Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial

医学 埃罗替尼 催眠药 内科学 阿法替尼 肿瘤科 临床终点 人口 安慰剂 肺癌 盐酸厄洛替尼 表皮生长因子受体 临床试验 癌症 病理 替代医学 环境卫生
作者
Kazuhiko Nakagawa,Edward B. Garon,Takashi Seto,Makoto Nishio,Santiago Ponce Aix,Luis Paz‐Ares,Chao‐Hua Chiu,Keunchil Park,Silvia Novello,Ernest Nadal,Fumio Imamura,Kiyotaka Yoh,Jin‐Yuan Shih,Kwok Hung Au,Denis Moro‐Sibilot,Sotaro Enatsu,Annamaria H. Zimmermann,Bente Frimodt‐Moller,Carla Visseren‐Grul,Martin Reck,Quincy Chu,Alexis B. Cortot,Jean-Louis Pujol,Denis Moro‐Sibilot,Elizabeth Fabre,Corinne Lamour,Helge Bischoff,Jens Kollmeier,Martin Reck,Martin Kimmich,Walburga Engel-Riedel,Stefan Hammerschmidt,Wolfgang Schütte,Konstantinos Syrigos,Jcm Ho,Kwok‐Hung Au,Silvia Novello,Andrea Ardizzoni,Giulia Pasello,Vanesa Gregorc,Alessandro Del Conte,Domenico Galetta,Toshiaki Takahashi,Kazuhiko Nakagawa,Makoto Nishio,Kiyotaka Yoh,Takashi Seto,Fumio Imamura,Toru Kumagai,Katsuyuki Hotta,Yasushi Goto,Yukio Hosomi,Hiroshi Sakai,Yuichi Takiguchi,Young Hak Kim,Takayasu Kurata,Hiroyuki Yamaguchi,Haruko Daga,Isamu Okamoto,Miyako Satouchi,Satoshi Ikeda,Kazuo Kasahara,Shinji Atagi,Koichi Azuma,Toru Kumagai,Keisuke Aoe,Toru Kumagai,Keisuke Aoe,Yoshitsugu Horio,Nobuyuki Yamamoto,Hiroshi Tanaka,Satoshi Watanabe,Naoyuki Nogami,Tomohiro Ozaki,Ryo Koyama,Tomonori Hirashima,Hiroyasu Kaneda,Keisuke Tomii,Yuka Fujita,Masahiro Seike,Naoki Nishimura,Terufumi Kato,Masao Ichiki,Hideo Saka,Katsuya Hirano,Yasuharu Nakahara,Shunichi Sugawara,Keunchil Park,Sang‐We Kim,Young Joo Min,Hyun Woo Lee,Jin‐Hyoung Kang,Ho Jung An,Ki Hyeong Lee,Jin-Soo Kim,Gyeong‐Won Lee,Sung Yong Lee,Aurelia Alexandru,Anghel Adrian Udrea,Óscar Juan,Ernest Nadal-Alforja,Ignacio Gil‐Bazo,Santiago Ponce-Aix,Luis Paz‐Ares,Belén Rubio‐Viqueira,M. Alonso Garcìa,E. Felip Font,José Fuentes Pradera,J. Coves Sarto,Meng‐Chih Lin,Wu‐Chou Su,Te‐Chun Hsia,Gee‐Chen Chang,Yu‐Feng Wei,Chao‐Hua Chiu,Jin‐Yuan Shih,Jian Su,İrfan Çiçin,Tuncay Göksel,Hakan Harputluoğlu,Özgür Özyılkan,I. von Henning,Sanjay Popat,Olivia Hatcher,Kathryn F. Mileham,Jared D. Acoba,Edward B. Garon,Gabriel Jung,Moses S. Raj,Martin Wj,Shaker R. Dakhil
出处
期刊:Lancet Oncology [Elsevier]
卷期号:20 (12): 1655-1669 被引量:481
标识
DOI:10.1016/s1470-2045(19)30634-5
摘要

Background Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC. Methods This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up. Findings Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8–27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4–21·6]) than in the placebo plus erlotinib group (12·4 months [11·0–13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46–0·76; p<0·0001). Grade 3–4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3–4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group. Interpretation Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC. Funding Eli Lilly.
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