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Neoadjuvant immunotherapies have shown antitumor activity in melanoma. Substudy 02C of the global, rolling-arm, phase 1/2, adaptive-design KEYMAKER-U02 trial is evaluating neoadjuvant pembrolizumab (anti-PD-1) alone or in combination, followed by adjuvant pembrolizumab, for stage IIIB-D melanoma. Here we report results from the first three arms: pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy. Pathologic complete responses occurred in 10 of 26 patients (38%) with pembrolizumab plus vibostolimab, 7 of 25 (28%) with pembrolizumab plus gebasaxturev and 6 of 15 (40%) with pembrolizumab monotherapy. Major pathologic responses occurred in 13 (50%), 10 (40%) and 7 (47%) patients, respectively. Safety was manageable. Treatment-related adverse events occurred in 24 of 26 patients (92%) with pembrolizumab plus vibostolimab, 21 of 25 (84%) with pembrolizumab plus gebasaxturev and 12 of 15 (80%) with pembrolizumab monotherapy; grade 3 or 4 treatment-related adverse events occurred in 2 (8%), 7 (28%) and 1 (7%) patient in each arm, respectively. No deaths due to adverse events occurred. Exploratory objective responses per RECIST v1.1 were observed in 13 (50%), 8 (32%) and 4 (27%) patients, in each arm, respectively. In a post hoc analysis, scores for tumor mutational burden and an 18-gene T cell-inflamed gene expression profile were generally higher in patients with major pathologic response. Longer follow-up will provide insight into the incremental benefit of combining neoadjuvant pembrolizumab with other therapies in stage IIIB-D melanoma. ClinicalTrials.gov registration: NCT04303169 ., Competing Interests: Competing interests: The authors declare the following competing interests: R.D. reports consulting fees and payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Takeda, Sanofi, Caralym, Second-Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME. C.R. reports consulting fees from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Sun Pharma and AstraZeneca and participation on a Data Safety Monitoring Board or Advisory Board for BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Sun Pharma and AstraZeneca. R.A.S. reports consulting fees from SkylineDx BV, F. Hoffman-La Roche Ltd, MetaOptima Technology Inc., Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc, Bristol Myers Squibb, Myriad Genetics, GlaxoSmithKline and IO Biotech ApS. J.M.T. reports grants or contracts to their institution from BMS; consulting fees from Merck & Co, BMS, AstraZeneca, Regeneron, Roche, Elephas, Lunaphore and Akoya Biosciences; a patent planned for machine learning for irPRC; and a Task Force role with the Society for Immunotherapy of Cancer. A.M.M. reports consulting fees from BMS, MSD, Novartis, Pierre Fabre, Roche and Qbiotics. M.T.T. reports support for the present paper to their institution from Merck and payment or honoraria and support for attending the Clinical Care Options, AACR 2023 companion course. A.H. has no conflicts of interest to declare. J.-J.G. reports consulting fees from Novartis and BMS, and participation on a Data Safety Monitoring Board or Advisory Board for Novartis, BMS, MSD, Philogen, Pierre Fabre, Sanofi, Roche and Amgen. D.C.P. has no conflicts of interest to declare. C.L. reports participating on an Advisory Board for MSD, BMS, Pierre Fabre, Novartis, Regenron and Seacraft; and travel expenses from BMS. M.A.K. reports consulting fees from MSD Australia, BMS Australia and Moderna; payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from MSD Australia and Moderna; and support for attending meetings and/or travel from Moderna and Pierre Fabre. J.C. has no conflicts of interest to declare. G.B.-S. reports payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from BMS, MSD, Merck, Novartis, Medison and Sanofi, and a role as the chairman of the Israeli Society of Clinical Oncology & Radiation Therapy. I.M. reports payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from BMS and Immunocore, and stock or stock options in Immunocore, Delcath and In8 Bio Iovance Ideaya. R.S.-F. reports medical writing support for the present paper; grants or contracts to their institution from MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from MSD, BMS, Novartis, Sanofi, Roche, AstraZeneca, Medison and Neopharm; and participation on an advisory board for MSD, Novartis and Clovis Oncology. N.M. reports grants or contracts from BMS, Novartis, Merck, MSD and Pierre Fabre; payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from BMS; payment for expert testimony from BMS, Pierre Fabre, MSD and Novartis; and support for attending meetings and/or travel from Pierre Fabre, Janssen, BMS and AbbVie. A.L.W. is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns stock in Merck & Co., Inc., Rahway, NJ, USA, and Organon. Y.R., M.F.-K. and C.K. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. G.V.L. reports consulting fees from and participation on a Data Safety Monitoring Board or Advisory Board for Agenus Inc, Amgen Inc, Array BioPharma, AstraZeneca, Bayer Health Care, BioNTech, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IO Biotech, Immunocore Ireland Limited, Innovent Biologics USA Inc, Merck Sharp & Dohme (Australia) Pty Limited, Novartis Pharma AG, PHMR Ltd, Pierre Fabre, Qbiotics Group Limited, Regeneron Pharmaceuticals, Scancell Limited and SkylineDX B.V.; and payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from Bristol Myers Squibb and Pierre Fabre., (© 2025. The Author(s).)

Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAF V600 -mutant melanoma. Sixty patients (42% females) were randomized to pembrolizumab alone (n = 20), sequential therapy (dabrafenib plus trametinib followed by pembrolizumab; n = 20) or concurrent (triple) therapy (n = 20), followed by surgery and adjuvant therapy. The primary outcome was pathological response; secondary outcomes included radiographic response, recurrence-free survival, overall survival, surgical outcomes, peripheral blood and tumor analyses and safety. The pathological response rate was 55% (11/20; including six pathological complete responses (pCRs)) with pembrolizumab, 50% (10/20; three pCRs) with sequential therapy and 80% (16/20; ten pCRs) with concurrent therapy, which met the primary outcome in each arm. Treatment-related adverse events affected 75-100% of patients during neoadjuvant treatment, with seven early discontinuations (all in the concurrent arm). At 2 years, event-free survival was 60% with pembrolizumab, 80% with sequential therapy and 71% with concurrent therapy. Recurrences after major pathological response were more common in the targeted therapy arms, suggesting a reduction in response 'quality' when targeted therapy is added to neoadjuvant immunotherapy. Risking the curative potential of immunotherapy in melanoma cannot be justified. Pending longer follow-up, we suggest that immunotherapy and targeted therapy should not be combined in the neoadjuvant setting for melanoma. ClinicalTrials.gov registration: NCT02858921 ., (© 2024. The Author(s).)

Patients with resected stage IIB/C melanoma have high recurrence risk, similar to those with resected stage IIIA/B disease. The phase 3, double-blind CheckMate 76K trial assessed 790 patients with resected stage IIB/C melanoma randomized 2:1 (stratified by tumor category) to nivolumab 480 mg or placebo every 4 weeks for 12 months. The primary endpoint was investigator-assessed recurrence-free survival (RFS). Secondary endpoints included distant metastasis-free survival (DMFS) and safety. At 7.8 months of minimum follow-up, nivolumab significantly improved RFS versus placebo (hazard ratio (HR) = 0.42; 95% confidence interval (CI): 0.30-0.59; P < 0.0001), with 12-month RFS of 89.0% versus 79.4% and benefit observed across subgroups; DMFS was also improved (HR = 0.47; 95% CI: 0.30-0.72). Treatment-related grade 3/4 adverse events occurred in 10.3% (nivolumab) and 2.3% (placebo) of patients. One treatment-related death (0.2%) occurred with nivolumab. Nivolumab is an effective and generally well-tolerated adjuvant treatment in patients with resected stage IIB/C melanoma. ClinicalTrials.gov identifier: NCT04099251 ., (© 2023. The Author(s).)

The gut microbiota shapes the response to immune checkpoint inhibitors (ICIs) in cancer, however dietary and geographic influences have not been well-studied in prospective trials. To address this, we prospectively profiled baseline gut (fecal) microbiota signatures and dietary patterns of 103 trial patients from Australia and the Netherlands treated with neoadjuvant ICIs for high risk resectable metastatic melanoma and performed an integrated analysis with data from 115 patients with melanoma treated with ICIs in the United States. We observed geographically distinct microbial signatures of response and immune-related adverse events (irAEs). Overall, response rates were higher in Ruminococcaceae-dominated microbiomes than in Bacteroidaceae-dominated microbiomes. Poor response was associated with lower fiber and omega 3 fatty acid consumption and elevated levels of C-reactive protein in the peripheral circulation at baseline. Together, these data provide insight into the relevance of native gut microbiota signatures, dietary intake and systemic inflammation in shaping the response to and toxicity from ICIs, prompting the need for further studies in this area., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free survival (RFS). The PRADO extension cohort of the OpACIN-neo trial ( NCT02977052 ) addressed the feasibility and effect on clinical outcome of using pathologic response after neoadjuvant ipilimumab and nivolumab as a criterion for further treatment personalization. In total, 99 patients with clinical stage IIIb-d nodal melanoma were included and treated with 6 weeks of neoadjuvant ipilimumab 1 mg kg -1 and nivolumab 3 mg kg -1 . In patients achieving major pathologic response (MPR, ≤10% viable tumor) in their index lymph node (ILN, the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with pathologic partial response (pPR; >10 to ≤50% viable tumor) underwent TLND only, whereas patients with pathologic non-response (pNR; >50% viable tumor) underwent TLND and adjuvant systemic therapy ± synchronous radiotherapy. Primary objectives were confirmation of pRR (ILN, at week 6) of the winner neoadjuvant combination scheme identified in OpACIN-neo; to investigate whether TLND can be safely omitted in patients achieving MPR; and to investigate whether RFS at 24 months can be improved for patients achieving pNR. ILN resection and ILN-response-tailored treatment were feasible. The pRR was 72%, including 61% MPR. Grade 3-4 toxicity within the first 12 weeks was observed in 22 (22%) patients. TLND was omitted in 59 of 60 patients with MPR, resulting in significantly lower surgical morbidity and better quality of life. The 24-month relapse-free survival and distant metastasis-free survival rates were 93% and 98% in patients with MPR, 64% and 64% in patients with pPR, and 71% and 76% in patients with pNR, respectively. These findings provide a strong rationale for randomized clinical trials testing response-directed treatment personalization after neoadjuvant ipilimumab and nivolumab., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

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 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-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ 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-γ 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.

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.

Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 + T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45RO + GZMB + Ki67 + ) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV + lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 + and CD8 + T cells as culprits of checkpoint inhibitor-associated immune encephalitis.