Survival benefit of oral systemic monotherapy in previously treated metastatic colorectal cancer: a meta-analysis

BACKGROUND: Guideline-recommended non-targeted systemic therapies for previously treated metastatic colorectal cancer (mCRC) include regorafenib, trifluridine/tipiracil, and fruquintinib, but no consensus exists on the definition of clinically meaningful improvements for later-line mCRC treatments. MATERIALS AND METHODS: Trials were identified from systematic searches in MEDLINE, Embase, and the Cochrane Library. Meta-analyses were performed to characterize overall survival (OS) and progression-free survival (PFS) improvements with systemic therapy versus placebo in previously treated mCRC. Meta-analyses were conducted using fixed effect and random effects (RE) frequentist models of difference in medians, hazard ratios (HRs), and 12-month restricted mean survival time (RMST). RESULTS: Six randomized, placebo-controlled, phase III trials of 3277 patients comparing oral systemic monotherapies with placebo were analyzed. Using the RE model, the meta-analyzed OS estimate for oral systemic monotherapy versus placebo was 1.86 months (95% confidence interval [CI], 1.30-2.42) for difference in medians, 0.69 (95% CI, 0.64-0.76) for HRs, and 1.25 months (95% CI, 0.69-1.82) for difference in 12-month RMST. For PFS, meta-analyzed median improvement was 0.97 months (95% CI, 0.28-1.66), HR was 0.38 (95% CI, 0.30-0.47), and 12-month RMST difference was 1.90 months (95% CI, 1.41-2.39). Sensitivity analyses, excluding the FRESCO-2 trial due to prior treatment differences, confirmed the primary meta-analysis results. CONCLUSION: When assessing clinical benefit of later-line mCRC treatments, the broad clinical picture including individualized treatment goals should be evaluated. Considering multiple survival measures in the later-line mCRC context, an incremental survival improvement with oral systemic monotherapy versus no active therapy is clinically meaningful.