New treatments for stage 4 colon cancer are being studied for patients whose disease has stopped responding to standard chemotherapy. One emerging approach combines targeted treatment with immunotherapy.
Who this is for
You have stage 4 colon cancer. You have already received oxaliplatin-based chemotherapy, irinotecan-based chemotherapy and perhaps even regorafenib. Your latest scan shows the cancer is growing. What can you do next?
Clinical observation
Recently, I reviewed a 51-year-old gentleman from Sri Lanka who sought an international second opinion.
His situation was unfortunately familiar.
He had already received oxaliplatin-based chemotherapy.
He had already received irinotecan-based chemotherapy.
His cancer had continued to grow.
He was then prescribed regorafenib.
Unfortunately, after only a short period of treatment he developed severe hand-foot syndrome. His hands became painful and sensitive. Walking became difficult. The treatment had to be stopped.
When we reviewed his latest scans together, there was no ambiguity.
The cancer was progressing.
He looked worried.
His wife looked worried.
His question was one that I hear frequently:
“Dr De Silva, have I run out of options?”
What surprised me
The most interesting aspect of the STELLAR-303 study was not simply the difference in median survival.
The combination extended median survival from 9.4 months to 10.9 months.
At first glance, that may appear modest.
However, the survival curves continued to favour the combination over time. At two years, approximately 20% of patients receiving the combination were alive, compared with approximately 10% receiving regorafenib.
That caught my attention.
However, we must interpret this carefully.
Only a small proportion of patients experienced measurable tumour shrinkage, and we do not yet know how to identify those most likely to achieve longer-term benefit.
Longer follow-up and further research are still needed.
An important limitation
The gentleman I reviewed had already received regorafenib.
This is important because patients who had previously received regorafenib were not included in STELLAR-303.
Therefore, the study does not directly tell us whether zanzalintinib and atezolizumab would benefit someone who has already received regorafenib.
For a patient in this situation, the next step would require an individual review of previous treatments, molecular results, general health and available clinical trials.
Why this study matters
For many years, immunotherapy has transformed outcomes for patients with MSI-high or dMMR colorectal cancer, including some patients with Lynch syndrome.
Some patients experience long-lasting responses that would have been difficult to imagine a decade ago.
However, most metastatic colorectal cancers are microsatellite stable, or MSS. For these patients, immunotherapy alone has generally provided little benefit.
The STELLAR-303 study asked an important question:
Could combining immunotherapy with a targeted medicine help some patients with MSS colorectal cancer?
Understanding the background
Cancer cells often hide from the immune system.
MSI-high cancers are easier for the immune system to recognise.
MSS cancers are much harder.
Researchers hypothesised that combining immunotherapy with a targeted drug might change the tumour environment and make cancer cells more visible to immune attack.
The combination tested was:
- Zanzalintinib (XL092)
- Atezolizumab
compared with:
- Regorafenib
which remains a standard later-line treatment.
Study methodology
Study
STELLAR-303
Type
International Phase III randomised study
Number of patients
The study included 901 patients.
Population
Previously treated metastatic colorectal cancer that was not MSI-high or dMMR.
Treatment arms
Experimental group
- Zanzalintinib plus atezolizumab
Control group
- Regorafenib
Primary endpoint
Overall survival
What did the study find?
Overall survival
- Zanzalintinib plus atezolizumab: 10.9 months
- Regorafenib: 9.4 months
- Hazard ratio: 0.80
This represented a 20% relative reduction in the risk of death during the study period.
It does not mean that every patient lived 20% longer.
Progression-free survival
The median time before the cancer grew was:
- 3.7 months with zanzalintinib and atezolizumab
- 2.0 months with regorafenib
The results favoured the combination, although the study’s statistical testing plan did not allow the researchers to make a definitive claim of statistical significance for this outcome.
Side effects
The combination also caused significant side effects.
Grade 3 or worse treatment-related side effects occurred in approximately:
- 60% of patients receiving zanzalintinib and atezolizumab
- 37% of patients receiving regorafenib
These are more severe side effects that may require medical treatment, dose changes or temporary interruption of therapy.
The possible benefit must therefore be balanced carefully against the risk of toxicity.
What about patients without liver metastases?
Early results suggested that patients without active liver metastases might receive greater benefit.
However, the final analysis did not confirm this with statistical certainty.
Median survival was:
- 15.9 months with zanzalintinib and atezolizumab
- 12.7 months with regorafenib
Although the numbers favoured the combination, the difference could have occurred by chance.
We therefore cannot currently say that the treatment works better specifically in patients without liver metastases.
The tail of the curve
Another encouraging finding was that the survival curves remained separated over time.
At two years, approximately:
- 20% of patients receiving the combination were alive
- 10% of patients receiving regorafenib were alive
This raises the possibility that some patients may experience longer-term benefit.
However, only a small number of patients had measurable tumour shrinkage, and the study has not yet identified a clear group of “exceptional responders.”
Longer follow-up and further research are needed.
What do these results mean today?
STELLAR-303 was the first phase III trial to show a statistically significant overall survival benefit from an immunotherapy-based combination in previously treated metastatic colorectal cancer that was not MSI-high or dMMR.
This represents genuine progress.
However, zanzalintinib remains an investigational medicine and is not yet a routine standard treatment.
The study also excluded patients who had previously received regorafenib. Therefore, its results may not directly apply to someone who has already taken and stopped regorafenib.
Patients in this situation should discuss approved later-line treatments, molecularly targeted options and suitable clinical trials with their oncologist.
Key takeaways
- STELLAR-303 showed that zanzalintinib combined with atezolizumab modestly improved overall survival compared with regorafenib in previously treated non-MSI-high or non-dMMR metastatic colorectal cancer.
- The treatment also caused more serious side effects, and the trial did not prove that patients without liver metastases receive greater benefit.
- Zanzalintinib remains investigational. The study also excluded patients who had previously received regorafenib, so the results may not directly apply to every heavily treated patient.
References
- Hecht JR, Park YS, Tabernero J, et al; STELLAR-303 Study Investigators. Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): a randomised, open-label, phase 3 trial. Lancet. 2025;406(10517):2360-2370. doi:10.1016/S0140-6736(25)02025-2
- Bray A, Chang GJ, Ciombor KK, et al. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2026. National Comprehensive Cancer Network; 2026. Accessed July 27, 2026. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428
- André T, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy in microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer: 5-year follow-up from the randomized phase III KEYNOTE-177 study. Ann Oncol. 2025;36(3):277-284. doi:10.1016/j.annonc.2024.11.012
- Prager GW, Taieb J, Fakih M, et al. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388(18):1657-1667. doi:10.1056/NEJMoa2214963
- Dasari A, Lonardi S, Garcia-Carbonero R, et al; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41-53. doi:10.1016/S0140-6736(23)00772-9
- Exelixis. Exelixis provides update on the phase 3 STELLAR-303 trial evaluating zanzalintinib in combination with an immune checkpoint inhibitor in patients with metastatic colorectal cancer. Published June 22, 2026. Accessed July 27, 2026. https://ir.exelixis.com/news-releases/news-release-details/exelixis-provides-update-phase-3-stellar-303-trial-evaluating
Frequently asked questions (FAQs)
- My cancer has progressed after all standard chemotherapy. Are there still options?
Possibly. Depending on previous treatments, tumour biology, general health and local availability, options may include:
- Trifluridine/tipiracil, often combined with bevacizumab
- Fruquintinib
- Regorafenib
- Treatment directed at a specific molecular alteration
- Clinical trials
Not every option will be suitable or available for every patient.
- Does immunotherapy only work in Lynch syndrome?
No. MSI-high or dMMR cancer can occur in people with Lynch syndrome, but it can also occur without an inherited condition.
Standard immunotherapy works best in MSI-high or dMMR metastatic colorectal cancer. For MSS disease, immunotherapy is not usually used alone. New combinations such as the one studied in STELLAR-303 are being investigated.
- What is microsatellite instability?
It is a genetic weakness in a tumour’s DNA repair system that makes the cancer much more visible to the immune system.
- Should I ask about molecular testing?
Absolutely. Molecular testing remains one of the most important investigations in modern colon cancer care.
Dr Dilanka De Silva
MBBS, MRCP(UK), MRCP(UK SCE Oncology), FRACP, PhD
Medical Oncologist & Cancer Genetics Physician
Memorial Sloan Kettering Cancer Center Fellow (New York, USA)