A phase 1/2 study of REGN7075 in combination with cemiplimab (cemi) in patients (pts) with advanced solid tumors: Efficacy and safety results.

2503 Background: REGN7075, a first-in-class costimulatory bispecific antibody (bsAb), aims to restore immune sensitivity in traditionally non-immunoresponsive tumors by bridging CD28+ T cells with EGFR-expressing tumor cells (unlike other bsAbs that target CD3), facilitating T-cell activation through endogenous tumor antigens. A first-in-human, open-label, Phase 1/2 study (NCT04626635) of REGN7075 (EGFR×CD28) ± cemi (anti–PD-1) in pts with advanced solid tumors was conducted, consisting of a dose escalation (Part 1) and dose expansion (Part 2) phase. This is the first report of efficacy data (Part 1) for this costimulatory bsAb EGFR×CD28 with a novel mechanism of action. Methods: In Part 1, pts with metastatic/locally advanced solid tumors who had exhausted standard treatment options received REGN7075 QW/Q3W + cemi Q3W, including a 3-week REGN7075 monotherapy QW lead-in. Primary objective: assess safety and tolerability of REGN7075 ± cemi; secondary objectives: PK characterization (REGN7075 ± cemi), preliminary efficacy (REGN7075 + cemi), and immunogenicity of REGN7075 and cemi. Biomarkers were also evaluated. Results: At Part 1 data cutoff (Oct 13, 2023), 94 pts (median age, 55.0 years; 48.9% female) were treated with REGN7075 up to the 900 mg IV dose. Most pts (65%) had microsatellite stable colorectal cancer (MSS CRC). Of the 15 pts with MSS CRC without liver metastases treated with active REGN7075 doses (≥100 mg), ORR was 20% and disease control rate was 80% (CR, n=1; PR, n=2; SD, n=9). After data cutoff, 1 additional pt with liver metastases achieved PR. No dose-limiting toxicities (DLTs) were reported; maximum tolerated dose was not reached. Most TRAEs were Grade 1–2; >95% of infusion-related reactions (IRRs) were Grade 1–2. IRRs were manageable with premedication and split/step-up dosing. One pt experienced cytokine release syndrome (CRS; Grade 1 fever). No treatment-related deaths were reported. REGN7075 concentration in serum increased more than dose-proportionally at the dose range studied (0.03–900 mg). T-cell activation-associated IFN-γ was observed with monotherapy lead-in and combination dosing. Conclusions: MSS CRC is historically unresponsive to immunotherapy. REGN7075 is one of the first immune therapies to demonstrate clinical activity in pts with MSS CRC (including a pt with liver metastases), and dose escalation was completed through 900 mg with an acceptable safety profile and no DLTs. One pt experienced Grade 1 CRS, demonstrating differentiation from CD28 superagonists and CD3-targeting bsAbs. IRRs were mitigated with premedication and split/step-up dosing. Efficacy data in non-immunoresponsive tumors, along with encouraging pharmacodynamic evidence, suggest that REGN7075 can enhance immune response and anti-tumor immunity. Initiation of dose expansion (Part 2) in select tumor cohorts with different EGFR levels is planned. Clinical trial information: NCT04626635 .