Dr Siu on the Rationale for Combining Petosemtamab With Pembrolizumab in HNSCC

Lillian L. Siu, MD, FRCPC, senior scientist, Cancer Clinical Research Unit, Princess Margaret Cancer Centre, discusses the background information that led to the initiation of a phase 3 trial (EudraCT 2023-510323-30-00) evaluating petosemtamab (MCLA-158) plus pembrolizumab (Keytruda) vs pembrolizumab alone in the first-line setting in patients with recurrent/metastatic PD-L1–positive head and neck squamous cell carcinoma (HNSCC). Notably, insights from this ongoing randomized, open-label study were shared at the 2024 ESMO Congress.

Petosemtamab is a bispecific antibody that targets 2 key receptors: EGFR and LGR5, both of which are overexpressed in head and neck cancer cells, Siu begins. By binding to these receptors, petosemtamab inhibits tumor growth and spread, she notes. This dual-targeting approach is designed to block tumor progression more effectively than targeting a single receptor, Siu explains.

In earlier studies, such as an expansion cohort of a phase 1/2 trial (NCT03526835) presented at the 2023 AACR Annual Meeting, petosemtamab demonstrated promising single-agent activity in patients with HNSCC, she states. Despite the promising overall response rate, the study included patients who had already received immunotherapy, raising questions about whether prior treatment with checkpoint inhibitors influenced the results, Siu emphasizes.

At the 2024 ASCO Annual Meeting, phase 2 results from the phase 1/2 trial showed the efficacy and safety of the combination of petosemtamab and pembrolizumab in the first-line HNSCC setting, she continues. This combination yielded a high overall response rate, although the trial involved a relatively small number of participants. Notably, the treatment showed activity in both human papillomavirus (HPV)-positive and HPV-negative cancers, Siu notes. This outcome is particularly intriguing because EGFR-targeted agents have not traditionally been effective in HPV-positive or p16-positive tumors, she relays, adding that the results from this trial offer hope that petosemtamab, as a bispecific antibody, may provide benefit even in these more difficult-to-treat populations. Further research will be essential to confirm these findings and explore the full potential of petosemtamab in head and neck cancer management, Siu concludes.