Cetuximab plus dalpiciclib in patients with HPV-negative, anti-PD-1-resistant recurrent or metastatic head and neck squamous cell carcinoma.

Abstract

6026 Background: Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is characterized by hyperactivation of the cyclin-dependent kinase 4/6 (CDK4/6) pathway. As immunotherapy has become the first-line treatment for HNSCC, resistance to anti-programmed death-1 (PD-1) agents has emerged as a pivotal challenge. This phase II study evaluated the efficacy and safety of dalpiciclib, a CDK4/6 inhibitor, combined with cetuximab in patients with anti-PD-1-resistant, HPV-negative recurrent or metastatic (R/M) HNSCC. Methods: Patients diagnosed with p16-negative R/M HNSCC resistant to first-line anti-PD-1 therapy and cetuximab-naïve were enrolled. Patients received oral dalpiciclib 150 mg daily for 21 consecutive days and intravenous cetuximab (400 mg/m² on day 1 of cycle 1, followed by 250 mg/m² weekly) in 28-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS). Simon's two-stage design was used, with study termination planned if ≤1 response was observed among the first 14 patients. If met, an additional 12 patients were enrolled. Results: A total of 28 patients were enrolled, with a median age of 58 years (range 30-75 years). Among 28 evaluable patients, 3 had disease progression, 6 had stable disease, and 19 achieved partial response. The ORR was 67.9% (95% confidence interval [CI], 49.0%-82.0%), and the disease control rate was 89.3% (95% CI, 72.0%-97.0%). As of December 31, 2024, 9 patients remained on treatment. With a median follow-up of 7.34 months, the median PFS was 5.3 months (95% CI, 1.33-9.27), and the median OS was 17.0 months. Treatment-related adverse events (TRAEs) occurred in all patients, predominantly grade 1-2. The most common TRAEs were neutrophil count decreased (25/28, 89.3%), white blood cell count decreased (25/28, 89.3%), and acneiform rash (16/28, 57.1%). Grade 3 TRAEs included neutrophil count decreased (9/28, 32.1%) and white blood cell count decreased (9/28, 32.1%). No grade 4/5 TRAEs were observed. Conclusions: Dalpiciclib combined with cetuximab was well-tolerated and demonstrated potentially favorable efficacy in patients with anti-PD-1-resistant, HPV-negative R/M HNSCC. Clinical trial information: NCT05721443 .