Background: Patients (pts) with advanced HCC and elevated AFP have a poorer prognosis compared to the general HCC population, and need effective, well tolerated treatment options. Increased VEGF and VEGFR2 expression is associated with high AFP expression in HCC tumors. Ramucirumab (RAM), a human IgG1 mAb, inhibits activation of VEGFR2. REACH-2 was designed to confirm the benefit of RAM treatment observed in the REACH study in pts with baseline AFP ≥400 ng/mL. Methods: Eligible pts were ≥18 yrs, had HCC with BCLC stage C or B disease refractory or not amenable to locoregional therapy, baseline AFP ≥400 ng/mL, Child-Pugh A, ECOG PS 0 or 1, adequate hematologic and biochemical parameters, had progressed on or following, or were intolerant to sorafenib. Pts were randomized (2:1) to receive RAM 8 mg/kg iv or placebo (PL) Q2W plus best supportive care, until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS), objective response rate (ORR) per RECIST v1.1 and safety. Results: 292 pts were randomized to RAM (197) or PL (95). Baseline characteristics were generally balanced between arms. RAM treatment significantly improved OS (median OS 8.5 mo vs 7.3 mo PL; HR 0.710; 95% CI 0.531, 0.949; p=.0199). RAM significantly improved PFS (median PFS 2.8 mo vs 1.6 mo PL; HR 0.452; 95% CI 0.339, 0.603; p<.0001). ORR was 4.6% RAM vs 1.1% PL (p=.1156) and disease control rate (ORR + stable disease) was 59.9% RAM vs 38.9% PL (p=.0006). Grade ≥ 3 adverse events occurring in ≥ 5% pts in the RAM arm were hypertension (12.2% RAM, 5.3% PL) and hyponatremia (5.6%, 0%). Conclusions: REACH-2 met its primary endpoint showing a significant survival benefit, with RAM treatment reducing the risk of death (29%) in pts with HCC and AFP ≥ 400 ng/mL who progressed on or were intolerant to sorafenib. Treatment was well tolerated, with a safety profile consistent with the established profile for single agent RAM. REACH-2 is the first positive phase 3 study conducted in a biomarker-selected pt population with HCC. Clinical trial information: NCT02435433