From the Guidelines
For second-line therapy in KRAS-mutated metastatic colon cancer after progression on FOLFOX+bevacizumab, FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) combined with bevacizumab is the recommended regimen, as supported by the most recent evidence from the NCCN guidelines 1. The typical FOLFIRI regimen consists of irinotecan 180 mg/m² IV on day 1, leucovorin 400 mg/m² IV on day 1,5-FU 400 mg/m² IV bolus on day 1, followed by 5-FU 2400-3000 mg/m² as a 46-hour continuous infusion, with bevacizumab 5 mg/kg IV every 2 weeks.
Rationale for Recommendation
This recommendation is based on the principle of changing the cytotoxic backbone while maintaining anti-angiogenic therapy. KRAS mutations preclude the use of EGFR inhibitors like cetuximab or panitumumab, as these are only effective in KRAS wild-type tumors. The continuation of bevacizumab beyond progression is supported by evidence showing improved outcomes with maintained anti-angiogenic pressure, as seen in studies such as the TML trial and the BEBYP trial 1.
Alternative Options
If the patient cannot tolerate FOLFIRI, alternatives include:
- Irinotecan monotherapy (180 mg/m² every 2 weeks)
- TAS-102 (trifluridine/tipiracil) 35 mg/m² twice daily on days 1-5 and 8-12 of a 28-day cycle Before initiating therapy, it is essential to assess the patient's performance status, organ function, and any residual toxicities from first-line treatment.
Considerations for Angiogenic Agents
When an angiogenic agent is used in second-line therapy, bevacizumab is preferred over ziv-aflibercept and ramucirumab, based on toxicity and/or cost, as indicated by the NCCN guidelines 1. Ramucirumab, another antiangiogenic agent, has shown efficacy in combination with FOLFIRI in the RAISE trial, but its use is not preferred over bevacizumab due to considerations of toxicity and cost 1.
From the Research
Second-Line Therapy for Metastatic Colon Cancer with KRAS Mutation
- The second-line therapy for metastatic colon cancer with a KRAS mutation after progressing on FOLFOX + Bevacizumab is FOLFIRI (Fluorouracil, Irinotecan, Leucovorin) plus either Bevacizumab or Aflibercept 2.
- A study comparing FOLFIRI plus Bevacizumab to FOLFIRI plus Aflibercept as second-line treatment in RAS-mutated metastatic colorectal cancer patients found that both regimens were equally effective, with a median overall survival of 8.9 months and 12.1 months, respectively 2.
- Another study explored the use of ziv-aflibercept plus FOLFIRI after progression on Bevacizumab plus FOLFIRI and found that it may be an active treatment option, with a median progression-free survival of 7.1 months and median overall survival of 13.8 months 3.
- The EAGLE study compared two doses of Bevacizumab combined with FOLFIRI in the second-line setting after first-line therapy with Bevacizumab plus oxaliplatin-based therapy and found that Bevacizumab 10 mg/kg plus FOLFIRI did not prolong progression-free survival compared to Bevacizumab 5 mg/kg plus FOLFIRI 4.
Treatment Options
- FOLFIRI plus Bevacizumab
- FOLFIRI plus Aflibercept
- ziv-aflibercept plus FOLFIRI (after progression on Bevacizumab plus FOLFIRI)