Efficacy Comparison of Zanzalintinib (XL092) and Pembrolizumab Versus Pembrolizumab Monotherapy in PD-L1 Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

The primary objective of this study is to compare the **efficacy** of zanzalintinib in combination with pembrolizumab versus pembrolizumab alone in subjects with recurrent or metastatic head and neck squamous cell carcinoma. This comparison is clinically relevant as it aims to determine whether the addition of zanzalintinib can enhance the therapeutic outcomes in this patient population, potentially offering a more effective treatment option.

Secondary objectives include:

• Assessing the safety and tolerability of zanzalintinib in combination with pembrolizumab versus pembrolizumab alone.
• Comparing additional efficacy outcomes such as progression-free survival (PFS), overall response rate (ORR), and duration of response (DOR) by both Investigator and Blinded Independent Central Review (BICR).
• Evaluating the effect of zanzalintinib on specified biomarkers and pharmacokinetics (PK) when administered in combination with pembrolizumab.

The clinical trial involves a total of **348 participants** diagnosed with **recurrent or metastatic head and neck squamous cell carcinoma**. The study population includes both male and female subjects, aged 18 years and older, with an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on specific inclusion criteria, such as having histologically or cytologically confirmed disease that is considered incurable by local therapy, and a **PD-L1 expression level Combined Positive Score (CPS) ≥ 1**. The trial also requires participants to have measurable disease according to RECIST 1.1 and adequate organ and marrow function. Lifestyle factors such as diet and physical activity are not specified, but participants must have recovered to baseline or ≤ Grade 1 severity from adverse events related to any prior treatments. The trial includes a vulnerable population, ensuring comprehensive representation of the affected demographic.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy of XL092 in combination with **pembrolizumab** versus pembrolizumab alone in subjects with **recurrent or metastatic head and neck squamous cell carcinoma**. The trial is structured in two phases, Phase 2 and Phase 3, and aims to assess the primary endpoints of progression-free survival (PFS) and overall survival (OS) as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR). Secondary endpoints include the incidence and severity of adverse events (AEs), changes in laboratory parameters and vital signs, and the correlation between pharmacokinetics of zanzalintinib and selected biomarkers.

The trial is expected to commence recruitment on April 1, 2024, and is estimated to conclude by May 30, 2029. Participants will be involved in the study for a maximum treatment period of 258 days for XL092 and 24 days for pembrolizumab. The study will include several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as histologically confirmed disease, PD-L1 expression level, and adequate organ function. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments conducted according to RECIST 1.1 criteria. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will ensure that all participants meet the inclusion criteria, such as being 18 years or older, having an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and providing necessary tumor samples. The study will be conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of **XL092**, a small molecule investigational drug, in the form of a **tablet**. The active substance in XL092 is **N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide**. The tablets are administered orally with a maximum daily dose of 100 mg. The total maximum dose over the treatment period is 180,600 mg, with a maximum treatment duration of 258 days. Compliance with the dosing schedule is monitored throughout the trial.

**KEYTRUDA** (pembrolizumab) is used as a comparator treatment in this study. It is provided as a 25 mg/mL concentrate for solution for infusion. Pembrolizumab is a protein-based therapeutic agent administered via **intravenous use**. The maximum daily dose is 200 mg, with a total maximum dose of 6,933.33 mg over a treatment period of 24 weeks. The administration schedule and participant adherence are closely monitored to ensure protocol compliance.

A **placebo** is also utilized in this trial, designed to be indistinguishable from the active zanzalintinib tablets in shape, size, color, and packaging. The placebo tablets are available in strengths of 20 mg, 40 mg, 60 mg, and 100 mg, with distinct shapes for each strength: round, triangle, oval, and caplet, respectively. The placebo is administered orally, and its use is integral to maintaining the double-blind nature of the study.

The efficacy of the investigational treatment in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) evaluated by Blinded Independent Central Review (BICR), and **Overall Survival (OS)**. These endpoints are critical in determining the effectiveness of the treatment in subjects with recurrent or metastatic head and neck squamous cell carcinoma.

Secondary endpoints will further evaluate the treatment's efficacy and safety profile. These include the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and adverse events of clinical interest (AECIs). Changes in laboratory parameters and vital signs will also be monitored. Additional efficacy measures include PFS per RECIST 1.1 by the Investigator, Overall Response Rate (ORR), and Duration of Response (DOR) as assessed by both BICR and the Investigator. The plasma concentration of zanzalintinib will be measured to assess pharmacokinetics, and correlations between pharmacokinetics and selected biomarkers will be analyzed to explore preliminary safety and efficacy outcomes.