Background: Pembrolizumab (P) is approved to treat patients (pts) with recurrent, metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). BCA101 is a first-in-class bifunctional EGFR antibody fused to a TGFβ immune modulating payload which is well tolerated and has clinical activity as monotherapy and in combination with pembrolizumab in advanced solid tumors (ESMO 2022 731MO). Here we report the results from the interim analysis of an expansion cohort combining BCA101+P as first line therapy in R/M HNSCC. Methods: This ongoing single-arm, open-label multicenter dose expansion cohort enrolled pts with R/M HNSCC with a tumor PD-L1 CPS≥1 with no prior systemic therapy for R/M disease, ECOG 0-1, and measurable disease (RECIST v1.1). Pts received BCA101 (1500 mg IV on days 1, 8, 15) with P (200 mg IV on day 1) every 21-days. Primary endpoint: safety; secondary endpoints: overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS). Exploratory: molecular and immunologic predictors of response. A Simon optimal two-stage design was employed: among 18 evaluable pts in stage 1, >3 pts in response triggered continuation to stage 2 enrolling 21 additional pts targeting an ORR>35%. Results: From 2/2022 to 1/2023, 20 pts enrolled while 18 were evaluable (had first restaging scans) in stage 1. Pts were more often men (n=13, 65%) with a median age of 66 (range: 31-77). Oropharynx (10, 50%) [7/10 (70%) were HPV/p16-pos] and oral cavity (7, 35%) were the most common primary subsites (larynx/hypopharynx: 3). Fifteen (75%) had distant metastatic disease. The ORR in stage 1 was 44% (8 PRs, 4 SD) with a clinical benefit rate (CBR=PR+SD) of 67%; 7/12 (58%) HPV-neg pts achieved a response. Median DOR not reached, but median time on-treatment was 6.7 months (range: 2.7-11.0+) among responders. Ten pts discontinued therapy; all but 1 for PD (n=1 for toxicity). Grade 3+ treatment-related adverse events (TRAEs) were observed in 4 pts (20%, most common: anemia). No treatment-related deaths were observed. Acneiform rash was the most common TRAE of any grade (15, 75%). PFS and OS estimates are forthcoming. Eight (44%) had baseline PD-L1 CPS scores of 0-19, while ten (56%) were ≥20. Stage 2 is actively enrolling with completion of accrual expected by the meeting. Conclusions: Stage 1 of this dose expansion cohort of BCA101+P shows encouraging anti-tumor activity with additive potential, particularly among HPV-neg pts; and the combination is well tolerated among this R/M HNSCC population. Further investigation is warranted. Study funded by Bicara Therapeutics and conducted in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. USA (NCT04429542). Clinical trial information: NCT04429542.