Background: REGN7075 is a human costimulatory bispecific antibody designed to bridge epidermal growth factor receptor (EGFR)-expressing tumor cells with CD28 on the surface of T cells to drive co-stimulation and recognition of endogenous tumor antigens. EGFR-targeted therapies are approved in head and neck squamous cell carcinoma, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC). Methods: This is an open-label, Phase 1/2, first-in-human, international study evaluating the safety, tolerability, PK, and anti-tumor activity of REGN7075 ± cemiplimab (anti–PD-1) in patients (pts) with solid tumors (NCT04626635). Here we focus on the cohorts of pts with microsatellite-stable-CRC (MSS-CRC). The study includes a dose-escalation phase (Part 1) and a dose-expansion phase (Part 2). In Part 1, pts will receive a 3-week REGN7075 monotherapy once-weekly (QW) lead-in prior to combination therapy with REGN7075 QW or every 3 weeks (Q3W) + cemiplimab Q3W. Concurrent Q3W dosing with cemiplimab may be conducted for dose levels for which the lead-in is tolerable; to date, this has been up to a dose of 900 mg. After a tolerable dose and schedule of interest is identified in Part 1, Part 2 may consist of eight tumor-specific expansion cohorts, including two cohorts of pts with metastatic MSS-CRC or locally advanced CRC (not candidates for curative surgery/radiation), who have received at least one prior line of therapy (anti–EGFR for RAS wild type disease, anti–VEGF, or documented reason why not appropriate). One cohort will include pts with MSS-CRC with active liver and/or peritoneal metastases, and the other will include pts with MSS-CRC with only lung and/or lymph node metastases. Overall, key inclusion criteria are: evidence of a protocol-defined advanced solid tumor, an ECOG performance status of 0 or 1, and no previous anti–PD-1/anti–PD-(L)1 therapy (Part 2 only). The analyses of Part 1 will be descriptive and exploratory in nature. Primary endpoints are safety and tolerability of REGN7075 ± cemiplimab (Part 1), and objective response rate per RECIST 1.1 (Part 2). Secondary endpoints include: REGN7075 concentrations in serum and overall survival (both parts); incidence and severity of treatment-emergent adverse events (AEs), AEs of special interest, serious AEs, and Grade ≥3 laboratory abnormalities; incidence and titer of ADA to REGN7075 + cemiplimab over time; pt-reported quality of life, symptoms, functioning, and general health status (Part 2 only). The study is expected to enroll ~769 pts: ~221 pts in Part 1 and ~548 pts in Part 2, including 74 pts in Cohort E and 73 pts in Cohort F. As of September 5, 2023, 93 pts were enrolled in Part 1. This study is ongoing and currently open to enrollment. Clinical trial information: NCT04626635.