Role of Regorafenib in Third-Line mCRC: Expert Insights on Treatment Strategies and Management Nuances

Treatment sequencing in refractory colorectal cancer requires careful consideration of patient performance status, prior toxicities, and individual drug characteristics. While regorafenib theoretically offers advantages as a multi-targeted tyrosine kinase inhibitor through "carpet bombing" multiple pathways, clinical experience has not demonstrated clear superiority over other options. The ReDOS trial strategy of starting regorafenib at reduced doses with weekly escalation has improved tolerability, making dose optimization a key consideration when using this agent.

Clinical preference increasingly favors TAS-102 plus bevacizumab combination in the third-line setting, given the meaningful progression-free survival of 5.6 months and overall survival of 10.8 months. This combination compares favorably to second-line FOLFIRI plus bevacizumab while often being better tolerated. Patient selection remains crucial, as trial populations typically included ECOG performance status 0-1 patients, though academic practices may see a referral bias toward better performance status patients than community settings.

Emerging combination strategies explore pairing tyrosine kinase inhibitors with immunotherapy, showing preliminary activity in selected populations. Some practitioners report anecdotal success with regorafenib plus nivolumab in liver metastases-free patients with tumor mutational burden ≥10, though this remains investigational. The future direction emphasizes identifying biomarker-selected populations and developing novel combinations rather than simply escalating treatment intensity. Clinical trial participation remains the optimal approach for advancing the field and potentially providing superior outcomes compared to standard sequential therapy approaches.