Initial safety and efficacy of PDL1V (PF-08046054), a vedotin-based ADC targeting PD-L1, in combination with pembrolizumab in patients with recurrent or metastatic (R/M) HNSCC.

6033 Background: PDL1V is a novel investigational antibody-drug conjugate that delivers monomethyl auristatin E (MMAE) to cells that express programmed cell death ligand 1 (PD-L1) without anticipated checkpoint blockade. Immunogenic cell death via the MMAE payload can be further amplified by traditional immune checkpoint inhibitors, providing strong scientific rationale for combination with pembrolizumab. The objective of Part D of the phase 1 trial is to assess the safety/tolerability and preliminary antitumor activity of PDL1V and pembrolizumab combination in patients with R/M HNSCC. Methods: C5851001 (NCT05208762) includes a phase 1 safety run-in cohort (Part D) enrolling patients with untreated R/M HNSCC with PD-L1 CPS ≥1 and no prior therapy with anti-PD-1/PD-L1 antibodies in any setting. Measurable disease per RECIST v1.1 and ECOG PS ≤1 were required. The first patient group received PDL1V 1.25 mg/kg on days 1 and 8 every 21 days (2Q3W) using adjusted ideal body weight (AIBW). Once safety was demonstrated, a second cohort was initiated at 1.5 mg/kg 2Q3W AIBW. All patients received pembrolizumab 200 mg every 3 weeks. The primary objectives of this study are safety/tolerability and pharmacokinetics. A secondary objective is antitumor activity. Results: As of December 20, 2024, 14 patients were dosed; median age was 61 years (range 36–76). Eight patients received 1.25 mg/kg and 6 received 1.5 mg/kg; 92.9% were male, 71.4% had ECOG PS 0, 64.3% were P16 positive oropharyngeal, and 57.1% had CPS 1–<20. Eight patients remain on active therapy at the data cut time. No dose-limiting toxicities (DLTs) were observed. The most frequent PDL1V treatment-related adverse events (TRAEs) were fatigue and nausea (50.0% each), peripheral sensory neuropathy (35.7%), diarrhea (28.6%), and anemia, constipation, decreased appetite, muscle spasms, pneumonitis, and pyrexia (14.3% each); pembrolizumab TRAEs were fatigue (42.9%), diarrhea, and nausea (28.6% each); and abdominal pain, decreased appetite, peripheral sensory neuropathy, pneumonitis, and pyrexia (14.3% each). The most frequent grade ≥3 TRAEs for either agent were diarrhea (14.3%) and anemia, decreased appetite, fatigue, and neutropenia (7.1% each). Treatment-related immune-mediated AEs by investigator assessment were observed in 7.1% of patients; 7.1% grade 3. Investigator-assessed, objective response rate at this time for 14 response-evaluable patients was 50.0%; complete response (CR) rate was 21.4%. The median duration of response has not been reached. Conclusions: The combination of PDL1V and pembrolizumab was generally well tolerated with no DLTs. Early encouraging objective responses were observed in half of the patients treated, including 21.4% with a CR. Enrollment in multiple combination expansion cohorts in PD-L1 expressing tumors is ongoing. Clinical trial information: NCT05208762 .