FDA Grants Breakthrough Therapy Designation to Petosemtamab Plus Pembrolizumab for PD-L1+ HNSCC

The FDA has granted breakthrough therapy designation to petosemtamab in combination with pembrolizumab (Keytruda) for the first-line treatment of adult patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with a PD-L1 combined positive score (CPS) of at least 1.1

The designation was supported by data from the phase 2 portion of a phase 1/2 trial (NCT03526835). Initial findings presented at the 2024 ASCO Annual Meeting showed that efficacy-evaluable patients treated with the combination (n = 24) experienced an overall response rate (ORR) of 67% (95% CI, 45%-84%); 1 patient achieved a complete response, 12 patients had a partial response, and 3 patients had an unconfirmed PR.2 The ORRs in patients with a PD-L1 CPS of 1 to 19 (n = 10) and those with a PD-L1 CPS of at least 20 (n = 14) were 60% and 71%, respectively.

Updated interim efficacy and safety data were submitted to the FDA with the breakthrough therapy designation application.1 Previously, the regulatory agency also granted breakthrough therapy designation and fast track designation to petosemtamab monotherapy for the treatment of patients with recurrent or metastatic HNSCC whose disease has progressed following treatment with platinum-based chemotherapy and an anti–PD-1 antibody.

“We believe petosemtamab’s second breakthrough therapy designation continues to validate its potential to become a new standard of care for patients with recurrent or metastatic HNSCC and underscores our commitment to accelerate development of petosemtamab for these patients,” Fabian Zohren, MD, PhD, chief medical officer of Merus N.V., stated in a news release. “Importantly, this designation indicates the interim clinical data we shared with the FDA demonstrates petosemtamab’s potential for substantial improvement over available therapies in the first-line, PD-L1–positive setting.”

The phase 2 portion of the study enrolled patients with first-line recurrent or metastatic HNSCC who had a PD-L1 CPS of at least 1.2 Patients were also required to have measurable disease and an ECOG performance status of 0 or 1.

All patients received petosemtamab at 1500 mg once every 2 weeks in combination with pembrolizumab at 400 mg once every 6 weeks. Tumor assessments occurred once every 8 weeks, and treatment continued until disease progression or unacceptable toxicity.

Investigator-assessed ORR per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included duration of response, progression-free survival, central review–assessed ORR, overall survival, pharmacokinetics, immunogenicity, and biomarkers.

In the safety-evaluable population (n = 45), any-grade treatment-emergent adverse effects (TEAEs) occurred in all patients; 40% of patients experienced grade 3 or higher TEAEs, including 24% of patients who had grade 3 or higher treatment-related TEAEs. Treatment-related TEAEs led to treatment discontinuation in 2 patients (4%).

The most common TEAEs reported in more than 15% of patients included acneiform dermatitis (any-grade, 44%; grade ≥ 3, 2%), rash (40%; 0%), asthenia (36%; 7%), skin fissures (33%; 0%), constipation (27%; 0%), folliculitis (27%; 0%), nausea (27%; 2%), decreased blood magnesium levels (22%; 2%), diarrhea (22%; 2%), dry skin (22%; 0%), pruritus (22%; 0%), stomatitis (22%; 2%), cough (16%; 0%), fatigue (16%; 2%), infusion-related reaction (16%; 2%), and paronychia (16%; 0%).

Overall, infusion-related reactions were reported in 38% of patients, including at grade 3 in 7% of patients; no grade 4 or 5 infusion-related reactions were reported. These AEs were managed with premedication and prolonged infusion. Rechallenge after an infusion-related reaction was successful in all patients. No patients discontinued treatment due to a grade 3 infusion-related reaction.

The ongoing phase 3 LiGeR-HN1 trial (NCT06525220) is further evaluating the combination of petosemtamab and pembrolizumab in the first-line treatment of patients with recurrent or metastatic HNSCC.1 Patients are being randomly assigned to receive the combination or pembrolizumab alone.

References

1. Petosemtamab granted breakthrough therapy designation by the U.S. FDA for 1L PD-L1 positive head and neck squamous cell carcinoma. News release. Merus N.V. February 18, 2025. Accessed February 19, 2025. https://ir.merus.nl/news-releases/news-release-details/petosemtamab-granted-breakthrough-therapy-designation-us-fda-1l
2. Fayette J, Clatot F, Brana 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