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 

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.

, 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.

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Lillian L. Siu, MD, FRCPC, discusses the background for evaluating first-line petosemtamab plus pembrolizumab in recurrent/metastatic PD-L1+ HNSCC.

Dr Siu on the Investigation of Petosemtamab Plus Pembrolizumab in PD-L1+ HNSCC

Lillian L Siu, MD, FRCPC, senior scientist, Cancer Clinical Research Unit, Princess Margaret Cancer Centre, discusses the methods utilized throughout an ongoing randomized, open-label, phase 3 trial (EudraCT 2023-510323-30-00) of petosemtamab (MCLA-158) plus pembrolizumab (Keytruda) vs pembrolizumab alone for the first-line treatment of patients with recurrent/metastatic PD-L1–positive head and neck squamous cell carcinoma (HNSCC) and highlights the future implications of potentially positive data to come out of the trial.

Upon enrollment onto the randomized investigation, participants with recurrent or metastatic PD-L1–positive HNSCC are randomly assigned 1:1 to receive pembrolizumab, dosed at 400 mg every 6 weeks, alone or in combination with petosemtamab, which is dosed at 1500 mg every 2 weeks, Siu begins. This dose of petosemtamab is the recommended monotherapy dose, she reports. The study will also stratify patients by p16 status for oropharyngeal cancer, ECOG performance status, and PD-L1 expression, Siu explains.

The primary end points are objective response rate, as assessed by blinded independent central review, and overall survival, she continues. If the trial demonstrates positive results favoring the combination therapy vs pembrolizumab monotherapy, these findings may shift the current treatment paradigm for patients with HNSCC, particularly the recurrent/metastatic PD-L1–positive population, Siu emphasizes. The HNSCC field has particular interest in chemotherapy-sparing regimens like this one, according to Siu. Should the combination show superiority over pembrolizumab alone in patients with a PD-L1 combined positive score of 1 or greater, it may replace pembrolizumab monotherapy as the standard of care, she adds.

However, this study does not compare petosemtamab plus pembrolizumab with pembrolizumab plus chemotherapy, Siu expands. If this trial is positive, in the future, oncologists may be able to choose between administering pembrolizumab plus chemotherapy and pembrolizumab plus petosemtamab, she states. If the trial yields positive results, it will confirm the combination’s advantage over pembrolizumab monotherapy, Siu concludes.

Lillian L Siu, MD, FRCPC, discusses a phase 3 trial of petosemtamab plus pembrolizumab vs pembrolizumab alone for recurrent/metastatic PD-L1+ HNSCC.

Lillian L Siu, MD, FRCPC

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

Dr Siu on the Investigation of Petosemtamab Plus Pembrolizumab in PD-L1+ HNSCC