Treatment Options for KRAS Wild-Type Metastatic Colorectal Cancer After FOLFOX, FOLFIRI, and Panitumumab
Switch to bevacizumab-based therapy as your next-line treatment, specifically FOLFOX plus bevacizumab if the patient has not received oxaliplatin recently, or consider regorafenib or trifluridine-tipiracil (TAS-102) as third-line options if the patient has exhausted all chemotherapy backbones. 1
Critical Decision Point: Anti-EGFR Rechallenge is NOT Recommended
Do not use cetuximab or panitumumab again after progression on panitumumab. 1 The NCCN explicitly states that no data support switching to either cetuximab or panitumumab after failure of the other drug, and this practice is not recommended. 1 For patients progressing on therapies that contained an EGFR inhibitor, administration of another EGFR inhibitor is not recommended in subsequent lines of therapy. 1
Preferred Second-Line Option: Bevacizumab-Based Therapy
If Patient Has Not Recently Received Oxaliplatin
FOLFOX plus bevacizumab is the recommended second-line treatment for patients previously treated with irinotecan-fluoropyrimidine-based chemotherapy alone. 1 This combination demonstrated improved overall survival and progression-free survival in phase III trials compared to FOLFOX alone. 1
Bevacizumab dosing: 5 mg/kg IV every 2 weeks in combination with FOLFOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU 400 mg/m² bolus followed by 2400 mg/m² continuous infusion over 46-48 hours, repeated every 2 weeks). 2
Alternative Antiangiogenic Options
Aflibercept plus FOLFIRI is an alternative to bevacizumab with FOLFIRI in patients progressing on first-line oxaliplatin-based chemotherapy. 1 The VELOUR trial demonstrated improvement in overall survival and progression-free survival with aflibercept in combination with FOLFIRI, including in the subgroup previously treated with bevacizumab. 1
Ramucirumab plus FOLFIRI is another option for patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and fluoropyrimidines. 1 The RAISE trial showed benefit in both overall survival and progression-free survival. 1
Key Principle: Antiangiogenic Therapy Regardless of Prior Bevacizumab
A second-line treatment with an antiangiogenic combined with chemotherapy should be used, regardless of whether the first-line treatment included bevacizumab or not, independently of RAS mutational status and primary tumor location. 1 This represents a Level I, Grade A recommendation from ESMO 2023. 1
Third-Line and Beyond: Oral Targeted Agents
When to Use Regorafenib or TAS-102
After progression on fluoropyrimidines, oxaliplatin, irinotecan, and biologics, you have two evidence-based options:
Regorafenib 160 mg orally once daily on days 1-21 of each 28-day cycle is recommended in patients pre-treated with all standard agents. 1 This oral multikinase inhibitor demonstrated improved median overall survival (6.4 months versus 5.0 months with placebo) and progression-free survival in phase III placebo-controlled trials. 1, 3
Trifluridine-tipiracil (TAS-102) is recommended in patients pre-treated with fluoropyrimidines, oxaliplatin, irinotecan, and biologics. 1 TAS-102 demonstrated improved progression-free survival and overall survival in refractory metastatic colorectal cancer in phase III trials. 1
Both agents have Level I, Grade A evidence and ESMO-MCBS v1.1 score of 1. 1
Important Molecular Testing Considerations
BRAF V600E Mutation Status
If the patient has BRAF V600E mutation, encorafenib plus cetuximab is the preferred second-line option with superior outcomes (Level I, Grade A evidence; ESMO-MCBS v1.1 score: 4). 1, 4 The median overall survival was 9.3 months with encorafenib-cetuximab versus 5.9 months with standard chemotherapy plus cetuximab. 1
MSI-H/dMMR Status
If the patient has dMMR/MSI-H tumors progressing after first-line chemotherapy, ipilimumab-nivolumab is recommended (Level III, Grade B evidence; ESMO-MCBS v1.1 score: 3). 1, 4
Treatment Algorithm Based on Prior Therapy
Patient Previously Received: FOLFOX → FOLFIRI + Panitumumab
Next step: FOLFOX (reintroduction) plus bevacizumab 1
Rationale: Reintroduction of initial induction therapy can be considered after second-line therapy, as long as the patient did not progress during the induction course of first-line chemotherapy. 1
The combination of FOLFOX and bevacizumab is recommended in patients previously treated with irinotecan-fluoropyrimidine-based chemotherapy. 1
If Progression Occurs Again
Third-line: Regorafenib or TAS-102 1
Common Pitfalls to Avoid
Never combine bevacizumab with anti-EGFR antibodies (cetuximab or panitumumab). 2 Two trials showed that an anti-EGFR antibody reduced median survival when added to bevacizumab in previously untreated patients. 5
Do not use single-agent cetuximab or panitumumab after progression on panitumumab. 1 There is no unequivocal evidence to administer the alternative anti-EGFR antibody if a patient is refractory to one of the anti-EGFR antibodies. 1
Monitor for regorafenib toxicities closely: The most common grade 3 adverse events are hand-foot syndrome, hypertension, increased liver enzymes, and rash. 1 Consider starting at a reduced dose (80-120 mg daily) rather than standard 160 mg daily in patients with baseline hepatic dysfunction. 3
Bevacizumab can be combined with a fluoropyrimidine-doublet with oxaliplatin or irinotecan, depending on the first-line chemotherapy backbone delivered. 1 Do not arbitrarily choose the chemotherapy backbone without considering prior exposure and cumulative toxicities.
Performance Status and Patient Selection
This patient should maintain ECOG performance status 0-2 to tolerate combination chemotherapy. 2 If performance status deteriorates to 3-4, consider single-agent fluoropyrimidine with bevacizumab or best supportive care. 4
Monitoring During Treatment
Reevaluate every 2 months with imaging during second-line therapy. 4 Monitor closely for: