Background
Phase III double-blind RCT, N=292 (randomized 2:1; ramucirumab n=197, placebo n=95), patients with advanced HCC, AFP ≥400 ng/mL, Child-Pugh A, ECOG PS 0–1, prior sorafenib. Conducted at 92 sites in 20 countries Jul 2015–Aug 2017. The AFP ≥400 threshold was selected from exploratory biomarker data in the REACH trial, where AFP-high patients appeared to benefit. REACH-2 was the first positive biomarker-selected phase III HCC trial.
Interventions and follow up
Arm A: Ramucirumab 8mg/kg IV q2wk + best supportive care
Arm B: Placebo IV q2wk + best supportive care
Primary endpoint: Overall survival
Median follow up: 7.6mo
Arm B: Placebo IV q2wk + best supportive care
Primary endpoint: Overall survival
Median follow up: 7.6mo
Results
OS: 8.5 vs 7.3mo, HR 0.710 (95% CI 0.531–0.949), P=.0199
PFS: 2.8 vs 1.6mo, HR 0.452 (0.339–0.603), P<.001
ORR: 5% vs 1%, P=.1697 (not significant)
PFS: 2.8 vs 1.6mo, HR 0.452 (0.339–0.603), P<.001
ORR: 5% vs 1%, P=.1697 (not significant)
Adverse events
Cardiovascular/metabolic: Grade ≥3 hypertension 13% vs 5%; hyponatraemia 6% vs 0.
Serious/fatal: Serious AEs any cause 35% (ramucirumab) vs 29% (placebo); treatment-related deaths 3 (1%) in the ramucirumab group (acute kidney injury, hepatorenal syndrome, renal failure).
Serious/fatal: Serious AEs any cause 35% (ramucirumab) vs 29% (placebo); treatment-related deaths 3 (1%) in the ramucirumab group (acute kidney injury, hepatorenal syndrome, renal failure).
Conclusions
Ramucirumab significantly improved OS in patients with HCC and AFP ≥400 ng/mL after sorafenib, establishing a biomarker-selected standard for second-line HCC treatment. This was the first phase III trial designed prospectively in a biomarker-selected HCC population, validating AFP as a predictive biomarker for VEGFR-2 inhibition.
Key Limitations
The absolute OS benefit is modest (1.2 months, HR 0.71), with the confidence interval nearly crossing 1.0. The AFP ≥400 threshold was derived post-hoc from REACH, raising concern about data-driven threshold selection, although prospective validation in REACH-2 substantially mitigates this. The ORR was low (5%) and not statistically improved, raising questions about whether AFP-guided selection is optimally predictive. Only patients with AFP ≥400 ng/mL (~35–40% of sorafenib-treated HCC patients) are eligible.
Clinical Context
REACH-2 established ramucirumab as a second-line standard for AFP ≥400 ng/mL HCC patients post-sorafenib. FDA approved ramucirumab for this indication in 2019. With first-line therapy now shifted to atezo+bev or nivo+ipi, the post-first-line population receiving sorafenib is smaller; nonetheless REACH-2 remains most relevant to patients who received sorafenib. It is considered alongside RESORCE (regorafenib) and CELESTIAL (cabozantinib) as defining second-line HCC options.