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Author(s): E. A. Rozeman [sup.1] , E. P. Hoefsmit [sup.2] , I. L. M. Reijers [sup.1] , R. P. M. Saw [sup.3] [sup.4] [sup.5] , J. M. Versluis [sup.1] , [...], Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN (NCT02437279) and phase 2 OpACIN-neo (NCT02977052) studies.sup.1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-[gamma] score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-[gamma] score/high TMB; patients with high IFN-[gamma] score/low TMB or low IFN-[gamma] score/high TMB had pRRs of 91% and 88%; while patients with low IFN-[gamma] score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-[gamma] score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma. Long-term outcomes and biomarker analyses of two neoadjuvant immunotherapy clinical trials in melanoma patients support the clinical benefit of this treatment approach and uncover prognostic correlates of response.

Background: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race., Patients and Methods: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted., Results: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01)., Conclusions: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival., Competing Interests: Disclosure FD: receives/received honoraria and travel support from Merck Sharp & Dohme Bristol-Myers Squibb and Sun Pharma. KN: honoraria from Ono Pharmaceutical, Novartis Pharma, Bristol-Myers Squibb and MSD. EIB: has received consulting fees from BMS and Novartis; has research funding paid to the institution from BMS, Merck, Novartis and Genentech. JAS: conference support from MSD. AZ: received travel support from Novartis, Sanofi Grenzyme and Bristol-Myers Squibb, outside the submitted work. MJM: served as a consultant for AstraZeneca, immunai, nektar therapeutics, catalyst pharmaceuticals and istari oncology. YN: consultant/advisory board—MSD, Novartis. Institutional research funding—Kaken, Ono pharma, Pola Pharma, Torii. Honoraria—BMS, Maruho, MSD, Novartis, Ono Pharma, Taisho Toyama, Taiho Pharma. XB: merit award supported by BMS.CA: Travel accommodations—meetings: Roche, BMS, AMGEN. AI: advisory board: Novartis. Honoraria for lectures: BMS, MSD, Novartis, Sanofi, Pierre-Fabre. MF: advisory board—Bayer. KCK: has served as consultant and/or has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. VA: personal fees: Bristol Myers Squibb, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Oncosec. OK: personal fees from Bristol Myers Squibb and Merck Sharp & Dohme, outside the submitted work. AH: has served on advisory boards for BMS, MSD, Novartis, Pierre Fabre and Q Biotic. RDC: consultant/advisory board—Alkermes, Aura Biosciences, Bristol Myers Squibb, Castle Biosciences, Chimeron, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Rgenix, Sanofi Genzyme, Sorrento Therapeutics, Trisalus. OH: speaker’s bureau honoraria from BMS, Novartis, Pfizer and Sanofi Regeneron, and is an advisory board member/consultant for Aduro, Akeso Bio, Amgen, Beigene, Bioatla, BMS, Roche Genentech, GSK, Immunocore, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi Regeneron, Seagen, Tempus and Zelluna. AH: received grants and personal fees from Amgen, BMS, Immunocore, Novartis, MerckSerono, MSD/Merck, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme and Sun Pharma, outside the submitted work. MSC: consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck and Sanofi, and received honoraria from BMS, MSD and Novartis. MM: received honoraria for participation at advisory boards from Novartis, BMS, MSD, Pierre Fabre, Sanofi, reports lecture from Novartis, BMS, MSD, Pierre Fabre, Sanofi and reports grants from Roche, Novartis. CR: advisor for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Merck, Roche, AstraZeneca and is scientific founder of Aglaia therapeutics. CL: BMS: research grant, honoraria, consultancy, speaker’s bureau, travel accommodations—meetings, advisory role, serving on an advisory board; MSD: honoraria, consultancy, advisory role, serving on an advisory board, travel accommodations—meetings; Novartis: honoraria, consultancy, speaker’s bureau, advisory role, serving on an advisory board; Amgen: honoraria, consultancy, speaker’s bureau, serving on an advisory board; Roche: research grant, honoraria, consultancy, speaker’s bureau, advisory role, serving on an advisory board; Avantis Medical Systems: board; Pierre-Fabre/Pfizer/Incyte: honoraria. JG: consultant/advisory boards for MSD, Roche, Pfizer, Bayer, Novartis, Simcere Pharmaceutical Group, Shanghai Junshi Biosciences and Oriengene. DBJ: advisory boards for Array Biopharma, Bristol Myers Squibb, Catalyst Biopharma, Iovance Biotherapeutics, Janssen, Merck, Novartis and OncoSec. Research support from Bristol Myers Squibb and Incyte. PAA: has/had a consultant/advisory role for 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. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. ANS: advisory board/personal fees: Bristol-Myers Squibb, Immunocore, Novartis, Castle Biosciences. Institutional trial support: Bristol-Myers Squibb, Immunocore, Novartis, Xcovery, Polaris, Pfizer, Checkmate Pharmaceuticals, Forghorn Therapeutics. RJS: advisory board—BMS, Merck, Novartis, Pfizer; research support from Merck. LZ: served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis. SS: grants from Novartis, AstraZeneca, Merck Sharp & Dohme and Genentech; and personal fees from AstraZeneca, Merck Sharp & Dohme and Bristol Myers Squibb, outside the submitted work. CUB: personal fees from BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, grants from BMS, Novartis, NanoString, other from Uniti Cars, Forty Seven, Neon Therapeutics, Verastem, other from Immagene B.V. RD: intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA and touchIME outside the submitted work. BCS: speaker’s bureau honoraria and personal fees from BMS, Novartis, MDS, Pierre Fabre. AMM: advisory board—BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. GVL: consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc. All other authors have declared no conflicts of interest. Data sharing Availability of data and material: patients’ medical records. All data were anonymized immediately after collection., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy., Patients and Methods: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined., Results: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%)., Conclusions: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE., Competing Interests: Disclosure CNO has received non-financial support from Merck Sharp & Dohme. XB receives a merit award supported by BMS. CA has received travel support from Amgen, BMS and Roche. PB has received sponsorship from MSD. WX has served on advisory boards for Merck Serono and Novartis and has received research funding from Merck Serono. BN has received personal financial compensation from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and AstraZeneca, for public speaking, consultancy and participation in advisory board meetings. His institution (UZ Brussel) received research funding related to research projects conducted by his team from Pfizer, Novartis, Roche and Merck-Serono. CUB has an advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre and Third Rock Ventures. He has received research funding from BMS, Novartis and NanoString. He has stock ownership in Uniti Cars and is co-founder of Immagene B.V. SJW has received travel support from Ipsen. SS has served on advisory boards for BMS, MSD, Merck, Novartis, Roche, Janssen, AstraZeneca and Amgen and has received research funding from Amgen, Endocyte, MSD and AstraZeneca. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers Squibb, Sanofi and Pierre Fabre and has received travel support from Ultrasun, L'oreal, Merck Sharp & Dohme, Bristol Myers Squibb and Pierre Fabre outside of the submitted work. JLM is consultant advisor for BMS, Roche and Novartis. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai and Regeneron. He also received research funds from Bristol Myers Squibb, Roche-Genentech and Array, and travel support from MSD. LZ has received honoraria from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre, research funding from Novartis and has served on advisory boards for Bristol Myers Squibb, Novartis, Pierre Fabre, Sun Pharma, Sanofi and Merck Sharp & Dohme. He has received travel support from Bristol Myers Squibb, Pierre Fabre, Sanofi, Amgen, Novartis and Sun Pharma. DBJ has served on advisory boards for Array Biopharma, BMS, Iovance, Jansen, Merck and Novartis, and received research funding from BMS and Incyte. CL has served on advisory boards for BMS, MSD, Novartis, Amgen, Roche, Merck, Serono and Sanofi. She has received honoraria from Roche, BMS, Novartis, Amgen, MSD, Pierre Fabre, Pfizer and Incyte, and speaker's bureau from Roche, BMS, Novartis, Amgen and MSD. She has received research funding from Roche and BMS. She has received travel support from BMS and MSD. She serves on the board of Avantis Medical Systems. MSC has served on advisory boards for Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar and Eisai and honoraria from Bristol Myers Squibb, MSD and Novartis. RJS has received research support from Amgen and Merck, as well as served as a paid consultant and/or on a scientific advisory board for Array, AstraZeneca, Asana Biosciences, Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, Oncosec, Pfizer and Replimune. GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc. AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre Fabre and QBiotics. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)