Ask AI
Back Back
Evolving Standards in mCRC
Evolving Standards in Metastatic Colorectal Cancer: Insights on Sequencing, Targeted Therapy, and Immunotherapy Integration

Released: October 31, 2025

Zev A. Wainberg
Zev A. Wainberg, MD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Biomarker testing drives therapy in mCRC; MSI, BRAF, KRAS G12C, and HER2 subtypes now each direct specific regimen.
  • BREAKWATER, SUNLIGHT, and MOUNTAINEER trials have redefined standard care across treatment lines.
  • Early toxicity recognition and proactive management can help maintain quality of life and therapy continuity.

The treatment landscape for metastatic colorectal cancer (mCRC) has shifted rapidly over the past few years with the integration of targeted therapies and immunotherapy combinations guided by molecular profiling. With the phase III BREAKWATER and SUNLIGHT studies redefining standards and the growing relevance of HER2-directed and KRAS G12C–directed options, healthcare professionals (HCPs) face an increasingly complex decision matrix. In this expert discussion, Zev A. Wainberg, MD, addresses key questions from oncology HCPs on optimal sequencing, management of treatment-related adverse events, and patient selection for novel and investigational therapies.

How do you select frontline therapy for patients with proficient mismatch repair (pMMR) (MSS) mCRC?
For pMMR or microsatellite stable (MSS) tumors when no other actionable biomarker is present, immunotherapy is generally not effective, so chemotherapy remains the backbone. The randomized phase III GERCOR trial showed that FOLFOX6 followed by FOLFIRI or the reverse sequence is appropriate, and the randomized phase II STEAM trial demonstrated that FOLFOXIRI plus bevacizumab (delivered concurrently or sequentially) improves outcomes vs FOLFOX plus bevacizumab. For patients requiring rapid disease control, the intensified FOLFOXIRI plus bevacizumab regimen remains a strong option, particularly in those with good performance status. After approximately 6 months, maintenance therapy with a fluoropyrimidine with or without bevacizumab is preferred to balance efficacy and neuropathy risk.

When is immunotherapy indicated in mCRC, and how durable are responses?
Immunotherapy should be reserved for patients with microsatellite instability (MSI)–high or deficient mismatch repair tumors, representing approximately 10% to 12% of advanced cases. The randomized phase III KEYNOTE-177 trial showed that pembrolizumab monotherapy was superior to chemotherapy in the first-line setting, and the randomized phase III CheckMate 8HW trial confirmed that nivolumab plus low-dose ipilimumab further improved progression-free survival (PFS) vs chemotherapy, with a 3-year overall survival (OS) rate approaching 70%; many of these patients may experience long-term remissions or functional cures, underscoring the importance of testing MSI status at diagnosis.

What are your preferred approaches to immune-related adverse events in these patients?
Most immune-related toxicities (ie, thyroiditis, diarrhea, dermatitis) can be managed with early recognition and corticosteroids. For grade ≥3 hepatitis or pneumonitis, hospitalization and IV immunosuppression may be warranted. For grade ≥3, I always remind HCPs to first hold therapy—do not push through toxicity. Recovery almost always allows safe rechallenge once symptoms resolve to grade 0/1.

How did the BREAKWATER trial change care for BRAF V600E–mutated mCRC?
The phase III BREAKWATER study was practice changing. BREAKWATER, a first-line trial in BRAF V600E–mutated, MSS mCRC, compared encorafenib plus cetuximab (EC) with or without mFOLFOX6 vs physician’s choice of standard chemotherapy (FOLFOX or FOLFIRI ± bevacizumab), with the EC-alone arm closing early for inferiority to chemotherapy. It established EC plus FOLFOX as the new frontline standard for BRAF V600E–mutated mCRC. The EC plus mFOLFOX6 triplet significantly improved overall response rate (ORR) (66% vs 37%), median PFS (12.8 vs 7.1 months), and median OS (30.3 vs 15.1 months) vs standard chemotherapy. Rash and anemia were more common with EC plus mFOLFOX6 but were manageable. The NCCN guidelines now list EC with or without FOLFOX as preferred for this subset.

What are the preferred treatment options after progression on standard chemotherapy?
After FOLFOXIRI plus bevacizumab or sequential doublets, second-line and third-line selection depends on prior biologic exposure, residual toxicities, tumor sidedness, and biomarkers. For RAS/BRAF wild-type disease that has not been treated with an EGFR antibody, add cetuximab or panitumumab, preferably with chemotherapy (eg, with FOLFIRI). Antibody monotherapy can be considered in later lines when combination therapy is not feasible.

For biomarker-negative disease (ie, no additional actionable targets), choose among VEGF pathway options supported by phase III trials:

  • SUNLIGHT: TAS-102 plus bevacizumab improved median OS vs TAS-102 alone (10.8 vs 7.5 months; HR: 0.61). Note that TAS-102 is not a VEGF agent, and the benefit in SUNLIGHT derives from adding the anti-VEGF antibody bevacizumab.
  • FRESCO-2: fruquintinib prolonged median OS vs placebo (7.4 vs 4.8 months; HR: 0.66).
  • CORRECT: regorafenib showed a modest but significant benefit in median OS vs placebo (6.4 vs 5.0 months; HR: 0.77).

Selection may be individualized based on prior anti-VEGF exposure, hypertension/proteinuria risk, hand–foot skin reaction risk, need for oral vs IV therapy, patient preference, and performance status.

How do you treat HER2-positive mCRC in later lines?
HER2 amplification occurs in approximately 2% to 4% of mCRCs, mostly left-sided and RAS wild-type tumors. EGFR inhibitors are ineffective in this subset. The phase II MOUNTAINEER trial established tucatinib plus trastuzumab as an effective chemotherapy-free regimen, with a confirmed ORR of 38% and median OS of approximately 24 months for previously treated, RAS wild-type, HER2‑positive mCRC. In January 2023, the FDA granted accelerated approval to tucatinib plus trastuzumab for adults with RAS wild-type, HER2-positive unresectable colorectal cancer or mCRC. More recently, the phase II DESTINY-CRC02 trial demonstrated high response rates with trastuzumab deruxtecan (T-DXd), particularly at the 5.4 mg/kg dose, which balances efficacy and safety. In 2024, the FDA issued a tumor-agnostic approval for T-DXd for previously treated, unresectable or metastatic HER2-positive solid tumors. For most patients, I start with tucatinib and trastuzumab and reserve T-DXd for later-line use or tucatinib intolerance.

How do you manage interstitial lung disease (ILD) associated with T-DXd?
Even asymptomatic (grade 1) ILD should prompt holding therapy until complete radiographic resolution. If resolution occurs within 28 days, treatment may resume at the same dose, but after 28 days, reduce the dose by 1 level. Any grade ≥2 ILD requires permanent discontinuation. Early recognition with regular CT review is key. Many cases resolve with corticosteroids when caught early.

What are the latest data on KRAS G12C–mutated mCRC?
KRAS G12C mutations occur in approximately 3% to 4% of mCRC cases. Both CodeBreaK 300 and phase I/II KRYSTAL-1 demonstrated clinically meaningful benefit from KRAS G12C inhibitors combined with EGFR blockade in previously treated mCRC that has progressed on standard chemotherapy:

  • CodeBreaK 300: sotorasib plus panitumumab improved median PFS vs standard care (5.7 vs 2.04 months; HR: 0.45).
  • KRYSTAL-1: adagrasib plus cetuximab yielded an ORR of 43% and median OS of 16 months.

Toxicities are mostly low-grade rash and diarrhea. Both combinations have accelerated FDA approval for chemotherapy-refractory KRAS G12C–mutated mCRC. Ongoing studies are exploring earlier-line use and combinations with VEGF inhibitors.

Do you routinely repeat molecular testing at progression?
Not routinely, but with one exception. KRAS, BRAF, and HER2 alterations tend to remain stable. However, I often use liquid biopsy (ctDNA) at progression when tissue is limited or to detect acquired resistance mechanisms, such as EGFR reactivation. Repeat testing can guide clinical trial enrollment but is not required by current guidelines.

What are your thoughts on rechallenge with chemotherapy in heavily pretreated mCRC?
For bulky symptomatic disease, especially after a long oxaliplatin-free interval, I often rechallenge with FOLFOX for palliation. In my experience, response rates are higher than with regorafenib or TAS-102, although durability is shorter. The decision should be individualized based on neuropathy recovery and patient goals.

When should patients with mCRC be referred for clinical trials?
Ideally, at diagnosis. Next-generation sequencing at baseline allows early identification for basket trials targeting broad alterations such as those in KRAS, BRAF, HER2, or NTRK. Patients without actionable mutations should be referred after standard VEGF and EGFR inhibitors, before performance status declines. Trials investigating pan-KRAS inhibitors, immunotherapy combinations for MSS tumors, and next-generation antibody–drug conjugates are particularly promising.

Your Thoughts
How are you integrating emerging targeted and immunotherapy options into your treatment sequencing for patients with mCRC? Join the discussion by posting a comment.

Continue

Poll

1.

How do you currently integrate biomarker-driven targeted therapy into your mCRC management?

Submit