What is the next systemic therapy for a patient with metastatic rectal adenocarcinoma harboring a KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation, who has progressed on both FOLFOX (Folinic acid, Fluorouracil, Oxaliplatin) and FOLFIRI (Folinic acid, Fluorouracil, Irinotecan) regimens with bevacizumab?

Third-Line Systemic Therapy for KRAS-Mutated Metastatic Rectal Adenocarcinoma After FOLFOX and FOLFIRI/Bevacizumab Failure

For a patient with KRAS-mutated metastatic rectal adenocarcinoma who has progressed on both FOLFOX and FOLFIRI with bevacizumab, the recommended third-line options are regorafenib (160 mg daily, days 1-21 of 28-day cycles) or trifluridine/tipiracil (35 mg/m² twice daily, days 1-5 and 8-12 every 28 days), with trifluridine/tipiracil plus bevacizumab being preferred if the patient can tolerate combination therapy. 1, 2

Primary Recommendation: Regorafenib or Trifluridine/Tipiracil

Regorafenib

• Regorafenib is FDA-approved for patients with metastatic colorectal cancer previously treated with fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF therapy (bevacizumab in this case). 3
• The CORRECT trial demonstrated that regorafenib improved median overall survival to 6.4 months versus 5.0 months with placebo (HR 0.77,95% CI 0.64-0.94, p=0.0102) in heavily pretreated patients. 3
• Median progression-free survival was 2.0 months with regorafenib versus 1.7 months with placebo (HR 0.49,95% CI 0.42-0.58, p<0.0001). 3
• Dosing: 160 mg orally once daily for days 1-21 of each 28-day cycle, taken with a low-fat breakfast containing less than 30% fat. 3

Trifluridine/Tipiracil (TAS-102)

• Trifluridine/tipiracil is an alternative oral agent with similar indications to regorafenib for patients who have failed fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF therapy. 2
• Dosing: 35 mg/m² twice daily on days 1-5 and 8-12 of each 28-day cycle. 2
• The combination of trifluridine/tipiracil with bevacizumab significantly prolongs overall survival and progression-free survival compared to trifluridine/tipiracil monotherapy. 2

Key Consideration: KRAS Mutation Status

Since this patient has KRAS-mutated disease, anti-EGFR antibodies (cetuximab or panitumumab) are NOT indicated and should NOT be used. 1

• EGFR inhibitors (cetuximab, panitumumab) are only effective in RAS wild-type tumors (both KRAS and NRAS wild-type). 1
• In patients with KRAS mutations, these agents provide no benefit and add unnecessary toxicity. 1

Alternative Considerations Based on Molecular Testing

If Additional Molecular Testing Reveals:

MSI-H/dMMR Status:

• If the tumor is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), ipilimumab-nivolumab is recommended after first-line chemotherapy failure. 2

HER2 Amplification:

• If HER2 amplification is present (occurs in 2-5% of colorectal cancers), consider trastuzumab plus pertuzumab, trastuzumab plus lapatinib, or trastuzumab deruxtecan in third-line or later settings. 2

BRAF V600E Mutation:

• If BRAF V600E mutation is present in addition to KRAS mutation, encorafenib plus cetuximab is the recommended option in second or third line. 2

Bevacizumab Continuation Beyond Progression

Bevacizumab can be continued with trifluridine/tipiracil in the third-line setting, as continuation of VEGF blockade offers a modest but statistically significant overall survival benefit. 1

• The TML (ML18147) trial demonstrated that continuing bevacizumab with a different chemotherapy regimen after progression improved overall survival (11.2 vs 9.8 months; HR 0.81,95% CI 0.69-0.94, p=0.0062). 1
• This benefit was independent of KRAS mutation status. 1
• When an angiogenic agent is used, bevacizumab is preferred over ziv-aflibercept and ramucirumab based on toxicity and cost considerations. 1

Agents to AVOID

Do NOT use the following agents as salvage therapy, as they have not shown efficacy in this setting: 1, 2

• Capecitabine monotherapy
• Mitomycin
• Alfa-interferon
• Taxanes
• Methotrexate
• Pemetrexed
• Sunitinib
• Sorafenib
• Erlotinib
• Gemcitabine

Important Toxicity Considerations

Regorafenib Toxicity Profile:

• Most common grade 3-4 adverse events include hand-foot skin reaction, fatigue, hypertension, and diarrhea. 3
• Approximately 47% of patients require dose reduction, most commonly for asthenia. 4
• Monitor for hepatotoxicity, hemorrhage, gastrointestinal perforation, and dermatologic toxicity. 3

Trifluridine/Tipiracil Toxicity Profile:

• Primary toxicity is myelosuppression, particularly neutropenia. 5
• Generally has a favorable safety profile that renders it suitable for combination with other therapies. 5

Clinical Pitfalls to Avoid

Do not rechallenge with the same chemotherapy backbone (FOLFOX or FOLFIRI) that the patient has already progressed on. 1

Do not switch between cetuximab and panitumumab after failure of one EGFR inhibitor, as no data support this practice. 1

Do not add bevacizumab to the same chemotherapy regimen after progression on that regimen—only add it to a different chemotherapy backbone. 1

Ensure adequate performance status (ECOG 0-2) before initiating third-line therapy, as patients with poor performance status are unlikely to benefit. 1

Monitoring During Treatment

Perform radiological evaluation every 8-12 weeks with CT or MRI and CEA levels during active treatment. 2