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.
Carla M.L. van Herpen, Amaury Daste, Virginia Arrazubi, Jan Paul de Boer, Katerin Ingrid Rojas, Florian Clatot, Elisa Fontana, Amir Harandi, Jessica A. Hellyer, Antoine Hollebecque, Christophe Le Tourneau, Thibault Mazard, Cesar A. Perez, Esma Saâda, Assuntina G. Sacco, Eduardo Pennella, Fabian Zohren, Yu-Ming Shen, Renée de Leeuw, Jérôme Fayette
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 .