HPV-unrelated Head and Neck Squamous Cell Carcinoma

The goal of this clinical trial is to evaluate if adding chemotherapy and immunotherapy as induction treatment prior to definitive chemoradiotherapy could improve the outcomes of locally advanced HPV-negative head and neck squamous cell that are not amenable to surgery. The study aims to answer: 1. Does this treatment improve the survival outcomes of participants? 2. How do the tumors of participants response to the treatment? 3. How is the safety of this treatment? Researchers will compare this treatment (induction chemoimmunotherapy, followed by concurrent chemoradiotherapy, and then immunotherapy as maintenance therapy) to concurrent chemoradiotherapy to see whether it provides additional clinical benefits.

This multicenter, open-label, randomized phase 3 trial will determine if palbociclib and cetuximab (Arm 1) improves overall survival (OS) in comparison to cetuximab monotherapy (Arm 2) in patients with CDKN2A-altered, HPV-unrelated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who experienced disease progression on a PD-1/L1 inhibitor (given as monotherapy or in combination with other therapy).