Ramucirumab for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma following disease progression on first-line platinum- or fluoropyrimidine-containing combination therapy in Japanese patients: a phase 2, open-label study
- 530 Downloads
Ramucirumab, a monoclonal antibody vascular endothelial growth factor receptor-2 antagonist, given as monotherapy improved survival in a global phase 3 study (REGARD) of patients with gastric cancer. However, REGARD did not include Japanese patients. This study evaluated the efficacy and safety of ramucirumab monotherapy in Japanese patients with advanced gastric cancer.
This multicenter, open-label, nonrandomized phase 2 study (Clinicaltrials.gov: NCT01983878) was performed at 16 Japanese sites. Patients with advanced gastric or gastroesophageal junction cancer after disease progression following first-line chemotherapy received intravenous ramucirumab 8 mg/kg every 2 weeks. Primary efficacy outcome: 12-week progression-free survival rate (PFS).
Thirty-six patients were enrolled. The 12-week PFS rate was 23.8% [90% confidence interval (CI) 12.4–37.2); the primary outcome was not met as the lower limit of the CI was outside the threshold of 16%. Median PFS was 6.6 weeks (90% CI 6.1–7.1). No patients achieved an objective response, and 11 (31%) patients achieved disease control. Median overall survival was 8.6 months (90% CI 5.7–10.7). The most frequent treatment-emergent adverse events (TEAEs) were diarrhea (9/36; 25%) and decreased appetite (8/36; 22%). Three patients reported Grade ≥ 3 ileus; all other Grade ≥ 3 TEAEs were reported by ≤ 2 patients. The most frequent adverse events of special interest (AESIs) were hypertension (10/36; 28%), bleeding/hemorrhage (7/36; 19%), and proteinuria (7/36; 19%). All Grade ≥ 3 AESIs were reported by ≤ 2 patients.
These findings suggest that ramucirumab monotherapy has clinical activity and a manageable safety profile in Japanese patients with gastric cancer after disease progression following first-line chemotherapy.
KeywordsAdenocarcinoma Japan Pharmacokinetics Ramucirumab Stomach neoplasms REGARD
The authors would like to thank all study participants.
All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. TK, KM, and TS were involved in designing the study. KY, KF, FN, YO, NM, and TN were study investigators and involved in data collection. MT was involved in the statistical analysis. TK was involved in the pharmacokinetics analysis.
This study was sponsored by Eli Lilly and Company, the manufacturer and licensee of CYRAMZA®. Medical writing assistance was provided by Luke Carey, PhD, and Justine Southby, PhD, CMPP, of ProScribe—Envision Pharma Group, and was funded by Eli Lilly and Company. ProScribe’s services complied with international guidelines for Good Publication Practice (GPP3).
Compliance with ethical standards
Role of the sponsor
Eli Lilly and Company was involved in the study design, data collection, data analysis, and preparation of the manuscript.
Conflict of interest
KY and NM have received grants and personal fees from Eli Lilly and Company. FN has received grants from Taiho Pharmaceutical, Merck Serono, Zeria Pharmaceutical, Yakult, OncoTherapy Science, J-Pharma, Eli Lilly Japan K.K., Janssen Pharmaceutical, Bayer Yakuhin, Kyowa Hakko Kirin, Shionogi, Daiichi Sankyo, Takeda, Chugai Pharmaceutical, GlaxoSmithKline, Nippon Kayaku, Bristol-Myers Squibb, Mochida Pharmaceutical, Astellas Pharma, Ono Pharmaceutical, Sanofi S.A., Novartis, Torii Pharmaceutical, MSD, Covance Inc., Baxalta Japan, Eisai, NanoCarrier, and NPO Japan Clinical Research Support Unit. YO and TN have received grants from Eli Lilly and Company. TK, MT, and KM are employees of and own shares in Eli Lilly and Company. TS has received grants or personal fees from Yakult Honsha, Chugai Pharmaceutical, Ono Pharmaceutical, Eli Lilly and Company, Merck-Serono, Bristol-Myers Squibb, Takeda Pharmaceutical, Taiho Pharmaceutical, and Takara Bio. KF has no potential conflicts of interest to declare.
Human rights statement and informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.
- 1.Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11. Lyon, France; International Agency for Research on Cancer. Available at http://globocan.iarc.fr. Accessed on 14 July 2016.
- 4.Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–9.CrossRefGoogle Scholar
- 5.Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–35.CrossRefGoogle Scholar
- 6.Pharmaceuticals and Medical Devices Agency, Japan. List of approved products (2016). Available at http://www.pmda.go.jp/files/000212691.pdf. Accessed on 28 June 2016.
- 8.Shitara K, Muro K, Shimada Y, Hironaka S, Sugimoto N, Komatsu Y, et al. Subgroup analyses of the safety and efficacy of ramucirumab in Japanese and Western patients in RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer. Gastric Cancer. 2016;19:927–38.CrossRefGoogle Scholar
- 10.Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013;31:4438–44.CrossRefGoogle Scholar
- 14.Tabernero J, Ohtsu A, Muro K, Van Cutsem E, Oh SC, Bodoky G, et al. Exposure-response (E-R) relationship of ramucirumab (RAM) from two global, randomized, double-blind, phase 3 studies of patients (Pts) with advanced second-line gastric cancer. J Clin Oncol. 2015;33(Suppl 3):121.CrossRefGoogle Scholar
- 15.Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28:780–7.CrossRefGoogle Scholar
- 16.Chiorean EG, Hurwitz HI, Cohen RB, Schwartz JD, Dalal RP, Fox FE, et al. Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors. Ann Oncol. 2015;26:1230–7.CrossRefGoogle Scholar