Genmab’s Petosemtamab Plus Pembrolizumab Cuts Risk of Death by 50% in Phase 3 Head and Neck Cancer Trial

Genmab’s petosemtamab, an EGFR×LGR5 bispecific antibody, combined with pembrolizumab reduced the risk of death by 50% compared with pembrolizumab alone in the Phase 3 LiGeR-HN1 trial in first-line recurrent or metastatic PD-L1-positive head and neck squamous cell carcinoma (HNSCC).¹ The trial met both of its primary endpoints, overall survival (OS) and objective response rate (ORR), at the first interim analysis.¹

“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.¹

How does petosemtamab work?

Petosemtamab is a low-fucose, fully human IgG1 bispecific antibody with an active Fc domain that binds EGFR and LGR5 on tumor cells.¹ According to Genmab, it acts through three complementary mechanisms: blocking EGFR signaling, promoting EGFR degradation in cells that express both targets, and enhancing natural killer cell-mediated killing through antibody-dependent cellular cytotoxicity.¹ LGR5 is expressed on a population of cancer stem-like cells implicated in tumor initiation, treatment resistance, and recurrence.¹

Genmab gained petosemtamab through its acquisition of Merus, announced in September 2025 at $97 per share in cash, or about $8.0 billion in equity value.²

What did LiGeR-HN1 show?

The randomized, open-label, global phase 3 trial (NCT06525220) assigned patients 1:1 to petosemtamab plus pembrolizumab or pembrolizumab alone.¹ At the first interim analysis, assessed by an independent data monitoring committee, the combination improved OS with a hazard ratio of 0.50 (95% CI, 0.37-0.67; P<.0001).¹ It also improved ORR, with an odds ratio of 3.17 (95% CI, 2.06-4.89; P<.0001).¹ The benefit was observed regardless of human papillomavirus (HPV) status.¹

The combination was generally well tolerated, with safety consistent with the known profiles of both drugs and no new safety signals.¹ Genmab did not disclose median OS, enrollment, or progression-free survival, a key secondary endpoint, and plans to present full results at a future medical meeting.¹

The results follow updated phase 2 data Genmab reported two days earlier, in which petosemtamab plus pembrolizumab produced a median OS of 28.2 months, an ORR of 63%, and a median progression-free survival of 9.0 months in 43 evaluable patients after a median follow-up of 25.5 months.³

Why does this matter for head and neck cancer?

HNSCC represents more than 90% of head and neck cancers and is the seventh most common cancer worldwide.¹ About half of patients with locally advanced disease experience recurrence after initial treatment, and recurrent or metastatic HNSCC carries a median OS of approximately 10 to 12 months.¹

Pembrolizumab monotherapy has been a first-line standard for patients with PD-L1-expressing recurrent or metastatic HNSCC since FDA approved it for tumors with a combined positive score of at least 1 in June 2019.⁴ Vokes said the results suggest the chemotherapy-free combination “could reshape the treatment of this devastating disease by establishing a new therapeutic option.”¹

Avoiding chemotherapy may matter as safety increasingly shapes treatment choices. In a BioPharm International® interview at BIO 2026, Sabeen Mekan, MD, senior vice president and chief medical officer of Zymeworks, said, “We are getting to a point where safety is becoming much, much more important than it used to be.” She added, “Patients want that, they deserve that.”

What happens next?

Petosemtamab holds two FDA Breakthrough Therapy designations, one for first-line use with pembrolizumab in PD-L1-positive recurrent or metastatic HNSCC and one for patients previously treated with platinum-based chemotherapy and anti-PD-1 therapy.¹ Genmab said it will engage regulators globally.¹ The drug is also being evaluated in the Phase 3 LiGeR-HN2 trial (NCT06496178) in second- and third-line recurrent or metastatic HNSCC.¹

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 28, 2026.
2. Genmab to acquire Merus, expanding late-stage pipeline and accelerating into a wholly owned model. News release. Genmab and Merus. September 29, 2025. Accessed October 28, 2026.
3. Genmab announces updated Phase 2 data demonstrating more than two-year median overall survival with petosemtamab plus pembrolizumab in first-line recurrent/metastatic head and neck squamous cell carcinoma. News release. Genmab. October 26, 2026. Accessed October 28, 2026.
4. FDA approves two new indications for Merck’s KEYTRUDA (pembrolizumab). News release. Merck. June 11, 2019. Accessed October 28, 2026.