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Background: There are no validated biomarkers that can aid clinicians in selecting who would best benefit from anticytotoxic T lymphocyte-associated antigen 4 monotherapy versus combination checkpoint blockade in patients with advanced melanoma who have progressive disease after programmed death 1 (PD-1) blockade., Methods: We conducted a randomized multicenter phase II trial in patients with advanced melanoma. Patients were randomly assigned to receive either 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab or 3 mg/kg of ipilimumab every 3 weeks for up to four doses. Patients were stratified by histological subtype and prior response to PD-1 therapy. The primary clinical objective was overall response rate by week 18. Translational biomarker analyses were conducted in patients with blood and tissue samples., Results: Objective responses were seen in 5 of 9 patients in the ipilimumab arm and 2 of 10 patients in the ipilimumab+nivolumab arm; disease control rates (DCRs) (66.7% vs 60.0%) and rates of grade 3-4 adverse events (56% vs 50%) were comparable between arms. In a pooled analysis, patients with clinical benefit (CB), defined as Response Evaluation Criteria in Solid Tumors response or progression-free for 6 months, showed increased circulating CD4+ T cells with higher polyfunctionality and interferon gamma production following treatment. Tumor profiling revealed enrichment of NRAS mutations and activation of transcriptional programs associated with innate and adaptive immunity in patients with CB., Conclusions: In patients with advanced melanoma that previously progressed on PD-1 blockade, objective responses were seen in both arms, with comparable DCRs. Findings from biomarker analyses provided hypothesis-generating signals for validation in future studies of larger patient cohorts., Trial Registration Number: NCT02731729., Competing Interests: Competing interests: CFF reports personal/consultancy fees from AstraZeneca, as well as participation in steering committees (compensation waived) for Merck and Genentech; these are outside the scope of the submitted work. She also reports institutional research funding from Genentech, Merck, Bristol Myers Squibb, Daiichi, and AstraZeneca. AR reports personal/consultancy fees from Amgen, Chugai, Genentech, Jounce, Merck, Novartis, Nurix, Sanofi, and Vedanta; stock from prior consulting with Advaxis, CytomX, Five Prime, RAPT, IsoPlexis, and Kite-Gilead; being a member of the scientific advisory board and stockholder in 4C Biomed, Apricity, Arcus, Highlight, Compugen, ImaginAb, MapKure, Merus, Rgenix, Lutris, PACT Pharma, and Tango; and receiving research funding to the institution from Agilent and Bristol-Myers Squibb through a Stand Up to Cancer Catalyst grant. KKT reports institutional research funding from Array/Pfizer, Bristol Myers Squibb. Oncosec, Regeneron, and Replimune. HT reports personal/consultancy fees from Genentech, Merck, BMS, Novartis, Iovance, and Eisai and research funding to institution from Genentech, Merck, BMS, Novartis, Celgene, and GSK. TL discloses the following: LISCure Biosciences Scientific Advisory Board, June 2020 up to the present and stock ownership in AstraZeneca; consulting: TRex Bio, Grey Wolf Therapeutics, Exosis, and BiOne Cure; these are outside the scope of the submitted work. MP reports personal/consultancy fees from Array BioPharma, Aduro Biotech, Bristol Myers Squibb, Incyte, Merck, Newlink Genetics, Novartis, and Eisai; honoraria from Bristol Myers Squibb and Merck; research funding from Array BioPharma, AstraZeneca/Medimmune, Bristol Myers Squibb, Infinity Pharmaceuticals, Merck, Novartis, and RgenixA. NS reports personal/consultancy fees from Bristol-Myers Squibb, Immunocore, and Castle Biosciences; research funding to institution from BMS, Immunocore, Xcovery, and Novartis. MC reports institutional research support and employment of a family member by Bristol-Myers Squibb, and consulting, advisory, or speaking compensation for AstraZeneca/MedImmune, Incyte, Moderna, Immunocore and Merck. PC reports consulting/advisory/or speaking compensation from Immunocore, Merck, Cell Medica, Takeda Millenium, and Astra Zeneca; stock ownership in Rgenix; and research funding from Pfizer. DKW is a scientific founder of, holds equity in, and receives consulting fees from Immunai. RI discloses the following: scientific advisory board membership at Harpoon, BitBio, and Arcus; board of directors at Surface Oncology; non-compensated board membership at Lyell; non-compensated scientific advisory board membership at ImaginAb; advisor: IMV and Georgiamune. JK discloses the following: either scientific advisory board membership, stock ownership, or receiving consulting fees from AstraZeneca, Arcus Biosciences, Tizona Therapeutics, Trishula Therapeutics, Primevax, and Elucida Oncology. JW is a consultant for Amgen, Apricity, Ascentage Pharma, Arsenal IO, Astellas, AstraZeneca, Bayer, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dragonfly, Eli Lilly, F Star, Georgiamune, Idera, Imvaq, Kyowa Hakko Kirin, Maverick Therapeutics, Merck, Neon Therapeutics, Psioxus, Recepta, Tizona, Trieza, Truvax, Trishula, Sellas, Surface Oncology, Syndax, Syntalogic, and Werewolf Therapeutics. JDW reports receiving grant/research support from Bristol Myers Squibb and Sephora; having equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, Georgiamune, Trieza, Maverick, and Ascentage., (© 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.)

Background: The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies., Methods: MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20 mg/kg. Two cohorts received 20 mg/kg once a week for 2 or 4 weeks, then 20 mg/kg Q2W. All were treated for 12 months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics., Results: Fifty-eight patients were treated. Median age was 62.5 years and 81% were male. Most had kidney cancer (n = 36) or melanoma (n = 9). There were no dose-limiting toxicities. Treatment-related adverse events occurred in 83% and were grade ≥ 3 in 21%. Objective clinical responses occurred in 8/58 patients (14%): 5 with kidney cancer, including 1 with a complete response, and 3 with melanoma. The relationship between dose and serum levels was predictable and linear, with apparent receptor saturation at 10 mg/kg Q2W and all 20 mg/kg cohorts., Conclusions: MEDI0680 induced peripheral T-cell proliferation and increased plasma IFNγ and associated chemokines regardless of clinical response. CD8+ T-cell tumor infiltration and tumoral gene expression of IFNG, CD8A, CXCL9, and granzyme K (GZMK) were also increased following MEDI0680 administration., Trial Registration: NCT02013804 ; date of registration December 12, 2013.