First-in-Class Bifunctional Antibody Plus Pembrolizumab Shows Activity in Head and Neck Squamous Cell Carcinoma

Get Permission

The first-in-class bifunctional antibody BCA101—which inhibits both the epidermal growth factor receptor (EGFR) and transforming growth factor-beta (TGF-β)—given with the immune checkpoint inhibitor pembrolizumab, is showing activity and tolerability in recurrent or metastatic head and neck squamous cell carcinoma, investigators reported at the 2023 ASCO Annual Meeting.1 According to Glenn J. Hanna, MD, of the Dana-Farber Cancer Institute, Boston, BCA101 appears to exert clinical activity as monotherapy and in combination with pembrolizumab in several advanced solid tumors.

The proposed mechanisms of action of BCA101 include: (1) localizing TGF-β inhibition to the tumor microenvironment through an EGFR-directed approach; (2) increasing antitumor activity via enhanced antibody-dependent cellular cytotoxicity and increased activation of natural killer cells; and (3) preventing epithelial-mesenchymal transition and metastasis through dual inhibition of EGFR and TGF-β.

The data warrant further evaluation of the combination [BCA101 and pembrolizumab] in patients with HPV-negative disease in a randomized study.
— Glenn J. Hanna, MD

Tweet this quote

Study Details

Dr. Hanna reported the interim analysis for an expansion cohort of an ongoing single-arm phase I/Ib study evaluating BCA101 plus pembrolizumab as first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma. The dose-expansion cohort included patients with relapsed or metastatic disease and a tumor PD-L1 combined positive score (CPS) of at least 1 who had no prior systemic therapy in the setting of advanced disease.

This cohort received the recommended dosing: BCA101 at 1,500 mg intravenously on days 1, 8, and 15 with pembrolizumab at 200 mg intravenously on day 1 every 21 days. A total of 18 patients were enrolled in stage I of the study, and 21 additional patients were enrolled in stage II, totaling 39 patients analyzed for safety and 31 patients assessed for efficacy (having undergone at least two restaging scans).

These patients were 70% male, had a median age of 66 years, and were most likely to have tumors of the oropharynx (55%; of these patients, 67% were human papillomavirus [HPV]-positive) or the oral cavity (30%). A total of 15 patients (76%) had distant metastatic disease.

Primary Endpoint: Safety

Commenting on the primary endpoint, Dr. Hanna noted that BCA101 had a manageable safety profile. The most common treatment-related toxicity was dermatitis (acneiform rash), which was observed in 73% of patients but was grade 3 in two patients. Fatigue and hypophosphatemia were each observed in 36%, virtually all grade 1 or 2. Mucosal bleeding was generally low grade and manageable without the need for dose interruptions; one patient had a drug-related tracheal hemorrhage.

Dose interruptions were necessary for 36%, including four patients with grade 2 infusion-related reactions. Three patients needed dose reductions for acneiform rash, maculopapular rash, and blood alkaline phosphatase increase. Three other patients discontinued the drug for grade 3 tracheal hemorrhage, grade 3 blood alkaline phosphatase increase, and grade 4 pericarditis, he reported.

Preliminary Clinical Activity

Of 31 patients evaluable for efficacy, 48% responded to BCA101 plus pembrolizumab in the first-line setting; one patient (3%) achieved a complete response, and 26% are maintaining stable disease. By HPV status, response rates were higher in the HPV-negative subset—65% vs 18% for the HPV-positive patients. In the HPV-negative subset, responses were observed across all tumor subsites and regardless of PD-L1 CPS (80% in the CPS ≥ 20 group and 50% in the CPS 1–19 group), whereas in the HPV-positive subset, responses were limited to the two patients with a CPS of at least 20, Dr. Hanna reported.

For the 18 patients from stage I of the study, median progression-free survival was 4.8 months. For the 12 patients with HPV-negative disease, median progression-free survival was not reached “but was at least 6.6 months, with seven responses ongoing,” he said. By contrast, it was 1.4 months in patients with HPV-positive disease.

“The data warrant further evaluation of the combination in patients with HPV-negative disease in a larger randomized study,” Dr. Hanna concluded. 

DISCLOSURE: Dr. Hanna reported financial relationships with Bristol Myers Squibb, Kura Oncology, Bicara Therapeutics, Boxer Capital, Exicure, General Catalyst, KSQ Therapeutics, Merck, Naveris, Prelude Therapeutics, Rain Therapeutics, Remix Therapeutics, Sanofi, and SIRPant Immunotherapeutics.


1. Hanna GJ, Kaczmar JM, Zandberg DP, et al: Dose expansion results of the bifunctional EGFR/TGFβ inhibitor BCA101 with pembrolizumab in patients with recurrent, metastatic head and neck squamous cell carcinoma. 2023 ASCO Annual Meeting. Abstract 6005. Presented June 5, 2023.