Phase 3 Randomized Open-Label Study of XL092 and Atezolizumab Versus Regorafenib in Metastatic Colorectal Cancer Patients

The primary objective of this study is to evaluate the **overall survival** of XL092 combined with atezolizumab versus regorafenib in subjects with metastatic colorectal cancer (mCRC) characterized by microsatellite stability (MSS) or low microsatellite instability (MSI-low) who have experienced disease progression during, after, or are intolerant to standard of care (SOC) therapy. This is clinically relevant as it aims to determine the potential survival benefit of the combination therapy over the current standard treatment, which could lead to improved treatment strategies for this patient population.

Secondary objectives include:

• Evaluating the overall survival of XL092 + atezolizumab versus regorafenib in all randomized subjects with MSS/MSI-low mCRC.
• Assessing the efficacy of XL092 + atezolizumab versus regorafenib in subjects without liver metastases (NLM) with MSS/MSI-low mCRC.
• Evaluating the efficacy of XL092 + atezolizumab versus regorafenib in all randomized subjects with MSS/MSI-low mCRC.
• Assessing the safety and tolerability of XL092 + atezolizumab versus regorafenib alone in all randomized subjects with MSS/MSI-low mCRC.
• Characterizing the pharmacokinetics (PK) of XL092, its potential metabolites, and atezolizumab, as well as the immunogenicity of atezolizumab in all randomized subjects with MSS/MSI-low mCRC.

The clinical trial involves a total of **616 participants** diagnosed with **Metastatic Colorectal Cancer**. The study population includes both male and female subjects, aged 18 years and older, who have histologically or cytologically confirmed adenocarcinoma of the colon or rectum. Participants are required to have progressed during, after, or shown intolerance to standard of care therapies. The trial population was selected based on specific inclusion criteria, including an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and adequate organ and marrow function. Participants must have measurable disease according to RECIST 1.1 criteria and provide either archival or fresh tumor biopsy material. The study also considers lifestyle factors such as the use of highly effective contraception methods for fertile subjects and their partners. The trial includes a vulnerable population, ensuring that all participants are capable of understanding and complying with the protocol requirements, having signed the informed consent document.

The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of **XL092** in combination with **atezolizumab** versus **regorafenib** in subjects with metastatic colorectal cancer. The primary objective is to assess overall survival in subjects with microsatellite stable (MSS) or microsatellite instability-low (MSI-low) metastatic colorectal cancer who have progressed during, after, or are intolerant to standard of care (SOC) therapy. The trial is expected to run until November 28, 2025, with recruitment having commenced on January 24, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically confirmed adenocarcinoma of the colon or rectum, measurable disease per RECIST 1.1, and adequate organ and marrow function. Following the screening, eligible participants will be randomized to receive either the investigational combination of XL092 and atezolizumab or the comparator, regorafenib. The treatment period is set for a maximum of 73 weeks, during which participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of progression-free survival, overall response rate, and duration of response.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants are expected to be involved in the study for the entire duration unless early termination criteria are met. The trial will also monitor secondary endpoints such as the incidence and severity of adverse events, plasma and serum concentrations of the investigational drugs, and the incidence of antidrug antibody responses.

The clinical trial involves the administration of several treatments, including **Tecentriq** (atezolizumab), **Stivarga** (regorafenib), and **XL092**. Tecentriq is provided as a 1,200 mg concentrate for solution for infusion, intended for **intravenous use**. The active substance, atezolizumab, is a protein of biological/biotechnological origin. The maximum daily and total dose amounts are set at 9999.99 mg/ml, with a treatment period of up to 73 weeks. The administration schedule and participant compliance are monitored according to the study protocol.

Stivarga, containing the active substance regorafenib, is administered in the form of 40 mg film-coated tablets for **oral use**. It is a chemical compound with a maximum daily dose of 160 mg and a total dose limit of 9999.99 mg. The treatment duration is also capped at 73 weeks. The tablets are labeled specifically for the study, and dosing schedules are adhered to as per the trial guidelines.

XL092 is another investigational product in the trial, available as a tablet for **oral use**. The active substance is a chemical compound, specifically a multi-targeted inhibitor of receptor tyrosine kinases. The maximum daily dose is 120 mg, with a total dose limit of 9999.99 mg, and the treatment period extends up to 73 weeks. The administration of XL092 is carefully monitored to ensure compliance with the dosing regimen outlined in the study protocol.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **Overall Survival** (OS) in subjects with metastatic colorectal cancer. This primary endpoint will be measured to compare the effectiveness of the combination of XL092 and atezolizumab against regorafenib. Secondary endpoints include Progression-Free Survival (PFS), Objective Response Rate (ORR), and Duration of Response (DOR), all assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Additionally, the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) will be monitored.

Plasma and serum concentrations of XL092 and atezolizumab, respectively, will be measured to evaluate pharmacokinetics, along with the incidence of antidrug antibody (ADA) response against atezolizumab when combined with XL092. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive data collection and analysis. The trial is designed to provide a robust evaluation of the therapeutic efficacy and safety profile of the investigational treatments in the target patient population.