Petosemtamab (MCLA-158) with pembrolizumab as first-line (1L) treatment of PD-L1+ recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC): Phase 2 trial.

Abstract

6024 Background: EGFR is a known oncogenic driver in HNSCC, and the leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is associated with cancer stem cells in solid tumors and expressed in HNSCC. Petosemtamab is a human, common light chain, IgG1 bispecific antibody with ADCC-enhanced activity, targeting EGFR and LGR5. Promising interim data from this phase 2, single-arm trial of petosemtamab 1500 mg every 2 weeks (Q2W; 28-day cycles) with pembrolizumab (400 mg Q6W) as 1L treatment in PD-L1+ HNSCC (NCT03526835) demonstrated a 67% overall response rate (ORR) in 24 efficacy evaluable patients (pts) [Fayette, ASCO 2024]. Methods: Primary endpoints are investigator-assessed ORR (RECIST v1.1) and safety. Secondary endpoints include duration of response (DOR), progression-free survival (per investigator), and overall survival (OS). Key eligibility criteria were r/m HNSCC with no prior systemic therapy in the r/m setting, PD-L1 combined positive score ≥1, ECOG PS 0–1, measurable disease, and primary tumor location in oropharynx (regardless of p16 status), oral cavity, hypopharynx, or larynx. Results: A total of 45 pts were treated; as of a September 16, 2024 data cutoff, 18 pts continuing on therapy. Median age was 64 years (range 23–80), ECOG PS 0/1 in 16/29 pts, and 78% were male. The most frequent primary tumor locations were oropharynx (31%), oral cavity (31%), larynx (16%), and hypopharynx (11%). A median of 8 cycles (range 1–17) were administered. Among 43 pts evaluable for efficacy (pts with ≥1 dose and ≥1 post-baseline scan, or who discontinued early due to progressive disease or death), the ORR was 60% (26/43) with 5 complete responses; median DOR was 11 months with 17 responders still on treatment at data cutoff. Of the 8 pts with p16+ oropharyngeal disease, 4 had confirmed responses (ORR 50%). The median follow-up for OS was 9.6 months; median OS was not reached. Kaplan–Meier estimate of OS at 6 months was 93%. The combination was well tolerated, and no significant overlapping toxicities were observed. Treatment-emergent adverse events (AEs) were reported in 45 pts, most were Grade (G) 1 or 2 in severity; one previously reported unrelated G5 AE occurred. The most frequent AEs (all G/G≥3) were acneiform dermatitis (49%/7%), asthenia (49%/7%), and rash (44%/0%). Infusion-related reactions (composite term) were reported in 38% (all G) and 7% (G3) of pts, mainly occurred at first infusion, and all resolved. Updated data to be presented. Conclusions: Petosemtamab, a first-in-class EGFR x LGR5 bispecific antibody, in combination with pembrolizumab continues to demonstrate promising clinical efficacy and a well-tolerated safety profile as 1L treatment for pts with r/m PD-L1+ HNSCC. A global phase 3 trial, LiGeR-HN1 (NCT06525220), is ongoing to evaluate petosemtamab in combination with pembrolizumab in 1L PD-L1+ r/m HNSCC. Clinical trial information: NCT03526835 .