OBJECTIVES: The prognosis of patients with metastatic colorectal cancer (mCRC) is poor and worsens in later lines. Based on randomized clinical trials (RCTs), the expected survival of patients with ≥2 prior treatment lines receiving best supportive care (BSC) is 4.8–7.1 months. New systemic treatments have recently become available for late-line mCRC. The objective was to characterize the survival benefit associated with oral monotherapies for patients with heavily pre-treated mCRC.

METHODS: A systematic literature review of MEDLINE, Embase, and the Cochrane Library identified six phase 3 RCTs of oral systemic monotherapy treatments+BSC (active treatment) versus placebo+BSC: CONCUR (regorafenib+BSC, N=204), CORRECT (regorafenib+BSC, N=760), FRESCO (fruquintinib+BSC, N=416), FRESCO-2 (fruquintinib+BSC, N=691), RECOURSE (trifluridine/tipiracil+BSC, N=800), and TERRA (trifluridine/tipiracil+BSC, N=406). Differences in median (m) overall survival (OS) and progression free survival (PFS) for active treatments over placebo+BSC were analyzed using random- and fixed-effects frequentist approaches.

RESULTS: The identified RCTs included populations with 21–73% of patients having progressed after >3 lines of chemotherapy. Across all studies included in the meta-analysis, improvement in mOS following active treatment versus placebo+BSC was 1.86 months (95% CI: 1.30, 2.42 [random effects]) and 1.84 months (1.35, 2.34 [fixed effects]); improvement in mPFS was 0.97 months (0.28, 1.66 [random effects]) and 0.63 (0.56, 0.70 [fixed effects]). Differences between study patient characteristics and when they were conducted are potential limitations of this meta-analysis; however, heterogeneity was low (I²=18.63%). As FRESCO-2 had a more heavily pre-treated population, it was excluded in a sensitivity analysis that demonstrated consistent results.

CONCLUSIONS: Oral systemic monotherapy treatments provide significant survival benefits for heavily pre-treated mCRC, including when used in the fourth-line setting and beyond. In this meta-analysis, the improvement in mOS following active treatment versus placebo+BSC was <2 months, indicating that the increases in mOS with oral systemic monotherapies versus placebo+BSC observed in RCTs, in heavily pre-treated mCRC, are meaningful.