Ramucirumab (RAM) was studied in patients with advanced HCC and AFP≥400 ng/mL following sorafenib in two global, randomized, double-blind, placebo (PL)-controlled phase 3 studies. REACH-2 met its primary endpoint demonstrating an improved overall survival (OS) for RAM treatment compared to PL, consistent with the benefit observed in pre-specified patients with AFP ≥400 ng/mL in REACH. Patient reported outcome (PRO) analyses of disease-related symptoms in patients from REACH-2, and pooled with patients from REACH with baseline AFP ≥400 ng/mL were performed.
Eligible patients had advanced HCC, Child-Pugh A, ECOG PS 0 or 1, AFP ≥400 ng/mL, and prior sorafenib. Patients received RAM 8 mg/kg or PL Q2W. PROs were assessed by Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index (FHSI)-8 at baseline, Q6W and end of treatment. Deterioration in FHSI-8 was defined as ≥ 3-point decrease in total score, or a decrease in one categorical response for an individual item. Time to deterioration (TTD) was time from the date of randomization to the first date of deterioration.Table: 622PD
Time to deterioration of FHSI-8
|Analysis population||REACH-2 N = 292 (RAM 197, PL 95)||REACH AFP ≥400 ng/mL N = 250 (RAM 119, PL 131)||Pooled REACH-2, REACH AFP ≥400 ng/mL N = 542 (RAM 316, PL 226)|
|Total score, median||3.7 mo RAM vs 2.8 mo PL||2.9 mo RAM vs 1.6 mo PL||3.3 mo RAM vs 1.9 mo PL|
|HR (95% CI)|
|Total score||0.799 (0.545, 1.171)||0.690 (0.470, 1.014)||0.725 (0.559, 0.941)|
|Lack of energy||1.098 (0.741, 1.627)||0.884 (0.605, 1.292)||0.942 (0.724, 1.225)|
|Nausea||0.809 (0.498, 1.315)||0.931 (0.586, 1.479)||0.821 (0.589, 1.145)|
|Pain||0.976 (0.651, 1.465)||0.641 (0.427, 0.962)||0.769 (0.588, 1.005)|
|Weight loss||0.745 (0.473, 1.172)||0.771 (0.467, 1.273)||0.699 (0.505, 0.969)|
|Back pain||0.564 (0.364, 0.876)||0.743 (0.486, 1.137)||0.668 (0.497, 0.899)|
|Fatigue||0.845 (0.584, 1.221)||0.775 (0.525, 1.142)||0.813 (0.626, 1.056)|
|Jaundice or yellow color or skin||0.592 (0.237, 1.476)||0.963 (0.461, 2.011)||0.725 (0.411, 1.278)|
|Discomfort or pain in stomach area||0.962 (0.636, 1.455)||1.062 (0.705, 1.601)||1.017 (0.767, 1.349)|
Analysis populations included REACH-2, REACH AFP ≥400 ng/mL, and the two populations pooled. FHSI-8 compliance was acceptable. Similar to REACH patients with AFP ≥400 ng/mL, RAM patients in REACH-2 reported a positive trend in TTD in FHSI-8 total score compared to PL. A similar trend was observed in most individual items, including a significant delay in back pain progression. In the pooled population, RAM treatment significantly delayed total FHSI-8 TTD, including the back pain, weight loss, and pain items, relative to PL.
Ramucirumab is the only agent specifically investigated in second line HCC patients with AFP >400 ng/mL to demonstrate a consistent trend for a benefit in disease-related symptoms.
Clinical trial identification
Legal entity responsible for the study
Eli Lilly and Company.
Eli Lilly and Company.
Nathalie Godinot of Eli Lilly and Company provided medical writing support.
A.X. Zhu: Consulting or advisory role: Eisai, Bristol-Myers Squibb, Merck, Novartis, Sanofi, AstraZeneca, Bayer, Exelixis, Eli Lilly; Research funding: Eli Lilly, Bayer, Bristol-Myers Squibb, Novartis, Merck. R.S. Finn: Consulting: AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Pfizer, Merck, Novartis, Roche/Genentech. P.R. Galle: Consulting or advisory roles: Bayer Schering Pharma, Sirtex Medical, Eli Lilly, Bristol-Myers Squibb, MSD; Honoraria: Eli Lilly, Bristol-Meyers Squibb, Sillagen, Bayer Schering Pharma, Sirtex Medical. J.M. Llovet: Consulting: Lilly, Bayer, Bristol-Myers Squibb, Blueprint Medicines, Eisai, Celsion, Boehringer Ingelheim, Incyte; Research funding; Bayer Schering Pharma, Blueprint medicines, Boehringer Ingelheim, Incyte and Bristol-Myers Squibb. J.F. Blanc: Personal fees: Lilly, Bayer, BMS, Esai, Ipsen, Onxeo, during the conduct of the study. T. Okusaka: Research grants, Honoraria, Advisory role: Eli Lilly, Novartis Pharma K.K., Kowa K.K., Takeda, Nippon Boehringer Ingelheim, Dainippon Simitomo Pharma, Pfizer Jana, Bayer Yakuhin, Chugai Pharmaceutical, Yakuruto Honsha, Ono Pharmaceutical, Eisai, AstraZeneca, Merck Serono, OncoTherapy Science, Kyowa Hakko Kirin, Shizuoka Industry, Baxter, Nano Carrier, Zeria Pharmaceutical, Glaxo Smith Kline K.K., Nobelpharma, Bristol-Myers Squibb, Nipponchemofa, EA Pharma, Fujifilm RI Pharma, Astellas Pharma, Nippon Kayaku, Daiichi Sankyo, Celgene, MSD, Teijin Pharma. I. Chau: Advisory board: Sanofi Oncology, Eli-Lilly, Bristol-Myers Squibb, MSD, Bayer, Roche, Merck Serono, Five Prime Therapeutics; Research funding: Eli-Lilly, Janssen-Cilag, Sanofi Oncology, Merck-Serono, Novartis; Honorarium: Taiho, Pfizer, Amgen, Eli-Lilly. D. Cella: Personal fees: Lilly, during the conduct of the study, Other: FACIT.org, outside the submitted work. A. Girvan, J. Gable, L. Bowman, Y. Hsu, P.B. Abada: Employee and minor shareholder: Eli Lilly and Company. M. Kudo: Consulting or advisory role: Kowa, MSD, Bristol-Myers Squibb, Bayer, Chugai Pharma, Taiho Pharmaceutical; Honoraria: Bayer, Eisai, MSD, Ajinomoto; Research funding: Chugai Pharma, Otsuka, Takeda, Taiho Pharmaceutical, Sumitomo Dainippon, Dalichi Sankyo, MSD, Eisai, Bayer, Abbvie.