Exelixis' Zanzalintinib Shows Promise in Late-Stage Colorectal Cancer Trial

Exelixis, a prominent player in the pharmaceutical industry, has unveiled promising results from its Phase III STELLAR-303 study, positioning its oral kinase inhibitor zanzalintinib as a potential new treatment option for patients with metastatic colorectal cancer (mCRC). The data, presented at the 2025 European Society for Medical Oncology (ESMO) meeting and simultaneously published in The Lancet, demonstrate significant improvements in overall survival rates, paving the way for a potential regulatory submission by year-end.

Survival Benefit in Third-Line Treatment

The STELLAR-303 trial, which enrolled over 900 patients with mCRC who had undergone prior lines of treatment, showed that zanzalintinib, when combined with Roche's Tecentriq, resulted in a median overall survival (OS) of 10.9 months. This compares favorably to the control group treated with Bayer's Stivarga, which achieved a median OS of 9.4 months. The 12- and 24-month OS estimates were also notably higher in the zanzalintinib group at 46% and 20%, respectively, versus 38% and 10% in the Stivarga arm.

William Blair analysts have described these results as setting a "new survival bar" in the third-line or later mCRC setting, surpassing the current record held by Taiho Oncology's Lonsurf chemotherapy and Roche's Avastin combination, which yielded an OS of 10.8 months.

Safety Profile and Market Potential

While the efficacy data is encouraging, the safety profile of zanzalintinib warrants careful consideration. The study reported that 59% of patients in the zanzalintinib arm developed grade 3/4 treatment-related toxicities, compared to 37% in the control group. Additionally, 18% of patients receiving zanzalintinib discontinued treatment due to side effects, and two deaths were deemed related to the drug.

Despite these safety concerns, market analysts remain optimistic about zanzalintinib's potential. William Blair projects U.S. sales for mCRC to reach $24 million next year, with a peak estimate of $850 million. The firm had previously modeled $4.5 billion in U.S. sales for zanzalintinib across all indications by 2033, viewing the STELLAR-303 results as "the first step toward achieving this goal."

Regulatory Outlook and Future Directions

With these positive results in hand, Exelixis is planning to submit a regulatory application for zanzalintinib by the end of 2025. The STELLAR-303 trial marks the first pivotal success from the zanzalintinib program, potentially opening doors for its use in other indications.

However, some questions remain regarding the optimal treatment regimen. Analysts at William Blair have questioned "the risk/benefit calculus" of adding Tecentriq to zanzalintinib, noting its "potential to increase side effects and out-of-pocket costs for patients." This suggests that further studies may be needed to refine the treatment approach and maximize patient benefit while minimizing risks.

As the pharmaceutical industry continues to evolve, the development of zanzalintinib represents a significant step forward in the treatment of metastatic colorectal cancer, offering new hope for patients with limited options in later-line settings.