Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab

Abstract

Background: Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).

Methods: Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.

Results: Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6-12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354-0.574; p < 0.0001).

Conclusions: AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.

Clinical trial registration: ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).

Conflict of interest statement

A.X.Z. reports that his institution received research support from Eli Lilly and Company. R.S.F. reports consultant/advisory roles with AstraZeneca, Bayer, Bristol-Myers Squibb, C-Stone, Eisai, Eli Lilly, Exelixis, F. Hoffmann-La Roche, Genentech, Merck, Novartis and Pfizer. Y.-K.K. reports consultant/advisory roles with Bristol-Myers Squibb, DAE HWA Pharmaceutical, Lilly/ImClone, Merck Serono, Ono Pharmaceutical, Roche/Genentech and Taiho Pharmaceutical; and research funding from DAE HWA Pharmaceutical and LSK Biopharma. C.-J.Y. has no relationships to disclose. P.R.G. has been on advisory boards and received lecture fees from Bayer, Bristol-Myers Squibb, MSD, Merck, Sirtex, AstraZeneca, Sillajen, Eli Lilly and Company, Ipsen, Roche and Novartis. J.M.L. received grants and personal fees from Bayer, Eisai Inc., Bristol-Myers Squibb, Ipsen, Blueprint and Incyte, as well as personal fees from Eli Lilly and Company, Celsion Corporation, Exelixis, Merck, Clycotest, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech Inc., Spring Bank Pharmaceuticals and Nucleix, outside the submitted work. E.A. has received honoraria from Bayer, Novartis and Sirtex Medical, and reports consultant/advisory roles with Ipsen and Sanofi. G.B. has no relationships to disclose. K.M. has received honoraria from Eisai. I.O. has had a consulting/advisory role with Merck Serono, and has been on the Speakers’ Bureau for Taiho Pharmaceutical. B.D. has received honoraria from Bayer, Eisai, Eli Lilly and Company, Ipsen and MSD, and reports consultant/advisory roles with AstraZeneca, Bayer, Eisai, Ipsen, MSD, Roche and Sanofi. A.V. reports consultant/advisory roles with Eli Lilly and Company, Bayer, MSD, Roche, Novartis, AstraZeneca and Beigene. T.Y. has been on the Speakers’ Bureau for Bayer, Eisai and Eli Lilly and Company. C.-H.H. reports consultant/advisory roles with Bristol-Myers Squibb, Ono, Merck/Serono and Roche/Genentech, and research funding from MSD. G.G. has no relationships to disclose. J.B. is an employee of Envision Pharma Group. Y.H., K.L., R.W., C.W., and P.A. are employees of Eli Lilly and Company and own stock from Eli Lilly and Company. M.K. has had a consulting/advisory role with Bayer, Bristol-Myers Squibb, Eisai Co., Ltd, MSD and Ono Pharmaceutical, has received honoraria from Bayer, EA Pharma Co., Ltd, Eisai Co., Ltd and MSD, and has received research funding from AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, EA Pharma Co., Ltd, Eisai Co., Ltd, Gilead Sciences, Inc., Medico’s Hirata Inc., Otsuka Pharmaceutical Co., Ltd, Taiho Pharmaceutical and Takeda Pharmaceutical Company Limited.

Figures

Fig. 1. OS HR by baseline AFP.

STEPP analysis showing OS HR by median baseline AFP in the a REACH study patients with AFP < 400 ng/ml (ITT population), b REACH study patients with AFP ≥ 400 ng/ml (ITT population), c REACH-2 study (ITT population) and d pooled population of patients with AFP ≥ 400 ng/ml in the REACH-2 and REACH studies. AFP alpha-fetoprotein, HR hazard ratio.

Fig. 2. OS and PFS by AFP response.

Kaplan–Meier graph of a OS and b PFS in patients with vs. without AFP response in the pooled population of patients with AFP ≥ 400 ng/ml in the REACH-2 and REACH studies. AFP alpha-fetoprotein, HR hazard ratio, N no, OS overall survival, PFS progression-free survival, Y yes.

Fig. 3. Time to AFP and radiographic progression.

Kaplan–Meier plots of a time to AFP progression and b time to radiographic progression in the pooled population of patients with AFP ≥ 400 ng/ml in the REACH-2 and REACH studies. AFP alpha-fetoprotein, HR hazard ratio.

Fig. 4. Best percentage change in AFP and radiographic tumour response by treatment arm.

Waterfall plots of response for patients by treatment arm in the pooled population of patients with AFP ≥ 400 ng/ml in the REACH-2 and REACH studies: a the best percentage change in AFP from baseline measurements by treatment arm and b best percentage change in radiographic tumour response and relationship with AFP response. AFP alpha-fetoprotein.

Fig. 5. AFP percentage change from baseline by cycle.

Medians of AFP percentage changes from baseline were plotted every three cycles for the pooled population of patients with AFP ≥ 400 ng/ml in the REACH-2 and REACH studies by treatment arm: a for all patients, b for patients with the best overall response of CR/PR, c for patients with the best overall response of CR/PR/SD and d) for patients with the best overall response of PD. AFP alpha-fetoprotein, CR complete response, ITT intent to treat, PBO placebo, PD progressive disease, PR partial response, RAM ramucirumab, SD stable disease.