Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma.

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