Background There is a need to develop novel immunotherapeutic approaches to enhance responses to immune checkpoint blockade. REGN7075 is a human costimulatory bispecific antibody designed to bridge epidermal growth factor receptor (EGFR)-expressing tumor cells with CD28-positive T cells to support further T-cell activation by endogenous tumor antigens [1, 2] (figure 1). We initiated a first-in-human, open-label, Phase 1/2 dose-escalation and expansion study evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of REGN7075 (EGFRxCD28) in combination with cemiplimab (anti–PD-1) in patients with advanced solid tumors (figure 2; NCT04626635).
Methods We report preliminary results of the dose-escalation phase (Bayesian optimal interval design; Part 1), in which heavily pre-treated patients with advanced solid tumors will receive a lead-in of REGN7075 monotherapy every week for 3 weeks, followed by combination therapy with cemiplimab 350mg every 3 weeks. Planned dose levels (DL) of REGN7075 are 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, and 900mg. Primary objective is to assess safety and tolerability of REGN7075 in combination with cemiplimab.
Results As of the data cutoff date (May 6, 2022), 18 patients (median age, 53.5 years, 56% female) were treated in the dose-escalation phase (table 1), up to the 30mg DL for REGN7075 in combination with cemiplimab. Most patients (67%) were treated for microsatellite stable colorectal cancer. No patients experienced dose-limiting toxicities; maximum tolerated dose was not reached. Table 2 summarizes treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs). The most frequent TEAEs (any grade) were increases in aspartate aminotransferase (AST), constipation, and fatigue (33% [n=6] each). The most frequent TRAEs (any grade) were fatigue (17% [n=3]), increases in AST, diarrhea, hypothyroidism, pyrexia, and rash (11% [n=2] each). One patient developed cytokine release syndrome which was characterized by isolated grade 1 fever without hypotension nor hypoxia. Five recorded deaths were not during study treatment and not attributed to study drug(s). Ongoing PK evaluation suggests possible target-mediated effects. T cell activation-associated cytokines were detected in monotherapy lead-in and combination dosing. Of all patients treated, 1 patient who received 1mg REGN7075 with cemiplimab for cervical cancer achieved an ongoing partial response.
Conclusions In this dose-escalation study, REGN7075 was safely administered up to the 30mg dose level in combination with cemiplimab without dose-limiting toxicities. Early data indicates that novel agent REGN7075 was generally well tolerated, with preliminary potential anti-tumor activity. Biomarker studies are ongoing. Clinical trial enrollment is ongoing; we are currently evaluating the 100mg cohort.
Acknowledgements This study was funded by Regeneron Pharmaceuticals, Inc. Medical writing support and typesetting was provided by John G Facciponte, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc.
Trial Registration NCT04626635
Ethics Approval The protocol and all amendments were approved by the appropriate institutional review board or independent ethics committee at each participating study site. The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.
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