Introduction

Three themes are reshaping how colorectal cancer is managed across every disease stage: a broad push to de-escalate treatment through non-operative management and radiation omission in rectal cancer; the rapid expansion of immunotherapy from the metastatic setting into neoadjuvant and adjuvant use; and a new generation of biomarker-directed regimens that are fundamentally changing survival expectations in metastatic disease. This review covers the most clinically significant recent data across all three themes, with practical guidance on what they mean for patients treated today.

De-escalation in Rectal Cancer: Non-Operative Management and Radiation Omission

The Foundation: Total Neoadjuvant Therapy

For locally advanced rectal cancer, the standard of care has evolved substantially over the past decade. Neoadjuvant chemoradiation, established by seminal trials including the German Rectal Cancer Study Group, has given way to total neoadjuvant therapy (TNT) as the preferred approach for many patients: delivering all systemic and radiation therapy before surgery to maximize tumor response and optimize outcomes. Several questions now define how we implement TNT.

OPRA: Sequence and Non-Operative Management

The OPRA trial (Organ Preservation in Rectal Adenocarcinoma) addressed two questions simultaneously: what is the optimal sequence of TNT components, and can non-operative management (watch and wait) be safely pursued after TNT? Patients received either induction chemotherapy followed by chemoradiation or chemoradiation followed by consolidation chemotherapy, then were assessed for response. Those with complete or near-complete response could pursue non-operative management; others proceeded to surgery.

Two key findings emerged. First, non-operative management after TNT is a viable and safe approach, without clearly inferior outcomes compared to surgery. Second, among the two TNT sequences tested, chemoradiation-first resulted in greater total mesorectal excision (TME)-free survival. The practical implication: unless there is a compelling reason to deviate, chemoradiation should come first in TNT sequencing, unless the goal is to omit radiation altogether.

PROSPECT: When Radiation Can Be Omitted

The PROSPECT trial demonstrated that radiation can be safely omitted in a carefully defined subset of patients with locally advanced rectal cancer. Key eligibility required clinical stage T2N1, T3N0, or T3N1 disease; patients with T4 tumors, N2 disease (four or more nodes ≥10 mm), mesorectal fascia involvement threatening R0 resection, or tumors requiring abdominoperineal resection at baseline were excluded. Patients received upfront FOLFOX; those achieving a ≥20% response threshold proceeded to surgery without radiation. The trial met its non-inferiority endpoint for omitting radiation in this population, and overall survival was not compromised.

Two caveats are essential. First, PROSPECT is a surgical endpoint trial; it was not designed to evaluate non-operative management. Patients who want to pursue watch-and-wait should receive full TNT, not the PROSPECT regimen. Second, the eligibility criteria are specific and must be applied carefully; patients with more advanced local disease do not qualify for a prospect like approach.

Dostarlimab: Non-Operative Management Without Surgery or Radiation in dMMR Rectal Cancer

The most dramatic development in rectal cancer management comes from a study by Cercek et al. examining PD-1 blockade with dostarlimab in patients with mismatch repair-deficient (dMMR) locally advanced rectal cancer. The original trial intent was to use dostarlimab as part of a total neoadjuvant approach, with assessment of response before proceeding to chemoradiation and potential non-operative management.

The results exceeded expectations. In the updated 2025 analysis, 49 of 49 patients with rectal cancer achieved a complete clinical response. No patient has required surgery. No patient has required chemoradiation. Relapse-free survival is 96% at two years. In the broader dMMR cohort that included non-rectal colorectal cancers, the complete clinical response rate was 65%.

These results establish immunotherapy as the preferred neoadjuvant approach for patients with dMMR locally advanced rectal cancer and represents a paradigm shift: for appropriately selected patients, the entire traditional treatment pathway of chemotherapy, radiation, and surgery may be avoidable. Biomarker testing for mismatch repair status is therefore non-negotiable and must be performed upfront in all newly diagnosed rectal cancer patients.

Immunotherapy Across the Disease Continuum

Neoadjuvant: NICHE-2

NICHE-2 evaluated a brief, intensive neoadjuvant immunotherapy regimen (a single dose of ipilimumab 1 mg/kg on day 1 combined with two doses of nivolumab 3 mg/kg on days 1 and 15, followed by surgery within six weeks) in patients with dMMR locally advanced colon cancer. The results were striking: 98% of patients underwent surgery on time (no meaningful delay), 98% achieved a pathological response, 95% achieved a major pathological response (≤10% residual viable tumor), and 68% achieved a pathological complete response. At a median follow-up of 26 months, there have been no recurrences.

NICHE-2 establishes short-course neoadjuvant immunotherapy as a highly effective option in dMMR locally advanced colon cancer.  y?

Adjuvant: ATOMIC

ATOMIC addressed the adjuvant setting, randomizing patients with stage III dMMR colon cancer to modified FOLFOX alone versus modified FOLFOX plus atezolizumab for one year. FOLFOX plus atezolizumab significantly improved disease-free survival over chemotherapy alone, establishing adjuvant immunotherapy as a new standard for this population.

The clinical dilemma these two trials create is genuine: NICHE-2 offers a short, highly active neoadjuvant regimen that may preclude the need for adjuvant therapy; ATOMIC offers proven adjuvant benefit after surgery. There is currently no direct comparison. Multidisciplinary discussion, weighing patient preference, surgical timing, institutional experience, and tolerance for a year-long adjuvant commitment, is essential.

These studies have led to a meaningful clinical question: should patients with dMMR colon cancer receive brief neoadjuvant IO followed by surgery, or undergo surgery first followed by a full year of adjuvant therapy?  Ongoing studies will be needed to help refine this space

Metastatic: CheckMate 8HW

CheckMate 8HW compared three arms in first-line metastatic MSI-H/dMMR colorectal cancer: nivolumab plus ipilimumab, nivolumab alone, and investigator's choice chemotherapy. The PFS data are among the most dramatic ever seen in colorectal cancer: median PFS with nivolumab plus ipilimumab was 54.1 months versus 5.9 months with chemotherapy in the first-line comparison. In the comparison across all lines, median PFS was not reached with the combination versus 39.3 months with nivolumab alone.

Updated data presented at ASCO 2026 confirmed disease-specific survival HR of 0.47 (95% CI 0.32–0.68), treatment-free survival of 82% for nivolumab plus ipilimumab versus 67% for nivolumab alone, and consistent benefit across all subgroups. Dual checkpoint inhibition enables deep, durable responses in metastatic dMMR colorectal cancer and should be the standard first-line approach in eligible patients.

A New Option in Refractory MSS Disease: STELLAR-303

For patients with microsatellite-stable (MSS) metastatic colorectal cancer (the vast majority of patients), immunotherapy has historically shown no meaningful benefit. The STELLAR-303 trial represents the first immunotherapy-based regimen to demonstrate an overall survival benefit in this population.

STELLAR-303 was a phase 3, global, randomized trial comparing zanzalintinib 100 mg daily plus atezolizumab versus regorafenib in patients with refractory MSS metastatic colorectal cancer who had progressed on prior fluoropyrimidine, oxaliplatin, irinotecan, and where appropriate anti-VEGF and anti-EGFR therapy. Median OS was 10.9 months with zanzalintinib plus atezolizumab versus 9.4 months with regorafenib (HR 0.80; p=0.0045). Twelve-month OS rates were 46% versus 38%; 24-month OS rates were 20% versus 10%. Median PFS was 3.7 versus 2.0 months (HR 0.68). ORR was 4% versus 1%; DCR was 54% versus 41%.

This result warrants context. The control arm performed better than historical regorafenib data, which complicates interpretation. Treatment-related adverse events were substantially higher with the experimental arm. Lonsurf plus bevacizumab is widely accepted as a third-line standard and was not included as a comparator. The combination's exact place in the treatment sequence is still being defined. Nonetheless, STELLAR-303 establishes a proof of concept that IO-based combinations can improve OS even in MSS disease, and zanzalintinib plus atezolizumab is a meaningful option for appropriately selected refractory patients.

Metastatic Disease: BREAKWATER and the BRAF V600E Standard of Care

BRAF V600E mutations are present in approximately 8–10% of metastatic colorectal cancers and have historically been associated with the worst prognosis among molecular subtypes, with median OS of approximately 12–14 months with standard chemotherapy.

The BREAKWATER trial has fundamentally changed this. BREAKWATER is a phase 3, randomized, first-line trial in BRAF V600E-mutated metastatic colorectal cancer, evaluating encorafenib (a BRAF inhibitor) plus cetuximab (an EGFR inhibitor) combined with either mFOLFOX6 or FOLFIRI versus investigator's choice chemotherapy with or without bevacizumab.

The results are transformative. In the encorafenib plus cetuximab plus mFOLFOX6 arm: ORR 60.9% versus 40.0% (OR 2.44; p<0.001), median PFS 12.8 versus 7.1 months (HR 0.53; p<0.001), and median OS 30.3 versus 15.1 months (HR 0.49; p<0.001), doubling overall survival. In the EC plus FOLFIRI arm: ORR 64.4% versus 39.2% (OR 2.76; p=0.001), median PFS 15.2 versus 8.3 months (HR 0.44; p=0.0002), and median OS not reached versus 20.3 months (HR 0.56). Duration of response was 13.9 months with EC plus mFOLFOX6.

Either mFOLFOX6 or FOLFIRI are reasonable chemotherapy backbones in combination with encorafenib plus cetuximab. The doubling of overall survival clearly establishes encorafenib plus cetuximab plus chemotherapy as the standard of care for first-line metastatic BRAF V600E-mutated colorectal cancer. This has transformed BRAF V600E from a marker of poor prognosis into a treatment-defining biomarker that should guide frontline therapy selection.

Early comprehensive biomarker testing is therefore mandatory for every patient with newly diagnosed metastatic colorectal cancer.

The Role of ctDNA

Circulating tumor DNA is increasingly used in colorectal cancer management, particularly for minimal residual disease (MRD) detection after curative-intent therapy. It has strong prognostic value: ctDNA positivity after resection identifies patients at substantially higher risk of recurrence. However, ctDNA is not yet an established predictive biomarker. A positive result does not reliably indicate that additional or different therapy will improve outcomes, and a negative result does not guarantee cure.

Clinically, ctDNA can be a useful surveillance tool, particularly in high-risk patients (T4 disease, node-positive, positive margins), but its use should be accompanied by a careful discussion of its limitations. Anxiety around a positive result is real and clinically significant; patients should be counseled before testing about what a positive result does and does not mean. ctDNA is not currently guideline-standard in the TNT setting and should not alone prompt surgical intervention without corroborating imaging or pathological evidence of disease.

Where the Field Is Heading

The dominant direction in colorectal cancer management is molecular precision. The shift from anatomic staging to biomarker-driven, molecularly stratified treatment algorithms is already underway and will accelerate. Organ preservation, radiation omission, and non-operative management will become increasingly standard for appropriately selected patients. Immunotherapy will continue to move earlier in the treatment pathway. And the experience with BRAF V600E in metastatic disease illustrates the broader principle: finding the right targeted therapy for the right molecular subgroup produces results that are impossible with standard chemotherapy alone.

For clinicians, the implication is clear: upfront, comprehensive biomarker testing is no longer optional. It should be reflex, prompt, and universal.

For Patients

If you have been diagnosed with colorectal cancer, ask for comprehensive biomarker testing before treatment begins. This includes mismatch repair (MMR) status, BRAF V600E mutation status, KRAS, NRAS, and HER2, at minimum. These results will determine whether you are eligible for immunotherapy, targeted therapy, or radiation omission, and they cannot be acted upon if they are not ordered upfront.

If you have locally advanced rectal cancer and your tumor is mismatch repair-deficient, ask your oncologist about immunotherapy. The data are compelling: in the right patient, this approach may allow you to avoid chemotherapy, radiation, and surgery entirely.

If you have BRAF V600E-mutated metastatic colorectal cancer, ask about encorafenib plus cetuximab plus chemotherapy. The survival benefit compared to standard chemotherapy alone is substantial.

Colorectal cancer is increasingly a disease where the molecular profile of your tumor shapes your treatment as much as its stage. Seek care at a center where multidisciplinary tumor board review, molecular testing, and access to clinical trials are available.

Key Takeaways

  • OPRA established the safety of non-operative management after TNT in rectal cancer; chemoradiation-first sequencing yields greater TME-free survival.

  • PROSPECT supports radiation omission in select T2N1/T3N0/T3N1 rectal cancer patients achieving ≥20% response to FOLFOX; T4, N2, and APR-requiring patients are excluded. PROSPECT is a surgical endpoint trial; patients seeking non-operative management should receive full TNT.

  • Dostarlimab in dMMR locally advanced rectal cancer achieved 100% complete clinical response in 49/49 patients, no surgery, no chemoradiation required, and 96% 2-year relapse-free survival (Cercek et al., NEJM 2022, updated NEJM 2025).

  • NICHE-2 showed 98% pathological response and 68% pathological complete response with brief neoadjuvant ipilimumab plus nivolumab in dMMR locally advanced colon cancer; no recurrences at median 26-month follow-up.

  • ATOMIC demonstrated that adjuvant FOLFOX plus atezolizumab significantly improves DFS over FOLFOX alone in stage III dMMR colon cancer.

  • CheckMate 8HW: nivolumab plus ipilimumab achieved a median PFS of 54.1 months versus 5.9 months with chemotherapy in first-line MSI-H/dMMR metastatic CRC; DSS HR 0.47 at ASCO 2026 update.

  • STELLAR-303: zanzalintinib plus atezolizumab is the first IO-based regimen to demonstrate OS benefit in refractory MSS metastatic CRC (10.9 vs 9.4 months, HR 0.80); its place in the treatment sequence is still being refined.

  • BREAKWATER: encorafenib plus cetuximab plus mFOLFOX6 doubled OS in first-line BRAF V600E-mutated metastatic CRC (30.3 vs 15.1 months, HR 0.49); either mFOLFOX6 or FOLFIRI are acceptable chemotherapy backbones.

  • Upfront, comprehensive biomarker testing is non-negotiable for all newly diagnosed colorectal cancer patients.

References

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