FOLFOX Plus Bevacizumab Rechallenge Versus Regorafenib as Third-Line Treatment in Metastatic Colorectal Cancer: The Role of the Oxaliplatin-Free Interval

Background: The optimal use of chemotherapy rechallenge in later-line metastatic colorectal cancer (mCRC) remains uncertain. We compared third-line FOLFOX plus bevacizumab rechallenge with regorafenib and examined whether the oxaliplatin-free interval was associated with treatment outcomes. Methods: This retrospective single-center study included 122 patients with metastatic left-sided, RAS (KRAS/NRAS) and BRAF wild-type, proficient mismatch repair (pMMR) colorectal adenocarcinoma treated between 2018 and 2025. All patients had received first-line FOLFOX plus cetuximab or panitumumab, followed by FOLFIRI plus bevacizumab after progression. In the third-line setting, 65 patients received FOLFOX plus bevacizumab as oxaliplatin rechallenge and 57 received regorafenib. The primary endpoint was progression-free survival (PFS). Cox regression, propensity score-based inverse probability of treatment weighting (IPTW), and treatment-by-oxaliplatin-free interval interaction analyses were performed. Results: Median third-line PFS was 7.33 months with FOLFOX plus bevacizumab rechallenge and 6.17 months with regorafenib (log-rank p < 0.001). FOLFOX plus bevacizumab rechallenge was associated with a lower hazard of progression in multivariable analysis (adjusted HR, 0.58; 95% CI, 0.39–0.88; p = 0.009), with consistent results in the propensity score-based IPTW sensitivity analysis (HR, 0.58; 95% CI, 0.40–0.86; p = 0.006). Restricted cubic spline analysis indicated a nonlinear association between OFI and PFS (p for nonlinearity = 0.005), while flexible modeling did not provide robust evidence of a treatment-by-OFI interaction (global p = 0.806). In exploratory subgroup analyses, FOLFOX plus bevacizumab rechallenge was associated with longer PFS than regorafenib among patients with an OFI of ≥6 months (adjusted HR, 0.39; 95% CI, 0.24–0.65; p < 0.001), whereas no significant difference was observed among those with an OFI of <6 months (adjusted HR, 0.66; 95% CI, 0.35–1.25; p = 0.199). Conclusions: FOLFOX plus bevacizumab rechallenge was associated with longer third-line PFS than regorafenib in this selected and uniformly treated mCRC cohort. OFI was associated with PFS in a nonlinear manner, but there was no robust evidence that it modified the relative treatment effect across its continuous range. Exploratory subgroup findings based on a 6-month cutoff require external validation.