Genmab Reports Positive Phase 3 LiGeR-HN1 Results for Petosemtamab Plus Pembrolizumab in Head and Neck Cancer
Genmab A/S, a biotechnology company focused on developing innovative antibody-based medicines for serious diseases, has announced positive topline results from the global Phase 3 LiGeR-HN1 clinical trial evaluating investigational petosemtamab in combination with pembrolizumab as a first-line treatment for patients with programmed death-ligand 1 (PD-L1)-positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).
The study demonstrated statistically significant and clinically meaningful improvements in both overall survival (OS) and objective response rate (ORR), meeting its dual primary endpoints at the first interim analysis. The results were assessed by an independent data monitoring committee (IDMC) and showed that the combination reduced the risk of death by 50% compared with pembrolizumab alone. The combination also produced a significantly higher objective response rate, with the findings observed regardless of patients’ human papillomavirus (HPV) status.
According to Genmab, the findings represent an important milestone in the development of petosemtamab and could support efforts to introduce a new treatment option for patients with recurrent or metastatic head and neck cancer. The company plans to engage with regulatory authorities worldwide following the positive results and intends to present the complete LiGeR-HN1 dataset at a future medical meeting.
The investigational combination is designed to provide a chemotherapy-free treatment approach for eligible patients in the first-line setting. If supported by the complete clinical dataset and subsequent regulatory review, the results could have implications for the treatment landscape of PD-L1-positive recurrent or metastatic HNSCC, a disease associated with substantial morbidity and a significant impact on patients’ daily lives.
Phase 3 LiGeR-HN1 Trial Meets Both Primary Endpoints
The global Phase 3 LiGeR-HN1 study, registered under ClinicalTrials.gov identifier NCT06525220, evaluated petosemtamab plus pembrolizumab against pembrolizumab alone in patients receiving first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.
The trial was designed to assess whether adding petosemtamab to pembrolizumab could improve key clinical outcomes compared with pembrolizumab monotherapy. Its dual primary endpoints were overall survival and objective response rate, two important measures used to evaluate the effectiveness of cancer treatments.
Overall survival measures the time patients live after a defined point in a clinical trial, while objective response rate measures the proportion of patients whose tumors demonstrate a predefined degree of reduction in size following treatment.
At the first interim analysis, the petosemtamab combination achieved a statistically significant improvement in both endpoints.
For overall survival, the combination demonstrated a hazard ratio (HR) of 0.50, with a 95% confidence interval (CI) of 0.37 to 0.67 and a p-value below 0.0001. These findings correspond to a 50% reduction in the risk of death compared with pembrolizumab alone during the period evaluated.
The hazard ratio indicates a relative difference in the rate of the event over time between the treatment groups. It should not be interpreted as a 50% increase in the percentage of patients cured or as a direct measure of the number of additional months patients live.
The improvement in overall survival is particularly notable because it represents a key clinical outcome for patients with advanced head and neck cancer. Demonstrating a survival benefit may provide important evidence of the potential value of a new treatment combination beyond tumor shrinkage alone.
The second primary endpoint, objective response rate, also favored the combination.
Petosemtamab plus pembrolizumab achieved an odds ratio of 3.17 for objective response compared with pembrolizumab alone, with a 95% CI of 2.06 to 4.89 and a p-value below 0.0001.
An odds ratio of 3.17 indicates substantially higher odds of achieving an objective response in the combination group than in the pembrolizumab-alone group. However, the odds ratio does not mean that the response rate was 3.17 times higher in absolute percentage terms.
Both primary endpoints met the trial’s statistical criteria at the first interim analysis, providing positive topline evidence for the investigational combination.
Genmab also reported that the improvements were observed regardless of HPV status. This finding is relevant because HPV status is an important biological and clinical characteristic in head and neck squamous cell carcinoma and can be associated with differences in disease characteristics and prognosis.
The company has not yet provided the complete dataset in the topline announcement. Further information from the full results will be needed to assess additional efficacy measures, the magnitude of absolute survival benefit, response durability, and other clinically relevant outcomes.
Petosemtamab’s Dual-Targeting Antibody Approach
Petosemtamab is an investigational immunoglobulin G1 (IgG1) bispecific antibody designed to target two proteins: epidermal growth factor receptor (EGFR) and leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5).
EGFR is a cell-surface receptor involved in signaling pathways that regulate cellular growth, proliferation, and survival. Abnormal EGFR activity is associated with several cancers, including head and neck squamous cell carcinoma, making the receptor an established target for cancer drug development.
LGR5 is another cell-surface protein that has attracted interest in oncology research because of its association with certain cellular populations involved in tissue renewal and tumor biology. Its expression in some cancers has made it a target of investigation for antibody-based therapeutic approaches.
By targeting both EGFR and LGR5, petosemtamab is designed to engage two distinct molecular targets through a single antibody-based therapeutic. This dual-targeting strategy distinguishes the investigational medicine from treatments directed at only one of these proteins.
The combination with pembrolizumab brings together petosemtamab’s dual-targeting approach and an established immunotherapy mechanism. Pembrolizumab is a programmed cell death protein 1 (PD-1) inhibitor that helps restore or enhance the immune system’s ability to recognize and attack cancer cells.
The rationale for combining these agents is to investigate whether targeting EGFR and LGR5 alongside immune checkpoint inhibition can produce better clinical outcomes than pembrolizumab alone.
The positive LiGeR-HN1 results provide clinical evidence supporting further development of this combination. Nevertheless, the precise contribution of each mechanism to the observed outcomes, along with other biological factors that may influence response, will require evaluation of the complete clinical data.
Petosemtamab remains investigational, and its safety and effectiveness for this indication have not been established through regulatory approval.
Addressing an Unmet Need in Recurrent or Metastatic HNSCC
Head and neck squamous cell carcinoma develops in the squamous cells lining structures of the head and neck, including areas of the oral cavity, pharynx, and larynx. The disease can affect essential functions such as speaking, swallowing, breathing, and eating, depending on the location and extent of the tumor.
Patients with recurrent or metastatic disease face particular treatment challenges. Recurrent cancer returns after previous treatment, while metastatic cancer has spread to distant parts of the body. In these settings, treatment goals often include prolonging survival, controlling disease progression, reducing symptoms, and preserving quality of life.
Treatment decisions depend on several factors, including disease extent, previous therapies, tumor characteristics, the patient’s overall health, and the expression of relevant biomarkers.
Pembrolizumab has an established role in selected first-line treatment settings for recurrent or metastatic HNSCC, including patients whose tumors meet applicable PD-L1 criteria. However, not all patients achieve a durable response, and additional treatment options remain an important area of clinical research.
The LiGeR-HN1 findings suggest that adding petosemtamab to pembrolizumab may improve survival and tumor response in the studied population. The chemotherapy-free nature of the combination may also be relevant to treatment planning, although the appropriateness of any regimen depends on its eventual approved indication, patient characteristics, and the complete benefit-risk profile.
Everett E. Vokes, MD, Chair of the Department of Medicine and Physician-in-Chief at University of Chicago Medicine, highlighted the importance of progress for patients living with recurrent or metastatic head and neck cancer.
“Patients with recurrent or metastatic head and neck cancer face a disease that can profoundly affect both survival and some of the most essential aspects of daily life, making progress in treatment urgently needed,” Vokes said.
He described LiGeR-HN1 as the first positive Phase 3 study in this patient population in several years and emphasized that meeting both primary endpoints at the first interim analysis demonstrated the potential of the investigational combination.
Vokes also noted that the findings were observed regardless of HPV status, supporting further investigation of petosemtamab plus pembrolizumab as a potential first-line treatment option for patients with PD-L1-positive disease.
He said the chemotherapy-free combination could potentially reshape first-line treatment by establishing an additional therapeutic option if the results lead to successful regulatory review and eventual approval.
Genmab Highlights Development Milestone
Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab, described the topline findings as a defining milestone for the company and an important development in petosemtamab’s clinical program.
“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,” van de Winkel said.
He emphasized that the value of scientific innovation ultimately depends on its potential to improve patient outcomes. According to van de Winkel, the LiGeR-HN1 findings represent an important step toward potentially making petosemtamab available to patients with recurrent or metastatic head and neck cancer.
Genmab plans to engage with regulatory authorities globally following the positive topline results. The company also intends to share the full dataset with the medical community at a future scientific meeting.
The complete results are expected to provide a more detailed understanding of the treatment’s efficacy, safety, and potential role in clinical practice. Regulatory discussions will be important in determining the next steps toward possible commercialization, including the evidence and submission requirements applicable in individual markets.
Safety Profile Consistent With Previous Findings
In addition to efficacy, safety is a central consideration in evaluating a new cancer treatment combination.
Genmab reported that petosemtamab administered with pembrolizumab was generally well tolerated. The observed safety profile was consistent with the previously reported safety profiles of the individual agents, and no new safety signals were identified in the topline analysis.
This finding is encouraging because combining cancer therapies can introduce additional tolerability challenges, even when each medicine has been studied independently.
A complete assessment of safety will require further details about the types and frequency of adverse events, their severity, treatment discontinuations, serious adverse events, and any events requiring specific medical intervention. These details will help clinicians and regulators evaluate the combination’s overall benefit-risk profile.
The company has not disclosed all safety data in its topline announcement. Therefore, the reported findings should be regarded as an initial summary rather than a comprehensive assessment of the treatment’s safety.
Petosemtamab Development Expands Beyond Head and Neck Cancer
Beyond LiGeR-HN1, Genmab is evaluating petosemtamab in several additional Phase 3 clinical trials, reflecting the company’s broader development strategy for the investigational antibody.
One study, LiGeR-HN2 (NCT06496178), is investigating petosemtamab in patients with second- and third-line recurrent or metastatic HNSCC. This trial will examine the medicine in a different treatment setting, involving patients whose disease has progressed or returned after earlier lines of therapy.
The results of LiGeR-HN2 could help clarify the potential role of petosemtamab beyond first-line treatment and determine whether its clinical benefits extend to patients with more heavily treated disease.
Genmab is also evaluating petosemtamab in colorectal cancer through two Phase 3 studies: LiGeR-CRC1 (NCT07702032) and LiGeR-CRC2 (NCT07775287).
These studies involve patients with previously treated, recurrent, unresectable, or metastatic colorectal cancer. Colorectal cancer is a distinct disease setting with its own biological characteristics and treatment considerations, and the trials will investigate the potential application of petosemtamab in this patient population.
The development program across head and neck and colorectal cancers illustrates the company’s interest in evaluating the antibody’s dual-targeting approach in multiple tumor types. However, each indication requires appropriate clinical evidence, and positive results in one cancer type do not establish effectiveness in another.
Following the positive LiGeR-HN1 topline results, Genmab plans to engage global regulatory authorities and submit the full findings for presentation at a future medical meeting. The company also scheduled an investor update for October 28 at 5:00 p.m. Central European Time and 12:00 p.m. Eastern Daylight Time, with registration information available through its investor relations events and presentations webpage.
The next stage of development will focus on reviewing the complete trial data, discussing the results with regulators, and determining the appropriate pathway toward potential regulatory submissions.
The positive results mark a significant development for Genmab’s oncology pipeline, particularly because the investigational combination met both primary endpoints in a global Phase 3 trial. The reported 50% reduction in the risk of death and the significant improvement in objective response rate provide a strong basis for further evaluation.
However, the full clinical dataset, additional regulatory review, and a complete assessment of benefits and risks will be essential to determine the treatment’s eventual place in clinical practice.
If subsequent steps support approval, petosemtamab plus pembrolizumab could potentially offer a new chemotherapy-free first-line option for patients with PD-L1-positive recurrent or metastatic HNSCC.
For now, the LiGeR-HN1 results represent an important clinical milestone while Genmab continues to advance petosemtamab through its broader development program in head and neck and colorectal cancers.
About the LiGeR-HN1 Trial (NCT06525220)
LiGeR-HN1 (NCT06525220) is a randomized, open-label, global, multicenter Phase 3 study evaluating the efficacy and safety of petosemtamab plus pembrolizumab vs pembrolizumab in first-line treatment of recurrent or metastatic PD-L1+ HNSCC. Patients are randomized 1:1 to receive either petosemtamab plus pembrolizumab or pembrolizumab alone. The study’s co-primary endpoints are overall survival (OS) and objective response rate (ORR). Key secondary endpoints include progression-free survival, duration of response, time to response, safety and patient-reported outcomes.
About Head and Neck Squamous Cell Carcinoma
Head and Neck Squamous Cell Carcinoma (HNSCC) is a group of biologically similar cancers that arise from the tissue lining the surfaces of the oral cavity, pharynx and larynx and represent more than 90% of all head and neck cancers.i It is the seventh most common cancer globally.ii Risk for HNSCC is approximately two to four times higher in men than women.iii
Treatment options vary depending on individual factors, including the location of the tumor, stage of the tumor and a person’s overall health.iii Despite current treatment options, there remains a high patient need for additional therapies, as approximately 50% of patients with locally advanced HNSCC will experience disease recurrence following initial treatment. Recurrent or metastatic HNSCC is associated with a median overall survival of approximately 10-12 months.iv
About Petosemtamab (GEN1158)
Petosemtamab is an investigational low-fucose, fully human immunoglobulin G1 (IgG1) bispecific antibody with an active Fc domain that binds to EGFR and LGR5 on tumor cells. LGR5 is expressed on a population of cancer stem-like cells implicated in tumor initiation, treatment resistance, and recurrence. Petosemtamab exerts anti-tumor activity through three distinct and complementary mechanisms.
Binding to EGFR blocks ligand binding and inhibits EGFR signaling functions regardless of LGR5 expression. In tumor cells co-expressing LGR5 and EGFR, simultaneous binding to LGR5 and EGFR enables degradation of EGFR through the natural internalization process of LGR5. In addition, engagement with tumor cells facilitates their destruction by innate immune cells, such as natural killer (NK) cells, through antibody-dependent cell-mediated cytotoxicity (ADCC).
Petosemtamab is currently being evaluated for the potential treatment of head and neck squamous cell carcinoma (HNSCC) and other solid tumors, including metastatic colorectal cancer (mCRC). The safety and efficacy of petosemtamab have not been established. Petosemtamab has received U.S. Food and Drug Administration (FDA) Breakthrough Therapy Designation for the first-line treatment of patients with recurrent or metastatic PD-L1-positive HNSCC in combination with pembrolizumab and for the treatment of patients with recurrent or metastatic HNSCC whose disease has progressed following platinum-based chemotherapy and anti-PD-1 therapy. Please visit https://clinicaltrials.gov/ for more information.
About Genmab
Genmab is an international biotechnology company dedicated to improving the lives of people with cancer and other serious diseases through innovative antibody medicines. For over 25 years, its passionate, innovative and collaborative team has advanced a broad range of antibody-based therapeutic formats, including bispecific antibodies, ADCs, immune-modulating antibodies and other next-generation modalities. Genmab’s science powers eight approved antibody medicines, and the company is advancing a strong late-stage clinical pipeline, including wholly owned programs, with the goal of delivering transformative medicines to patients.