Background: Lenvatinib (LEN) was shown to be noninferior to sorafenib (SOR) for overall survival (OS) in REFLECT (median OS [mOS], 13.6 vs 12.3 months [mo]; HR 0.92; 95% CI 0.79–1.06). LEN was superior vs SOR for secondary endpoints including objective response rate (ORR) per mRECIST: 24.1% vs 9.2% by investigator and 40.6% vs 12.4% by independent review (Kudo M et al. Lancet 2018). We report a posthoc responder analysis of patients (pts) who received first-line LEN in REFLECT and subsequent anticancer medication during survival follow up. Methods: In REFLECT, pts with unresectable hepatocellular carcinoma were randomized 1:1 to receive first-line LEN or SOR. Objective response was defined as complete or partial response by mRECIST per investigator. Pts with disease progression and who discontinued treatment were followed for survival every 12 weeks; subsequent anticancer medication during survival follow up were recorded until time of death. Data cutoff: Nov 13, 2016. mOS was calculated using Kaplan-Meier estimates with 2-sided 95% CIs. Results: In REFLECT, one third of the overall study population (156/478 pts randomized to LEN and 184/476 to SOR) received subsequent anticancer medication, most commonly SOR (25% in LEN arm). ECOG performance status and laboratory assessments, including liver function tests, were comparable between arms prior to subsequent treatments. Among these pts, mOS was 21 vs 17 mo and ORR was 27.6% vs 8.7% for LEN vs SOR arms, respectively. In a subset analysis of LEN responders who received any subsequent anticancer medication (n = 43), mOS was 26 mo (95% CI 18.5–34.6). For SOR responders who received any subsequent anticancer medication (n = 16), mOS was 22 mo (95% CI, 14.6–NE). For LEN responders who subsequently received SOR (n = 35), mOS was 26 mo (95% CI 18.2–34.6). Conclusions: In REFLECT, one third of pts randomized to first-line LEN received subsequent anticancer medication, including SOR, with a mOS of 21 mo. In this exploratory, posthoc analysis of pts who responded to LEN and received any subsequent anticancer medication or SOR, mOS was 26 mo. Clinical trial information: NCT01761266