Zanzalintinib-Tecentriq Combo Demonstrates Overall Survival Benefit Over Stivarga in Phase 3 Colorectal Cancer Trial

A combination therapy featuring Exelixis’ investigational drug zanzalintinib has demonstrated a statistically significant improvement in overall survival compared to Bayer’s Stivarga in a global Phase 3 clinical trial involving patients with previously treated metastatic colorectal cancer. The study, known as STELLAR-303, included more than 900 participants and evaluated zanzalintinib administered alongside Roche’s PD-L1 inhibitor Tecentriq.

The trial focused on patients with non-microsatellite instability-high (non-MSI-H) metastatic colorectal cancer. According to Exelixis, the regimen led to a longer overall survival compared to patients treated with Stivarga alone. The improvement was observed in the trial’s intention-to-treat (ITT) population, which included all randomized participants regardless of the presence of liver metastases.
Exelixis is developing zanzalintinib as a follow-up to its current oncology drug, cabozantinib, marketed as Cabometyx and Cometriq, depending on the cancer type. The company designed zanzalintinib to address limitations associated with cabozantinib, including improving its pharmacokinetic profile. The company aims to expand the investigational drug’s use across multiple tumor types, with gastrointestinal cancers being a central component of that strategy.
The colorectal cancer indication in STELLAR-303 is a key element in Exelixis’ broader commercial outlook. Gastrointestinal cancers currently make up 10% of Cabometyx’s revenue but are projected to contribute 45% of the $5 billion in annual sales that Exelixis anticipates for zanzalintinib by 2033. Zanzalintinib’s performance in STELLAR-303 is viewed by analysts as a step toward achieving this target.
“This is the first pivotal success from the zanzalintinib program,” William Blair analysts stated in a note published on Monday. They also identified the ITT population in the study as representing “the largest commercial opportunity” for the drug, estimating U.S. peak sales at $875 million on a risk-adjusted basis.
While specific numerical data from the trial were not disclosed, Exelixis confirmed that no new safety concerns were identified. Analysts at Leerink Partners noted the strategic implications of the results, writing, “We think the topline success of this trial likely provides additional fundamental and strategic value to shares, suggesting [zanzalintinib] may be able to extend the company’s revenue stream beyond the [cabozantinib] loss of exclusivity in 2030.”

Zanzalintinib is an oral tyrosine kinase inhibitor that targets several cancer-related signaling pathways. The STELLAR-303 readout, announced Sunday, coincided with a roughly 12% increase in Exelixis’ stock price, reaching approximately $45 per share.
In addition to colorectal cancer, Exelixis is evaluating zanzalintinib in other cancer types. A Phase 3 trial in renal cell carcinoma is expected to deliver topline data later this year. A go/no-go decision for zanzalintinib as a potential first-line therapy for head and neck cancer is also scheduled for the second half of the year.
The colorectal cancer space includes treatments from multiple drugmakers, such as Amgen, Taiho Oncology, and Takeda. Zanzalintinib, in combination with Tecentriq, will potentially compete with therapies like Lumakras, Lonsurf, and Fruzaqla.