Background: Patients (pts) with advanced hepatocellular carcinoma (HCC) and elevated α-fetoprotein (AFP) have poor prognosis, and need effective, well-tolerated treatment options. Ramucirumab has been shown to improve survival and is currently approved as second-line therapy for pts with a baseline elevated AFP that have progressed on prior sorafenib. However, new options now exist in the front-line setting. This global open-label expansion cohort of REACH-2 (NCT02435433) was initiated to study ramucirumab in pts with advanced HCC and baseline AFP ≥400 ng/mL following a non-sorafenib based systemic therapy, representing one of the first sequencing studies in HCC. Methods: This single-arm study investigated ramucirumab in pts with advanced HCC (BCLC stage C or B disease), Child-Pugh A, ECOG PS 0/1, and baseline AFP ≥400 ng/mL who received 1-2 prior systemic regimens for advanced HCC, excluding prior sorafenib or chemotherapy. Enrolled pts received ramucirumab 8 mg/kg IV once every 14 days. The primary endpoint was safety. Secondary endpoints included overall survival (OS), progression-free survival (PFS) objective response rate (RECIST 1.1) and time to progression (TTP). Final analysis occurred after all enrolled pts completed ≥ 3 treatment cycles or discontinued treatment. Results: 47 pts were treated at 21 investigative sites in the USA (n = 12), Taiwan (n = 10), mainland China (n = 8), Hong Kong (n = 8), Germany (n = 8), and Switzerland (n = 1). At baseline, these pts with 2nd to 3rd+ line advanced HCC had ECOG PS 1 (51%), with vascular invasion or extrahepatic spread (85%), viral hepatitis B (55%), BCLC stage C disease (92%), and a median AFP of 3236 ng/mL (IQR: 1332, 18210). Prior systemic regimens included lenvatinib (n = 20), checkpoint inhibitor (CPI) monotherapy (n = 11), CPI + antiangiogenic (n = 15), and CPI + CPI (n = 4). Grade ≥ 3 treatment-emergent adverse events (AEs) were reported in 27 (57%) pts and were deemed to be treatment-related in 11 (23%) pts. Grade ≥ 3 AEs occurring in ≥ 5% pts were hypertension (n = 5; 11%), proteinuria (n = 3; 6%), hyponatremia (6%) and AST increased (6%). Two deaths occurred due to treatment-related AEs on therapy or within 30 days of treatment discontinuation (myocardial infarction and upper GI hemorrhage). Median OS was 8.7 months (95% CI 4.6-12.2), median PFS was 1.7 months (95% CI 1.5-4.1), and median TTP was 2.8 months (95% CI 1.5-4.2). The number of pts achieving an objective response was 5 (10.6%, 95% CI 1.8-19.5), with a median duration of response of 8.3 months (95% CI 2.4-NR). Conclusions: This expansion cohort of REACH-2 represents a non-sorafenib sequencing study in pts with advanced HCC. The safety/efficacy profile of ramucirumab following a non-sorafenib based systemic therapy was consistent with that observed in pts who received prior sorafenib in the Ph3 REACH-2 study. Clinical trial information: NCT02435433.