Background: HCC progression may be due to tumor growth or new intrahepatic or extrahepatic lesions. RECIST does not discriminate between progression patterns even though the prognosis may differ (Reig, Hepatology 2013). REG improves overall survival (OS) in patients with HCC who progress during SOR treatment (HR 0.63; 95% CI 0.50, 0.79; P < 0.001). This exploratory analysis aimed to validate the pattern of progression concept in a global cohort treated with prior SOR and to assess the impact of REG on survival by prior progression. Methods: Adults with HCC who tolerated SOR and had radiologic progression during SOR, Child–Pugh A liver function, and ECOG PS 0–1 were randomized 2:1 to REG 160 mg/day or placebo during weeks 1–3 of each 4-week cycle. Progression during SOR was due to tumor growth or new lesions. Post-progression survival (PPS) was the time from progression on SOR until death. Results: Baseline characteristics of the 573 randomized patients (REG = 379; placebo = 194) were balanced; median age was 63 years, 88% were male, 87% were BCLC stage C, 29% had macrovascular invasion, and 72% had extrahepatic disease. Hazard ratios favored REG irrespective of pattern of progression during prior SOR, but differed according to progression pattern (Table). Conclusions: The development of new extrahepatic lesions is associated with worse survival irrespective of treatment. REG provided an OS benefit, regardless of progression pattern. Progression pattern may be a key prognostic parameter and should be considered in future trial design and analysis. Clinical trial information: NCT01774344