BACKGROUND & AIMS: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). METHODS: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods (stratified by study) assessed OS, progression-free survival (PFS), time to progression (TTP) and patient-reported outcomes (Functional Hepatobiliary System Index-8 [FHSI-8] score). RESULTS: A total of 542 patients (<65 years: n = 302; ≥65 to <75 years: n = 160; ≥75 years: n = 80) showed similar baseline characteristics between ramucirumab and placebo. Older subgroups had higher hepatitis C and steatohepatitis incidences, and lower AFP levels, than the <65 years subgroup. Ramucirumab prolonged OS in patients <65 years (hazard ratio [HR], 0.753; 95% CI 0.581-0.975), ≥65 to <75 years (0.602; 0.419-0.866) and ≥75 years (0.709; 0.420-1.199), PFS and TTP irrespective of age. Ramucirumab showed similar overall safety profiles across subgroups, with a consistent median relative dose intensity ≥97.8%. A trend towards a delay in symptom deterioration in FHSI-8 with ramucirumab was observed in all subgroups. CONCLUSIONS: In this post-hoc analysis, ramucirumab showed a survival benefit across age subgroups with a tolerable safety profile, supporting its use in advanced HCC with elevated AFP, irrespective of age, including ≥75 years.

Department of Clinical and Experimental Oncology Medical Oncology Unit 1 Veneto Institute of Oncology IRCCS Padua Italy

Department of Complex Oncology Care Masaryk Memorial Cancer Institute Masaryk University Brno Czech Republic

Department of Experimental Diagnostic and Speciality Medicicne University Hospital S Orsola Malpighi Bologna Italy

Department of Gastroenterology and Hepatology Kindai University Faculty of Medicine Osaka Japan

Department of Hepatobiliary and Pancreatic Oncology Kanagawa Cancer Center Yokohama Japan

Department of Hepatobiliary and Pancreatic Oncology National Cancer Center Hospital Tokyo Japan

Department of Hepatology Aso Iizuka Hospital Fukuoka Japan

Department of Hepatology Gastroenterology and Endocrinology Medizinische Hochschule Hannover Hannover Germany

Department of Internal Medicine Mainz University Medical Center Mainz Germany

Department of Medical Oncology Centre Eugène Marquis Rennes France

Department of Medical Oncology CHU de Montpellier Montpellier France

Department of Medical Oncology University Hospital of Besançon Besançon France

Department of Medicine Division of Hematology Oncology Geffen School of Medicine at UCLA Los Angeles CA USA

Department of Medicine Massachusetts General Hospital Cancer Center Harvard Medical School Boston MA USA

Department of Oncology Azienda Ospedaliera Gaetano Rummo Benevento Italy

Global Statistical Sciences Eli Lilly and Company Surrey UK

Hepatology and Gastroenterology Unit Croix Rousse Hospital Northern Lyon Hospital Group Lyon France

Medicines Development Unit Japan Eli Lilly Japan K K Kobe Japan

Mount Sinai Liver Cancer Program Division of Liver Diseases Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA

Oncology Eli Lilly and Company Indianapolis IN USA

Translational Research in Hepatic Oncology Group Liver Unit IDIBAPS Hospital Clinic Barcelona University of Barcelona Barcelona Catalonia Spain

Zobrazit více v PubMed

EASL Clinical Practice Guidelines. Management of hepatocellular carcinoma. J Hepatol. 2018;69:182-236.

MarreroJA, KulikLM, SirlinCB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68:723-750.

VogelA, CervantesA, ChauI, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv238-iv255.

BrunotA, Le SourdS, PrachtM, EdelineJ. Hepatocellular carcinoma in elderly patients: challenges and solutions. J Hepatocell Carcinoma. 2016;3:9-18.

ArellanoLM, AroraSP. Systemic treatment of advanced hepatocellular carcinoma in older adults. J Nat Sci. 2018;4:e518.

ChoE, ChoHA, JunCH, KimHJ, ChoSB, ChoiSK. A review of hepatocellular carcinoma in elderly patients focused on management and outcomes. In Vivo. 2019;33:1411-1420.

Abou-AlfaGK, MeyerT, ChengA-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54-63.

BruixJ, QinS, MerleP, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56-66.

KudoM, FinnRS, QinS, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163-1173.

FinnRS, RyooB-Y, MerleP, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38:193-202.

YauT, ParkJW, FinnRS, et al. LBA38_PRCheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;459:v874-v875.

ChengA-L, QinS, IkedaM, et al. LBA3IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol. ;150:ix186-ix187.

RimassaL, DanesiR, PressianiT, MerleP. Management of adverse events associated with tyrosine kinase inhibitors: improving outcomes for patients with hepatocellular carcinoma. Cancer Treat Rev. 2019;77:20-28.

ZhuAX, KangY-K, YenC-J, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:282-296.

ZhuAX, ParkJO, RyooB-Y, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16:859-870.

YountS, CellaD, WebsterK, et al. Assessment of patient-reported clinical outcome in pancreatic and other hepatobiliary cancers: the FACT Hepatobiliary Symptom Index. J Pain Symptom Manage. 2002;24:32-44.

LlovetJ, KudoM, KangY-K, et al. Ramucirumab in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): an exposure-response analysis. Ann Oncol. 2019;30:758P.

RimassaL, CicinI, BlancJ-F, et al. Outcomes based on age in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36:4090-4090.

MuroK, ChoJY, BodokyG, et al. Age does not influence efficacy of ramucirumab in advanced gastric cancer: subgroup analyses of REGARD and RAINBOW. J Gastroenterol Hepatol. 2018;33:814-824.

ArnoldD, FuchsCS, TaberneroJ, et al. Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann Oncol. 2017;28:2932-2942.

NishikawaH, KimuraT, KitaR, OsakiY. Treatment for hepatocellular carcinoma in elderly patients: a literature review. J Cancer. 2013;4:635-643.

ZhouK, FountzilasC. Outcomes and quality of life of systemic therapy in advanced hepatocellular carcinoma. Cancers. 2019;11:861.

PallisAG, FortpiedC, WeddingU, et al. EORTC elderly task force position paper: approach to the older cancer patient. Eur J Cancer. 2010;46:1502-1513.