Dr Perez on the Efficacy and Safety of Frontline Petosemtamab Plus Pembrolizumab in HNSCC

Cesar A. Perez, MD, director, drug development, Sarah Cannon Research Institute, Florida Cancer Specialists & Research Institute; associate professor, medicine, University of Miami; discusses the ongoing investigation of frontline petosemtamab (MCLA-158) plus pembrolizumab (Keytruda) in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

Data from a phase 2 trial (NCT03526835) evaluating the combination in 24 efficacy-evaluable patients with previously untreated, recurrent or metastatic PD-L1–positive HNSCC were presented at the 2024 ASCO Annual Meeting. The combination demonstrated an overall response rate (ORR) of 67% (95% CI, 45%-84%), comprising 1 complete response (CR), 12 partial responses (PRs), and 3 unconfirmed PRs, which is substantially higher than the expected response rate with pembrolizumab alone.

Responses occurred in different patient subgroups, including those who were HPV-positive and HPV-negative, as well as across PD-L1–high and PD-L1–low populations. Specifically, 42% of patients had a PD-L1 combined positive score (CPS) of 1 to 19, and 56% had a PD-L1 CPS of 20 or higher. Among patients with a low PD-L1 CPS, the ORR was 60%. Best response to treatment included 2 cases of progressive disease (PD), 2 cases of stable disease (SD), 1 unconfirmed PR, 4 PRs, and 1 CR. For patients with a high PD-L1 CPS, the ORR was 71%, with 1 case of PD, 3 instances of SD, 2 unconfirmed PRs, and 8 PRs as the best responses. Additionally, among patients with HPV type 16 (57%) and those without (36%), the ORRs were 75% and 65%, respectively.

Regarding safety, no new safety signals were observed with the combination of petosemtamab and pembrolizumab, Perez details. Adverse effects (AEs) were as expected, with infusion reactions occurring in 38% of participants. Notably, 7% of these reactions were grade 3, and there were no grade 4 or 5 infusion reactions. Other AEs included known effects of EGFR targeting, such as cutaneous reactions, low magnesium levels, and fatigue. These AEs were manageable, and the absence of new safety signals was encouraging.

Despite the relatively short follow-up and small cohort size, these findings are promising, Perez states. Responses were observed early, often at the first response assessment, and clinical improvement was typically seen after the first infusion, he details. This rapid onset of response is particularly significant for a chemotherapy-free regimen, Perez emphasizes.

Overall, the combination of petosemtamab and pembrolizumab holds potential for changing the treatment paradigm for PD-L1–positive HNSCC since more patients may be potential candidates for a chemotherapy-free regimen, Perez says. High response rates and a longer duration of response could lead to significant improvements in overall survival. Future studies and longer follow-up will be essential to confirm these findings and to further evaluate the efficacy and safety of this combination therapy, he concludes.