Cetuximab with dalpicilib in patients with HPV-negative, anti-PD-1 resistant R/M HNSCC

BackgroundHPV-negative HNSCC is characterized by the hyperactivation of CDK4/6 pathway. As immunotherapy increasingly emerges as the first-line treatment for HNSCC, resistance to anti-PD-1 agents has become a pivotal challenge. We conducted this phase II study to evaluate the efficacy and safety of dalpiciclib, a CDK4/6 inhibitor, combined with cetuximab in patients with anti-PD-1-resistant, HPV-negative HNSCC.MethodsThe patients diagnosed with p16-negative recurrent or metastatic HNSCC resistant to the first-line anti-PD-1 therapy, who had not previously treated with cetuximab, were enrolled in this study. Patients received oral dalpiciclib 150 mg once daily for 21 consecutive days, and intravenous cetuximab (400 mg/m2 on day 1 of the first cycle followed by 250 mg/m2 once per week) in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, progression free survival (PFS), and overall survival (OS). A Simon's two-stage design was used, the study would be terminated if 1 or fewer responses were observed among the 14 patients enrolled in the first stage. If the first stage was fulfilled, further 12 patients would be enrolled.ResultsIn the first stage, 14 patients who met the inclusion criteria were enrolled, with a median age of 50.5 years (range 30-75 years). Of 14 evaluable patients, 4 patients experienced disease progression, 1 had stable disease and 9 achieved PR. The ORR and DCR were 64.3% (95% CI, 38.6-83.8) and 71.4%, respectively. By the cutoff date, 5 patients remained on treatment. With a median follow-up of 5.7 months, the median PFS was 3.8 months (95% CI, 3.2-4.4), and the median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 100.0% of patients, mainly grade 1-2. The most common TRAEs were neutrophil count decreased (12/14, 85.7%), white blood cell decreased (12/14, 85.7%), and acneiform rash (8/14, 57.1%). Grade 3 TRAEs included neutrophil count decreased (5/14, 35.7%), white blood cell count (5/14, 35.7%), and oral cavity ulcer (1/14, 7.1%). No grade 4/5 TRAEs were reported.ConclusionsOur data suggests that dalpiciclib combined with cetuximab was well-tolerated and demonstrated potentially favorable efficacy in patients with anti-PD-1-resistant, HPV-negative HNSCC.Clinical trial identificationNCT05721443.FundingShanghai Municipal Health Commission Clinical Research Programme (20234Y0137).DisclosureAll authors have declared no conflicts of interest.