Petosemtamab Plus Pembrolizumab Improves OS in PD-L1+ HNSCC

Adding the investigational EGFR x LGR5 bispecific antibody petosemtamab (GEN1158) to pembrolizumab (Keytruda) significantly prolonged overall survival (OS) and increased the objective response rate (ORR) compared with pembrolizumab alone as first-line treatment for PD-L1–positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).¹

At the first interim analysis of the phase 3 LiGeR-HN1 trial (NCT06525220), the combination reduced the risk of death vs pembrolizumab alone by 50% (HR, 0.50; 95% CI, 0.37-0.67; P <.0001). The odds of achieving an objective response were more than 3 times higher with the combination (OR, 3.17; 95% CI, 2.06-4.89; P < .0001). The trial met both of its primary end points regardless of human papillomavirus (HPV) status. Additionally, the combination was generally well tolerated, with a safety profile in line with those previously reported for each agent, and no new safety signals were observed, according to a news release from Genmab.

"As the first positive phase 3 study in this patient population in several years, LiGeR-HN1 represents a major milestone with the potential to redefine care," said Everett E. Vokes, MD, chair of the Department of Medicine and physician-in-chief at University of Chicago Medicine, in the news release.

Background and Trial Design

Petosemtamab is a low-fucose, fully human IgG1 bispecific antibody with an active Fc domain, simultaneously binding to EGFR and to LGR5, a marker of cancer stem–like cells. The antibody also recruits innate immune cells such as natural killer cells through antibody-dependent cell-mediated cytotoxicity.

The combination previously showed early efficacy in a phase 2 trial (NCT03526835) presented at the 2024 American Society of Clinical Oncology Annual Meeting, in which the ORR was 67% (95% CI, 45%-84%) among 24 efficacy-evaluable patients with first-line recurrent or metastatic HNSCC.²

LiGeR-HN1 is a global, randomized, open-label trial comparing petosemtamab plus pembrolizumab with pembrolizumab monotherapy, assigned on a 1:1 basis, in patients with previously untreated recurrent or metastatic PD-L1–positive HNSCC.³ Overall survival and ORR are the dual primary end points. Key secondary end points include progression-free survival, duration of response, time to response, safety, and patient-reported outcomes. The interim results were assessed by an independent data monitoring committee.

The trial has an approximate enrollment of 699 patients across 202 locations worldwide. Eligible patients cannot have received systemic therapy in the metastatic or recurrent setting but can have received prior systemic therapy as part of multimodal therapy for locally advanced disease. They cannot have received prior anti–PD-1/PD-L1 or anti-EGFR therapies, and if they received cetuximab (Erbitux) with radiotherapy, they are only eligible if they had progressive disease over 1 year after the last dose of cetuximab. Patients must have tumors expressing PD-L1 with a combined positive score of 1 or higher.

Mechanism and Development Background

The FDA has granted breakthrough therapy designation to petosemtamab with pembrolizumab in the first-line PD-L1–positive setting and to petosemtamab alone in patients whose disease progressed after platinum-based chemotherapy and anti–PD-1 therapy.¹

Petosemtamab is also being evaluated in the phase 3 LiGeR-HN2 trial (NCT06496178) in second- and third-line recurrent or metastatic HNSCC, as well as in 2 phase 3 trials in previously treated colorectal cancer, LiGeR-CRC1 (NCT07702032) and LiGeR-CRC2 (NCT07775287).

Genmab plans to discuss the findings with regulators worldwide and to present the full data at an upcoming medical meeting.

"These results suggest this chemotherapy-free combination could reshape the treatment of this devastating disease by establishing a new therapeutic option," Vokes said.

REFERENCES

1. Genmab announces statistically significant, clinically meaningful improvement in overall survival and objective response with petosemtamab combination at first interim analysis in first-line R/M patients with PD-L1+ head and neck cancer. News release. Genmab. October 28, 2026. Accessed October 29, 2026. https://tinyurl.com/4am588zz

2. Fayette J, Clatot F, Braña I, et al. Petosemtamab (MCLA-158) with pembrolizumab as first-line (1L) treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): phase 2 study. J Clin Oncol. 2024;42(suppl 16):6014. doi:10.1200/JCO.2024.42.16_suppl.6014

3. A phase 3 study to evaluate petosemtamab plus pembrolizumab vs pembrolizumab in first-line treatment of head and neck cancer (LiGeR - HN1). ClinicalTrials.gov. Updated September 25, 2026. Accessed October 29, 2026. https://clinicaltrials.gov/study/NCT06525220