Background: The Phase III RECOURSE trial, in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard therapies, demonstrated that trifluridine/tipiracil (FTD/TPI) significantly extended overall survival (OS) and progression-free survival (PFS) versus placebo in all subgroups, regardless of age, geographical origin, or KRAS status, with acceptable safety. Literature reports have shown optimal benefit for pts with low tumor burden (< 3 metastatic sites), indolent disease (≥ 18 mo since diagnosis of first metastasis), ECOG PS 0-1, and no liver metastasis when treated in late line mCRC. Methods: This exploratory post hoc analysis of RECOURSE (all ECOG 0-1) compared pts on FTD/TPI or placebo with good prognostic characteristics (GPC; low tumor burden and indolent disease) and poor prognostic characteristics (PPC; high tumor burden and/or aggressive disease). These subgroups were then analyzed by liver metastasis at baseline, ECOG PS, KRAS status and age. Results: Baseline characteristics were generally similar between the two groups. GPC placebo pts performed better than the PPC placebo pts, but worse than the GPC pts treated with FTD/TPI. GPC pts treated with FTD/TPI showed median OS of 9.3 mo versus 5.3 mo in PPC pts (HR 0.46; 95% CI: 0.37, 0.57; p < 0.0001); there was a similar effect for PFS. GPC pts had significantly better mOS and mPFS regardless of age (≥ 65 vs. < 65 y), ECOG PS (0–1), KRAS status (mutant vs. wildtype), and liver metastasis (y/n). No liver metastasis was the best prognostic factor: mOS in such pts treated with FTD/TPI was 16.4 mo and 7.6 mo in the GPC (n = 97) and PPC (n = 35) groups, respectively (HR 0.42; 95% CI: 0.24, 0.74; p < 0.0019); there was a similar effect for PFS. Pts with ECOG PS 0 at baseline remained PS 0-1 at discontinuation in 96% of the GPC group. Conclusions: Low tumor burden and indolent disease indicate good prognosis in late line mCRC. Pts with no liver metastasis have the best prognosis and are likely to have longer OS. GPCs might explain the percentage of long-term responders on FTD/TPI in RECOURSE. Maintenance of ECOG PS 0–1 during treatment is crucial in the continuum of care, allowing pts to benefit from further treatment options. Clinical trial information: NCT01607957