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Introduction: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma., Patients and Methods: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation., Results: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p = 0.006), without OS differences., Conclusion: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes., Competing Interests: Conflict of interest statement All authors declare no direct conflict with this work. For unrelated conflicts, K.P.M.S. has an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, AbbVie and Pierre Fabre and has received honoraria from Merck Sharp & Dohme, Novartis and Roche. L.Z. has an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Sun Pharma; has received research funding from Novartis; has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre and Roche and has received travel support from Amgen, Bristol Myers Squibb, Novartis, Pierre Fabre, Sanofi and Sun Pharma. E.W.K. has an advisory role for Bristol Myers Squibb, Merck, Novartis and Pierre Fabre; has received research funding from Bristol Myers Squibb and has received travel support from Roche. C.A. has received travel support from Amgen, Bristol Myers Squibb and Roche. D.B.J. has an advisory role for Array BioPharma, Bristol Myers Squibb, Incyte, Merck and Novartis; has received research funding from Bristol Myers Squibb and Incyte and has received travel support from Genentech. Adriana H. is an employee of AstraZeneca with stock options in the company, has received honoraria from Novartis; has an advisory role for L.E.K. Consulting and has received travel support from Roche. J.M. has received honoraria from Amgen, Bristol Myers Squibb, Merck-Pfizer, MSD, Novartis and Pierre Fabre; has an advisory role for Amgen, Merck-Pfizer, Merck Sharp & Dohme, Novartis and Pierre Fabre and has received travel support from Bristol Myers Squibb, L'Oreal, MSD, Pierre Fabre and Ultrasun. P.B. has received travel support from MSD. Y.J.L.J. has received travel support from Bristol Myers Squibb, MSD and Pfizer. V.A. has received honoraria from Bristol Myers Squibb, Genentech, Merck Serono, Merck Sharp & Dohme, Novartis and Pierre Fabre; has an advisory role for Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre and Roche and has received travel support from Bristol Myers Squibb, Merck Sharp & Dohme, OncoSec and Pierre Fabre. P.A.A. has an advisory role for 4SC, Alkermes, Amgen, Array BioPharma, Bristol Myers Squibb, Genentech, Genmab, Idera, Immunoscore, Incyte, Italfarmaco, MedImmune, Merck Serono, Merck Sharp & Dohme, Nektar, NewLink Genetics, Novartis, Pierre Fabre, Sandoz, Sanofi, Sun Pharma, Syndax and Ultimovacs; has received research funding from Array BioPharma, Bristol Myers Squibb and Genentech; has received travel support from Merck Sharp & Dohme and is a stockowner of PrimeVax. Andrew H. has received honoraria from Merck and Novartis and has an advisory role for Novartis and Pierre Fabre. A.M.M. has an advisory role for Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre and Roche. G.V.L. is a consultant advisor for Aduro Biotech, Inc., Amgen Inc., Array BioPharma Inc., Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Highlight Therapeutics S.L., Merck Sharp & Dohme, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals, Inc. and SkylineDX B.V. C.L. had received honoraria from Amgen, Bristol Myers Squibb, Incyte, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre and Roche; has an advisory role for Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Roche and Sanofi; has received research funding from Bristol Myers Squibb and Roche and has received travel support from Bristol Myers Squibb and Merck Sharp & Dohme. A.A.M.v.d.V. has an advisory role for Bristol Myers Squibb, Eisai, Ipsen, MSD Oncology, Merck, Novartis, Pfizer, Pierre Fabre, Roche and Sanofi and has received research funding from Bayer and travel support from Bayer, MSD Oncology, Novartis and Roche. M.S.C. has an advisory role for Amgen, Bristol Myers Squibb, Eisai, IDEAYA Biosciences, Merck and Co, Merck Sharp & Dohme, Nektar, Novartis, Pierre Fabre, Roche, Sanofi and QBiotics and has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme and Novartis. S.S. has received honoraria from AstraZeneca, Bristol Myers Squibb, Merck and Merck Serono; has an advisory role for Amgen, Bristol Myers Squibb, MSD, Novartis and Roche outside the submitted work and has received research funding from Amgen, AstraZeneca, Endocyte, Genentech and Merck Sharp & Dohme. E.G.E.d.V. has an advisory role for Daiichi Sankyo, NSABP and Sanofi; has received research funding from Amgen, AstraZeneca, Bayer, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier and Synthon and is the chair of ESMO Cancer Medicines Working Group, chair of RECITS committee and member of the ESMO-MCBS working group. C.U.B. has received research funding from Bristol Myers Squibb, Novartis and NanoString; has an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, Genmab and Pierre Fabre and is a stockowner of Uniti Cars. M.J. has an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, AstraZeneca, Tesaro and Pierre Fabre., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS-mutated or Val600 BRAF-mutated advanced melanoma., Methods: In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS-mutated or BRAF-mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS-mutated melanoma, twice-daily MEK162 45 mg for BRAF-mutated melanoma, and twice-daily MEK162 60 mg for BRAF-mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment)., Findings: Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6-8·7; IQR 2·2-5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 [60%] patients with NRAS -mutated melanoma and 15 [37%] patients with the BRAF-mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema (ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea (eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and nine [22%]). Increased creatine phosphokinase was the most common grade 3-4 adverse event (seven [23%] and seven [17%]). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes., Interpretation: To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments., Funding: Novartis Pharmaceuticals., (Copyright © 2013 Elsevier Ltd. All rights reserved.)