A combination of two drugs called zanzalintinib and atezolizumab improved overall survival in patients with advanced colorectal cancer that had already been treated, according to results from a large clinical trial. However, the treatment did not show the same benefit for patients without liver metastases, a finding that highlights how cancer responses can vary dramatically depending on where the disease has spread.

What Did the Clinical Trial Show?

The STELLAR-303 trial enrolled 901 patients with metastatic colorectal cancer, meaning the cancer had spread beyond the colon. Researchers randomly assigned them to receive either the zanzalintinib and atezolizumab combination or a standard drug called regorafenib. The study had two main goals: to measure survival in all patients enrolled and to measure survival specifically in patients without active liver metastases.

In the overall patient population, the combination therapy delivered meaningful results. Patients receiving zanzalintinib plus atezolizumab lived a median of 10.9 months compared with 9.4 months for those on regorafenib, representing a statistically significant survival advantage. This benefit held up across multiple patient subgroups, including those with different genetic profiles and those who had received prior anti-cancer treatments.

However, when researchers looked specifically at patients without liver metastases, the picture changed. The combination therapy showed a median survival of 15.9 months versus 12.7 months with regorafenib, but this difference was not statistically significant. In practical terms, this means the difference could have occurred by chance rather than from the drug's actual effect.

How Do These Drugs Work Against Colorectal Cancer?

Zanzalintinib is an oral medication that works by blocking multiple pathways involved in tumor growth and spread. Specifically, it targets proteins called TAM kinases, MET, and VEGF receptors. These pathways are involved in several processes that help cancer cells survive and resist treatment, including tumor cell growth, metastasis (spread to other organs), the formation of new blood vessels that feed tumors, drug resistance, and evasion of the immune system.

Atezolizumab, also known by the brand name Tecentriq, is an immunotherapy drug that works differently. It helps the body's own immune system recognize and attack cancer cells by blocking a protein that tumors use to hide from immune surveillance.

What Side Effects Should Patients Expect?

The combination therapy was more likely to cause serious side effects compared with the standard treatment. Grade 3 and 4 adverse events, meaning severe or life-threatening complications, occurred in 59% of patients receiving the combination versus 37% receiving regorafenib alone.

The most common serious side effects included:

• High Blood Pressure: Occurred in 15% of patients on the combination therapy versus 9% on regorafenib
• Fatigue: Affected 6% of combination therapy patients compared with 2% on regorafenib
• Diarrhea: Occurred in 6% of patients on the combination versus 2% on the standard drug
• Proteinuria: A condition involving protein in the urine, seen in 6% of combination therapy patients versus 2% on regorafenib

Treatment had to be stopped in 18% of patients receiving the combination therapy due to side effects, compared with 15% of those on regorafenib. Additionally, four deaths were deemed by investigators to be related to the study drugs: two linked to zanzalintinib, one to the combination regimen, and one to regorafenib.

What's Next for This Treatment?

The U.S. Food and Drug Administration (FDA) has accepted the new drug application for zanzalintinib in combination with atezolizumab for patients with previously treated metastatic colorectal cancer. The FDA assigned a target decision date of December 3, 2026, meaning a regulatory decision is expected by that date.

Beyond colorectal cancer, zanzalintinib is being evaluated in ongoing clinical trials for other cancer types, including kidney cancer, neuroendocrine tumors, and castration-resistant prostate cancer. Earlier-stage investigations are also underway in meningioma and lung cancer.

How Should Patients Interpret These Mixed Results?

The trial results underscore an important principle in modern cancer treatment: not all patients respond the same way to the same drug. The combination therapy clearly helped the overall population of patients with advanced colorectal cancer, but the lack of benefit in the liver metastases subgroup suggests that the location and extent of cancer spread may influence how well this treatment works.

For patients considering this treatment, conversations with their oncologist should focus on individual factors such as where their cancer has spread, their overall health status, their ability to tolerate side effects, and whether they might be candidates for other available treatments. The detailed findings from the subgroup analysis are expected to be presented at an upcoming medical conference, which may provide additional insights into which patients are most likely to benefit.