Cracking the Code of MSS Colorectal Cancer: What's Next in Phase 3 Trials

The Majority Nobody Talks About

If you or someone you love has colorectal cancer, you may have heard stories about immunotherapy making tumors disappear. Those stories are real, but they describe a small group of patients. Most people have a tumor type called microsatellite stable (MSS), also known as proficient mismatch repair (pMMR), and for them immunotherapy alone has rarely worked.

MSS/pMMR tumors make up roughly 85% of all colorectal cancers and about 95% of cancers that have spread. The good news is that a wave of phase 3 trials, the large, late-stage studies that can lead to new approved treatments, is now testing drugs designed for exactly this group.

Decoding the Letters

Every time a cell divides, a team of "spell-check" proteins called the mismatch repair (MMR) system fixes copying errors in its DNA. When that system works, the tumor is pMMR (proficient mismatch repair), and its short repeating stretches of DNA, called microsatellites, stay steady, making it MSS (microsatellite stable). When the system is broken, the tumor is dMMR (deficient mismatch repair) or MSI-H (microsatellite instability – high). It piles up thousands of mutations and looks so "foreign" to the immune system that immunotherapy drugs work very well.

Your status comes from biomarker testing of your tumor, which international guidelines recommend for everyone diagnosed with colorectal cancer. If you do not know yours, ask your care team.

Many clinical trials are looking for people who have not yet received treatment. This could include people who are newly diagnosed and have never been treated, or people who have never received treatment for metastatic disease. This is why biomarker testing and getting your results before starting treatment are so important. Knowing your biomarker status early can help you and your care team identify treatment options and clinical trials that may be right for you.

Why MSS Tumors Are Hard to Reach

MSS tumors are often called immunologically "cold." With fewer mutations, they raise fewer red flags, and many surround themselves with signals that keep immune cells out or switched off. Releasing the immune system's brakes is not enough on its own; the tumor first has to be turned "hot." Cancer that has spread to the liver is especially hard to reach, which is why many trials now report results separately for people with and without liver metastases.

Today, most people with metastatic MSS disease start with chemotherapy plus a targeted antibody such as bevacizumab, cetuximab or panitumumab. Later options such as trifluridine/tipiracil, regorafenib and fruquintinib can extend life, but often by months. That is the gap the new trials aim to close.

Inside the Phase 3 Pipeline

Starting stronger

Several first-line trials are testing bispecific antibodies, single molecules that block an immune checkpoint and a tumor defense at the same time, alongside standard chemotherapy. HARMONi-GI3 pairs ivonescimab (PD-1 and VEGF) with mFOLFOX6 (NCT07228832), and Symbiotic-GI-03 pairs PF-08634404 (PD-1 and VEGF) with mFOLFOX6 (NCT07222800). Both compare against bevacizumab with chemotherapy. INCA033890-303 adds INCA33890 (PD-1 and TGF-beta) to FOLFOX and bevacizumab (NCT07284849), and the phase 2/3 ROSETTA CRC-203 tests pumitamig (PD-L1 and VEGF-A) with chemotherapy (NCT07221357).

These trials only enroll people who have not yet been treated for metastatic disease, so the conversation about joining has to happen before chemotherapy begins.

When standard options run out

STELLAR-303 has the most advanced result. In 901 people with previously treated, non-MSI-H disease, zanzalintinib plus the immunotherapy atezolizumab extended median survival to 10.9 months, compared with 9.4 months on regorafenib, though serious side effects were more common. The U.S. Food and Drug Administration expects to decide on the combination by March 3, 2027.

BATTMAN is testing two immunotherapies, botensilimab and balstilimab, against best supportive care in about 830 people whose MSS cancer no longer responds to chemotherapy (NCT07152821). In an earlier study, some responses were long lasting, mainly in people without active liver metastases.

PROCEADE-CRC-03 is testing precemtabart tocentecan, an antibody-drug conjugate that carries chemotherapy straight to cancer cells displaying a protein called CEACAM5. It is compared with trifluridine/tipiracil plus bevacizumab after one or two prior treatment regimens (NCT07549412).

Other phase 3 trials select patients by a specific gene change rather than MSS status, such as KANDLELIT-012 for KRAS G12C, MOUNTAINEER-03 for HER2 and OrigAMI-2 and OrigAMI-3 for RAS/BRAF wild-type disease. Most people who qualify will still have MSS tumors, which is one more reason full biomarker testing matters.

Turning Hope Into Action

No trial guarantees an answer, but MSS colorectal cancer is now at the center of a global research effort rather than an afterthought. A few questions worth bringing to your care team:

• What are my biomarkers? Ask for your MMR/MSI status along with your RAS, BRAF and HER2 results.

• Is there a trial I should consider now? Many first-line trials close to you once treatment starts.  

• Does my liver matter? If your cancer has spread to the liver, ask how that shapes your options.

• Where else can I look? Search ClinicalTrials.gov or the WHO trial registry and bring what you find to your oncologist.

MSS colorectal cancer is now one of the most active areas of cancer research, and that momentum is reason for hope.

Disclaimer: This article is provided for educational and informational purposes only and is not intended as medical advice. It should not be used to diagnose or treat any condition or to replace a consultation with a qualified healthcare professional. Treatments described here may be investigational and not approved in your country, and clinical trial details, including eligibility and recruitment status, can change. Inclusion of a trial or treatment does not imply endorsement by the Global Colon Cancer Association. Always talk with your doctor or healthcare team about your diagnosis, treatment options and whether a clinical trial may be right for you.

Sources:

• Li K, et al. Molecular genetics of microsatellite-unstable colorectal cancer for pathologists. Diagnostic Pathology. 2017.

• Gandini A, et al. The role of immunotherapy in microsatellites stable metastatic colorectal cancer. Frontiers in Oncology. 2023.

• Hecht JR, et al. Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303). The Lancet. 2025;406:2360-2370. PMID 41130252.

• Bullock AJ, et al. Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nature Medicine. 2024;30:2558-2567. PMID 38871975.

• Kopetz S, et al. Precemtabart tocentecan, an anti-CEACAM5 antibody-drug conjugate, in metastatic colorectal cancer: a phase 1 trial. Nature Medicine. 2025; 31:3504-3513. PMID 40739424.

• ClinicalTrials.gov records: NCT07228832 (HARMONi-GI3), NCT07222800 (Symbiotic-GI-03), NCT07284849 (INCA033890-303), NCT07221357 (ROSETTA CRC-203), NCT07549412 (PROCEADE-CRC-03), NCT05425940 (STELLAR-303), NCT07152821 (BATTMAN), NCT06997497 (KANDLELIT-012), NCT05253651 (MOUNTAINEER-03), NCT06662786 (OrigAMI-2), NCT06750094 (OrigAMI-3)

• OncLive, FDA Extends Review Period for Zanzalintinib Plus Atezolizumab NDA. 2026.

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