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Background: The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with BRAF V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival., Methods: We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival., Results: The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports., Conclusions: After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.)., (Copyright © 2024 Massachusetts Medical Society.)

Aims: The MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel., Patients and Methods: Seventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level., Results: The median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved., Conclusions: SelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. JJS reports institutional funding for trial delivery from Amgen, AstraZeneca, Bristol-Myers Squibb, Delcath Systems, Merck, Replimune, Transgene; research grants from AstraZeneca, Bristol-Myers Squibb, Immunocore; paint consultancy/advisory Board membership from Bristol-Myers Squibb, Delcath Systems, Immunocore, Merck; and sponsorship for congress attendance: Bristol-Myers Squibb, Merck. TRJE has received honoraria for consultancies (payable to the employing institution) from Ascelia, Astra Zeneca, Bayer, Bicycle Therapeutics, Bristol-Myers Squibb, Celgene, Eisai, Karus Therapeutics, Medivir, MSD, Otsuka, Roche, and Seagen; honoraria for speaker’s fees (payable to employing institution) from Astra Zeneca, Ascelia, Bayer, Bristol Myers Squibb, Celgene, Eisai, Nucana, MSD, Roche, Medivir, and United Medical; has received support of costs of commercial clinical trials (payable to employing institution) from Astra Zeneca, Basilea, Bayer, Celgene, Exscientia; Exelexis; MiNa Therapeutics, Roche, Pfizer, Sierra, Lilly, Eisai, GSK, Novartis, Bicycle Therapeutics, Johnson and Johnson, CytomX, Vertex, Plexxikon, Boehringer, Athinex, Adaptimmune, Bristol Myers Squibb, MSD, Medivir, Versatem, Nucana, Immunocore, Berg, Beigene, Iovance, Modulate, BiolinerX, Merck Serono, Nurix Therapeutics, T3P, Janssen Clovis, Sanofi-Aventis, Halozyme, Starpharma, UCB, Sapience, Seagen, Avacta, and Codiak; has received funding from Cancer Research UK, Chief Scientist’s Office Scotland, and the MRC; (payable to employing institution); has received support to attend national & international congresses from Bristol-Myers Squibb, Roche, MSD, Celgene, Pierre-Fabre (personal). SO reports honoraria from BMS. Merck, MSD, AstraZeneca and Janssen; and consulting fees from MSD, Immuncore, Janssen and Genmab. JL reports research funding from Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics; Consulting fees from iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte; and Honoraria from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMSIK reports consulting fees from Merck Serono; and research funding from Genetech, Achilles Therapeutics and Replimune. PL reports honoraria from Norvartis, PierreFabre, Merck , BMS, NeraCare GmbH, Amgen, Roche and oncology Education Canada; and research funding from BMS, PierreFabre. RP report honoraria for attending advisory boards from Pierre Faber, Bayer, Novartis, BMS, Ellipses, Immunocore, Genmab, Astex Therapeutics, MSD, Nerviano, AmLo, Incyte, Cybrexa Benevolent AI and Sanofi Aventis; honoraria for working as an IDMC member for Alligator Biosciences, GSK, Onxeo, SOTIO Biotech AG, and AstraZeneca; honoraria for delivery of educational talks or chairing educational meetings by AstraZeneca, Novartis, Bayer, MSD and BMS; and funds to support attendance at conferences from MSD and BMS. PP reports research funding from AstraZeneca. AO-B reports honoraria from BMS, MSD, Eisai, Roche, Novartis, AZ; and research Funding from BMS UCB pharma, Roche, Novartis and Eli Lily. HS report paid consultancy for Novartis, BMS, MSD, Immunocore, Idera, Iovance, Genmab, Sanofi Genzyme/Regeneron, Macrogenics, Roche, Agenus, Ideaya, iOnctura, CDR-Life, NovalGen, Therakos/Mallinkrodt Pharmaceuticals, ScanCelll; and speakers bureau for Novartis, BMS, MSD, Sanofi Genzyme/Regeneron, AstraZeneca, Eisai. SL reports consulting for Bayer, Immunocore; and expenses from Bayer. PN discloses Data and Safety Monitoring for 4SC, Achilles; and Consultant/Advisory Board for 4SC, Bristol-Myers Squibb, Immunocore, Merck, Merck Sharp and Dohme, Novartis, Pfizer; Research Grant/Contract: Immunocore. The other authors do not report any potential conflicting interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49)., Competing Interests: Declaration of interests J.L. declares the following: honoraria: Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS, Immatics, Insighter, and GCO; consultancy: iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte, Pfizer, and Novartis; speaker’s fees: Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, Inselgruppe, Pfizer, Goldman Sachs, MSD, Regional British Society of Gastroenterology, and Agence Unik; institutional research support: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, and Aveo; grants: Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, and Pharmacyclics. R.M. is an expert witness for Pfizer and may benefit financially from commercialized programs. P.L. declares the following: honoraria: Novartis, PierreFabre, Merck, BMS, MSD, NeraCare GmbH, Amgen, Roche, OncologyEducation Canada, and Nektar; consultancy: Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre Fabre, Novartis, Nektar, and NeraCare GmbH; speakers’ bureaus: Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, and Pierre Fabre; institutional research funding: BMS and Pierre Fabre; travel, accommodations, expenses: Merck Sharp & Dohme and Bristol-Myers Squibb. T.R.J.E. reported the following competing interests: honoraria (payable to employing institution): Ascelia, AstraZeneca, Bicycle Therapeutics, BMS, Eisai, Medivir, MSD, Nucana, Roche/Genentech, and Seagen; advisory/consulting (payable to employing institution): Karus Therapeutics; speakers’ bureaus (payable to employing institution): AstraZeneca, BMS, Eisai, Medivir, MSD, Nucana, Roche/Genentech, and United Medical; research funding (payable to employing institution): Adaptimmune, Astellas Pharma, AstraZeneca, Athenex, Avacta, Basilea, Bayer, Beigene, Berg Pharma, Bicycle Therapeutics, BiolineRx, Boehringer Ingelheim, BMS, Celgene, Clovis Oncology, Codiak, CytomX Therapeutics, Eisai, GlaxoSmithKline, Halozyme, Immunocore, iOnctura, Iovance Biotherapeutics, Janssen, Johnson & Johnson, Lilly, Medivir, Merck Serono, MSD, MiNA Therapeutics, Modulate Pharma, Novartis, Nucana, Nurix, Plexxikon, Roche/Genentech, Sanofi/Aventis, Sapience Therapeutics, Seagen, Seattle Genetics, Sierra Pharma, Starpharma, T3P, UCB, Verastem, and Vertex; expert testimony (payable to employing institution): Medivir; support to attend international conferences (personal): BMS, Celgene, Eisai, MSD, Nucana, Pierre Fabre, and Roche; other relationship (payable to employing institution): Genmab. M.R.M. is supported by the NIHR Biomedical Research Center in Oxford and reports grants from Roche, AstraZeneca, GSK, GRAIL (outside the submitted work), grants and other from Immunocore, and other from Novartis, BMS, Pfizer, Merck/MSD, Regeneron, BiolineRx, and Replimune. P.N. reported having received funding for advisory boards and/or speakers’ bureau from the following sources: AstraZeneca, BMS, Esai, Ideaya, Immunocore, Ipsen, Medicenna, MSD, Merck, Novartis, and Pfizer. R.P. reported, in the last 4 years, having received honoraria for attending advisory boards from Pierre Faber, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Immunocore, Genmab, Astex Therapeutics, Medivir, and Sanofi Aventis; honoraria as an IDMC member for Alligator Biosciences, GSK, Onxeo, SOTIO Biotech AG, and AstraZeneca; having been paid for delivery of educational talks or chairing educational meetings by AstraZeneca, Novartis, Bayer, MSD, and BMS; and received funds to support attendance at conferences from MSD and BMS. J. Bliss reported receiving grants to ICR-CTSU from AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Pfizer, Roche, Novartis (previously GlaxoSmithKline), Eli Lilly, Janssen-Cilag, Clovis Oncology, and Cancer Research UK; and nonfinancial support from the National Institute for Health Research. S.V. is a recipient of a research grant from Amgen. S.T. is funded by CRUK (grant no. A29911), the Francis Crick Institute, which receives its core funding from CRUK (FC10988), the UK Medical Research Council (FC10988), the Wellcome Trust (FC10988), the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (grant no. A109), the Royal Marsden Cancer Charity, The Rosetrees Trust (grant no. A2204), Ventana Medical Systems (grant nos. 10467 and 10530), the National Institutes of Health (U01 CA247439), and the Melanoma Research Alliance (Award Ref no 686061). S.T. has received speaking fees from Roche, Astra Zeneca, Novartis, and Ipsen. S.T. has filed the following patents: Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 and PCTGB2018/051893 and P113326GB., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib., Methods: This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics., Results: Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg., Conclusions: The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings., Gov Identifier: NCT01425008., (© 2023. The Author(s).)

Background: Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site., Methods: Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS)., Results: In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites., Conclusion: While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype., Competing Interests: Competing interests: PB: sponsorship: Bristol Myers Squibb, MSD, Novartis; paid speaker: Novartis. AS: advisory board: Bristol Myers Squibb, Immunocore, Novartis, Castle Biosciences; trial support to institution: Bristol Myers Squibb, Imunocore, Xcovery, Polaris, Novartis, Pfizer, Checkmate Pharmaceuticals, Foghorn Therapeautics. AZ: travel support: Novartis, Sanofi Grenzyme, Sun Pharma, Bristol Myers Squibb. JM: consultant advisor: Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Sanofi, Bristol Myers Squibb and Pierre Fabre; travel support: Ultrasun, L’Oreal, Merck Sharp & Dohme, Bristol Myers Squibb, Pierre Fabre. MW: grants, personal fees, non-financial support and other: Novartis, BMS, Merck/MSD; personal fees, and other: Merck Serono, Amgen, Sanofi/Regeneron, Pierre Fabre, Roche, Takeda, Medac. LS: honoraria: MSD, Roche, Novartis, Shanghai Junshi Biosciences, Oriengene. TL: consultant: MSD, Novartis, Pierre Fabre. CR: consultant for Novartis, BMS, Merck, MSD, Sanofi, Pierre Fabre, AstraZeneca, Roche, and scientic founder of Aglaia Therapeutics CA: Travel accommodations-Meetings: Roche, Bristol Myers Squibb, Amgen. JKS: sponsorship: MSD, Amgen; honoraria: Novartis. MJM: consultant advisor: AstraZeneca, Nektar Therapeutics, Catalyst Pharmaceuticals Immunia, Istari Oncology; paid speaker: Bristol Myers Squibb. RR-T: advisory board fees: Novartis, Bristol Myer Squibb, Merck, Sharp and Dohme, Pfizer; honoraria: Bristol Myer Squibb, Roche, AstraZeneca, Merck Sharp and Dohme, Novartis. AM: honoraria from Novartis. LZ: consultant and/or honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma; travel support: Amgen, Merck Sharp & Dohme, BristolMyers Squibb, Pierre Fabre, Sanofi, Sunpharma, Novartis. CB (all paid to the institute except TRV): advisory board: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures; research funding: Bristol Myers Squibb, Novartis, NanoString; stockownership & co-founder: Immagene BV. ER: consultant advisor or paid speaker: Sanofi, Amgen, BMS. KK: consultant or/and honoraria: Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, Novartis; travel support: Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac, Novartis. PAA: consultant/advisory role: Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos; research funding: Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. OM: consulting/advisory roles: Bristol Myers Squibb, MSD, Roche, Novartis, Amgen, Pierre Fabre, Neracare; research grants: Bristol Myers Squibb, MSD, Amgen. PCL: Consultant advisor or paid speaker: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Amgen, Nektar. Research funding: Bristol Myers Squibb, Pierre Fabre. DBJ: advisory boards/consultant: BMS, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, and Targovax. Research funding: BMS and Incyte. RP: advisory boards: Pierre Faber, Bayer, Novartis, Biosceptre, Bristol Myers Squibb, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapeutics, Medivir, GammaDelta Therapeutics, Sanofi Aventis; paid speaker: AstraZeneca, Novartis, Bayer, Tesaro, Bristol Myers Squibb. CL: BMS: Research grant, Honoraria, Consultancy, Speakers bureau, Travel accommodations, Meetings, Advisory role, advisory board. MSD: Honoraria, Consultancy, Advisory role, advisory board, Travel accommodations-Meetings. Novartis: Honoraria, Consultancy, Speakers bureau, Advisory role, advisory board. Amgen: Honoraria, Consultancy, Speakers bureau, advisory board. Roche: Research grant, Honoraria, Consultancy, Speakers bureau, Advisory role, advisory board. Avantis Medical Systems: Board. Pierre-Fabre/Pfizer/Incyte: Honoraria. BN: Personal financial compensation from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Amgen and AstraZeneca for public speaking, consultancy and participation in advisory board meetings. My institution (UZ Brussel) received funding related to research projects conducted by my academic research team from Pfizer, Novartis, Roche, and Merck-Serono. RJS: Consultant: AstraZeneca, Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, Pfizer; research funding: Merck. OH: consultant advisor: Aduro, Akeso, Amgen, Beigene, Bioatla, BMS, Roche Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Tempus, Zelluna; speaker bureau: BMS, Novartis, Pfizer, Sanofi/Regeneron; contracted research (for institution): Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck-Serono, NextCure, Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Torque, Zelluna. GAM: reimbursement of trials costs to the Peter MacCallum Cancer Centre: Array/Pfizer Roche/Genetech; non-reimbursed advisor: Novartis, Bristol Myers Squibb. AMH: advisory board member for Amgen, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre-Fabre, and Qbiotics, GVL: advisor: Aduro Biotech, Agenus, Amgen, Array Biopharma, Boehringer, Bristol Myers Squibb, Evaxion, Highlight Therapeutics S.L, Merck Sharp and Dohme, Novartis, Pierre Fabre, QBiotics, Regeneron, Specialised Therapeutics Australia. AM: advisory board: Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Roche, Pierre-Fabre, QBiotics. MC: consultant advisor: Amgen, Bristol Myers Squibb, Eisai, Ideaya, Merck Sharp and Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche; honoraria: Bristol Myers Squibb, Merck Sharp and Dohme, Novartis. All other authors declare no competing interests., (© 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: To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study., Methods: In phase 1, patients with advanced solid tumors received intravenous cetrelimab 80, 240, 460, or 800 mg every 2 weeks (Q2W) or 480 mg Q4W. In phase 2, patients with melanoma, non-small-cell lung cancer (NSCLC), and microsatellite instability-high (MSI-H)/DNA mismatch repair-deficient colorectal cancer (CRC) received cetrelimab 240 mg Q2W. Response was assessed Q8W until Week 24 and Q12W thereafter., Results: In phase 1, 58 patients received cetrelimab. Two dose-limiting toxicities were reported and two recommended phase 2 doses (RP2D) were defined (240 mg Q2W or 480 mg Q4W). After a first dose, mean maximum serum concentrations (C max ) ranged from 24.7 to 227.0 µg/mL; median time to C max ranged from 2.0 to 3.2 h. Pharmacodynamic effect was maintained throughout the dosing period across doses. In phase 2, 146 patients received cetrelimab 240 mg Q2W. Grade ≥ 3 adverse events (AEs) occurred in 53.9% of patients. Immune-related AEs (any grade) occurred in 35.3% of patients (grade ≥ 3 in 6.9%). Overall response rate was 18.6% across tumor types, 34.3% in NSCLC, 52.6% in programmed death ligand 1-high (≥ 50% by immunohistochemistry) NSCLC, 28.0% in melanoma, and 23.8% in centrally confirmed MSI-H CRC., Conclusions: The RP2D for cetrelimab was established. Pharmacokinetic/pharmacodynamic characteristics, safety profile, and clinical activity of cetrelimab in immune-sensitive advanced cancers were consistent with known PD-1 inhibitors., Trial Registrations: NCT02908906 at ClinicalTrials.gov, September 21, 2016; EudraCT 2016-002,017-22 at clinicaltrialsregister.eu, Jan 11, 2017., (© 2022. The Author(s).)

Checkpoint inhibitor (CPI) therapy has vastly improved long-term outcomes in metastatic malignant melanoma (MMM). Therapy takes the form of monoclonal antibody infusions that target immune cell checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed death 1/programmed death ligand 1 (PD1/PDL1). Cutaneous immune-related adverse effects (IrAEs) are frequent in patients with MMM treated with CPIs. Our aim was to review the clinical presentations of cutaneous IrAEs associated with CPI therapy in adult patients with MMM. We carried out a literature review of clinical trials, case series and case reports of patients with melanoma and those with other cancers treated with anti-CTLA4, anti-PD1/PDL1, or a combination of these therapies. Diverse clinical presentations of cutaneous IrAEs are recognized. Anti-CTLA4 therapy has a higher associated rate of cutaneous IrAEs than anti-PD1/PDL1 therapies. Low-grade cutaneous IrAEs are common and are usually managed supportively while continuing CPI therapy. Delayed presentations arising after established use of CPIs can make therapy-associated cutaneous IrAEs difficult to distinguish from coincidental dermatological disease. Vitiligo-like depigmentation is a good prognostic indicator of outcome in patients with melanoma. Life-threatening adverse events including toxic epidermal necrolysis are rare. The identification of predictive biomarkers that highlight patients at risk of life-threatening IrAEs remains an unmet need. The involvement of dermatologists in the multidisciplinary assessment of cutaneous IrAEs is increasingly pertinent in the management and care of CPI-treated patients with melanoma., (© 2021 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial., Methods: DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/- CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers., Discussion: DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs., Trial Registration: ISRCTN15837212 , 31 July 2018.

Background: Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown., Methods: Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined., Results: Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy (p = 0.028)., Conclusions: Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.

Background: In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed., Methods: We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached., Results: The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period., Conclusions: In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.)., (Copyright © 2020 Massachusetts Medical Society.)

Mature cystic teratomas are common in women of all ages; however, malignant transformation within them is rare and difficult to diagnosis preoperatively. Primary melanoma of the ovary is exceptionally rare and only occurs in relation to a teratoma where it can originate from sporadic somatic mutagenesis within epidermal junctional melanocytes, through malignant transformation of a benign nevus formed within the mature cystic teratoma or from other well differentiated pigment-containing structures such as the uvea. We present a case of primary malignant melanoma arising within a mature cystic teratoma in a young patient, who ultimately developed widespread metastasis necessitating systemic therapy. Our case highlights the role of molecular medicine not only in forming an understanding the origin of the melanoma, but also guiding targeted systemic therapies. Alongside the case we present a review of the literature describing the incidence of molecular aberrations within melanoma as well as the established and emerging techniques and cytotoxic agents for malignant melanoma.

A 47-year-old man with metastatic melanoma presented with refractory hyperlactaemic acidosis following the first dose of the mono-carboxylase transporter 1 inhibitor AZD3965 within a "first time in man" clinical trial. The mechanism of the agent and the temporal relationship suggested that this event was potentially drug related and recruitment was suspended. However, urinary metabolomics showed extensive abnormalities even prior to drug administration, leading to investigations for an underlying metabolic disorder. The lack of clinical symptoms from the elevated lactate and low blood glucose suggested a diagnosis of "hyper-Warburgism", where the high tumour burden was associated with extensive glucose uptake and lactate efflux from malignant cells, and the subsequent impact on blood biochemistry. This was supported by an FDG-PET scan showing extensive glucose uptake in numerous metastases and lack of uptake in the brain. A review of the literature showed 16 case reports of "hyper-Warburgism" in non-haematological malignancies, none of them with melanoma, with most associated with a poor outcome. The patient was treated symptomatically, but died 2 months later. The development of AZD3965 continues with the exclusion of patients with elevated plasma lactate at screening added to the protocol as a safety measure.Trial identification number ClinicalTrials.Gov. NCT01791595.

Background: Limited data are available on nivolumab in challenging subgroups with advanced melanoma. We report outcomes of nivolumab after prior ipilimumab in patients who are typically excluded from clinical trials., Patients and Methods: In this phase II, single-arm, open-label, multicentre study (CheckMate 172), patients with advanced melanoma who progressed on or after ipilimumab received nivolumab 3 mg/kg, every 2 weeks for up to 2 years. The primary objective was incidence of grade ≥3, treatment-related select adverse events (AEs)., Results: At a minimum follow-up of 18 months, grade ≥3 treatment-related select AEs with the most variation across subgroups were diarrhoea and colitis (1.1% [n = 11] and 0.3% [n = 3] for the total population [n = 1008]; 0.6% [n = 1] and 0.6% [n = 1] for patients with an asymptomatic central nervous system [CNS] metastasis [n = 165; 16.4%]; 4.5% [n = 3] and 3.0% [n = 2] for patients with an Eastern Cooperative Oncology Group performance status [ECOG PS] of 2 [n = 66; 6.5%]; 2.4% [n = 2] and 0% for those who experienced a grade 3/4 immune-related AE [irAE] with prior ipilimumab [n = 84; 8.3%]; and 0% and 0% for autoimmune disease [n = 25; 2.5%], respectively). Median overall survival was 21.4 months in the total population and was 11.6, 2.4, 21.5, and 18.6 months in patients with a CNS metastasis, ECOG PS 2, a grade 3/4 irAE with prior ipilimumab, and autoimmune disease, respectively., Conclusions: In this large, phase II clinical trial of patients with advanced melanoma who progressed on or after ipilimumab, nivolumab demonstrated a safety profile consistent with that of prior clinical trials. ClinicalTrials.gov ID: NCT02156804., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Nivolumab has been widely studied in non-acral cutaneous melanoma; however, limited data are available in other melanoma subtypes. We report outcomes by melanoma subtype in patients who received nivolumab after progression on prior ipilimumab., Patients and Methods: CheckMate 172 was a phase II, single-arm, open-label, multicentre study that evaluated nivolumab in patients with advanced melanoma who progressed on or after ipilimumab. Patients received 3 mg/kg of nivolumab, every 2 weeks for up to 2 years. The primary end-point was incidence of grade ≥3, treatment-related select adverse events (AEs)., Results: Among 1008 treated patients, we report data on patients with non-acral cutaneous melanoma (n = 723 [71.7%]), ocular melanoma (n = 103 [10.2%]), mucosal melanoma (n = 63 [6.3%]), acral cutaneous melanoma (n = 55 [5.5%]) and other melanoma subtypes (n = 64 [6.3%]). There were no meaningful differences in the incidence of grade ≥3, treatment-related select AEs among melanoma subtypes or compared with the total population. No new safety signals emerged. At a minimum follow-up of 18 months, median overall survival was 25.3 months for non-acral cutaneous melanoma and 25.8 months for acral cutaneous melanoma, with 18-month overall survival rates of 57.5% and 59.0%, respectively. Median overall survival was 12.6 months for ocular melanoma and 11.5 months for mucosal melanoma, with 18-month overall survival rates of 34.8% and 31.5%, respectively., Conclusions: The safety profile of nivolumab after ipilimumab is similar across melanoma subtypes. Compared with non-acral cutaneous melanoma, patients with acral cutaneous melanoma had similar survival outcomes, whereas those with ocular and mucosal melanoma had lower median overall survival. CLINICALTRIALS., Gov Id: NCT02156804., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAF V600E or BRAF V600K mutations received adjuvant dabrafenib plus trametinib or placebo. The primary analysis showed that dabrafenib plus trametinib significantly improved relapse-free survival at 3 years. These results led to US Food and Drug Administration approval of dabrafenib plus trametinib as adjuvant treatment for patients with resected stage III melanoma with BRAF V600E or BRAF V600K mutations. Here, we report the patient-reported outcomes from COMBI-AD., Methods: COMBI-AD was a randomised, double-blind, placebo-controlled, phase 3 study done at 169 sites in 25 countries. Study participants were aged 18 years or older and had complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma as per American Joint Committee on Cancer 7th edition criteria, with BRAF V600E or BRAF V600K mutations, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system, stratified by mutation type and disease stage, to receive oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) or matching placebos for 12 months. Patients, physicians, and the investigators who analysed the data were masked to treatment allocation. The primary endpoint was relapse-free survival, reported elsewhere. Health-related quality of life, reported here, was a prespecified exploratory endpoint, and was assessed with the European Quality of Life 5-Dimensions 3-Levels (EQ-5D-3L) questionnaire in the intention-to-treat population. We used a mixed-model repeated-measures analysis to assess differences in health-related quality of life between groups. This study is registered with ClinicalTrials.gov, number NCT01682083. The trial is ongoing, but is no longer recruiting participants., Findings: Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled and randomly assigned to receive dabrafenib plus trametinib (n=438) or matching placebos (n=432). Data were collected until the data cutoff for analyses of the primary endpoint (June 30, 2017). The median follow-up was 34 months (IQR 28-39) in the dabrafenib plus trametinib group and 33 months (20·5-39) in the placebo group. During the 12-month treatment phase, there were no significant or clinically meaningful changes from baseline between groups in EQ-5D-3L visual analogue scale (EQ-VAS) or utility scores. During treatment, there were no clinically meaningful differences in VAS scores or utility scores in the dabrafenib plus trametinib group between patients who did and did not experience the most common adverse events. During long-term follow-up (range 15-48 months), VAS and utility scores were similar between groups and did not differ from baseline scores. At recurrence, there were significant decreases in VAS scores in both the dabrafenib plus trametinib group (mean change -6·02, SD 20·57; p=0·0032) and the placebo group (-6·84, 20·86; p<0·0001); the mean change in utility score also differed significantly at recurrence for both groups (dabrafenib plus trametinib -0·0626, 0·1911, p<0·0001; placebo -0·0748, 0·2182, p<0·0001)., Interpretation: These findings show that dabrafenib plus trametinib did not affect patient-reported outcome scores during or after adjuvant treatment, and suggest that preventing or delaying relapse with adjuvant therapy could be beneficial in this setting., Funding: Novartis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Patients with malignant melanoma often relapse after treatment with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors (MEKi) owing to development of drug resistance., Objectives: To establish the temporal pattern of CD271 regulation during development of resistance by melanoma to trametinib, and determine the association between development of resistance to trametinib and induction of prosurvival autophagy., Methods: Immunohistochemistry for CD271 and p62 was performed on human naevi and primary malignant melanoma tumours. Western blotting was used to analyse expression of CD271, p62 and LC3 in melanoma subpopulations. Flow cytometry and immunofluorescence microscopy was used to evaluate trametinib-induced cell death and CD271 expression. MTS viability assays and zebrafish xenografts were used to evaluate the effect of CD271 and autophagy modulation on trametinib-resistant melanoma cell survival and invasion, respectively., Results: CD271 and autophagic signalling are increased in stage III primary melanomas vs. benign naevi. In vitro studies demonstrate MEKi of BRAF-mutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271-expressing subpopulations. Trametinib-induced CD271 reduced autophagic flux, leading to activation of prosurvival autophagy and development of MEKi resistance. Treatment of CD271-expressing melanoma subpopulations with RNA interference and small-molecule inhibitors to CD271 reduced the development of MEKi resistance, while clinically applicable autophagy modulatory agents - including Δ9-tetrahydrocannabinol and Vps34 - reduced survival of MEKi-resistant melanoma cells. Combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKi-resistant cells in an in vivo zebrafish xenograft., Conclusions: These results highlight a novel mechanism of MEKi-induced drug resistance and suggest that targeting autophagy may be a translatable approach to resensitize drug-resistant melanoma cells to the cytotoxic effects of MEKi., (© 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Purpose: Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; P < .001) in patients with resected BRAF V600-mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083). We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term., Methods: In this phase III trial, patients with resected BRAF V600-mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo. We report updated RFS (primary end point) and distant metastasis-free survival. RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model., Results: At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis-free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration., Conclusion: Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.

Background: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations., Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety., Results: At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma., Conclusions: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).

Background: Expression of the chemokine receptor CXCR4 is known to regulate melanoma metastasis to distant sites with high expression of the CXCL12 ligand. However, the prognostic impact of CXCR4 expression and potential for autocrine-mediated activation of prosurvival mitogen-activated protein kinase signalling remains enigmatic. Furthermore, expression of the decoy receptor CXCR7 within the local cutaneous melanoma microenvironment remains undefined., Objectives: To define the contribution and prognostic impact of CXCR4-CXCR7-CXCL12 signalling in primary cutaneous melanomas and the immediate tumour microenvironment., Methods: Immunohistochemical/immunofluorescent expression of CXCR4, CXCR7 or CXC12 was analysed in human metastatic melanoma cell lines, primary cutaneous cell types and a retrospective cohort of primary melanomas/benign naevi. CXCL12 secretion by melanoma/cutaneous cells was evaluated by enzyme-linked immunosorbent assay, and autocrine CXCR4-CXCL12 signalling was investigated by addition of a CXCL12-neutralizing antibody., Results: CXCR4 expression was significantly higher in primary melanomas that subsequently metastasized after 7 years (P = 0·037). Stratification for American Joint Committee on Cancer (AJCC) stage II disease revealed significantly decreased disease-free survival in patients with > 50% CXCR4 expression (P = 0·036), while comparative analysis of CXCL12 expression in the adjacent epidermis of all AJCC stage melanomas revealed increased CXCL12 correlated with prolonged time to metastasis (P = 0·014). CXCR7 was expressed within the primary melanoma microenvironment but was absent on primary tumours. Addition of anti-CXCL12 to BRAF-mutant melanoma cells resulted in downregulation of phospho-CXCR4 and phospho-extracellular signal-related kinase, indicating autocrine CXCR4-CXCL12 signalling., Conclusions: CXCR4 expression defines a potential prognostic biomarker for AJCC stage II melanoma. Moreover, targeting the CXCR4-CXCR7-CXCL12 axis may represent a novel therapeutic strategy to prevent early melanoma progression., (© 2016 British Association of Dermatologists.)

Background: Veliparib (ABT-888) is a potent, orally bioavailable, small-molecule inhibitor of the DNA repair enzymes poly ADP-ribose polymerase-1 and -2. Veliparib enhances the efficacy of temozolomide (TMZ) and other cytotoxic agents in preclinical tumor models., Patients and Methods: In this multicenter, double-blind trial, adults with unresectable stage III or IV metastatic melanoma were randomized 1:1:1 to TMZ plus veliparib 20 or 40 mg, or placebo twice daily. Efficacy end points included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR)., Results: Patients (N = 346) were randomized between February 2009 and January 2010. Median [95% confidence interval (CI)] PFS was 3.7 (3.0-5.5), 3.6 (1.9-4.1), and 2 (1.9-3.7) months in the 20-mg, 40-mg, and placebo arms, respectively. Median (95% CI) OS was 10.8 (9.0-13.1), 13.6 (11.4-15.9), and 12.9 (9.8-14.3) months, respectively; ORR was 10.3%, 8.7%, and 7.0%. Exploratory analyses showed patients with low ERCC1 expression had longer PFS when TMZ was combined with veliparib. Toxicities were as expected for TMZ. The frequencies of thrombocytopenia, neutropenia, and leukopenia were significantly increased in the veliparib groups. Grade 3 or 4 adverse events, mainly hematologic toxicities, were seen in 55%, 63%, and 41% of patients in the 20-mg, 40-mg, and placebo arms, respectively., Conclusions: Median PFS with 20 and 40 mg veliparib almost doubled numerically compared with placebo, but the improvements did not reach statistical significance. OS was not increased with veliparib. Toxicities were similar to TMZ monotherapy, but with increased frequency., (© 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.)

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.

Background: Treatment options for wild-type BRAF melanoma patients remain limited. Selumetinib, a MEK 1/2 inhibitor, suppresses pERK levels independent of BRAF and NRAS mutation status, and combination with docetaxel has demonstrated synergy in xenograft models. The aim of this study was to assess the efficacy and safety of selumetinib plus docetaxel as first-line treatment in patients with wild-type BRAF advanced melanoma., Patients and Methods: In this double-blind multicentre phase II trial patients with wild-type BRAF melanoma were randomized (1:1) to docetaxel with selumetinib or placebo. Docetaxel 75 mg/m(2) was administered intravenously every 3 weeks up to six cycles. Selumetinib 75 mg or placebo was given orally twice daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Tumour NRAS mutation status was analysed retrospectively and correlated with treatment outcomes., Results: Eighty-three patients were randomized to docetaxel plus selumetinib (n = 41) or docetaxel plus placebo (n = 42). The PFS hazard ratio (HR) (selumetinib:placebo) was 0.75 [90% confidence interval (CI) 0.50-1.14; P = 0.130], with a median PFS of 4.23 months (90% CI 3.63-6.90) for docetaxel plus selumetinib and 3.93 months (90% CI 2.07-4.16) for docetaxel alone. There was no significant difference in overall survival. The objective response rate was 32% with selumetinib versus 14% with placebo (P = 0.059). In a retrospective subset analysis, NRAS mutation status did not affect significantly upon clinical outcomes in either arm. The combination of docetaxel and selumetinib could be administered effectively to patients with metastatic melanoma, although the combination was less well tolerated than docetaxel alone., Conclusions: The combination of docetaxel with selumetinib showed no significant improvement in PFS compared with docetaxel alone, although more patients showed a response to combination therapy. We found no evidence to support using tumour NRAS mutation as a basis for selecting patients for combined MEK inhibitor and chemotherapy., Clinical Trial: DOC-MEK (EudraCT no: 2009-018153-23).

Vemurafenib is an oral BRAF inhibitor licenced for the treatment of locally advanced or metastatic BRAF V600-mutation positive malignant melanoma. The manufacturer of vemurafenib, Roche Products Limited, was invited by the National Institute for Health and Care Excellence (NICE) to submit evidence of the drug's clinical- and cost-effectiveness for its licenced indication, to inform the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG) for this appraisal. This article summarises the ERG's review of the evidence submitted by the manufacturer and also includes a summary of the NICE Appraisal Committee (AC) decision. The ERG reviewed the clinical- and cost-effectiveness evidence in accordance with the decision problem defined by NICE. The ERG's analysis of the submitted economic model assessed the appropriateness of the approach taken by the manufacturer in modelling the decision problem. It also included an assessment of the reliability of model implementation and the extent of conformity to published standards and prevailing norms of practice within the health economics modelling community. Particular attention was paid to issues likely to impact substantially on the base-case cost-effectiveness results. The clinical evidence was derived from BRIM 3 (BRAF Inhibitor in Melanoma 3), a well-designed, multi-centre, multi-national, phase III, randomised controlled trial (RCT). Clinical outcome results from the October 2011 data cut showed that median overall survival for patients treated with vemurafenib was 13.2 months compared with 9.6 months for those treated with dacarbazine. The ERG's main concern with the trial was the potential for confounding because of the early introduction of the crossover from the comparator drug to vemurafenib or another BRAF inhibitor. The submitted incremental cost-effectiveness ratio (ICER) was considered above the NICE threshold, even when end-of-life criteria were taken into account. The ERG questioned the submitted economic model on a number of grounds, particularly the approach used to project trial results. After the ERG had made appropriate corrections to the model and employed an alternative form of projective modelling, the ICER per quality-adjusted life year more than doubled. Additional evidence was submitted by the manufacturer for consideration at a second AC meeting and at their third meeting the AC concluded that vemurafenib could be recommended as first-line maintenance treatment for patients with locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma.

Background: This phase I-II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma., Methods: The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m(-2) (n = 20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m(-2) on days 1, 8 and 15 q4wk combined with DTIC 800 mg m(-2) q4wk (n = 38)., Results: The overall response rate with plitidepsin/DTIC was 21.4%; all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ≤ 1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug-drug pharmacokinetic interactions were found., Conclusion: This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m(-2) fortnightly and DTIC 800 mg m(-2) q4wk is recommended.

Purpose: poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma., Methods: Patients with chemotherapy naïve measurable metastatic melanoma, performance status ≤2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored., Results: Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months., Conclusions: This study showed that temozolomide (150-200 mg/m(2)/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.

Background: Despite intensive research and novel adjuvant therapies, there is currently no cure for metastatic melanoma. The chemokine receptor CXCR4 controls metastasis to sites such as the liver; however, the therapeutic blockade with the existing agents has proven difficult., Methods: AMD11070, a novel orally bioavailable inhibitor of CXCR4, was tested for its ability to inhibit the migration of melanoma cells compared with the commonly described antagonist AMD3100., Results: AMD11070 abrogated melanoma cell migration and was significantly more effective than AMD3100. Importantly for the clinical context, the expression of B-RAF-V600E did not the affect the sensitivity of AMD11070., Conclusion: Liver-resident myofibroblasts excrete CXCL12, which is able to promote the migration of CXCR4-expressing tumour cells from the blood into the liver. Blockade of this axis by AMD11070 thus represents a novel therapeutic strategy for both B-RAF wild-type and mutated melanomas.

Current systemic treatments for metastatic uveal melanoma (UM) have not improved overall survival (OS). The fully human anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, ipilimumab, improved OS of patients with advanced cutaneous melanoma in a phase 3 trial; however, UM patients were excluded. The aim of this subanalysis, performed by the ipilimumab-ocular melanoma expanded access program (I-OMEAP) study group, was to assess the activity and safety of ipilimumab in patients with UM in a setting similar to daily clinical practice. Patients participating in a multicenter expanded access program (EAP) received induction treatment with ipilimumab 10 mg/kg. Maintenance doses were administered in patients who experienced clinical benefit or at physicians' discretion. Tumor assessment was evaluated per modified World Health Organization criteria at baseline, Week 12, Week 24, and Week 36. Adverse events (AEs) and immune-related AEs (irAEs) were collected according to Common Terminology Criteria for Adverse Events version 3.0. Thirteen pretreated patients with metastatic UM were treated at 6 European institutions. All patients received at least one dose of ipilimumab. Overall, no objective responses were observed; however, two patients had stable disease (SD), with a third patient achieving SD after initial progressive disease. Median OS as of July 1, 2011, was 36 weeks (range 2-172+ weeks). No grade 3/4 AEs of non-immune origin were reported. Three patients (23%) experienced grade 3 irAEs (1 thrombocytopenia, 1 diarrhea, and 1 alanine/aspartate aminotransferase elevation) that resolved with steroid therapy. The results indicate UM is a potential indication for ipilimumab treatment that should be further investigated in clinical trials.

Summary: Malignant melanoma tumour cells often carry mutations in the BRAF protein, which activates a second protein called MEK to fuel tumour growth. Using drugs that block the mutant form of BRAF and MEK, we can specifically target and kill most of these tumour cells, but a subset of tumour cells often become resistant to BRAF and MEK inhibiting drugs, and cause the tumour to regrow. The aim of this study was to determine how changes in a protein called CD271, which has previously been shown to increase tumour growth and aggressiveness, contributes to the resistance of BRAF mutant melanoma cells to the MEK inhibiting drug, trametinib. Furthermore, we have previously shown that a cell survival process within tumour cells called autophagy is increased in BRAF mutant melanoma cells, so we also aimed to determine the contribution of autophagy to the resistance of BRAF mutant melanoma cells to trametinib. We show that CD271 and autophagy are increased in advanced malignant melanoma tumours compared to normal moles, and that treatment of melanoma cells in the laboratory with trametinib results in the emergence of a subset of melanoma cells with increased CD271 and autophagy. However, specific inhibition of CD271 reduced the number of resistant melanoma cells following trametinib treatment, while either blocking or activating autophagy resulted in death of trametinib‐resistant melanoma cells. We also show that combined treatment with drugs that specifically block both MEK and autophagy reduced the invasion of trametinib‐resistant melanoma cells in embryonic zebrafish up to 5 days old. Our results show that embryonic zebrafish at an early stage of development may replace mice as a more ethical alternative animal model for the study of cancer metastasis (spreading) and drug response, and highlight an important new way to prevent drug‐resistance by blocking autophagy in patients with BRAF mutant melanoma cells. Linked Article: Verykiou et al. Br J Dermatol 2019; 180:346–356 [ABSTRACT FROM AUTHOR]