Petosemtamab Combo Earns Breakthrough Therapy Status in PD-L1+ HNSCC
Investigators will assess treatment with petosemtamab among patients with PD-L1–positive HNSCC in the phase 3 LiGeR-HN1 and LiGeR-HN2 trials.
Supporting data for the newest breakthrough therapy designation came from an ongoing phase 1/2 study (NCT03526835) assessing petosemtamab/pembrolizumab among patients with PD-L1–positive HNSCC.
The FDA has granted breakthrough therapy designation to petosemtamab (MCLA-158) plus pembrolizumab (Keytruda) as a frontline treatment for adults with metastatic or recurrent head and neck squamous cell carcinoma (HNSCC) harboring a PD-L1 combined positive score (CPS) of at least 1, according to a press release from the developer, Merus N.V.1
Previously, petosemtamab earned breakthrough therapy designation from the FDA in metastatic or recurrent HNSCC in May 2024.2 This prior designation supported the agent’s use in patients with progressive disease after prior platinum-based chemotherapy in combination with anti–PD-1 or anti–PD-L1 treatment.
Supporting data for the newest breakthrough therapy designation came from an ongoing phase 1/2 study (NCT03526835) assessing petosemtamab/pembrolizumab among patients with PD-L1–positive HNSCC. Investigators presented findings from this cohort at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.3
Among 24 evaluable patients, data showed an overall response rate (ORR) of 67% (n = 16/24; 95% CI, 45%-84%), which included 1 complete response (CR), 12 partial responses (PRs), and 3 unconfirmed PRs. Additionally, the ORR was 75% (n = 3/4) and 65% (n = 13/20) in patients with p16-psitive and p16-negative disease, respectively. Among patients with a CPS of 1 to 19 and those with a CPS of 20 or higher, the respective ORRs were 60% (n = 6/10) and 71% (n = 10/14).
At the time of data cutoff, 14 of 16 patients with a response were continuing to receive treatment with petosemtamab plus pembrolizumab.
All 45 patients (100%) in the safety population experienced at least 1 treatment-emergent adverse effect (TEAE), which included acneiform dermatitis (44%), rash (40%), asthenia (36%), skin fissures (33%), and constipation (27%). Grade 1/2 treatment-related TEAEs resulted in treatment discontinuation for 2 patients (4%).
“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 at Merus, stated in the press release.1 “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 [frontline PD-L1–positive] setting.”
Developers designed petosemtamab as an IgG1 antibody directed towards EGFR and LGR5 that functions via 3 independent mechanisms of action. These mechanisms include inhibiting EGFR-dependent signaling, binding to LGR5 to facilitate EGFR internalization and degradation in cancer cells, and prompting antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis activity.
In the ongoing, open-label, multicenter phase 1/2 trial, patients were assigned to receive petosemtamab at 1500 mg intravenously every 2 weeks in each 28-day cycle plus pembrolizumab at 400 mg intravenously every 6 weeks. Study treatment continued until disease progression or toxicity, and investigators conducted tumor assessments once every 8 weeks.
The trial’s primary end points are investigator-assessed ORR per RECIST v1.1 criteria and safety and tolerability. Secondary end points include duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetics, and immunogenicity.
Investigators will also assess the safety and efficacy of petosemtamab plus pembrolizumab vs pembrolizumab alone in first-line PD-L1–positive recurrent or metastatic HNSCC as part of the phase 3 LiGeR-HN1 trial (NCT06525220). The trial’s primary end points will be ORR based on blinded independent central review (BICR) per RECIST v1.1 criteria and OS; secondary end points will include DOR and PFS. Developers intend to enroll an approximate total of 500 patients in the LiGeR-HN1 trial.
Additionally, the phase 3 LiGeR-HN2 trial (NCT06496178) will evaluate petosemtamab vs investigator’s choice of methotrexate, docetaxel, or cetuximab (Erbitux) as second- or third-line therapy for approximately 500 adult patients with recurrent/metastatic HNSCC who have progressed on prior anti–PD-1 therapy and platinum-based treatment. The trial’s primary end points are ORR per BICR using RECIST v1.1 criteria and OS. Secondary end points include PFS and DOR.
References
- 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://tinyurl.com/5dstt46d
- Petosemtamab granted breakthrough therapy designation by the U.S. FDA. News release. Merus N.V. May 13, 2024. Accessed February 19, 2025. https://tinyurl.com/wmhnw8dc
- Fayette J, Clatot F, Braña 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
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