Head and neck cancers represent approximately 4% of all cancer cases in the United States. Despite significant advances in molecular research, biomarker discovery, and the development of novel therapies, patient outcomes have improved only marginally over the past several decades. These cancers are more commonly diagnosed in individuals over the age of 50 and occur two to three times more frequently in men than in women—primarily due to higher rates of tobacco and alcohol use among men.

As of October 25, 2024, 32 patients received at least one dose of brentuximab vedotin plus pembrolizumab. Among all patients, the confirmed overall response rate (ORR) was 34%, with a median follow-up of 9.7 months. The median duration of response (DOR) was not reached. Responses were observed regardless of HPV status and across PD-L1 combined positive score (CPS) subgroups, with response rates of 34% in the CPS ≥1 group and 36% (9 of 25) in the CPS ≥20 group. The Kaplan-Meier estimate for DOR ≥6 months was 89%. Median progression-free survival (PFS) was 7.2 months, and the 6-month PFS rate was 56%. 

Peripheral blood biomarker analyses showed that regulatory T cells (Tregs) expressed higher levels of CD30 compared with other T-cell subsets. Treatment with brentuximab vedotin plus pembrolizumab was associated with a trend toward Treg depletion, along with increased T-cell proliferation and activation. The pharmacokinetics of brentuximab vedotin in combination with pembrolizumab in HNSCC were consistent with those observed for brentuximab vedotin monotherapy. All patients experienced at least one treatment-emergent adverse event (TEAE), and 75% (24 patients) had Grade ≥3 TEAEs. Treatment-related Grade ≥3 TEAEs occurred in 31% (10 patients), with the most common being decreased lymphocyte count (13%), and increased ALT, fatigue, neutropenia, and decreased neutrophil count (each in 6%).

The Phase II study highlights a promising approach in HNSCC, showing that targeting CD30-positive T-regulatory cells with brentuximab vedotin in combination with pembrolizumab may enhance immune response and improve treatment outcomes.

KOL insights: 

An interesting and novel concept of combining brentuximab vedotin and pembrolizumab in HNSCC to explore if targeting CD30-positive T-regulatory cells with [brentuximab vedotin] will enhance the immune response and improve treatment outcomes was tested in a Phase II open-label study.” – Expert Opinion.

Conclusion:

Brentuximab vedotin combined with pembrolizumab showed promising clinical activity and a manageable safety profile in treatment-naive patients with metastatic HNSCC and PD-L1 CPS ≥1. Responses were observed across biomarker subgroups, including HPV-negative patients, with evidence of durable benefit. Biomarker data support an immunomodulatory mechanism, including Treg depletion and increased T-cell activation, aligned with prior findings in other solid tumors. Pharmacokinetics were consistent with brentuximab vedotin alone. While all patients experienced adverse events, the combination’s safety profile was consistent with known effects of the individual agents.