A phase 1/2 study of REGN7075 in combination with cemiplimab (cemi) in patients (pts) with advanced solid tumors: Efficacy and safety results.
Authors: Neil Howard Segal, Eugenia Girda, Davendra Sohal, Nehal J. Lakhani, Anthony J. Olszanski, Lawrence Fong, Michael David Kinnaman, Hyunsil Han, Dimitris Skokos, Kerry A. Casey, JuAn Wang, Bei Wang, Yi Hao, Siyu Li, Samit Ganguly, Israel Lowy, Frank A. Seebach, Melissa Divya Mathias, Melissa Lynne Johnson
Journal: Journal of Clinical Oncology (2024)

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; &gt;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 .