at 5 MedStar Health hospitals from January 2011 to April 2018., Results: We identified 50 patients including 16 HIV, 29 HBV/HCV, and 5 with concurrent HIV and either HBV or HCV. In the HIV cohort (n = 21), any grade immune-related adverse events (irAEs) were 24% with grade ≥ 3 irAEs 14%. Among 5 patients with matched pre/post-treatment results, no significant changes in HIV viral load and CD4+ T-cell counts were observed. RECIST confirmed (n = 18) overall response rate (ORR) was 28% with 2 complete responses (CR) and 3 partial responses (PR). Responders included 2 patients with low baseline CD4+ T-cell counts (40 and 77 cells/ul, respectively). In the HBV/HCV cohort (n = 34), any grade irAEs were 44% with grade ≥ 3 irAEs 29%. RECIST confirmed ORR was 21% (6 PR). Among the 6 patients with known pre/post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation., Conclusions: Our retrospective series is one of the largest case series to report clinical outcomes among HIV, HBV and HCV patients treated with ICI therapy. Toxicity and efficacy rates were similar to those observed in patients without chronic viral infections. Viral reactivation was not observed. Tumor responses occurred in HIV patients with low CD4 T-cell counts. While prospective studies are needed to validate above findings, these data support not excluding such patients from ICI-based clinical trials or treatment.

Immunotherapy has advanced the treatment of solid organ malignancies. Although generally well tolerated, treatment with immune checkpoint inhibitors can be complicated by immune-related adverse events, some of which are relatively uncommon. We report the first case of gingival linear immunoglobulin A disease related to treatment with an antiprogrammed cell death protein 1 antibody. A 73-year-old male with advanced non-small cell lung cancer achieved a durable response to nivolumab monotherapy. After 1 year of treatment, he developed gingival swelling and pain. Biopsy revealed linear immunoglobulin A disease of the gingiva which was effectively treated with systemic steroids. Ongoing vigilance for immune-mediated toxicity is paramount during and after treatment with immune checkpoint inhibitors.

The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumors. New agents have been approved based on molecular testing instead of tumor site of origin. Molecular profiling methodologies have likewise changed such that tests that were performed on patients a few years ago are no longer complete and possibly inaccurate today. As with all rapid change, medical providers can quickly fall behind or struggle to find up-to-date sources to ensure he or she provides optimum care. In this review, the authors provide the current state of the art for molecular profiling/precision medicine, practice standards, and a view into the future ahead., (© 2019 The Authors. CA A Cancer Journal for Clinicians published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Merlin/NF2 is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome neurofibromatosis type 2 (NF2), as well as various sporadic cancers including kidney cancer. Multiple Merlin/NF2 effector pathways including the Hippo-YAP/TAZ pathway have been identified. However, the molecular mechanisms underpinning the growth and survival of NF2-mutant tumors remain poorly understood. Using an inducible orthotopic kidney tumor model, we demonstrate that YAP/TAZ silencing is sufficient to induce regression of pre-established NF2-deficient tumors. Mechanistically, YAP/TAZ depletion diminishes glycolysis-dependent growth and increases mitochondrial respiration and reactive oxygen species (ROS) buildup, resulting in oxidative-stress-induced cell death when challenged by nutrient stress. Furthermore, we identify lysosome-mediated cAMP-PKA/EPAC-dependent activation of RAF-MEK-ERK signaling as a resistance mechanism to YAP/TAZ inhibition. Finally, unbiased analysis of TCGA primary kidney tumor transcriptomes confirms a positive correlation of a YAP/TAZ signature with glycolysis and inverse correlations with oxidative phosphorylation and lysosomal gene expression, supporting the clinical relevance of our findings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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 identifier, NCT01604889 . Registration date, May 9, 2012, retrospectively registered.

Purpose: BRAF inhibitors are clinically active in patients with advanced BRAF V600 -mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888. Patients and Methods: Vemurafenib (960 mg p.o. b.i.d.) combined with escalating doses of XL888 (30, 45, 90, or 135 mg p.o. twice weekly) was investigated in 21 patients with advanced BRAF V600 -mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity. Results: Objective responses were observed in 15 of 20 evaluable patients [75%; 95% confidence interval (CI), 51%-91%], with 3 complete and 12 partial responses. Median progression-free survival and overall survival were 9.2 months (95% CI, 3.8-not reached) and 34.6 months (6.2-not reached), respectively. The most common grade 3/4 toxicities were skin toxicities, such as rash ( n = 4, 19%) and cutaneous squamous cell carcinomas ( n = 3, 14%), along with diarrhea ( n = 3, 14%). Pharmacodynamic analysis of patients' peripheral blood mononuclear cells (PBMC) showed increased day 8 HSP70 expression compared with baseline in the three cohorts with XL888 doses ≥45 mg. Diverse effects of vemurafenib-XL888 upon intratumoral HSP client protein expression were noted, with the expression of multiple proteins (including ERBB3 and BAD) modulated on therapy. Conclusions: XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAF V600 -mutant melanoma, with a tolerable side-effect profile. HSP90 inhibitors warrant further evaluation in combination with current standard-of-care BRAF plus MEK inhibitors in BRAF V600 -mutant melanoma. Clin Cancer Res; 24(22); 5516-24. ©2018 AACR See related commentary by Sullivan, p. 5496 ., (©2018 American Association for Cancer Research.)

Colitis is a frequent, clinically-significant immune-related adverse event caused by anti-programmed death-1 (PD-1). The clinical features, timing, and management of colitis with anti-PD-1-based regimens are not well-characterized. Patients with advanced melanoma that received either anti-PD-1 monotherapy ("monotherapy") or combined with ipilimumab ("combination therapy") were screened from 8 academic medical centers, to identify those with clinically-relevant colitis (colitis requiring systemic steroids). Of 1261 patients who received anti-PD-1-based therapy, 109 experienced colitis. The incidence was 3.2% (30/937) and 24.4% (79/324) in the monotherapy and combination therapy cohorts, respectively. Patients with colitis from combination therapy had significantly earlier symptom onset (7.2 weeks vs 25.4 weeks, p  < 0.0001), received higher steroid doses (median prednisone equivalent 1.5 mg/kg vs 1.0 mg/kg, p  = 0.0015) and experienced longer steroid tapers (median 6.0 vs 4.0 weeks, p  = 0.0065) compared to monotherapy. Infliximab use and steroid-dose escalation occurred more frequently in the combination therapy cohort compared to monotherapy. Nearly all patients had resolution of their symptoms although one patient died from complications. Anti-PD-1 associated colitis has a variable clinical presentation, and is more frequent and severe when associated with combination therapy. This variability in checkpoint-inhibitor associated colitis suggests that further optimization of treatment algorithms is needed.

Background: The use of immune checkpoint inhibitors is increasing in cancer therapy today. It is critical that treatment teams become familiar with the organ systems potentially impacted by immune-related adverse events associated with these drugs. Here, we report adverse skeletal effects of immunotherapy, a phenomenon not previously described., Case Presentations: In this retrospective case series, clinical, laboratory and imaging data were obtained in patients referred to endocrinology or rheumatology with new fractures (n = 3) or resorptive bone lesions (n = 3) that developed while on agents targeting PD-1, CTLA-4 or both. The average age of patients was 59.3 (SD 8.6), and five were male. Cancer types included melanoma, renal cell carcinoma and non-small cell lung cancer. All fracture patients had vertebral compression, and two of the three had multiple fracture sites involved. Sites of resorptive lesions included the shoulder, hand and clavicle. Biochemically, elevated or high-normal markers of bone resorption were seen in five of the six patients. Erythrocyte sedimentation rate was elevated in three of the four patients where checked., Conclusions: This case series represents the first description of potential skeletal adverse effects related to immune checkpoint inhibitors. These findings are important for providers caring for patients who experience musculoskeletal symptoms and may merit additional evaluation.

Background: The development of brain metastases is common for systemic treatment failure in patients with melanoma and has been associated with a poor prognosis. Recent advances with BRAF and immune checkpoint therapies have led to improved patient survival. Herein, the authors evaluated the risk of de novo brain metastases and survival among patients with melanoma brain metastases (MBM) since the introduction of more effective therapies., Methods: Patients with unresectable AJCC stage III/IV melanoma who received first-line systemic therapy at Moffitt Cancer Center between 2000 and 2012 were identified. Data were collected regarding patient characteristics, stage of disease, systemic therapies, MBM status/management, and overall survival (OS). The risk of de novo MBM was calculated using a generalized estimating equation model and survival comparisons were performed using Kaplan-Meier and Cox proportional analyses., Results: A total of 610 patients were included, 243 of whom were diagnosed with MBM (40%). Patients with MBM were younger, with a lower frequency of regional metastasis. No significant differences were noted with regard to sex, BRAF status, or therapeutic class. The risk of de novo MBM was found to be similar among patients treated with chemotherapy, biochemotherapy, BRAF-targeted therapy, ipilimumab, and anti-programmed cell death protein 1/programmed death-ligand 1 regimens. The median OS of patients with MBM was significantly shorter when determined from the time of first regional/distant metastasis but not when determined from the time of first systemic therapy. The median OS from the time of MBM diagnosis was 7.5 months, 8.5 months, and 22.7 months, respectively, for patients diagnosed from 2000 to 2008, 2009 to 2010, and 2011 to the time of last follow-up (P = .002)., Conclusions: Brain metastases remain a common source of systemic treatment failure. The OS for patients with MBM has improved significantly. Further research into MBM prevention is needed. Cancer 2018;124:297-305. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAF-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety. Planned (V600K vs. non-V600K mutations) subgroup analyses were carried out. Thirty-one patients were enrolled; 13 (42%) had V600K mutations and 18 (58%) had other mutations. Investigator-assessed confirmed that the best overall response rate was 23% (95% confidence interval=10-41%) in the overall population, and was similar between patients with V600K mutations (23%; 95% confidence interval=5-54%) versus other mutations (22%; 95% confidence interval=6-48%). Responses were observed in patients with V600K (n=3), V600E2 (n=1), V600R (n=1), L597S (n=1) and D594G (n=1) mutations. No new safety signals were reported. Vemurafenib showed activity in patients with advanced melanoma with rarer BRAF mutations.

Targeted therapies have revolutionized cancer care, but the development of resistance remains a challenge in the clinic. To identify rational targets for combination strategies, we used an established melanoma mouse model and selected for resistant tumors following genetic suppression of NRAS expression. Complete tumor regression was observed in all mice, but 40% of tumors recurred. Analysis of resistant tumors showed that the most common mechanism of resistance was overexpression and activation of receptor tyrosine kinases (RTKs). Interestingly, the most commonly overexpressed RTK was Met and inhibition of Met overcame NRAS resistance in this context. Analysis of NRAS mutant human melanoma cells showed enhanced efficacy of cytotoxicity with combined RTK and mitogen-activated protein kinase kinase inhibition. In this study, we establish the importance of adaptive RTK signaling in the escape of NRAS mutant melanoma from inhibition of RAS and provide the rationale for combined blockade of RAS and RTK signaling in this context.

In recent years, the field of oncology has witnessed many breakthroughs in the treatment of advanced malignancies, particularly in patients with advanced melanoma. Targeted and immune checkpoint therapies have emerged as the primary treatment strategies for these patients. Molecular profiling of melanoma is incorporated into routine practice to identify potential therapeutic targets, and patients are offered either a targeted or immune checkpoint inhibitor therapy approach. Both strategies have limitations where not all patients experience durable responses. Preclinical data have demonstrated the ability of targeted therapy to enhance activity of effector T cells, reduce immunosuppressive cytokine production, and increase tumor cell antigen presentation, which can augment antitumor immunity. In vivo models have shown synergy with improved tumor control when targeted and immune checkpoint agents are combined. Therefore, combination strategies with targeted and immune checkpoint therapy may improve patient outcomes. Early clinical data with anti-programmed cell-death protein 1/programmed cell-death ligand 1 agents in combination with targeted inhibitors appear to have acceptable toxicity rates and the potential for enhanced antitumor activity. This review explores the current status of preclinical and clinical development for these combination approaches in patients with advanced melanoma.

The clinical development of checkpoint inhibitor-based immunotherapy has ushered in an exciting era of anticancer therapy. Durable responses can be seen in patients with melanoma and other malignancies. Although monotherapy with PD-1 or PD-L1 agents are typically well tolerated, the risk of immune-related adverse events increases with combination regimens. The development of predictive biomarkers is needed to optimise patient benefit, minimise risk of toxicities, and guide combination approaches. The greatest focus has been on tumour-cell PD-L1 expression. Although PD-L1 positivity enriches for populations with clinical benefit, PD-L1 testing alone is insufficient for patient selection in most malignancies. In this Review, we discuss the status of PD-L1 testing and explore emerging data on new biomarker strategies with tumour-infiltrating lymphocytes, mutational burden, immune gene signatures, and multiplex immunohistochemistry. Future development of an effective predictive biomarker for checkpoint inhibitor-based immunotherapy will integrate multiple approaches for optimal characterisation of the immune tumour microenvironment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The prognosis of patients with gastrointestinal (GI) melanoma metastases is poor. Surgery renders select patients disease free and/or palliates symptoms. We reviewed our single-institution experience of resection with GI melanoma metastases. A retrospective review was performed on patients who underwent surgery for GI melanoma metastases from 2007 to 2013. Fifty-four patients were identified and separated based on completeness of resection into curative 13 (24%) and palliative 41 (75.9%) groups. Thiry-six (63.2%) were symptomatic preoperatively with bleeding and/or obstruction/pain with 91.7 per cent achieving objective symptom relief. Thirty-day operative mortality was 0 per cent. The most common complication was wound infection (n = 5); major complications like anastomotic leak (n = 1) were uncommon. With a median follow-up of 9.5 months (range 0.2-75.8), median overall survival was not reached (curative) versus 9.53 months (palliative group). Median recurrence-free and progression-free survival after resection were 18.89 and 1.97 months in the curative versus palliative groups, respectively. On multivariate analysis, resection to no clinical evidence of disease (P = 0.012) and presence of single metastases (P = 0.031) were associated with improved overall survival. Surgery for GI metastases from melanoma provides symptomatic relief without major morbidity. Fewer metastases and curative resection were associated with improved survival.

The mechanisms by which some melanoma cells adapt to Serine/threonine-protein kinase B-Raf (BRAF) inhibitor therapy are incompletely understood. In the present study, we used mass spectrometry-based phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF mutant and PTEN null. Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent. These effects were recapitulated through BRAF siRNA knockdown and following treatment with chemotherapeutic drugs. Increased fibronectin expression was also observed in mouse xenograft models as well as specimens from melanoma patients undergoing BRAF inhibitor treatment. Analysis of a melanoma tissue microarray showed loss of PTEN expression to predict for a lower overall survival, with a trend for even lower survival being seen when loss of fibronectin was included in the analysis. Mechanistically, the induction of fibronectin limited the responses of these PTEN-null melanoma cell lines to vemurafenib, with enhanced cytotoxicity observed following the knockdown of either fibronectin or its receptor α5β1 integrin. This in turn abrogated the cytotoxic response to BRAF inhibition via increased AKT signaling, which prevented the induction of cell death by maintaining the expression of the pro-survival protein Mcl-1. The protection conveyed by the induction of FN expression could be overcome through combined treatment with a BRAF and PI3K inhibitor.

Background: The anti-programmed death-1 (anti-PD-1) therapy nivolumab has significant clinical activity in patients with metastatic melanoma. However, little is known about the safety and outcomes in patients receiving anti-PD-1 therapy and stereotactic radiation for the treatment of brain metastases (BMs)., Patients and Methods: Data were analyzed retrospectively from two prospective nivolumab protocols enrolling 160 patients with advanced resected and unresectable melanoma at a single institution. Patients were included if BMs were diagnosed and treated with stereotactic radiation within 6 months of receiving nivolumab. The primary end point of this study was neurotoxicity; secondary end points included BM control and survival., Results: Twenty-six patients with a total of 73 BMs treated over 30 sessions were identified. Radiation was administered before, during and after nivolumab in 33 lesions (45%), 5 lesions (7%), and 35 lesions (48%), respectively. All BMs were treated with stereotactic radiosurgery (SRS) in a single session except 12 BMs treated with fractionated stereotactic radiation therapy, nine of which were in the postoperative setting. One patient experienced grade 2 headaches following SRS with symptomatic relief with steroid treatment. No other treatment-related neurologic toxicities or scalp reactions were reported. Eight (11%) local BM failures with a ≥20% increase in volume were noted. Of these lesions, hemorrhage was noted in 4, and edema was noted in 7. Kaplan-Meier estimates for local BM control following radiation at 6 and 12 months were 91% and 85%, respectively. Median overall survival (OS) from the date of stereotactic radiation and nivolumab initiation was 11.8 and 12.0 months, respectively, in patients receiving nivolumab for unresected disease (median OS was not reached in patients treated in the resected setting)., Conclusions: In our series, stereotactic radiation to melanoma BMs is well tolerated in patients who received nivolumab. BM control and OS appear prolonged compared with standard current treatment. Prospective evaluation is warranted., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients.

Selective BRAF inhibitors (BRAFi) yield objective responses in 50% of patients with metastatic BRAF V600E mutant melanoma. Adding an MEK inhibitor increases this response rate to 70%. Limited data are available on the outcomes of unresectable stage III patients, and it remains unclear whether BRAF-targeted therapy can be utilized as a neoadjuvant strategy. Data on patients with advanced locoregional BRAF V600E mutant melanoma treated with BRAF-targeted therapy at Moffitt Cancer Center were analyzed to determine response rates, subsequent resection rates after tumor downsizing, pathologic responses, and patient survival. Fifteen patients with locoregional disease treated with BRAF-targeted therapy, either BRAFi alone (vemurafenib; 11 patients) or a combination of BRAFi and an MEK inhibitor (dabrafenib plus trametinib or placebo; four patients), were identified. The median age was 50 years; the median follow-up was 25.4 months. The median BRAF-targeted therapy treatment duration was 6.0 months (range 1.2-29.4 months). Response Evaluation Criteria In Solid Tumors-based evaluation demonstrated objective response in 11 patients (73.3%). Six patients underwent resection of the remaining disease after therapy. Pathological analysis showed complete pathologic response (n=2), partial pathologic response (n=2), or no pathologic response (n=2). Four of six patients undergoing surgery have been alive for more than 2 years, including three patients currently free from active disease. No complications attributable to BRAF-targeted therapy were observed in the perioperative period. Dose reduction or discontinuation because of toxicities occurred in 10/15 patients. Neoadjuvant BRAF-targeted therapy may be effective in advanced locoregional BRAF V600E mutant melanoma patients in increasing resectability, yielding pathological responses, and achieving prolonged survival.

Brain metastases are a common and serious complication among patients with metastatic melanoma. The selective BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases (MBM). We examined the real-world application and clinical outcomes of vemurafenib in this patient population. Demographic, treatment patterns, response, and survival data were collected from medical charts. Clinical data on 283 patients with active BRAF V600E-mutant MBM treated with vemurafenib were provided by 70 US oncologists. Mean age was 57.2 years, 60.8% were male, 67.5% had ECOG performance status of 0-1, and 43.1% used corticosteroids at vemurafenib initiation. Median follow-up was 5.7 months. Following vemurafenib initiation, 48.1% of patients experienced intracranial response and 45.6% experienced extracranial response. The Kaplan-Meier estimate for overall survival was 59% at 12 months. Multivariate analyses showed associations between intracranial response and both corticosteroid use and vemurafenib as initial therapy after MBM diagnosis. Larger size (5-10 mm vs. < 5 mm) and number of brain metastases (≥ 5 vs. < 2) and progressive extracranial disease at treatment initiation were associated with decreased intracranial response and increased risk of disease progression. Multiple extracranial sites (2 vs. < 2) and the absence of local treatments were also associated with increased risk of progression. Increased risk of death was associated with ≥ 2 extracranial disease sites, progressive extracranial disease, and ≥ 5 brain metastases. Subgroups of MBM patients may derive more benefit with vemurafenib, warranting prospective investigation., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The recent developments in BRAF-targeted therapy and checkpoint inhibitor immunotherapies for metastatic melanoma patients have led to better tolerability and markedly improved clinical outcomes, including higher objective response rates and longer survival. Treatment planning has become complex in patients with metastatic BRAF-mutant melanoma, with several options for BRAF- and/or MEK-targeted therapy (vemurafenib, dabrafenib, and trametinib) and immunotherapy (interleukin 2, ipilimumab, pembrolizumab, and nivolumab). Clinicians must weigh various patient factors, including the extent of disease (eg, symptomatic visceral metastases vs limited disease) and central nervous system involvement, as well as factors related to the therapeutic agent, such as rate of clinical response, durability of response, and impact on median and long-term survival. The combination regimen of dabrafenib plus trametinib has become a standard treatment strategy, and ipilimumab plus nivolumab is emerging as a promising treatment strategy. In this review, we discuss the benchmark trials leading to the approval of these new agents and provide emerging data on their use in sequence and impact on overall survival, with the goal of helping oncologists navigate treatment decisions for patients with metastatic BRAF-mutant melanoma.

A 40-year-old man with stage III melanoma arising from his left shoulder underwent wide local excision, sentinel lymph node biopsy, and lymph node dissection. Nine months after receiving adjuvant biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2 (IL-2), and interferon alfa as part of a clinical trial, he developed headaches and right-hand weakness and was found to have a 2-cm left parietal CNS metastasis. A comprehensive staging workup identified multiple nonspecific subcentimeter pulmonary nodules. The brain mass was resected and confirmed to be metastatic melanoma; the surgical bed was treated with stereotactic radiosurgery. He was monitored off therapy, but 5 months later, he developed a second left parietal CNS metastasis and enlarging lung nodules. The new brain lesion was treated with stereotactic radiosurgery, and he began systemic therapy with ipilimumab on a clinical trial. After the third dose, he presented with headache, nausea, and vomiting; a brain magnetic resonance imaging scan showed left anterior temporal enhancement, possibly representing new disease. His symptoms improved with a course of corticosteroids. Restaging of the chest showed a mixed response among the pulmonary nodules. After tapering off corticosteroids, he received the fourth dose of ipilimumab, which was complicated by grade 3 transaminitis and hypophysitis with documented hypothyroidism and adrenal insufficiency. They were managed with corticosteroids and thyroid and adrenal hormone replacement. Restaging scans showed further disease regression except for new confluent enhancing nodules and edema in the left temporal lobe. Craniotomy and resection of this area showed only necrotic tissue with no viable melanoma cells. Nine years after treatment with ipilimumab, he is alive and shows no evidence of melanoma on the basis of annual computed tomography scans of the chest, abdomen, and pelvis and magnetic resonance imaging scans of the brain. He has full neurologic function but still requires hormone replacement for persistent hypopituitarism.

Unlabelled: Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry-based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy., Significance: This study provides evidence that BRAF inhibition promotes the adoption of a reversible, therapy-driven metastatic phenotype in melanoma. The cotargeting of ligand-independent EPHA2 signaling and BRAF may be one strategy to prevent the development of therapy-mediated disease at new sites., (©2014 American Association for Cancer Research.)

While selective BRAF inhibitors have demonstrated improved outcomes in patients with metastatic BRAF V600E mutant melanoma, management of brain metastases prior to and during therapy presents challenges. Stereotactic radiosurgery (SRS) is an effective treatment for melanoma brain metastases, but there is limited safety and efficacy data on the use of SRS during BRAF therapy. An analysis was performed of patients with metastatic melanoma and brain metastases treated with SRS while on vemurafenib. MRI scans were reviewed post-SRS to evaluate local control (LC) as well as distant control. We identified 80 metastatic melanoma brain lesions treated in 24 patients. The median planning target volume was 0.28 cm(3) (range 0.05-4.19 cm(3)), and lesions were treated to a median dose of 24 Gy (range 15-24 Gy). The median follow up was 5.1 months (range 2-25.2 months). Eight (10 %) lesions showed progression at a median of 6.1 months (range 2-20.1 months) following SRS. Kaplan-Meier LC estimates at 6 and 12 months were 92 and 75 %, respectively. Fourteen (58 %) patients were noted to have distant brain failure at a median of 3.4 months (range 1.9-16.1 months) following treatment with SRS. Median overall (OS) from the date of SRS was 7.2 months (range 1.5-26.8 months) with a median of 11.9 months (range 1.5-28.5 months) since the date of brain metastases diagnosis. There was no evidence of increased toxicity with the combination of SRS and vemurafenib. SRS to brain metastases appears to be both safe and effective for patients treated concurrently with BRAF inhibitors.

Purpose: The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients., Experimental Design: HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies., Results: Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4(+)/CD4(+), CD25(+)Treg/CD4(+), and tetramer specific CD8(+) T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25(+)Treg/CD4(+) populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS., Conclusions: Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study., (©2014 American Association for Cancer Research.)

In recent years, melanoma has become a poster-child for the development of oncogene-directed targeted therapies. This approach, which has been exemplified by the development of small-molecule BRAF inhibitors and the BRAF/MEK inhibitor combination for BRAF-mutant melanoma, has brought new hope to patients. Despite these successes, treatment failure seems near inevitable in the majority of cases—even in individuals treated with the BRAF/MEK inhibitor doublet. In the current review, we discuss the future of combination strategies for patients with BRAF-mutant melanoma as well as the emerging therapeutic options for patients with NRAS-mutant and BRAF/NRAS-wild-type melanoma. We also outline some of the newest developments in the in-depth personalisation of therapy that should allow melanoma treatment to continue shaping the field precision cancer medicine.

Basal and kinase inhibitor driven adaptive signaling has been examined in a panel of melanoma cell lines using phosphoproteomics in conjunction with pathway analysis. A considerable divergence in the spectrum of tyrosine-phosphorylated peptides was noted at the cell line level. The unification of genotype-specific cell line data revealed the enrichment for the tyrosine-phosphorylated cytoskeletal proteins to be associated with the presence of a BRAF mutation and oncogenic NRAS to be associated with increased receptor tyrosine kinase phosphorylation. A number of proteins including cell cycle regulators (cyclin dependent kinase 1, cyclin dependent kinase 2, and cyclin dependent kinase 3), MAPK pathway components (Extracellular signal regulated kinase 1 and Extracellular signal regulated kinase 2), interferon regulators (tyrosine kinase-2), GTPase regulators (Ras-Rasb interactor 1), and controllers of protein tyrosine phosphorylation (dual specificity tyrosine (Y) phosphorylation regulated kinase 1A and protein tyrosine phosphatase receptor type A) were common to all genotypes. Treatment of a BRAF-mutant/phosphatase and tensin homologue (PTEN) null melanoma cell line with vemurafenib led to decreased phosphorylation of ERK, phospholipase C1, and β-catenin with increases in receptor tyrosine kinase phosphorylation, signal transduction and activator of signaling 3, and glycogen synthase kinase 3α noted. In NRAS-mutant melanoma, MEK inhibition led to increased phosphorylation of epidermal growth factor receptor signaling pathway components, Src family kinases, and protein kinase Cδ with decreased phosphorylation seen in STAT3 and ERK1/2. Together these data present the first systems level view of adaptive and basal phosphotyrosine signaling in BRAF- and NRAS-mutant melanoma., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)