Zanzalintinib/Atezolizumab Improves CRC Survival, Expands TKI's Role in Solid Tumors
New trial results reveal zanzalintinib and atezolizumab significantly enhance survival in metastatic colorectal cancer, marking a breakthrough in treatment options.
Microscopic image of colorectal cancer cells - Generated with Google Gemini AI
Promising new data from the phase 3 STELLAR-303 pivotal trial (NCT05425940) indicate that zanzalintinib (XL092) in combination with atezolizumab (Tecentriq) significantly improved overall survival (OS) compared with regorafenib (Stivarga) in patients with previously treated metastatic colorectal cancer (CRC).1
This marks a critical advancement in the clinical development program for zanzalintinib, an investigational tyrosine kinase inhibitor (TKI) designed to target various receptor tyrosine kinases implicated in cancer growth and progression, including VEGF receptors, MET, AXL, and MER.
STELLAR-303 is a global, multicenter, randomized, open-label study that randomly assigned 901 patients with previously treated nonmicrosatellite instability-high (non–MSI-H) metastatic CRC to receive either zanzalintinib 100 mg in combination with atezolizumab or regorafenib. The study's dual primary end points were OS in the intent-to-treat (ITT) population and in the non-liver metastases (NLM) subgroup. Secondary end points included progression-free survival (PFS), objective response rate (ORR), and duration of response in both the ITT and NLM populations.
“The STELLAR-303 results, which showed a survival benefit with the combination of zanzalintinib and atezolizumab vs regorafenib across all randomized patients with previously treated metastatic colorectal cancer, marks an important first milestone for our zanzalintinib pivotal development program,” Amy Peterson, MD, executive vice president, Product Development & Medical Affairs, and chief medical officer, Exelixis, said in a press release. “We look forward to discussing the findings with regulatory authorities and presenting the detailed results at an upcoming medical conference.”
The observed safety profiles for both the zanzalintinib/atezolizumab combination and regorafenib were consistent with previously reported data, with no new safety signals identified. This is particularly important for a clinical audience, as it suggests a predictable tolerability profile for the combination therapy. Detailed results from the STELLAR-303 trial are anticipated to be presented at a forthcoming medical conference, providing clinicians with a comprehensive understanding of the efficacy and safety metrics.
Expanding the Clinical Utility of Zanzalintinib
Beyond the recent CRC data, zanzalintinib has demonstrated encouraging activity in other advanced solid tumors. Earlier this year, results from an expansion cohort of the phase 1b/2 STELLAR-002 trial(NCT05176483) evaluating zanzalintinib in combination with immune checkpoint inhibitors in advanced renal cell carcinoma (RCC) were presented at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting.2
In this cohort, zanzalintinib combined with nivolumab (Opdivo) demonstrated an ORR of 63% (95% CI, 46%-77%) and a disease control rate (DCR) of 90% (95% CI, 76%-97%) in patients with previously untreated advanced clear cell RCC. Median PFS was 18.5 months (95% CI, 9.5 months-not estimable [NE]). For patients receiving zanzalintinib in combination with a fixed-dose combination of nivolumab and relatlimab, the ORR was 40% (95% CI, 25%-57%) and the DCR was 90% (95% CI, 76%-97%), with a median PFS of 13.0 months (95% CI, 7.4-NE).
Treatment-emergent adverse events (TEAEs) observed in the STELLAR-002 trial were generally manageable and aligned with the known profiles of the individual agents. For the zanzalintinib/nivolumab arm, common grade 3/4 TEAEs included hypertension, diarrhea, and elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase). In the zanzalintinib, nivolumab, and relatlimab arm, hypertension, rash, lipase increase, and pulmonary embolism were among the notable grade 3/4 TEAEs. These findings reinforce the potential of zanzalintinib-based regimens in the challenging landscape of advanced RCC, where effective and tolerable therapies remain a significant clinical need.
The Rationale Behind Combination Therapy
The mechanism of action of zanzalintinib, as a potent oral TKI, involves inhibiting multiple receptor tyrosine kinases crucial for oncogenesis, including VEGF receptors, MET, AXL, and MER. These targets are involved in tumor angiogenesis, proliferation, metastasis, and resistance to various therapies, including immune checkpoint inhibitors. Immune checkpoint inhibitors, such as atezolizumab and nivolumab, function by blocking checkpoint proteins like PD-1 or PD-L1, which tumor cells exploit to evade immune surveillance. By disinhibiting the immune system, these agents enable T cells to recognize and attack cancer cells.3,4
The rationale for combining a TKI like zanzalintinib with immune checkpoint inhibitors stems from the understanding that these classes of agents can exert complementary antitumor effects. TKIs can reduce tumor burden, alter the tumor microenvironment to be more conducive to immune cell infiltration, and potentially overcome resistance mechanisms to immunotherapy. Conversely, immune checkpoint inhibitors can unleash a robust antitumor immune response. This dual approach aims to enhance therapeutic efficacy and potentially achieve more durable responses in patients with advanced malignancies.
Clinical Implications and Future Directions
The positive results from STELLAR-303 for metastatic CRC are particularly noteworthy, given the high unmet medical need in this patient population, especially those with previously treated, non–MSI-H disease. For clinicians, these data suggest that zanzalintinib in combination with atezolizumab could offer a new systemic treatment option, potentially improving survival outcomes. The consistency in safety profiles with established agents is a critical factor in evaluating new treatment paradigms.
The cumulative evidence from the STELLAR-303 and STELLAR-002 trials underscores zanzalintinib's potential as a foundational component in combination regimens for advanced solid tumors. Ongoing and future studies will further elucidate its role across various cancer types, including head and neck cancer and neuroendocrine tumors, for which zanzalintinib is also under development.
As an investigational agent, zanzalintinib is not yet approved for any use, and further clinical evaluation is ongoing. The upcoming detailed presentation of the STELLAR-303 data will provide a more granular understanding for the oncology community as they consider evolving treatment strategies for their patients.
