Open-label, Phase Ib dose-expansion study assessing the efficacy of the CD137/FAP agonist BI 765179 plus pembrolizumab as first-line therapy in metastatic or incurable, recurrent PD-L1-positive head and neck squamous cell carcinoma

Background: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally and is often associated with poor quality of life and a dismal prognosis. Median overall survival for recurrent/metastatic HNSCC with first-line standard-of-care pembrolizumab ± chemotherapy is approximately 13 months, highlighting the need for new therapies. Fibroblast activation protein (FAP)-positive fibroblasts are present in the tumor stroma across all anatomical sites of HNSCC, representing a potential therapeutic target and/or targeting mechanism to the tumor tissue. BI 765179 is a bispecific antibody that simultaneously binds to FAP and cluster of differentiation 137 (CD137) expressed on activated T-cells. The Phase Ia part of the present study tested safety and doses for dose-escalated BI 765179, both as monotherapy and in combination with an anti-programmed cell death protein 1 (anti-PD-1) antibody, ezabenlimab, in patients with advanced solid tumors. The study design of the Phase Ib dose expansion part will be presented. Methods: In the Phase Ib dose-expansion part, approximately 60 patients with a histologically or cytologically confirmed diagnosis of metastatic or incurable, recurrent HNSCC whose tumors express programmed cell death ligand 1 (PD-L1) will be enrolled (NCT04958239). This part of the study is designed to assess the preliminary efficacy of two doses of BI 765179 in combination with pembrolizumab. Key inclusion criteria include no prior systemic therapy administered in the metastatic or incurable recurrent setting; primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx; ≥1 measurable lesion outside of the central nervous system (modified Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1); a PD-L1-positive tumor (combined positive score ≥1, local assessment); and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients who have previously received CD137-targeted or anti-PD-1/PD-L1 agents are not eligible. Patients will be randomized 1:1 to receive either Dose 1 or 2 of BI 765179 intravenously in combination with pembrolizumab. The primary endpoint is objective response (OR), defined as best overall response of confirmed complete or partial response (RECIST v1.1). Secondary endpoints include occurrence of adverse events (AEs) and serious AEs, OR (immune-related RECIST v1.1), duration of response, progression-free survival, and overall survival.