Exelixis Reports Positive STELLAR-001 Results for Zanzalintinib in Metastatic CRC at ASCO GI 2025
Exelixis Announces Promising Results from Phase 1b/2 STELLAR-001 Trial for Zanzalintinib in Metastatic Colorectal Cancer at ASCO GI 2025
Exelixis, Inc. (Nasdaq: EXEL) recently presented data from the expansion cohort of the Phase 1b/2 STELLAR-001 trial, which assessed the efficacy of zanzalintinib, both as a monotherapy and in combination with atezolizumab (Tecentriq®), in patients with previously treated metastatic colorectal cancer (CRC). The findings were shared at the American Society of Clinical Oncology 2025 Gastrointestinal Cancers Symposium (ASCO GI 2025) during Poster Session C: Cancers of the Colon, Rectum, and Anus, held on January 25, 2025.
Study Design and Patient Population
The STELLAR-001 trial is an ongoing clinical study evaluating the combination of zanzalintinib, an oral tyrosine kinase inhibitor targeting multiple pathways involved in cancer progression, with atezolizumab, a PD-L1 inhibitor. The trial aims to explore the potential benefits of combining these two agents in the treatment of metastatic CRC, a challenging and often treatment-resistant form of cancer.
This specific cohort involved 107 patients with unresectable, locally advanced, or metastatic CRC. All participants had previously undergone treatment and were either RAS wild-type, non-microsatellite instability-high, or non-mismatch repair-deficient. Patients were randomized in a 1:1 ratio to receive either single-agent zanzalintinib or a combination of zanzalintinib and atezolizumab.
The study included patients who had received a median of 3.0 prior treatment lines in the zanzalintinib monotherapy group and 2.5 prior lines in the combination group. A substantial portion of the patients—32% of those on monotherapy and 31% on the combination—had no liver metastases at baseline. These factors allowed for a comprehensive analysis of the treatment’s impact across a broad spectrum of metastatic CRC cases.
Efficacy Results
The primary endpoint for the study was progression-free survival (PFS), and secondary endpoints included overall survival (OS) and overall response rate (ORR). The data showed promising results, with the combination of zanzalintinib and atezolizumab demonstrating numerically improved outcomes compared to zanzalintinib alone.
- PFS: The median PFS for patients receiving zanzalintinib alone was 3.0 months, while for those on the combination therapy, the median PFS was 4.0 months. The hazard ratio (HR) for PFS in favor of the combination was 0.65 (95% confidence interval [CI], 0.42-0.99), indicating a 35% reduction in the risk of disease progression in the combination group.
- OS: The median OS for patients on single-agent zanzalintinib was 11.1 months, while those receiving the combination treatment had a median OS of 11.7 months. The HR for OS was 0.89 (95% CI, 0.56-1.42), suggesting a modest benefit in survival with the addition of atezolizumab.
- Objective Response Rate (ORR): The ORR, which is defined as the percentage of patients achieving a partial or complete response to treatment, was low in both groups. However, the combination group had a higher ORR of 7.4% compared to just 1.9% for the zanzalintinib monotherapy group. Specifically, 4 patients in the combination arm achieved a partial response, whereas only 1 patient in the monotherapy group did.
A subgroup analysis focusing on patients who did not have liver metastases further supported the benefits of the combination therapy. In this group:
- PFS: The median PFS was significantly improved in the combination group (8.2 months) compared to the monotherapy group (3.3 months), with an HR of 0.37 (95% CI, 0.15-0.91), representing a 63% reduction in the risk of progression.
- OS: The median OS was comparable between the two groups (21.1 months for monotherapy versus 18.5 months for the combination), though there was a trend toward a longer survival in the monotherapy group.
- Survival Rates: The combination therapy group showed significantly improved 6-month and 12-month survival rates (87.8% and 62.7%, respectively) compared to the monotherapy group (64.7% and 52.3%, respectively). The combination group also demonstrated a higher ORR of 18.0% versus 5.9% in the monotherapy group.
Biomarker analysis from the study revealed that patients with a PD-L1 combined positive score (CPS) greater than 1 experienced improved PFS and OS when treated with zanzalintinib in combination with atezolizumab compared to those receiving zanzalintinib alone. This biomarker may help identify patients most likely to benefit from the combination treatment.
Safety Profile
As with any cancer therapy, safety is a critical consideration. The safety profile of zanzalintinib, both as a monotherapy and in combination with atezolizumab, was closely monitored during the trial.
- Grade 3/4 Treatment-Related Adverse Events (TRAEs): The incidence of grade 3/4 TRAEs was 40% for patients receiving zanzalintinib alone and 48% for those receiving the combination therapy. This difference suggests that the addition of atezolizumab may slightly increase the frequency of severe side effects.
- Discontinuations: Treatment-related adverse events (TRAEs) led to discontinuation in 19% of patients on single-agent zanzalintinib and 30% of those on the combination regimen. Discontinuations due to any drug-related AEs occurred in 8% of patients on zanzalintinib alone and 19% in the combination arm.
The most common grade 3/4 TRAEs across both treatment groups included:
- Nausea: 36% for monotherapy vs. 54% for combination therapy
- Diarrhea: 49% for monotherapy vs. 52% for combination therapy
- Fatigue: 21% for monotherapy vs. 43% for combination therapy
- Hypertension: 30% for monotherapy vs. 19% for combination therapy
Other less frequent but notable adverse events included proteinuria, palmar-plantar erythrodysesthesia, and stomatitis.
While the side effects observed were consistent with those typically associated with tyrosine kinase inhibitors and immune checkpoint inhibitors, they highlight the need for ongoing monitoring and management of treatment-related toxicities.
Future Directions
The results from the STELLAR-001 trial provide valuable insight into the potential of combining zanzalintinib with atezolizumab in metastatic colorectal cancer. Exelixis is encouraged by the findings, particularly the numerical improvements in PFS and OS in the combination group, and the enhanced efficacy seen in patients without liver metastases. These promising results have informed the design of further clinical studies.
The company is moving forward with the STELLAR-303 trial, which is evaluating the combination of zanzalintinib and atezolizumab against regorafenib, a standard treatment option for metastatic CRC. Enrollment for STELLAR-303 was completed in August 2024, and Exelixis anticipates data from this trial in the second half of 2025, depending on the study event rates.
Dr. Amy Peterson, Executive Vice President of Product Development & Medical Affairs and Chief Medical Exelixis Officer at Exelixis, emphasized the importance of these findings in guiding the company’s next steps. She stated, “Data from this randomized expansion cohort reaffirm our decision to initiate STELLAR-303 and evaluate the combination Exelixis of zanzalintinib and atezolizumab compared with regorafenib in patients with metastatic CRC Exelixis .”
About STELLAR-001
STELLAR-001 (NCT03845166) is a global, open-label phase 1b/2 study of zanzalintinib as a single agent or in combination with atezolizumab in patients with inoperable locally advanced or metastatic solid tumors. The trial is divided into two parts: a dose-escalation stage and an expansion cohort stage. The expansion cohorts evaluating zanzalintinib (100 mg) as a single agent or in combination with atezolizumab also include patients with clear cell renal cell carcinoma (RCC), non-clear cell RCC, breast cancer that is hormone receptor-positive and HER-2 negative and castration-resistant prostate cancer. More information about the trial is available at ClinicalTrials.gov.
About STELLAR-303
The global phase 3 pivotal study, STELLAR-303, is evaluating zanzalintinib (100 mg) in combination with atezolizumab compared with regorafenib in patients with metastatic, refractory non-microsatellite instability-high or non-mismatch repair-deficient CRC. The primary endpoint in the study is OS in patients without active liver metastases. If OS is positive in the population of patients without liver metastases, the study will evaluate OS in the intent-to-treat population that includes patients with and without liver metastases. The study completed enrollment in the third quarter of 2024, and preliminary results are expected in the second half of 2025, dependent on study event rates. More information about the trial is available at ClinicalTrials.gov.
About Zanzalintinib
Zanzalintinib is a third-generation oral tyrosine kinase inhibitor that inhibits the activity of receptor tyrosine kinases implicated in cancer growth and spread, including VEGF receptors, MET, AXL and MER. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and resistance to multiple therapies, including immune checkpoint inhibitors. With zanzalintinib, Exelixis sought to build upon its extensive experience with the target profile of cabozantinib, the company’s flagship medicine, while improving key characteristics, including pharmacokinetic half-life. Zanzalintinib is currently being developed for the treatment of advanced solid tumors, including genitourinary, colorectal and head and neck cancers. A phase 3 pivotal trial evaluating zanzalintinib compared with everolimus as a first oral therapy in patients with advanced neuroendocrine tumors (NET), regardless of site of origin, is expected to be initiated in the first half of 2025.
About CRC
Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths in the U.S.1 Approximately 154,000 new cases will be diagnosed in the U.S. with around 53,000 expected deaths from the disease in 2025.1 Colorectal cancer is most frequently diagnosed among people aged 65-74 and is more common in men and in people of non-Hispanic American Indian/Alaska Native descent.2 Nearly a quarter of colorectal cancer cases are diagnosed at the metastatic stage, at which point the five-year survival rate is just 15.7%.2
About Exelixis
Exelixis is a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care. Powered by drug discovery and development excellence, we are rapidly evolving our product portfolio to target an expanding range of tumor types and indications with our clinically differentiated pipeline of small molecules, antibody-drug conjugates and other biotherapeutics. This comprehensive approach harnesses decades of robust investment in our science and partnerships to advance our investigational programs and extend the impact of our flagship commercial product, CABOMETYX® (cabozantinib). Exelixis is driven by a bold scientific pursuit to create transformational treatments that give more patients hope for the future. For information about the company and its mission to help cancer patients recover stronger and live longer, visit www.exelixis.com, follow @ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and follow Exelixis on LinkedIn.
