Evolving care in colon cancer

Colorectal cancer remains the third most common cancer in the United States, with approximately 158,850 new diagnoses and 55,000 deaths estimated in 2026. Although the numbers are high, over the past 18 months, practice-changing advances across targeted therapy, immunotherapy, emerging agents and molecular biomarkers have expanded options for patients with metastatic and early-stage disease. 

This summary highlights the most important updates to help patients understand today’s treatment options and support informed conversations with their health care provider.

New treatments for BRAF V600E-mutated metastatic cancer

About 8%-12% of people with metastatic colon cancer have a change in a gene called BRAF V600E. This type of cancer has historically been associated with poor prognosis.

The phase 3 BREAKWATER trial established a new first-line regimen, showing that the combination of encorafenib, cetuximab and chemotherapy can shrink tumors more often and delay tumor growth. Another part of the trial found similar benefits with a different chemotherapy backbone, giving doctors flexibility to tailor treatment based on individual needs.

Immunotherapy for MSI-H or dMMR colon cancer

Approximately 5% of patients with metastatic colon cancer have tumors that are MSI-H (microsatellite instability-high) or dMMR (deficient mismatch repair). Frontline immunotherapy has transformed the management of these tumors, which often respond very well to immunotherapy, helping the immune system recognize and attack cancer cells.

Three strategies now carry FDA approval:

• Pembrolizumab, established by KEYNOTE-177, remains a strong first‑line treatment for MSI‑H/dMMR metastatic disease.
• The combination of nivolumab and ipilimumab showed even stronger outcomes for many patients in the phase 3 CheckMate 8HW trial.
• The phase 3 COMMIT trial further demonstrated that mFOLFOX6, bevacizumab and atezolizumab significantly improved progression-free survival over atezolizumab monotherapy in untreated dMMR/MSI-H metastatic colon cancer.

In the adjuvant setting, the phase 3 ATOMIC trial enrolled 712 patients with resected stage III dMMR colon cancer. It demonstrated that adding atezolizumab to mFOLFOX6 improved three-year survival (86.4% vs. 76.6%), with benefits seen across all groups, including those over 70 and with both low- and high-risk disease.

Emerging therapeutics for MSS colon cancer

Most people with colon cancer — about 85% to 90% — have microsatellite‑stable (MSS) tumors. These cancers typically do not respond well to immunotherapy, but new options are emerging.

Pelareorep
Pelareorep is an intravenously delivered therapy that uses a modified virus to help the immune system attack cancer cells. Early studies in patients with KRAS-mutant MSS metastatic cancer — a population representing the largest unmet need in colorectal oncology — showed better outcomes and longer survival than expected. Larger trials are in progress.

Zanzalintinib plus atezolizumab
A newer treatment approach combines zanzalintinib, a targeted therapy, with atezolizumab, an immunotherapy drug. The STELLAR‑303 trial found that this combination helped patients live longer than the current standard drug, regorafenib. This is the first immunotherapy‑based regimen to show a survival benefit in MSS metastatic colon cancer.

Circulating tumor DNA (ctDNA) testing
A newer blood test called circulating tumor DNA (ctDNA) can detect very small amounts of cancer DNA after surgery. Multiple studies have shown the test emerging as a powerful way to predict whether cancer might return.

• Patients who test positive for ctDNA after surgery face a higher risk of recurrence.
• These patients more often benefit from chemotherapy.
• Patients with negative ctDNA results may not need as much treatment.

At present, ctDNA is a powerful prognostic tool to guide adjuvant therapy decisions in MRD (minimal residual disease)-positive patients, but doctors are still learning how to use this information. Ongoing clinical trials aim to clarify when treatment should be adjusted based on ctDNA results.

Clinical takeaways

Colon cancer treatment is evolving rapidly, and many therapies can now be tailored to each person’s tumor. Talk to your health care provider about what is right for you.

• Comprehensive molecular profiling at diagnosis is no longer optional; it represents the cornerstone of contemporary colorectal cancer care.
• Reflex testing for KRAS/NRAS/BRAF, MSI/MMR status, HER2, and KRAS G12C should be standard for all patients with metastatic disease. Targeted therapy has improved outcomes for some patients, and immunotherapy has helped those with MSI-H or dMMR disease. New treatments may also offer hope for the still-challenging MSS population.
• In the adjuvant setting, ATOMIC establishes chemoimmunotherapy as the new standard for stage III dMMR colon cancer and ctDNA is rapidly maturing as a biomarker to guide treatment intensity.

As the therapeutic landscape continues to evolve, early integration of comprehensive genomic profiling and sustained expansion of clinical trial efforts, particularly in MSS disease, will be central to improving outcomes and advancing precision oncology in colorectal cancer.

Thanks to these advances, many people with colon cancer — across all stages — now have more treatment options and more hope.

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