HNSCC remains a challenging malignancy marked by aggressive clinical behavior and limited long-term survival, particularly in advanced-stage disease. While multimodal treatment strategies have improved short-term outcomes, the persistently high recurrence rates and resistance to standard therapies highlight an urgent need for more effective, durable treatment approaches.

PDL1V is a novel investigational antibody-drug conjugate (ADC) designed to selectively deliver monomethyl auristatin E (MMAE) to cells expressing programmed death-ligand 1 (PD-L1), without engaging checkpoint blockade. The MMAE payload induces immunogenic cell death, which can be further enhanced by co-administration of immune checkpoint inhibitors. This provides a strong scientific rationale for combining PDL1V with pembrolizumab to potentiate antitumor immune responses.

As of December 20, 2024, 14 patients had been dosed. Eight patients received 1.25 mg/kg and six received 1.5 mg/kg. At the data cutoff, eight patients remained on active therapy. 

Efficacy: Among 14 response-evaluable patients, the ORR was 50.0%, with a complete response (CR) rate of 21.4%. The median duration of response had not yet been reached at the time of analysis.

Safety: No dose-limiting toxicities (DLTs) were observed. The most common PDL1V-related treatment-emergent adverse events (TRAEs) included fatigue and nausea (50.0% each), peripheral sensory neuropathy (35.7%), and diarrhea (28.6%). Other PDL1V-related TRAEs (14.3% each) were anemia, constipation, decreased appetite, muscle spasms, pneumonitis, and pyrexia. For pembrolizumab, common TRAEs included fatigue (42.9%), and diarrhea and nausea (28.6% each). Additional TRAEs (14.3% each) were abdominal pain, decreased appetite, peripheral sensory neuropathy, pneumonitis, and pyrexia. Grade ≥3 TRAEs for either agent included diarrhea (14.3%), anemia, decreased appetite, fatigue, and neutropenia (7.1% each). Immune-mediated adverse events (AEs) attributed to treatment were reported in 7.1% of patients, including one Grade 3 event. 

KOL insights: 

“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.” – Expert Opinion.

Conclusion:

The combination of PDL1V and pembrolizumab demonstrated a favorable safety profile, with no dose-limiting toxicities and manageable adverse events consistent with known effects of each agent. The treatment was generally well tolerated, with fatigue, nausea, neuropathy, and gastrointestinal symptoms being the most common. Immune-related events were infrequent and largely low grade. Preliminary signs of antitumor activity were encouraging, with a substantial proportion of patients achieving objective responses, including complete responses. The sustained treatment duration in several patients suggests ongoing clinical benefit. These early findings support the therapeutic potential of combining targeted cytotoxic delivery with immune checkpoint inhibition. Continued evaluation in expansion cohorts across PD-L1–expressing tumors will be critical to further define efficacy, safety, and the scope of clinical benefit.