Prognostic and predictive value of baseline alpha-fetoprotein (AFP) in patients with advanced hepatocellular carcinoma (HCC) treated with ramucirumab from two phase III studies (REACH, REACH-2)

Background Elevated AFP in patients (pts) with HCC is associated with worse prognosis. Two placebo (P)-controlled trials (REACH, REACH-2) have studied ramucirumab (RAM, anti-VEGFR2 antibody) in pts with HCC after sorafenib, with REACH-2 enrolling only pts with baseline AFP ≥400ng/mL. In REACH-2 RAM treatment (trt) improved overall survival (OS) compared to P, consistent with REACH (AFP ≥400ng/mL) pts. Here we present post-hoc analyses assessing the prognostic and predictive value of baseline AFP in both studies. Methods Pts with HCC, Child-Pugh A, ECOG PS 0-1, and prior sorafenib were randomized to RAM 8mg/kg or P Q2W. The prognostic value of baseline AFP was assessed by Cox regression models with either continuous or dichotomous (≥400 vs<400ng/ml) AFP (REACH, N=565), and confirmed using Cox model with continuous AFP ≥400ng/mL (REACH-2, N=292). Cox model with AFP and its trt interaction assessed the predictive value of baseline AFP in REACH. Subpopulation trt effect pattern plot (STEPP) assessed the interaction between RAM trt and AFP in REACH, REACH-2 and pooled individual pt data analysis of both studies (AFP ≥400mg/mL). Results Baseline AFP was confirmed as a significant continuous (REACH and REACH-2; p<.0001) and dichotomous (REACH; p<.01) prognostic factor for OS. AFP remained the predominant prognostic factor after adjusting for other significant prognostic factors, including macrovascular invasion and ECOG PS. The interaction between AFP and trt effect was significant in REACH (p=.0042 continuous; p<.0001 dichotomous), suggesting the predictive value of AFP in RAM OS benefit. Based on Cox regression of OS on continuous AFP level and its interaction with trt, the estimated OS hazard ratio in REACH (<0.8, 95% CI below 1) was significant at each AFP value ≥400ng/mL, supporting AFP ≥400ng/mL as selection criterion for RAM OS benefit. STEPP supported these results with OS benefits at each AFP value ≥400ng/mL. Conclusions The prognostic impact of baseline AFP is an important factor to consider in trial design. The findings suggest AFP may be predictive of RAM OS benefit. Results also confirm AFP ≥400ng/mL is appropriate selection criterion for RAM OS benefit. Clinical trial identification NCT01140347, NCT02435433. Editorial acknowledgement Nathalie Godinot, funded by Eli Lilly and Company. Legal entity responsible for the study Eli Lilly and Company. Funding Eli Lilly and Company. Disclosure A.X. Zhu: Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy: Roche/Genentech. P.R. Galle: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Schering Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sirtex Medical; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy: Bristol-Meyers Squibb; Advisory / Consultancy: MSD; Honoraria (self): Sillajen. J.M. Llovet: Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Celsion; Advisory / Consultancy: Incyte; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Glycotest; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Bayer Schering Pharma. R.S. Finn: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche Genentech; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Exelixis. Y. Kang: Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche Genentech; Advisory / Consultancy: Merck Serono; Advisory / Consultancy, Research grant / Funding (self): DAE HWA Pharmaceutical; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (self): LSK Biopharma. E. Assenat: Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Terasphere; Honoraria (self), Advisory / Consultancy: Sirtex Medical; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Servier. G. Brandi: Advisory / Consultancy: Eli Lilly and Company. K. Motomura: Honoraria (self): Eisai. I. Ohno: Advisory / Consultancy: Merck Serono; Speaker Bureau / Expert testimony: Taiho Pharmaceutical. B. Daniele: Honoraria (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Incyte; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Celgene. A. Vogel: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Delcath Systems; Honoraria (self), Advisory / Consultancy: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Baxalta; Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Sanofi; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD. T. Yamashita: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Eisai. C. Hsu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Taiho Pharmaceutical. T. Meyer: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy: Tarveda Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): BTG; Advisory / Consultancy: Beigene; Advisory / Consultancy: MSD; Research grant / Funding (institution): Bayer. R. Widau: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. W. Schelman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. C. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. Y. Hsu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. M. Kudo: Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Research grant / Funding (institution): AbbVie; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Gilead Sciences; Honoraria (self): Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: EA Pharma; Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Bristol-Myers Squibb Japan. All other authors have declared no conflicts of interest.