A Phase 2/3, Randomized, Double-Blind, Controlled Study of XL092 in Combination With Pembrolizumab vs Pembrolizumab in the First-Line Treatment of Subjects With PD-L1 Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

PI: Prof.ssa Lisa Licitra 

The Stellar study is a global, multicenter clinical trial evaluating the activity of Zanzalintinib (XL092) in combination with pembrolizumab versus pembrolizumab alone in the treatment of patients with locally and/or distantly recurrent squamous cell carcinoma of the head and neck, who are PD-L1 (Programmed Cell Death Protein 1) positive and eligible for first-line systemic therapy. 

Zanzalintinib is a next-generation tyrosine kinase inhibitor (TKI) currently under development for several types of advanced cancers. Its activity modulates various cellular processes such as proliferation, differentiation, and signal transduction—that is, the conversion of an external stimulus into a specific cellular response. It is, therefore, a drug capable of highly selectively regulating the signaling pathways involved in tumor growth and tumor angiogenesis. Recent preclinical and clinical studies suggest that Zanzalintinib may enhance its anti-tumor activity through synergy with PD-L1 inhibitors. 

Pembrolizumab is a humanized monoclonal antibody that binds to the PD-1 protein (Programmed Cell Death-1), blocking its interaction with its ligands (PD-L1 and PD-L2), and stimulating immune cells to eliminate cancer cells. 

This study, conducted in accordance with international ethical guidelines, is considered experimental, as Zanzalintinib has not yet been approved by regulatory health authorities for the treatment of head and neck cancer. However, its potential impact has already been demonstrated in previous studies, supporting the biological and clinical rationale for its use in this patient population. 

Pembrolizumab, on the other hand, is an approved therapy by both the U.S. Food and Drug Administration (FDA) and the Italian Medicines Agency (AIFA) for the treatment of head and neck cancer. 

• Study Objective: 

The objective of this study is to evaluate the efficacy of the combination Zanzalintinib + Pembrolizumab, as measured by progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) according to RECIST v1.1 criteria, assessed by a Blinded Independent Radiology Committee (BIRC). 

This is a randomized, double-blind clinical trial. 

The term “randomized” means that study treatment allocation is determined randomly—like the flip of a coin. Assignment to one treatment arm (Zanzalintinib + Pembrolizumab) or the other (placebo + Pembrolizumab) occurs through a computerized randomization process, with no influence from either the investigator or the patient. There is a 50% chance of being assigned to the experimental arm and a 50% chance of being assigned to the control arm: 

• Experimental Arm: Zanzalintinib + Pembrolizumab 
• Control Arm: Placebo + Pembrolizumab 

The assignment is double-blind, meaning neither the patient nor the study doctor will know which treatment is being received. 

Zanzalintinib is an orally administered drug, taken once daily at a fixed dose. Similarly, the placebo is an oral product without any active drug, but identical in appearance (color, size) to the active drug. 

Pembrolizumab is administered at a fixed dose via intravenous infusion every 3 weeks. 

• Enrollment Criteria: 

Feasibility of enrollment in the study will depend on: patient characteristics (demographic data, cancer history, and comorbidities), laboratory test results, and radiologic parameters, which will be evaluated through specific screening exams conducted at this Institution and according to a defined schedule. 

Patients will be monitored not only for oncologic response, but also for potential treatment-related side effects. It is possible that the treatment may cause adverse events—many of which are already known—for which symptomatic therapies (e.g., corticosteroids) and targeted management strategies (e.g., dose reductions, treatment pauses) will be implemented to reduce the severity of side effects. Patients will be closely monitored to ensure their safety during treatment. 

• Treatment Duration: 

Treatment will continue according to study protocol and timelines until maximum response is achieved. If disease remains stable or decreases in size and treatment is well tolerated: 

• Zanzalintinib may be continued indefinitely; 
• Pembrolizumab will be administered for a maximum of 2 years. 

Treatment will be discontinued in the event of: 

• Disease progression; 
• Unacceptable toxicity; 
• Or, as always in clinical trials, a decision by either the patient or the investigator. In such cases, the patient will continue to receive medical care and will not lose any legal rights or entitled benefits. 

The Stellar study team remains available to provide more detailed information regarding the clinical trial (email: amo@istitutotumori.mi.it).