Interim results of PDL1V (PF-08046054), a vedotin-based ADC targeting PD-L1, in patients with NSCLC in a phase 1 trial.

8611 Background: PDL1V is an investigational antibody-drug conjugate that delivers the cytotoxic agent monomethyl auristatin E to cells expressing programmed cell death ligand 1 (PD-L1). In addition to cytotoxicity, PDL1V elicits antitumor activity via the bystander effect and immunogenic cell death. Here we present the safety profile and preliminary efficacy in patients with metastatic, relapsed/refractory non-small cell lung cancer (NSCLC) enrolled in the phase 1 trial. Methods: C5851001 (NCT05208762) is a phase 1 study enrolling patients with relapsed or refractory solid tumors, including NSCLC, whose disease has progressed on standard-of-care therapies. Patients received the PDL1V recommended expansion dose of 1.5 mg/kg on days 1 and 8 of a 21-day cycle using adjusted ideal body weight, and were required to have measurable disease per RECIST v1.1 and ECOG PS ≤1. Patients with genomic alterations were not excluded. The primary objectives of this study are safety, tolerability, and pharmacokinetics, with antitumor activity as a secondary objective. Results: As of December 20, 2024, 30 patients with NSCLC have been treated at the recommended expansion dose. The median age was 60 years (range 44-73); 43.3% were male, 66.7% had ECOG PS 1, 23.3% had squamous histology, and 83.3% were PD-L1 positive. The median number of prior lines of therapy was 2.0 (1, 8); 96.7% and 66.7% of patients were previously exposed to anti-PD-1/PD-L1 antibodies and taxanes, respectively. There have been no dose-limiting toxicities at the recommended expansion dose. Peripheral sensory neuropathy (27.2%), nausea (25.0%), diarrhea (23.9%), and fatigue (21.7%) were the most common treatment-related adverse events (TRAEs) for all patients treated in the Phase 1 trial at the recommended expansion dose (N=92); the majority of TRAEs were grade 1-2 in severity, and 5.4% of patients discontinued therapy due to TRAEs. The most common grade ≥3 TRAE was anemia (5.4%). The incidence of treatment-related immune-mediated AEs by investigator assessment was 14.1%; 5.4% for grade 3, with no grades 4 or 5. The investigator-assessed confirmed objective response rate (cORR) for patients with NSCLC was 26.7%, while the cORR was 32.0% for those with PD-L1 expressing tumors. The median duration of confirmed response was 7.8 months (95% CI 4.8, –), and the median follow-up was 10.0 months (95% CI 4.9, 13.1). Objective responses were observed in patients with PD-L1 expressing squamous (n=6) and non-squamous (n=19) tumors (33.3% and 31.6% cORR, respectively). Conclusions: PDL1V monotherapy at the recommended expansion dose was generally well tolerated with a manageable safety profile. Encouraging preliminary efficacy in NSCLC was observed, independent of histology. Based on these results, further development of PDL1V in NSCLC is ongoing. Clinical trial information: NCT05208762 .

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