Ramucirumab (RAM) as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC) following first-line therapy with sorafenib in the randomized phase III REACH study: Analysis of alpha-fetoprotein (AFP) kinetics during treatment

Background: REACH, a global, randomized, double-blinded Phase III study, evaluated efficacy and safety of single-agent RAM for patients with advanced HCC after prior sorafenib. Significant improvement in overall survival (OS) in the ITT population was not achieved. However, a clinically meaningful improvement in OS was observed in patients with elevated baseline AFP levels. Analyses of AFP response and progression during the course of treatment were performed.

Material and Methods: Patients received either RAM 8mg/kg or placebo (PBO) i.v. on a q2w cycle until disease progression, unacceptable toxicity or withdrawal of consent. Serum AFP levels were measured at baseline and every 3 cycles. Percent change in AFP from baseline was analyzed for each arm at each time point up to Cycle 12. AFP response was defined as ≥20% decrease from baseline in the population subset with baseline AFP ≥1.5 ULN. AFP progression was defined as ≥20% increase from non-zero baseline and absolute increase ≥10ng/mL, or absolute increase AFP ≥10ng/mL from zero baseline. Analyses evaluated the association between the events of AFP progression and radiographic progression in each AFP level measurement time interval (Fisher's exact test and odds ratio [OR]). Time to AFP progression was evaluated by the Kaplan–Meier (KM) method and compared using a stratified log-rank test. Hazard ratio (HR) was generated using a stratified Cox regression model.

Results: Baseline AFP level distributions were similar in both arms. The median percent increase in AFP level from baseline was numerically smaller in the RAM arm (4%, 0%, 3%, 33%) than in the PBO arm (37%, 50%, 99%, 78%) at Cycles 3, 6, 9 and 12, respectively. Time to AFP progression (HR 0.609, p<0.0001) and time to radiographic progression (TTP) (HR 0.593, p<0.0001) favored a RAM benefit; subsequent analyses demonstrated a strong association between AFP progression and radiographic progression at 6 weeks (OR 6.44, 95%CI 4.03, 10.29; p<0.0001) and 12 weeks (OR 2.28, 95%CI 1.47, 3.53; p=0.0002). AFP response was significantly higher for the RAM arm compared with PBO (p<0.0001). In the population with baseline AFP ≥1.5 ULN, waterfall plot analyses reveal more patients on the RAM arm experienced tumor shrinkage and AFP response compared with the PBO arm.

Conclusion: Additional REACH analyses show changes in AFP levels are associated with tumor shrinkage and TTP. Treatment with RAM prolonged both time to AFP progression and radiographic TTP, and appeared to slow the rate of AFP increase over time. Whether the suppression of AFP progression from RAM treatment translates to an OS benefit warrants further investigation.

Conflict of interest: Ownership: NA. Advisory Board: J-F Blanc – Eli Lilly. I. Chau – Sanofi Oncology, Eli Lilly, Bristol Meyers Squibb, Meck Serono, Gilead Science, Bayer. T. Okusaka – Eli Lilly. J.M. Phelip – Eli Lilly, Roche, Merck, Sanofi, Amgen, Bayer. Board of Directors: NA. Corporate-sponsored Research: I. Chau – Novartis, Roche, Merck-Sorono. H.C. Chung – Eli Lilly. T. Okusaka – Eli Lilly. J.M. Phelip – Merck, Roche, Chugai, Amgen. Other Substantive Relationships: L. Yang is an employee of Eli Lilly. P. Abada is an employee of Eli Lilly.