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Most patients with metastatic colorectal cancer (mCRC) have limited treatment options following standard-of-care therapy. VEGFR-tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in mCRC in combination with immune checkpoint inhibitors (ICIs), particularly in patients without liver metastases. The TKI zanzalintinib (XL092) targets VEGFR, MET and TAM kinases, proteins that are involved in tumor growth, angiogenesis, metastasis and immunosuppression. Zanzalintinib has immunomodulatory properties that may enhance response to ICIs. Presented is the design of STELLAR-303, a global, phase III, open-label, randomized study evaluating zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-H mCRC who progressed during/after or are refractory/intolerant to standard-of-care therapy. The primary end point is overall survival in patients without liver metastases. Clinical Trial Registration:NCT05425940 (ClinicalTrials.gov) Plain Language Summary Metastatic colorectal cancer (mCRC) is cancer of the colon or rectum that has spread to other parts of the body, most often to the liver, lungs and abdomen. People with mCRC that has worsened after initial treatment have limited options. Zanzalintinib is a novel oral investigational drug that can slow or stop cancer growth. It works by blocking certain proteins that play important roles in the development, growth and spread of cancer. Zanzalintinib may also help improve the effectiveness of another class of cancer drugs called immune checkpoint inhibitors (ICIs), which work by activating the patient's immune system to fight cancer. Here, we describe the design of STELLAR-303, an ongoing study that is comparing the effects of combining zanzalintinib and an ICI drug called atezolizumab with an approved treatment for mCRC called regorafenib. About 900 participants with mCRC will be enrolled in the study worldwide. To be included in the study, participants must have mCRC that worsened after previous therapies and must not have a high level of microsatellite instability, which is a specific feature of some mCRCs. Participants will be randomly given one of the two treatments. The main goal of the study is to evaluate zanzalintinib plus atezolizumab compared with regorafenib by measuring the length of time participants are alive after starting treatment, specifically in patients with mCRC that has not spread to the liver. Additionally, the study will look at the side effects with each treatment. The study is currently seeking participants. Tweetable Abstract STELLAR-303 is a randomized phase III study evaluating the novel TKI zanzalintinib plus the ICI atezolizumab in patients with previously treated non-MSI-H metastatic colorectal cancer. Patient enrollment is ongoing globally. Article highlights Background & rationale Patients with metastatic colorectal cancer (mCRC) have a poor prognosis and limited treatment options following progression on standard of care therapies. Immune checkpoint inhibitors (ICIs) are approved in microsatellite instability-high (MSI-H) and mismatch repair-deficient mCRC. However, efficacy of these treatments is limited in non-MSI-H or proficient mismatch repair (pMMR) disease. Agents targeting the VEGF pathway in combination with ICIs have been evaluated in non-MSI-H mCRC and have demonstrated encouraging clinical activity. Studies have shown that mCRC patients without liver metastases may derive greater benefit from TKI-ICI combinations than those with liver metastases. Zanzalintinib (XL092) is a tyrosine kinase inhibitor that targets MET, VEGFR and the TAM kinases. Inhibition of these kinases may suppress tumor growth and proliferation and promote an immunopermissive tumor microenvironment, which may enhance response to ICIs such as atezolizumab. Zanzalintinib has shown anti-tumor activity alone and in combination with ICIs in the preclinical setting and has demonstrated immunomodulatory effects, increasing pro-inflammatory immune cells and decreasing immunosuppressive cells. STELLAR-303 study design STELLAR-303 (NCT05425940) is a global, open-label, randomized, phase III study. Approximately 874 patients with non-MSI-H mCRC (with and without liver metastases) who have progressed during/after or are intolerant to standard of care therapies will be randomized 1:1 to oral zanzalintinib plus intravenous atezolizumab or to oral regorafenib. Eligibility criteria Eligible patients are aged ≥18 years and have histologically/cytologically confirmed adenocarcinoma of the colon or rectum that is non-MSI-H and pMMR; MSI/MMR status will be documented and determined by tissue-based analysis. A prespecified number of patients with/without liver metastases will be enrolled. Patients must have received standard of care therapy for mCRC and radiographically progressed or be refractory or intolerant to these therapies; progression during treatment or within 4 months of the most recent therapy is required. Patients who received prior zanzalintinib, regorafenib, trifluridine-tipiracil, or PD-L1/PD-1 targeting ICIs are ineligible. End points The primary end point is overall survival (OS) in patients without liver metastases. Secondary end points are OS in all randomized patients (assessed with hierarchical testing); progression-free survival, objective response rate and duration of response per RECIST v1.1 by investigator in patients without liver metastases and in all randomized patients; and safety. Status The study is actively enrolling patients in the USA, Europe and Asia-Pacific regions. Conclusion STELLAR-303 will assess the efficacy and safety of zanzalintinib plus atezolizumab in patients with previously treated non-MSI-H mCRC, a population with unmet need. [ABSTRACT FROM AUTHOR] |
