Ramucirumab in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): An exposure-response analysis

Background REACH (NCT01140347) and REACH-2 (NCT02435433) studied ramucirumab (RAM) 8mg/kg Q2W in patients with HCC after sorafenib, with REACH-2 only enrolling patients with baseline AFP ≥400ng/mL. In REACH-2 RAM treatment improved overall survival (OS) compared to placebo (P), consistent with REACH (AFP ≥400ng/mL) patients. Here we describe exposure–response analyses (efficacy and safety) in patients from the studies. Methods Individual patient data from patients with Child–Pugh A, BCLC stage B/C, and AFP ≥400ng/mL were pooled for exposure–response analyses (n=311 RAM with evaluable RAM exposure vs n=216 P). Estimates of exposure (minimum concentration after first dose [Cmin,1]) were treated as either continuous or categorical (group to quartiles) to evaluate the relationship to OS, progression-free survival (PFS), and as categorical to evaluate the relationship to selected safety endpoints. Multivariate Cox regression or case-matched control analysis was used to evaluate OS/PFS and adjust potential imbalance in baseline prognostic factors between each quartile and the P groups. Results Several poor prognostic factors, including Child–Pugh A6 and macrovascular invasion, appeared to be more frequent in the lower exposure quartiles. Increasing RAM exposure was significantly associated with improved OS (p<0.0001), but not PFS (p=0.12), when treated as a continuous variable. While smaller hazard ratios were observed in the higher exposure quartiles for OS, a strong RAM treatment effect on PFS was observed over all exposure ranges (Table). No apparent association between increased RAM exposure and incidences of selected adverse events was observed except Grade ≥3 hypertension. Conclusions RAM 8mg/kg Q2W is a safe and effective dosing regimen for patients with HCC and AFP ≥400ng/mL, after sorafenib. Potential disease-PK interaction may confound interpretation of exposure-efficacy relationships and warrants further exploration. Table 758P Cox regression of overall survival and progression-free survival for matched case-control groups for patients with HCC and AFP ≥400ng/mL Table Matched Case-Control Group Cmin,1 Quartiles Ramucirumab (Case) N/Events Placebo (Control) N/Events Hazard Ratio (95% CI) Overall survival a, b Q1 77/67 77/65 0.967 (0.687, 1.362) Q2 78/63 78/63 0.821 (0.578, 1.164) Q3 78/60 78/66 0.613 (0.431, 0.870) Q4 78/51 78/61 0.547 (0.377, 0.794) Progression-free survival a, c Q1 77/69 77/74 0.589 (0.423, 0.820) Q2 78/66 78/72 0.575 (0.410, 0.808) Q3 78/72 78/77 0.488 (0.352, 0.676) Q4 78/66 78/75 0.458 (0.328, 0.639) a Evaluated using case-matched control analysis b Matching factors adjusted for OS: macrovascular invasion, baseline ECOG PS, and baseline AFP (log-transformed) c Matching factors adjusted for PFS: age (<65 years vs≥65 years) and baseline AFP (log-transformed) CI, confidence interval; Q1–Q4, Cmin,1 quartiles, Q1 being the lowest exposure quartile and Q4 the highest exposure quartile;. Clinical trial identification REACH (NCT01140347) and REACH-2 (NCT02435433). Editorial acknowledgement Sotiris Georgantopoulos and Gillian Gummer, Rx Communications, Mold, UK. Legal entity responsible for the study Eli Lilly and Company. Funding Eli Lilly and Company. Disclosure J. Llovet: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer Healthcare Pharmaceuticals; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): EISAI Inc; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Blueprint; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Incyte; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celsion Corporation; Advisory / Consultancy, Speaker Bureau / Expert testimony: Exelixis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Glycotest; Advisory / Consultancy, Speaker Bureau / Expert testimony: Navigant; Advisory / Consultancy, Speaker Bureau / Expert testimony: Leerink Swann LLC; Advisory / Consultancy, Speaker Bureau / Expert testimony: Midatech Ltd; Advisory / Consultancy, Speaker Bureau / Expert testimony: Fortress Biotech Inc; Advisory / Consultancy, Speaker Bureau / Expert testimony: Spring Bank Pharmaceuticals; Advisory / Consultancy, Speaker Bureau / Expert testimony: Nucleix. M. Kudo: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony: Ajinomoto; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: BMS; Advisory / Consultancy: Ono Pharmaceutical. Y. Kang: Advisory / Consultancy: Ono; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (self): DAE HWA Pharmaceutical; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (self): LSK Biopharma. R.S. Finn: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Eisai. P.R. Galle: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: SIRTEX; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sillajen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly. T. Okusaka: Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Novartis Pharma K.K.; Research grant / Funding (institution): Kowa K.K.; Research grant / Funding (institution): Takeda Bio Development Centre Ltd; Advisory / Consultancy, Research grant / Funding (institution): Nippon Boehringer Ingelheim Co.,Ltd.; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Dainippon Simitomo Pharma Co., Ltd; Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Pfizer Jana Inc.; Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Bayer Yakuhin, Ltd.; Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Yakuruto Honsha Co., Ltd.; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical Co., Ltd.; Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Eisai Co., Ltd.; Honoraria (self), Honoraria (institution), Research grant / Funding (institution): AstraZeneca K.K.; Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Merck Serono Co., Ltd.; Research grant / Funding (institution): OncoTherapy Science Inc.; Research grant / Funding (institution): Kyowa Hakko Kirin Co.,; Research grant / Funding (institution): Shizuoka Industry; Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Baxter; Advisory / Consultancy, Research grant / Funding (institution): Nano Carrier Co., Ltd.; Advisory / Consultancy, Research grant / Funding (institution): Zeria Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Glaxo Smith Kline K.K.; Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Nobelpharma Co., Ltd.; Honoraria (self), Honoraria (institution): Bristol-Myers Squibb Company; Honoraria (self), Honoraria (institution): Nipponchemofa; Honoraria (self), Honoraria (institution): EA Pharma Co., Ltd.; Honoraria (self), Honoraria (institution): FUJIFILM RI Pharma Co., Ltd.; Honoraria (self), Honoraria (institution): Astellas Pharma Inc.; Honoraria (self), Honoraria (institution): Nippon Kayaku Co., Ltd.; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Daiichi Sankyo Co., Ltd.; Honoraria (self), Honoraria (institution): Celgene, K.K.; Honoraria (self), Honoraria (institution): MSD, K.K.; Honoraria (self), Honoraria (institution): Teijin Pharma, Ltd. T. Berg: Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: AbbVie; Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: Gilead; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Intercept; Advisory / Consultancy, Research grant / Funding (institution): Merck/MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sequana Medical; Advisory / Consultancy, Speaker Bureau / Expert testimony: SIRTEX; Advisory / Consultancy, Speaker Bureau / Expert testimony: Alexion; Research grant / Funding (institution): Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Esai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ipsen. C. Hsu: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (self), Honoraria (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genetech; Research grant / Funding (institution): Taiho Pharmaceutical. M. Ikeda: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company - Japan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer Yakuhin; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Sumitomo Dainippon Pharma; Honoraria (self), Advisory / Consultancy: Teijin Pharma; Honoraria (self): EA Pharma; Honoraria (self): Kaken Pharmaceutical; Honoraria (self): MSD; Honoraria (self): Gilead; Advisory / Consultancy: Otsuka Pharmaceutical; Advisory / Consultancy: Daiichi-Sankyo; Advisory / Consultancy: Shire; Advisory / Consultancy, Research grant / Funding (institution): ASLAN Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Micron; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Yakult; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Nano Carrier; Research grant / Funding (institution): Takeda Pharmaceutical; Research grant / Funding (institution): J-Pharma. Y. Hsu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. K. Liang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. 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. L. O’Brien: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. L. Gao: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. 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: Sanofi; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Exelixis. All other authors have declared no conflicts of interest.