FDA Grants Breakthrough Therapy Status to Petosemtamab/Pembrolizumab in HNSCC

• The FDA granted breakthrough therapy designation to the combination of petosemtamab plus pembrolizumab (Keytruda) as a first-line treatment for 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.
• Findings from the phase 2 portion of a phase 1/2 trial (NCT03526835) evaluating the combination support this designation.
• The ongoing phase 3 LiGeR-HN1 trial (NCT06525220) is also evaluating the combination in this patient population.

The FDA has granted the combination of petosemtamab plus pembrolizumab breakthrough therapy designation as a first-line treatment for adult patients with recurrent or metastatic HNSCC with a PD-L1 CPS of at least 1.¹

Data from the phase 2 portion of a phase 1/2 trial (NCT03526835) support this breakthrough therapy designation. According to initial findings presented at the 2024 American Society of Clinical Oncology Annual Meeting and at a median follow-up of 3.58 months (range, 0.5-10.3), the overall response rate (ORR) among the 24 efficacy-evaluable patients treated with the combination was 67% (95% CI, 45%-84%), with 1 patient reaching a complete response, 12 patients with a partial response, and 3 patients with an unconfirmed PR.²

The ORR seen with the combination in patients with human papillomavirus (HPV)–related or p16-positive tumors was 75% (n = 3/4); in those with p16-negative tumors, this rate was 65% (n = 13/20). Among patients with a PD-L1 CPS ranging from 1 to 19, the ORR with the regimen was 60% (n = 6/10); in those with a PD-L1 CPS of 20 or higher, this rate was 71% (n = 10/14).

“One of the interesting things I’ve learned about these molecules is that responses can be seen quite early, which is unusual for checkpoint inhibitors—we typically have to wait longer. For unknown reasons, this antibody shows activity early in the treatment course, which is crucial for symptomatic patients. This is especially important for those with life-threatening disease in the immediate term, as we aim not to lose patients,” Cesar Augusto Perez, MD, hematologist and medical oncologist at Florida Cancer Specialists & Research Institute’s Lake Nona Cancer Center & Drug Development Unit, told Targeted Oncology^TM, in an interview.

Head and neck cancer: © steph photographies - stock.adobe.com

“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., said in a press release.¹

Updated interim efficacy and safety data were included in the breakthrough therapy designation application submitted to the FDA.

Previously, the agency had granted both breakthrough therapy and fast track designations to petosemtamab monotherapy for patients with recurrent or metastatic HNSCC who experienced disease progression after platinum-based chemotherapy and anti–PD-1 therapy.

In addition to this study, investigators are further evaluating petosemtamab plus pembrolizumab in the phase 3 LiGeR-HN1 trial. Here, the combination is being assessed as a first-line treatment for patients with recurrent or metastatic HNSCC.

“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,” added Zohren.

Additional Data From the Phase 1/2 Trial

The phase 2 portion of the phase 1/2 trial evaluating the combination of petosemtamab and pembrolizumab included patients with first-line recurrent or metastatic HNSCC who had a PD-L1 CPS of at least 1.² Patients must have had an ECOG performance status of 0 or 1 and measurable disease to be included in the study.

Patients were administered 1500 mg of petosemtamab via intravenous (IV) infusion every 2 weeks as part of a 28-day cycle, combined with 400 mg of IV pembrolizumab every 6 weeks. Treatment continued until disease progression or unacceptable toxicity. Tumor assessments were conducted every 8 weeks, and the survival follow-up period is 3 years.

The primary end point of the study was investigator-assessed ORR per RECIST 1.1 criteria. Secondary end points were duration of response, progression-free survival, central review–assessed ORR, overall survival, pharmacokinetics, immunogenicity, and biomarkers.

Looking at safety, treatment-emergent adverse events (TEAEs) were seen in all patients but most of the events were deemed grade 1 or 2 in severity. Grade 3 or higher TEAEs were observed in 40% of patients and 24% of these events were related to study treatment. Treatment-related AEs (both grade 1/2) led to study discontinuation in 2 patients. Further, there were no significant overlapping toxicities observed.

The most common TEAEs seen in more than 15% of patients, irrespective of causality, included acneiform dermatitis (all grade, 44%; grade 3-5, 2%), rash (40%; 0%), asthenia (36%; 7%), skin fissures (33%; 0%), constipation (27%; 0%), folliculitis (27%; 0%), nausea (27%; 2%), decreased blood magnesium (22%; 2%), diarrhea (22%; 2%), dry skin (22%; 0%), pruritus (22%; 0%), stomatitis (22%; 2%), cough (16%; 0%), fatigue (16%; 2%), infusion-related reaction (IRR [16%; 2%]), paronychia (16%; 0%), and tumor pain (16%; 2%).

Moreover, 38% of patients experienced IRRs, 7% of which were grade 3. No grade 4 or 5 events were reported. Most of these events were seen during the first infusion and had resolved. Rechallenge after an IRR was successful in all patients and no patients discontinued due to an IRR that was grade 3 to 5 in severity. Additionally, IRRs were managed with premedication and prolonged infusion.

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 20, 2025. https://tinyurl.com/4cv4nads

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