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.
Authors: Jerome Fayette, Florian Clatot, Irene Brana, Esma Saada, Carla M.L.- van Herpen, Thibault Mazard, Cesar Augusto Perez, Josep Tabernero, Christophe Le Tourneau, Antoine Hollebecque, Virginia Arrazubi Arrula, Elisa Fontana, Shumei Kato, Assuntina G. Sacco, Amir Harandi, J.P. De Boer, Jessica Hellyer, Eduardo Pennella, Andrew K. Joe, Amaury Daste
Journal: Journal of Clinical Oncology (2024)

6014 Background: EGFR is a known oncogenic driver in HNSCC, and the leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a receptor expressed on cancer stem cells, including in HNSCC. Petosemtamab is a human, common light chain, IgG1 bispecific antibody with ADCC-enhanced activity, targeting EGFR and LGR5. In the dose escalation part of a phase 1/2 study, the recommended phase 2 dose (RP2D) was determined to be 1500 mg every 2 weeks (Q2W). Interim data of petosemtamab monotherapy at the RP2D in 2L/3L HNSCC led to a 37.2% overall response rate (ORR; per investigator) with 6.0 months (mo) median duration of response (DOR) [Cohen, Cancer Research 2023]. Petosemtamab (RP2D) with pembrolizumab (400 mg Q6W) is being investigated in an expansion cohort of the ongoing phase 2 study (NCT03526835) in 1L HNSCC. Methods: Primary endpoints are safety and investigator-assessed ORR (RECIST v1.1). Secondary endpoints include DOR, progression-free survival (per investigator), and overall survival. Key eligibility criteria were r/m HNSCC with no prior systemic therapy, 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: No dose-limiting toxicities were observed in the safety run-in. As of a November 6, 2023 data cutoff, 26 pts were treated (24 continuing therapy at the data cutoff) and median follow-up was 1.35 mo. Median age was 62.5 years (range 23–80), ECOG PS 0/1 in 10/16 pts, and 65.4% were male. The most frequent primary tumor locations were oropharynx (34.6%), oral cavity (19.2%), and hypopharynx (19.2%). A median of 2 cycles (range 1–8) were administered. The combination was well tolerated and no significant overlapping toxicities were observed. Treatment-emergent adverse events (AEs) were reported in 26 pts, and most were Grade (G) 1 or 2 in severity (no G4–5 were observed). The most frequent AEs (all Gs/G3) were acneiform dermatitis (30.8%/0%), asthenia (26.9%/0%), and rash (26.9%/0%). Infusion-related reactions (composite term) were reported in 26.9% (all Gs) and 3.8% (G3) of pts, all occurred during the first infusion and resolved. Among 10 pts evaluable for efficacy (≥2 cycles and ≥1 post-baseline scan, or early progressive disease), there were 1 confirmed complete response, 2 confirmed and 3 unconfirmed partial responses (2 confirmed after data cutoff), 3 stable disease, and 1 progressive disease; with all 6 responders on treatment at data cutoff. Enrollment has been completed and updated data will be presented. Conclusions: Petosemtamab, a first-in-class EGFR x LGR5 bispecific antibody, in combination with pembrolizumab demonstrates a well-tolerated safety profile and promising preliminary clinical efficacy as 1L treatment for pts with r/m HNSCC. Clinical trial information: NCT03526835 .