O-005 - Ramucirumab (RAM) as second-Line treatment in patients with advanced hepatocellular carcinoma (HCC) following first-line therapy with sorafenib: com...

Date 04 July 2015
Event WorldGI 2015
Session Oral and LBA abstracts
Topics Anti-Cancer Agents & Biologic Therapy
Hepatobiliary Cancers
Presenter A. Zhu
Citation Annals of Oncology (2015) 26 (suppl_4): 108-116. 10.1093/annonc/mdv235
Authors A. Zhu1, D. Pastorelli2, J.O. Park3, I. Chau4, T. Okusaka5, M. Kudo6, M. Peck-Radosavljevic7, B.-. Ryoo8, C.-. Yen9, H.-. Chung10, A. Baron11, R. Poon12, J.-. Blanc13, T. Flesch Pfiffer14, K. Kubackova15, J. Trojan16, J. Sastre17, P. Malfertheiner18, S.-. Chang19, P. Abada1, L. Yang20, A. Girvan1
  • 1Massachusetts General Hospital Cancer Center, Boston/US
  • 2Istituto Oncologico Veneto (IOV) – IRCCS, Padova/IT
  • 3Samsung Medical Center, Seoul/KR
  • 4Royal Marsden Hospital, Sutton/UK
  • 5National Cancer Center Hospital, Chuo-ku/JP
  • 6Kinki University School of Medicine, Osaka-Sayama City/JP
  • 7Medizinische Universität Wien, Vienna/AT
  • 8Asan Medical Center, Seoul/KR
  • 9National Cheng Kung University Hospital, Tainan/TW
  • 10Yonsei University College of Medicine, Seoul/KR
  • 11California Pacific Medical Center, San Francisco/US
  • 12The University of Hong Kong, Hong Kong/CN
  • 13Hôpital Saint-André, Bordeaux/FR
  • 14Instituto do Cancer do Estado de São Paulo, São Paulo/BR
  • 15University Hospital in Motol, Prague/CZ
  • 16Goethe-Universität, Frankfurt/DE
  • 17Hospital Clínico San Carlos, Madrid/ES
  • 18Universitätsklinikum Magdeburg, Magdeburg/DE
  • 19Massachusetts General Hospital Cancer Center, Boston/
  • 20Eli Lilly and Company, Bridgewater/

Abstract

Introduction

REACH was a global, multicenter, double-blind, phase 3 study evaluating the efficacy and safety of RAM as a single agent for patients with advanced HCC after prior sorafenib. Comprehensive results from the REACH study are presented.

Methods

Eligible intention-to-treat (ITT) population included Child-Pugh (CP) A; advanced HCC; stage BCLC C or B refractory or not amenable to locoregional therapy; ECOG PS 0-1; prior sorafenib; and adequate hematologic and biochemical parameters. Patients were randomized 1:1 to receive RAM (8 mg/kg IV) or placebo (PBO) every 2 weeks until progression, unacceptable toxicity, or death. CP B patients were enrolled initially; analyses in this population are exploratory. Data on RAM treatment efficacy, safety, and impact on patient-focused outcomes are presented for the ITT (CP A) and CP score 7 + 8 (CP B) populations. The primary analysis compared overall survival (OS) using a stratified log-rank test. HR was generated using a stratified Cox regression model.

Results

The OS HR for the ITT population (RAM 283; PBO 282) was 0.866 (95% CI 0.717–1.046; p = 0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. Median progression-free survival with RAM and PBO was 2.8m and 2.1m, respectively (HR 0.63; 95% CI 0.52–0.75; p < 0.0001). Objective response rate was 7.1% for RAM and 0.7% for PBO (p < 0.0001). In the ITT population, time to deterioration of symptoms in FACT Hepatobiliary Symptom Index (FHSI)-8 (HR 1.04; 95% CI 0.80–1.34; p = 0.78) and time to ECOG PS ≥2 (HR 0.89; 95% CI 0.65–1.22; p = 0.47) were similar between treatment arms. The OS HR for patients with CP B (N = 39 RAM; N = 39 PBO) was 0.998 (95% CI 0.623–1.599; p = 0.9946).

The observed safety profile in the ITT population was consistent with advanced HCC and the previously demonstrated safety profile for single-agent RAM. In CP B patients, an increase in liver events grade ≥3 was observed on the RAM versus PBO arm (58% vs 42%), including an increase in hepatic encephalopathy grade ≥3 (11% vs 0%). Analyses suggest the risk of encephalopathy is reduced in patients with no prior history of this adverse event.

In ITT patients with baseline alpha-fetoprotein (AFP) ≥400 ng/mL, OS HR was 0.674 (95% CI 0.508–0.895; p = 0.0059); there was a strong trend toward a delay in the deterioration of symptoms in FHSI-8 (p = 0.054) and ECOG PS (p = 0.057) for RAM-treated patients compared to PBO. In CP B patients with AFP ≥400 ng/mL, OS HR was 0.674 (0.332–1.368; p = 0.2756). The safety profiles in ITT patients with baseline AFP ≥ or <400 ng/mL were consistent with the overall ITT safety population.

Conclusion

A statistically significant improvement in OS was not met in REACH. A consistent and clinically meaningful improvement in OS was observed in ITT patients with baseline AFP levels ≥400 ng/mL, with a similar trend in CP B patients. In the ITT population with baseline AFP ≥400 ng/mL, a strong trend for delay in symptoms and PS deterioration was observed. The safety profile of RAM in the ITT population is considered manageable, regardless of baseline AFP.