Genmab Reports Significant Survival Benefit in LiGeR-HN1 Trial

Genmab has announced positive topline results from the first interim analysis of LiGeR-HN1, a global Phase 3 trial evaluating petosemtamab plus pembrolizumab against pembrolizumab alone in patients with first-line, PD-L1-positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The combination met both co-primary endpoints, overall survival (OS) and objective response rate (ORR), with benefits reported regardless of human papillomavirus (HPV) status.

An independent data monitoring committee assessed the interim results. Petosemtamab plus pembrolizumab reduced the relative hazard of death by 50% compared with pembrolizumab alone (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.37–0.67; p<0.0001). The combination also improved ORR, with an odds ratio of 3.17 (95% CI, 2.06–4.89; p<0.0001).

The survival finding is the strongest signal from the interim analysis. However, the HR represents a relative reduction in the instantaneous risk of death over the analysed period, not a 50% increase in median survival or a 50-percentage-point improvement in survival probability. Similarly, the ORR odds ratio does not establish that the absolute response rate was three times higher.

Genmab has not disclosed median OS, absolute response rates, median follow-up or the number of patients included in this interim analysis. These omissions limit independent assessment of the magnitude and maturity of the treatment benefit.

A Bispecific Antibody Targeting EGFR and LGR5

Petosemtamab (GEN1158) is an investigational, low-fucose, fully human IgG1 bispecific antibody targeting epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5).

The antibody blocks ligand binding to EGFR and inhibits its signalling independently of LGR5 expression. In tumour cells expressing both EGFR and LGR5, simultaneous binding facilitates EGFR degradation through natural internalisation mediated by LGR5. Its active Fc domain also supports antibody-dependent cellular cytotoxicity, enabling immune cells, including natural killer cells, to contribute to tumour-cell destruction.

These mechanisms provide a biological rationale for combining petosemtamab with pembrolizumab, an anti-PD-1 therapy. Nevertheless, the topline findings do not establish the contribution of each mechanism to the observed clinical benefit or identify subgroups with a greater treatment effect.

Safety Profile Requires Further Evaluation

Genmab reported that the combination was generally well tolerated, with a safety profile consistent with the previously reported profiles of petosemtamab and pembrolizumab. No new safety signals were identified.

However, the announcement did not provide detailed adverse-event frequencies, Grade 3 or higher toxicities, treatment discontinuations or patient-reported outcomes. These data will be necessary to evaluate the treatment’s benefit-risk profile, particularly in the first-line setting, where tolerability and sustained treatment exposure are important considerations.

LiGeR-HN1 (NCT06525220) is a randomised, open-label, global, multicentre Phase 3 study in which patients were assigned in a 1:1 ratio to petosemtamab plus pembrolizumab or pembrolizumab alone. Key secondary endpoints include progression-free survival, duration of response, time to response, safety and patient-reported outcomes.

Regulatory Plans and Broader Development

Genmab plans to engage global regulatory authorities and present the full LiGeR-HN1 results at a future medical meeting. Petosemtamab has received US Food and Drug Administration (FDA) Breakthrough Therapy Designation for first-line recurrent or metastatic PD-L1-positive HNSCC in combination with pembrolizumab, as well as for previously treated recurrent or metastatic HNSCC following platinum-based chemotherapy and anti-PD-1 therapy. The designation does not constitute marketing approval.

The broader clinical programme includes LiGeR-HN2 (NCT06496178) in second- and third-line recurrent or metastatic HNSCC, alongside LiGeR-CRC1 (NCT07702032) and LiGeR-CRC2 (NCT07775287) in previously treated recurrent, unresectable or metastatic colorectal cancer.

Clinical Interpretation

LiGeR-HN1 provides a substantial efficacy signal for petosemtamab plus pembrolizumab, with statistically significant improvements in both overall survival and objective response rate. The reported HR of 0.50 strengthens the case for further clinical and regulatory evaluation.

The clinical significance of the findings, however, cannot be fully established from topline data alone. Median survival, absolute response rates, follow-up duration, subgroup estimates and detailed safety results are needed to assess the magnitude and durability of benefit and its consistency across clinically relevant populations.

For now, the results support continued development and regulatory engagement, but do not establish that the combination should replace existing first-line treatment options. The full dataset will be important in determining whether the observed survival advantage translates into a clinically meaningful benefit with an acceptable safety profile.

Reference

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, Genmab, 28 October 2026.

A Phase 3 Study to Evaluate Petosemtamab Plus Pembrolizumab vs Pembrolizumab in First-line Treatment of Head and Neck Cancer (LiGeR – HN1), ClinicalTrials.gov ID NCT06525220