Breakthrough Trial: Zanzalintinib and Atezolizumab Enhance CRC Survival

Recent data from the phase 3 STELLAR-303 trial has revealed promising results in the treatment of metastatic colorectal cancer (CRC) with the combination of zanzalintinib (XL092) and atezolizumab (Tecentriq). This study, conducted by Exelixis, Inc., involved 901 patients with previously treated non-microsatellite instability-high (non–MSI-H) metastatic CRC. The findings suggest a significant improvement in overall survival (OS) compared to regorafenib (Stivarga), marking a pivotal moment in the treatment landscape for CRC.

According to Dr. Amy Peterson, Executive Vice President and Chief Medical Officer at Exelixis, "The STELLAR-303 results... mark an important first milestone for our zanzalintinib pivotal development program." The trial's dual primary endpoints focused on OS in the intent-to-treat (ITT) population and in a subgroup of patients without liver metastases. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response, which were all analyzed to assess the treatment's efficacy.

The study's open-label design allowed for a comprehensive evaluation of the safety profiles associated with both treatment regimens. Importantly, the safety profiles for the zanzalintinib/atezolizumab combination were consistent with previously reported data, indicating a predictable tolerability profile for this novel therapy.

Zanzalintinib, a tyrosine kinase inhibitor (TKI), targets multiple receptor tyrosine kinases, such as VEGF receptors and MET, which play critical roles in tumor growth and progression. By inhibiting these pathways, zanzalintinib not only aims to reduce tumor burden but also to enhance the efficacy of immune checkpoint inhibitors like atezolizumab, which work by restoring immune system function against cancer cells. This combined approach is based on evidence suggesting that TKIs can modify the tumor microenvironment to facilitate immune cell infiltration, thereby improving outcomes in patients with advanced malignancies.

The results of the STELLAR-303 trial are particularly significant given the high unmet medical need among CRC patients, especially those with previously treated non–MSI-H disease. The combination of zanzalintinib and atezolizumab could potentially provide a new systemic treatment option, improving survival rates for this patient population.

In addition to the promising data for metastatic CRC, zanzalintinib has shown encouraging activity in other solid tumors, including advanced renal cell carcinoma (RCC). Results from another trial, STELLAR-002, presented at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting, demonstrated an ORR of 63% for patients treated with zanzalintinib in combination with nivolumab (Opdivo).

As zanzalintinib moves forward in clinical trials, its role in combination therapies for various cancers will continue to be explored. Further evaluation and discussions with regulatory authorities are anticipated, with detailed results from the STELLAR-303 trial expected to be presented at an upcoming medical conference. The efficacy and safety data from these trials will be crucial for oncologists as they consider the evolving treatment strategies for patients with advanced solid tumors. The future of zanzalintinib remains bright as it represents a promising option in the challenging landscape of cancer therapy, particularly for underserved populations with high unmet needs.