A 62-year-old woman with metastatic colorectal cancer (KRAS wild-type, EGFR positive) presents with progressive disease on first-line FOLFOX. What is the drug of choice to add to her regimen for second-line therapy?

Explanation

## Second-Line Therapy for Metastatic Colorectal Cancer (KRAS WT, EGFR+) **Key Point:** In KRAS wild-type metastatic colorectal cancer, anti-EGFR monoclonal antibodies (cetuximab or panitumumab) are the preferred second-line agents when added to chemotherapy after progression on first-line FOLFOX. ### EGFR Status and Drug Selection **High-Yield:** EGFR expression and KRAS mutation status determine eligibility for anti-EGFR therapy: - **KRAS wild-type + EGFR+:** Benefit from cetuximab or panitumumab (level 1 evidence). - **KRAS mutant:** No benefit from anti-EGFR agents; use anti-VEGF (bevacizumab) instead. - **BRAF mutant:** Poor prognosis; consider triplet chemotherapy or enroll in clinical trials. ### Mechanism and Evidence | Agent | Mechanism | Evidence Base | Second-Line Role | |-------|-----------|---------------|------------------| | Cetuximab | Chimeric anti-EGFR mAb | CRYSTAL, FIRE-3 trials | Standard of care (KRAS WT) | | Panitumumab | Fully human anti-EGFR mAb | PRIME trial | Alternative to cetuximab | | Bevacizumab | Anti-VEGF mAb | ECOG 3200 trial | Used if KRAS mutant or after EGFR failure | | Regorafenib | Multi-kinase inhibitor | CORRECT trial | Third-line (after 2 prior regimens) | ### Clinical Pearl **Clinical Pearl:** Cetuximab is preferred over panitumumab in second-line because: 1. Chimeric structure (mouse-human) may reduce immunogenicity compared to fully human panitumumab. 2. Infusion reactions are manageable with premedication. 3. Cost-effectiveness in resource-limited settings. 4. Extensive clinical trial data (CRYSTAL, FIRE-3). ### Sequencing Strategy **Mnemonic: KRAS-EGFR Decision Tree** — - **K**RAS wild-type → Use **E**GFR inhibitor (cetuximab/panitumumab) - **K**RAS mutant → Use **B**evacizumab (anti-VEGF) **Warning:** Do not use anti-EGFR agents in KRAS-mutant tumours — they confer no survival benefit and may increase toxicity. Always perform KRAS and BRAF mutation testing before selecting second-line therapy.