Introduction: Testing All Patients Is the Foundation

Before discussing any of the specific advances from ASCO 2026, the single most important principle in colorectal cancer is straightforward: test all patients for microsatellite instability (MSI). The distinction between MSI-high (mismatch repair deficient, dMMR) and MSS (mismatch repair proficient, pMMR) disease governs every treatment decision, from immunotherapy eligibility to Lynch syndrome screening to BRAF-targeted therapy selection. NCCN guidelines position this as the first decision point. There is no optional approach to molecular testing in colorectal cancer in 2026; it should happen for every patient, at every stage, at or before the time treatment begins.

MSI-High Disease: When Is It Safe to Stop Immunotherapy?

The landmark studies (NICHE-2, MSKCC dostarlimab, and CheckMate-8HW) have established that MSI-high colorectal cancer has remarkable sensitivity to immune checkpoint inhibition, with complete response rates and survival outcomes that were unimaginable a decade ago.

The question ASCO 2026 began to address is equally important: once a clinical complete response is achieved, when is it safe to stop immunotherapy?

A retrospective cohort analysis from Asia examined this question by comparing patients who stopped PD-1 inhibitor therapy after achieving a clinical complete response (observation group) versus patients who received at least two additional doses beyond their clinical complete response (maintenance group). Median time to clinical complete response was six months, consistent with data from MSK and other institutions for predominantly localized disease.

The headline finding: there was no clinically meaningful difference in disease-free survival between the two groups. Stopping immunotherapy after a confirmed clinical complete response did not appear to increase the risk of recurrence compared to continuing it. Patients who were observed had essentially equivalent disease-free survival curves, with less than one percent differences in most landmark analyses.

Important caveats: this was a real-world retrospective analysis, not a prospective trial. The vast majority of patients had localized (not metastatic) disease, which limits the applicability to the metastatic setting where most practitioners face this question. Most patients received PD-1 inhibitor monotherapy, whereas current practice in metastatic disease increasingly favors PD-1 plus CTLA-4 doublet combinations. The definition of a clinical complete response was heterogeneous; endoscopy was used for all patients with localized disease, but imaging standards varied. Finally, the mismatch repair status determination was by local (not central) testing, which matters because locally-called MSI by immunohistochemistry alone is not always confirmed centrally, as evidenced in other large MSI-H CRC trials.

Clinical takeaway: Discussing stopping immunotherapy when a clinical complete response is observed is now a reasonable conversation to have with patients. The more pressing clinical challenge is determining how best to confirm that a complete response has actually been achieved: CT, PET, MRI, ctDNA, and endoscopy each have different sensitivities and the optimal approach remains to be defined prospectively.

BRAF V600E: First-Line Targeted Therapy Is the Standard, Not the Exception

NCCN guidelines have now removed "subsequent BRAF therapy" as a listed option after first-line treatment, a deliberate editorial choice that emphasizes: if a patient has BRAF V600E-mutant colorectal cancer, they need to receive BRAF-targeted therapy in the first line. Waiting until second or third line means inferior outcomes.

The BREAKWATER trial provided the evidence base for first-line encorafenib plus cetuximab (EC) in BRAF V600E-mutant, MSS metastatic CRC. ASCO 2026 brought updated data from the FOLFIRI plus EC arm, which is particularly relevant because most practitioners want to know whether FOLFIRI or FOLFOX is the better chemotherapy backbone.

FOLFIRI plus EC (new data): Median PFS 15.2 months. 18-month OS 72%.

FOLFOX plus EC (prior data): Median PFS 12.8 months. 18-month OS approximately 68%.

This cross-arm comparison of the two chemotherapy backbones was not powered as a head-to-head comparison, and direct inference should be made with caution. But the numerical suggestion is that FOLFIRI combined with encorafenib and cetuximab may provide slightly more benefit than FOLFOX, possibly because FOLFIRI is more synergistic with this targeted combination. If choosing between the two, the FOLFIRI data is numerically more favorable, though either remains acceptable per guidelines.

Adding immunotherapy to EC (SWOG S2107): A separate trial tested EC with or without nivolumab in patients with BRAF V600E MSS CRC who had one or more prior lines (but no prior BRAF therapy, since this predated first-line BRAF approval). Despite preclinical rationale and early data suggesting immunotherapy might synergize with BRAF inhibition in MSS tumors, the trial showed no difference in progression-free or overall survival. Adding nivolumab to EC in MSS BRAF-mutant disease did not improve outcomes.

A future trial, SEAMARK, will evaluate encorafenib plus cetuximab plus pembrolizumab specifically in MSI-high BRAF V600E patients, where this combination in an immunotherapy-sensitive population may tell a different story.

Clinical takeaway: Encorafenib plus cetuximab (or panitumumab) with FOLFIRI or FOLFOX is the new standard of care for first-line treatment of BRAF V600E MSS metastatic colorectal cancer. Do not wait until second line; do not add nivolumab to this combination for MSS disease. If the patient is MSI-high, give immunotherapy instead.

Hepatic Arterial Infusion: Not Proven for Low-Risk Resectable Disease

Hepatic arterial infusion (HAI) chemotherapy, implanting a pump to deliver floxuridine (FUDR) directly into the liver, allows approximately four hundred times the drug exposure to the liver compared to systemic administration, with minimal systemic circulation. The historical retrospective data, mostly from MSKCC, suggested benefit for patients with resectable liver-only colorectal metastases. Whether this benefit can be confirmed in a prospective randomized trial has been a longstanding question.

The Dutch PUMP trial attempted to answer it. This investigator-initiated phase 3 RCT at twelve centers randomized patients with resectable CRC liver metastases and a low clinical risk score (Fong score) to surgery alone or surgery plus implanted HAI pump with adjuvant floxuridine. Notably, fewer than half of patients had been exposed to chemotherapy before randomization (unusual in a metastatic CRC trial), and the majority had only one liver lesion, a population many practitioners would not reflexively recommend for a pump in the US.

The trial did not meet its primary endpoint of progression-free survival. Hepatic PFS showed a small exploratory benefit, but overall survival trended in the wrong direction. The conclusion is clear: adjuvant HAI is not beneficial for CRC patients with a low clinical risk score who are resectable.

The likely explanation is that the Fong score is not the right selector for HAI benefit; patients with low-volume, low-risk resectable disease may not have enough disease burden for the intrahepatic delivery to provide additive benefit. The more appropriate candidates are likely those with higher-volume or higher-risk disease, or patients with unresectable but liver-dominant disease who might achieve resectability with HAI.

The ECOG ACRIN EA2222 trial (also called the PUMP trial), which is randomized and enrolling in the United States, will provide more definitive prospective data in a broader population. Consider referring eligible patients.

Exercise and Aspirin: Two Survivorship Tools With Real Evidence

Structured Exercise Saves Lives (CHALLENGE Trial Update)

The CHALLENGE trial enrolled patients with stage three or high-risk stage two colon cancer who had completed surgery and adjuvant chemotherapy, randomizing them to a structured exercise program for three years (with a goal of increasing physical activity by ten metabolic equivalent (MET) hours per week, roughly equivalent to adding a brisk walk several times a week) versus standard health education. The primary results, previously published in the New England Journal of Medicine, showed improved disease-free, cancer-specific, and overall survival with the structured exercise program. Merely telling patients to exercise did not achieve the same result.

The ASCO 2026 update addressed whether this intervention is cost-effective. The structured program cost approximately $3,000 upfront compared to effectively nothing for educational materials. But because exercise-group patients had fewer cancer recurrences and therefore received less anti-cancer therapy, the program produced a net cost saving overall. Calculated in Canadian dollars (this is a Canadian trial), the exercise intervention was cost-effective, and would likely be even more so in US dollars given higher drug costs.

Clinical takeaway: Structured exercise, not passive advice, improves survival and is cost-effective in colon cancer survivors. Implementing structured exercise programs in the clinic should be a priority. Encourage all patients to reach at least 150 minutes of moderate to strenuous physical activity per week.

Aspirin and PIK3CA Mutation: Know Your Patient's Molecular Profile

Multiple trials (ASCOLT, A0702) have examined post-diagnostic aspirin use for prevention of colorectal cancer recurrence, without finding a benefit in unselected populations. Biomarker studies, however, identified PIK3CA mutation as a predictor of aspirin benefit; the proposed mechanism is that COX-2 inhibition by aspirin cuts off a key resistance pathway activated by PI3K signaling.

ASCO 2026 presented the EPISODE-III trial, which randomized stage three colon cancer patients to aspirin 100 mg daily for three years versus placebo. The primary endpoint of disease-free survival showed a very modest, non-statistically significant benefit for unselected patients, consistent with prior negative results.

Critically, this trial has not yet analyzed the PIK3CA-mutant subgroup, which is the relevant population. The ALASCCA trial previously showed a significant benefit from aspirin (160 mg daily) in PIK3CA-mutant colorectal cancer, including patients with classical hotspot exon 9 and 20 mutations and those with PIK3R1, PTEN, and other PIK3CA pathway alterations.

Two practical points: First, approximately one third of CRC patients carry PIK3CA mutations. Second, if your institution uses a hotspot molecular panel, it may not capture PIK3CA mutations beyond exons 9 and 20. Full NGS testing is necessary to identify the complete PIK3CA mutation landscape. The NCCN guidelines now list aspirin as guideline-concordant care after chemotherapy for CRC survivors, with a recommended range of 100 to 162 mg daily.

Clinical takeaway: Adjuvant aspirin is emerging for survivorship but remains most clearly beneficial in PIK3CA-mutant disease. Test all patients for PIK3CA with full NGS; do not rely on hotspot panels. Consider aspirin for PIK3CA-mutant patients who have completed chemotherapy.


For Patients

If you have been diagnosed with colorectal cancer, the most important first step is making sure your tumor has been tested for mismatch repair status, BRAF mutation status, and PIK3CA mutation status before treatment begins. These results guide which therapies are most effective for your specific cancer.

If you have mismatch repair-deficient colorectal cancer that is responding completely to immunotherapy, ask your oncologist whether it may be appropriate to discuss stopping therapy once a clinical complete response is confirmed. If you have BRAF-mutant colorectal cancer, a targeted combination called encorafenib plus cetuximab, combined with chemotherapy, should be offered at the start of treatment, not held in reserve for later. And if you have completed colorectal cancer treatment, know that a structured exercise program, more than just general advice to exercise, has been shown to meaningfully reduce the risk of cancer coming back.

Key Takeaways


  • Test all CRC patients for MSI/dMMR status, BRAF V600E mutation, and PIK3CA mutation using full NGS — not hotspot panels.
  • No clear survival benefit from continuing immunotherapy beyond a clinical complete response in MSI-high CRC (retrospective data); discussing stopping is now reasonable; definition of cCR and optimal imaging confirmation remain open.
  • BREAKWATER update: FOLFIRI plus encorafenib plus cetuximab: median PFS 15.2 months, 18-month OS ~72%; numerically better than FOLFOX plus EC (12.8 months, ~68%); either acceptable first-line for BRAF V600E MSS mCRC.
    S2107: Adding nivolumab to EC in MSS BRAF V600E did not improve PFS or OS; no benefit from immunotherapy addition in MSS disease.
  • PUMP trial: Adjuvant HAI not beneficial in low-risk (Fong score) resectable CRC; Fong score may not be the right patient selector; EA2222 trial enrolling.
  • CHALLENGE update: Structured exercise in colon cancer survivors is cost-effective in addition to life-extending; structured program required; passive advice is insufficient.
  • EPISODE-III: Aspirin non-significant in unselected stage three colon cancer; PIK3CA subgroup not yet analyzed; aspirin is guideline-concordant care for CRC survivors (100–162 mg daily).

About the Author

Stacey A. Cohen, MD, is a Professor at Fred Hutchinson Cancer Center and the University of Washington in Seattle, specializing in gastrointestinal cancers with a focus on colorectal cancer. She has served on advisory boards for multiple oncology companies and leads clinical and translational research in this field.

References

  1. Gao S, et al. Observation vs maintenance immunotherapy after clinical complete response in MSI-H CRC. ASCO 2026.
  2. Elez E, et al. BREAKWATER: encorafenib plus cetuximab plus FOLFIRI vs chemotherapy in BRAF V600E mCRC. Annals of Oncology, 2026.
  3. Kopetz S, et al. BREAKWATER FOLFOX arm. New England Journal of Medicine, 2025.
  4. S2107: EC with or without nivolumab in BRAF V600E MSS mCRC. ASCO 2026.
  5. Courneya KS, et al. CHALLENGE: structured exercise in colon cancer survivors. New England Journal of Medicine, 2025; cost-effectiveness update ASCO 2026.
  6. Liang J, et al. ALASKA trial: aspirin in PIK3CA-mutated CRC. New England Journal of Medicine, 2025.
  7. EPISODE-III: adjuvant aspirin in stage three colon cancer. ASCO 2026.
  8. Cohen SA. "Best of ASCO 2026: Colorectal Cancer." Presented at the 2026 Best of Oncology, Seattle, WA, June 2026.