LBA16 - Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC) following first-line therapy with sorafen...

Date 28 September 2014
Event ESMO 2014
Session Gastrointestinal tumours, non-colorectal
Topics Anti-Cancer Agents & Biologic Therapy
Hepatobiliary Cancers
Presenter Andrew Zhu
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors A.X. Zhu1, B. Ryoo2, C.J. Yen3, M. Kudo4, R.T.P. Poon5, D. Pastorelli6, J.F. Blanc7, H.C. Chung8, A.D. Baron9, T.E.F. Pfiffer10, T. Okusaka11, K. Kubackova12, J. Trojan13, J. Sastre14, I. Chau15, S. Chang16, P. Abada16, L. Yang17, J. Schwartz18, J.O. Park19
  • 1Hematology/oncology, Massachusetts General Hospital, 02114 - Boston/US
  • 2Oncology, Asan Medical Center, 138-736 - Seoul/KP
  • 3Internal Medicine, National Cheng Kung University Hospital, Tainan City/TW
  • 4Gastroenterology And Hepatology, Kinki University School of Medicine, Osaka-Sayama/JP
  • 5Surgery, Queen Mary Hospital, The University of Hong Kong, - - -/HK
  • 6Istituto Oncologico Veneto (iov) – Irccs, Università degli Studi di Padova, 64-35128 - Padova/IT
  • 7Digestive Oncology, Saint André Hospital, Bordeaux/FR
  • 8Division Of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul/KR
  • 9Oncology/hematology, Sutter Health California Pacific Medical Center, 94115 - San Francisco/US
  • 10Do Estado De São Paulo, Instituto do Cancer, Sao Paulo/BR
  • 11Division Of Hepatobiliary And Pancreatic Oncology, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 12Oncology And Radiotherapy, Fakultni Nemocnice V Motole, Praha /CZ
  • 13Gastrointestinal Oncology, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt/DE
  • 14Medical Oncology, Hospital Clinico San Carlos, Madrid/ES
  • 15Medicine, The Royal Marsden NHS Foundation Trust, SM2 5PT - Sutton/GB
  • 16Oncology, Eli Lilly and Company, Indianapolis/US
  • 17Oncology, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Co., Bridgewater/US
  • 18Stemline Therapeutics, Stemline Therapeutics, Inc., 10022 - New York/US
  • 19Department Of Internal Medicine, Hematology, Oncology, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul/KR

 

Abstract

Aim

Vascular endothelial growth factor (VEGF) and VEGF-receptor 2-mediated signaling and angiogenesis likely contribute to HCC pathogenesis. RAM is a fully human IgG1 monoclonal antibody and a VEGF-receptor 2 antagonist.

Methods

Eligible pts had advanced HCC, stage BCLC C or B refractory or not amenable to locoregional therapy; Child-Pugh A; ECOG PS 0 or 1; intolerance to sorafenib despite dose reduction, or disease progression during or following sorafenib; and adequate hematologic and biochemical parameters. Pts were randomized 1:1 to receive RAM (8 mg/kg IV) plus best supportive care (BSC) or placebo (PBO) plus BSC every 2 weeks until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The sample size of 544 pts was calculated to enable 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.75.

Results

Between Nov 2010 and April 2013, 565 eligible pts were randomized (RAM 283; PBO 282). Baseline pt characteristics were balanced between arms. The OS HR 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 PFS with RAM and PBO was 2.8m and 2.1m, respectively (HR 0.63, 95% CI 0.52–0.75; p <0.0001). ORR was 7.1% RAM; 0.7% PBO (p < 0.0001). Grade ≥3 adverse events occurring in >5% of treated RAM pts included: hypertension (12.3% RAM arm vs 3.6% PBO arm), asthenia (5.1% vs 1.8%), aspartate aminotransferase increased (5.4% vs 8.3%), and malignant neoplasm progression (6.5% vs 4.0%). In 250 pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL (pre-specified), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059) median OS was 7.8m for RAM vs 4.2m for PBO.

Conclusions

No new safety signals were observed. The primary end point was not met. In a selected pt population with an elevated baseline AFP, a meaningful OS improvement in the RAM arm was observed. The relationship between AFP and RAM benefit warrants further investigation.

Disclosure

J.F. Blanc: reports personal fees from Imclone systems / Lilly, during the conduct of the study; T.E. Pfiffer: reports Lilly, the sponsor of REACH trial, gave financial support to "Instituto do Cancer do Estado de São Paulo" ICESP to run part of the trial, during the conduct of the study; personal fees from Lilly, outside the submitted work; T. Okusaka: received grant money and personal fees from Eli Lilly. Relevant financial activities outside the submitted work include grant money and personal fees from several companies; J. Trojan: reports participation as a speaker and on the advisory board for Eli Lilly; J. Sastre: reports receiving personal fees for lectures from Eli Lilly, Roche, Merck, Bayer, Sanofi, and MSD; I. Chau: received research support from Eli Lilly & Co, honorarium from ImClone LLC and Eli Lilly & Co., has also been a consultant, received payment for lectures, educational presentations, and travel and meeting expenses from several other companies; S. Chang and P.B. Abada: is an employee of and has stock ownership in Eli Lilly & Co.; L. Yang: is an employee of ImClone Systems, a wholly owned subsidiary of Eli Lilly and Co., and has stock ownership in Eli Lilly and Co.; J. Schwartz: was an employee of Imclone Systems and has stock ownership in Eli Lilly. All other authors have declared no conflicts of interest.