Case report of fatal immune-mediated myocarditis following treatment with davoceticept (ALPN-202), a PD-L1-dependent CD28 costimulator and dual PD-L1/CTLA-4 checkpoint inhibitor, in combination with pembrolizumab.

Engagement of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) can interfere with the CD28 signaling requisite for T-cell activation. While immune checkpoint inhibitors (ICIs) can relieve this suppression, they are unable to drive CD28 costimulation that may mechanistically contribute to ICI resistance. Thus, CD28 costimulation in the context of checkpoint inhibition may activate immunosuppressed T-cells in the tumor microenvironment. Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain (vIgD) designed to mediate PD-L1-dependent CD28 costimulation while inhibiting the PD-L1 and CTLA-4 checkpoints. PD-L1-restriction of davoceticept's CD28 costimulatory activity may minimize systemic T-cell activation and avoid untoward systemic toxicities. At the same time, preclinical studies have suggested that treatment with davoceticept during PD-1 inhibition may enhance antitumor activity by upregulating PD-L1, potentially synergizing with davoceticept's PD-L1-dependent costimulatory mechanism. This report details two cases of fatal cardiac events following treatment with davoceticept in combination with pembrolizumab (anti-PD-1) in the phase 1 study, NEON-2. Both events occurred in females in their 60s; one with choroidal melanoma and prior immunotherapy, the other with ICI-naïve microsatellite stable colorectal cancer. The clinical courses were fulminant with symptom onset at 2 weeks, followed by rapid decline. Cardiac autopsy from one patient confirmed immune-related myocarditis, and immunosequencing revealed expansion of a single T-cell clone that was not present in the pretreatment tumor. These cases highlight the importance of understanding risk factors that may contribute to immune-related myocarditis and other severe immune-related adverse events when CD28 agonism is targeted in the context of checkpoint inhibition.NEON-2 (NCT04920383).

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Competing interests: LC: Consultant: Janssen, AstraZeneca, Pliant Therapeutics, CDR-Life, Actuate TherapeuticsSRC: Research Support (institutional): Alpine Immune SciencesKL: Nothing to disclose. FS: Grants or Contracts: NIH P01 (Deciphering LKB1-associated immunotherapy resistance in lung adenocarcinoma). NL: Support for the present manuscript (institutional): Alpine Immune Sciences; Consulting Fees: SK Life Sciences; Research Funding (institutional): Alexo Therapeutics, Ascentage Pharma, BeiGene, Constellation Pharmaceuticals, Forty Seven, Loxo, Macrogenics, Merck, Pfizer, Regeneron, Apexian Pharmaceuticals, Coordination Therapeutics, Symphogen, CytomX Therapeutics, InhibRx, Incyte, Jounce Therapeutics, Livzon, Northern Biologics, Tesaro, Innovent Biologics, LAM Therapeutics, Ikena, Celgene, Shattuck Labs, Alpine Immune Sciences, Genmab, Odonate, Mersana, Seagen, Alpine Biosciences, Astellas Pharma, Celgene, Helsinn, Therapeutics, Ikena Oncology, Lilly, Sapience Therapeutics, Epizyme, Gilead, Glaxo Smith Kline, Tizona, Servier, Alkermes, KSQ, Repare Therapeutics, Biosplice/Samumed, Sapience Therapeutics, SK Life Sciences, Janssen, Arcus, Artios, BioNTech SE, Alkermes/Mural OncologyAE: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences; Support for attending meetings: Alpine Immune Sciences; Patents planned, issued or pending: Tempest Therapeutics, University of CaliforniaHL: Former employee of Alpine Immune Sciences; Holds stock or stock options in Alpine Immune SciencesJS: Employee of Adaptive Biotechnologies; Holds stock in Adaptive Biotechnologies. HT: Support for present manuscript: Biostatistician supporting work on the manuscript; Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune SciencesMJC: Employee of Merck Sharp & Dohme, a subsidiary of Merck & Co., Rahway, New Jersey, USA; Owns stock in Merck & Co. SLP: Employee of Alpine Immune Sciences; Holds stock or stock options in Alpine Immune Sciences. AN: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune SciencesDD: Support for present manuscript: Alpine Immune Sciences; Grants/Research Support (institutional): Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals, Tesaro/GSK. Consulting Fees: ACM Bio, Ascendis Pharma; Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Merck, Medical Learning Group (MLG), Xilio Therapeutics. Payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events: Castle Biosciences. Patents planned, issued or pending: US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, December 11, 2020 US Patent 63/208,719, “Compositions and Methods For Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021.