A New Combination Provides Hope For Advanced Colorectal Cancer
- Promising trial results show that a new treatment combination can extend survival for patients with metastatic colorectal cancer after chemotherapy stops working.
- The STELLAR-303 trial illustrated that targeted therapy zanzalintinib plus immunotherapy drug atezolizumab reduced the risk of death or disease progression by 30% compared to regorafenib, one of the current standards.
- “Immunotherapy in combination with targeted therapy — I would say that increases the hope for … survival with quality of life,” Dr. Maen Abdelrahim, a gastrointestinal medical oncologist at Houston Methodist, tells SurvivorNet.
- The new combination approach is not yet approved by the Food and Drug Administration and there isn’t clear data currently on whether it is a better option than drugs already approved in this space, but Dr. Abdelrahim notes that more treatment options is a good thing. It means more potential for managing disease.
The STELLAR-303 trial, published in The Lancet in late 2025, tested a two-drug combination, targeted therapy zanzalintinib plus immunotherapy drug atezolizumab, against regorafenib, one of the current standard treatments for metastatic colorectal cancer after chemotherapy fails.
Read MoreThe STELLAR-303 Trial: Breaking Down The Data
The trial enrolled nearly 900 patients across 16 countries. All had metastatic colorectal cancer, that means stage 4 disease, and all had already been through standard chemotherapy.They were randomly split: half received zanzalintinib plus atezolizumab, half received regorafenib.
The trial results were promising:
- Patients on the zanzalintinib plus atezolizumab combination lived a median of 10.9 months v. 9.4 months on regorafenib. That’s a 20% reduction in the risk of death.
- At two years, 20% of patients on the combination were still alive, versus 10% on regorafenib.
In a disease this advanced, doubling the two-year survival rate really matters.
“The trial was positive for the secondary objective which is progression-free survival,” Dr. Abdelrahim adds. “The median PFS for rego was 2 months and for zanzalintinib plus atezo 3.8 months, with 30% reduction of death and disease progression.”
What makes the results unusual to oncologists is that atezolizumab is an immunotherapy drug. Immunotherapy typically does not work in most colorectal cancer patients.
About 95% of people with metastatic colorectal cancer have what’s called microsatellite stable (or MSS) tumors. In these patients, the tumor is essentially invisible to the immune system as it has found ways to hide. Immunotherapy drugs work by waking the immune system up, but if the tumor is hiding too well, there’s nothing to wake up. Multiple trials have tried immunotherapy in MSS colorectal cancer patients and most have failed.
STELLAR-303 only enrolled MSS patients, and it worked.
What Makes Zanzalintinib Different?
The reason may come down to zanzalintinib’s unusual profile. It’s not just cutting off blood supply to the tumor, the way most drugs in its class do. It also blocks certain receptors that tumors use to suppress the immune response around them.
“Zanzalintinib can modulate the microenvironment or the immuno-microenvironment of the tumor,” Dr. Abdelrahim explains. “Not only is it targeting VEGF and decreasing angiogenesis, but it also changes the microenvironment and makes it more susceptible … priming the immuno-microenvironment to immunotherapy.”
For the 95% of metastatic colorectal cancer patients who have never been candidates for immunotherapy, that’s a meaningful shift.
“Patients always ask us: am I eligible for immunotherapy?” Dr. Abdelrahim adds. “Immunotherapy is not always available or eligible for all patients who didn’t have the criteria. But now, for 95% of the patients who have microsatellite stable disease, giving immunotherapy in combination with targeted therapy. This opens a new door.”
An Alternative To Chemo
Zanzalintinib is a pill and atezolizumab is an infusion every three weeks. Neither is chemotherapy.
For patients who have spent months on chemotherapy combinations like FOLFOX or FOLFIRI, trying a different kind of treatment that lets them avoid side effects typically associated with chemo can be a very welcome change.
“Immunotherapy in combination with targeted therapy — I would say that increases the hope for increasing survival with quality of life,” Dr. Abdelrahim says.
The combination does have side effects, such as:
- High blood pressure
- Fatigue
- Diarrhea
- Protein in the urine
Sixty percent of patients experienced a serious side effect, compared to 37% on regorafenib, and there were five treatment-related deaths in the combination group versus one with regorafenib.
But one side effect that was dramatically less common was hand-foot syndrome, a painful skin reaction that affects half of all patients on regorafenib. The condition occurred in only 16% of patients on the new combination.
Who Should Get The New Combination?
After chemotherapy stops working, doctors already have several options: regorafenib, trifluridine-tipiracil (sometimes combined with bevacizumab), fruquintinib, and, for patients with specific genetic alterations, targeted therapies. Now zanzalintinib plus atezolizumab has been added to that list.
The problem is that no one has run a head-to-head trial comparing all of these. Doctors are choosing based on trial data, patient factors, and clinical judgment, not a defined roadmap.
“A sequence of treatment is not well studied yet because there’s no head-to-head comparison between all these options,” Dr. Abdelrahim says. The important thing for patients to take away is that more options means more potential for managing disease.
“In some patients you can choose between chemo-based in the third line and beyond, or maybe a TKI and chemotherapy-free regimen. So it’s going to be case by case, based on molecular profiling [and] on the patient performance status,” he adds.
In practice, that means a patient’s molecular profile (what specific mutations their tumor carries) will drive a lot of these decisions. So will how well they’re feeling, and how much more chemotherapy their body can handle.
Zanzalintinib plus atezolizumab being chemo-free gives it an edge for patients who are exhausted by cytotoxic treatment, or who simply can’t tolerate more of it.
Zanzalintinib + Atezolizumab Awaits Approval
The combination is not FDA-approved. The trial data is published, the regulatory process is in motion, and doctors are watching closely. But patients cannot receive this outside of a clinical trial right now.
When approval comes, it will be for patients who have already received the three core chemotherapy drugs used in colorectal cancer (fluorouracil, oxaliplatin, and irinotecan) and whose cancer kept growing anyway.
Down the road, there’s an open question about whether this combination could move earlier to patients who can’t tolerate chemotherapy at all, for instance, or as a first option for certain groups. Dr. Abdelrahim was careful not to overstate where things stand.
“Is it the guideline? Not yet,” he says. “But in the future, clinical trials could be conducted to prove its efficacy in the earlier line of treatment.”
The five-year survival rate for stage 4 colorectal cancer is about 15% — so developments are welcome and needed, and progress is being made.
“After chemotherapy, the third line and fourth line, the overall survival is actually like decimal. So adding treatment options, adding another line for treatment that is chemotherapy-free and has survival benefit — this is an area of unmet need,” Dr. Abdelrahim adds.
The sequencing debate is ongoing, but it’s a better debate to be having than the one from a decade ago, when there was almost nothing left to sequence.
Questions To Ask Your Doctor
- Am I a candidate for the new zanzalintinib plus atezolizumab combination?
- Should I consider enrolling in a clinical trial?
- What are the risks of trying a newer treatment compared to the standard?
- What if I continue to progress on the new combination?
Learn more about SurvivorNet's rigorous medical review process.
