Petosemtamab/Pembrolizumab Improves OS in First-Line PD-L1–Positive HNSCC

Petosemtamab plus pembrolizumab (Keytruda) produced a statistically significant and clinically meaningful improvement in overall survival (OS) and objective response rate (ORR) compared with pembrolizumab alone in the first-line treatment of patients with recurrent or metastatic PD-L1–positive head and neck squamous cell carcinoma (HNSCC), according to results from the first interim analysis of the phase 3 LiGeR-HN1 trial (NCT06525220) reported in a news release from the developer, Genmab.¹ An independent data monitoring committee assessed the results, and both dual primary end points were met.

What were the topline results from LiGeR-HN1?

At the first interim analysis, petosemtamab plus pembrolizumab reduced the risk of death by 50% compared with pembrolizumab monotherapy (HR, 0.50; 95% CI, 0.37-0.67; P <.0001). The combination also improved the ORR, with an odds ratio of 3.17 (95% CI, 2.06-4.89; P <.0001).

The combination was generally well tolerated, with a safety profile consistent with the known profiles of each agent. No new safety signals were identified. The developers plan to submit the full results for presentation at a future medical meeting and to engage with global regulatory authorities.

"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.¹

How was the LiGeR-HN1 trial designed?

LiGeR-HN1 is a global, multicenter, randomized, open-label phase 3 trial. Patients were randomly assigned 1:1 to receive petosemtamab plus pembrolizumab or pembrolizumab alone.² Eligible patients were 18 years or older and had histologically confirmed HNSCC of the oropharynx, oral cavity, hypopharynx, or larynx that was recurrent or metastatic and not amenable to curative local therapy. Patients also were required to have:

• tumors with a PD-L1 combined positive score (CPS) of 1 or higher, making them eligible for first-line pembrolizumab monotherapy;
• measurable disease per RECIST v1.1 criteria;
• an ECOG performance status of 0 or 1.

Patients were enrolled regardless of HPV status. Those who had received prior systemic therapy in the recurrent or metastatic setting, or prior anti–PD-(L)1 or anti-EGFR therapy, were excluded, as were patients with nasopharyngeal or sinonasal primary tumors.

OS and ORR were the dual primary end points. Key secondary end points included progression-free survival, duration of response, time to response, safety, and patient-reported outcomes.

What is petosemtamab, and how does it work?

Petosemtamab is an investigational, low-fucose, fully human IgG1 bispecific antibody with an active Fc domain that targets EGFR and LGR5. According to the developers, it works through 3 mechanisms:

• blocking EGFR signaling;
• inducing EGFR degradation in cancer cells that coexpress LGR5 and EGFR;
• enhancing antibody-dependent cellular cytotoxicity mediated by natural killer cells.

Petosemtamab was originally developed by Merus, which Genmab acquired in 2025.

What is petosemtamab's clinical and regulatory history?

Previous data from the phase 2 portion of a phase 1/2 study (NCT03526835) presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, frontline petosemtamab plus pembrolizumab produced an ORR of 67% (95% CI, 45%-84%) among 24 efficacy-evaluable patients with recurrent or metastatic HNSCC.³

The FDA granted petosemtamab breakthrough therapy designation in May 2024 for recurrent or metastatic HNSCC that had progressed after platinum-based chemotherapy and an anti–PD-1 or anti–PD-L1 agent.⁴ The agent has also received breakthrough therapy designation in combination with pembrolizumab for first-line PD-L1–positive recurrent or metastatic HNSCC.

Petosemtamab is also being evaluated in other phase 3 trials:

• LiGeR-HN2 trial (NCT06496178): petosemtamab vs investigator’s choice of methotrexate, docetaxel, or cetuximab (Erbitux) in second- and third-line recurrent or metastatic HNSCC.⁵
• LiGeR-CRC1 (NCT07702032) and LiGeR-CRC2 (NCT07775287): petosemtamab plus chemotherapy vs cetuximab or bevacizumab plus chemotherapy in previously treated recurrent, unresectable, or metastatic colorectal cancer.^6,7

“These topline phase 3 results represent a defining milestone for Genmab and further strengthen our conviction in petosemtamab as a potential first-in-class treatment option for patients with this difficult-to-treat cancer,” Jan van de Winkel, PhD, chief executive officer of Genmab, said in the news release.¹ “The LiGeR-HN1 topline findings mark an important step toward potentially bringing petosemtamab to patients with recurrent or metastatic head and neck cancer, and we look forward to engaging with regulatory authorities globally and sharing the full dataset with the medical community.”

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 A/S. October 28, 2026. Accessed October 29, 2026. https://tinyurl.com/3dd8ncrc
2. 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://tinyurl.com/4sw9wdcm
3. Fayette J, Clatot F, Braña I, et al. Phase 2 study of petosemtamab (MCLA-158) with pembrolizumab as first-line treatment of recurrent/metastatic HNSCC. J Clin Oncol. 2024;42(suppl 16):6014. doi:10.1200/JCO.2024.42.16_suppl.6014
4. Petosemtamab granted breakthrough therapy designation by the U.S. FDA. News release. Merus N.V. May 13, 2024. Accessed October 29, 2026. https://tinyurl.com/wmhnw8dc
5. A phase 3 study to evaluate petosemtamab compared with investigator's choice monotherapy in previously treated head and neck squamous cell carcinoma patients (LiGeR-HN2). ClinicalTrials.gov. Updated October 19, 2026. Accessed October 29, 2026. https://tinyurl.com/mspj7d7p
6. Study of petosemtamab plus chemotherapy versus cetuximab plus chemotherapy in RAS and BRAF wild-type, unresectable or metastatic, left-sided colorectal cancer (LiGeR-CRC1). ClinicalTrials.gov. Updated October 6, 2026. Accessed October 29, 2026. https://tinyurl.com/5375xxre
7. Study of petosemtamab plus chemotherapy versus cetuximab or bevacizumab plus chemotherapy in RAS and BRAF wild type, recurrent, unresectable or metastatic colorectal cancer (LiGeR-CRC2). ClinicalTrials.gov. Updated October 9, 2026. Accessed October 29, 2026. https://tinyurl.com/36juuarv