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

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 Zimmermann, Bente Frimodt-Moller, Carla Visseren-Grul, Martin ReckQuincy Chu, Alexis Cortot, Jean Louis Pujol, Elizabeth Fabre, Corinne Lamour, Helge Bischoff, Jens Kollmeier, Martin Kimmich, Walburga Engel-Riedel, Stefan Hammerschmidt, Wolfgang Schütte, Konstantinos Syrigos, James Chung Man Ho, Kwok Hung Au, Andrea Ardizzoni, Giulia Pasello, Vanessa Gregorc, Alessandro Del Conte, Domenico Galetta, Toshiaki Takahashi, 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, 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, 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-Vidal, Ernest Nadal-Alforja, Ignacio Gil-Bazo, Santiago Ponce-Aix, Belén Rubio-Viqueira, Miriam Alonso Garcia, Enriqueta Felip Font, Jose Fuentes Pradera, Juan Coves Sarto, Meng Chih Lin, Wu Chou Su, Te Chun Hsia, Gee Chen Chang, Yu Feng Wei, Jian Su, Irfan Cicin, Tuncay Goksel, Hakan Harputluoglu, Ozgur Ozyilkan, Ivo Henning, Sanjay Popat, Olivia Hatcher, Kathryn Mileham, Jared Acoba, Edward Garon, Gabriel Jung, Moses Raj, William Martin, Shaker Dakhil

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1655-1669
Number of pages15
JournalThe Lancet Oncology
Volume20
Issue number12
DOIs
Publication statusPublished - Dec 2019

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Non-Small Cell Lung Carcinoma
Placebos
Disease-Free Survival
ramucirumab
Erlotinib Hydrochloride
Dermatitis
Pneumothorax
Therapeutics
Safety
Exons
Pleural Empyema
Hemothorax
Mutation
Cellulitis
Time and Motion Studies
Standard of Care
Random Allocation
Alanine Transaminase
Taiwan
Protein-Tyrosine Kinases

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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. / Nakagawa, Kazuhiko; Garon, Edward B.; Seto, Takashi; Nishio, Makoto; Ponce Aix, Santiago; Paz-Ares, Luis; Chiu, Chao Hua; Park, Keunchil; Novello, Silvia; Nadal, Ernest; Imamura, Fumio; Yoh, Kiyotaka; Shih, Jin Yuan; Au, Kwok Hung; Moro-Sibilot, Denis; Enatsu, Sotaro; Zimmermann, Annamaria; Frimodt-Moller, Bente; Visseren-Grul, Carla; Reck, Martin; Chu, Quincy; Cortot, Alexis; Pujol, Jean Louis; Fabre, Elizabeth; Lamour, Corinne; Bischoff, Helge; Kollmeier, Jens; Kimmich, Martin; Engel-Riedel, Walburga; Hammerschmidt, Stefan; Schütte, Wolfgang; Syrigos, Konstantinos; Ho, James Chung Man; Au, Kwok Hung; Ardizzoni, Andrea; Pasello, Giulia; Gregorc, Vanessa; Del Conte, Alessandro; Galetta, Domenico; Takahashi, Toshiaki; Kumagai, Toru; Hotta, Katsuyuki; Goto, Yasushi; Hosomi, Yukio; Sakai, Hiroshi; Takiguchi, Yuichi; Kim, Young Hak; Kurata, Takayasu; Yamaguchi, Hiroyuki; Daga, Haruko; Okamoto, Isamu; Satouchi, Miyako; Ikeda, Satoshi; Kasahara, Kazuo; Atagi, Shinji; Azuma, Koichi; Aoe, Keisuke; Horio, Yoshitsugu; Yamamoto, Nobuyuki; Tanaka, Hiroshi; Watanabe, Satoshi; Nogami, Naoyuki; Ozaki, Tomohiro; Koyama, Ryo; Hirashima, Tomonori; Kaneda, Hiroyasu; Tomii, Keisuke; Fujita, Yuka; Seike, Masahiro; Nishimura, Naoki; Kato, Terufumi; Ichiki, Masao; Saka, Hideo; Hirano, Katsuya; Nakahara, Yasuharu; Sugawara, Shunichi; Kim, Sang We; Min, Young Joo; Lee, Hyun Woo; Kang, Jin Hyoung; An, Ho Jung; Lee, Ki Hyeong; Kim, Jin Soo; Lee, Gyeong Won; Lee, Sung Yong; Alexandru, Aurelia; Udrea, Anghel Adrian; Juan-Vidal, Óscar; Nadal-Alforja, Ernest; Gil-Bazo, Ignacio; Ponce-Aix, Santiago; Rubio-Viqueira, Belén; Alonso Garcia, Miriam; Felip Font, Enriqueta; Fuentes Pradera, Jose; Coves Sarto, Juan; Lin, Meng Chih; Su, Wu Chou; Hsia, Te Chun; Chang, Gee Chen; Wei, Yu Feng; Su, Jian; Cicin, Irfan; Goksel, Tuncay; Harputluoglu, Hakan; Ozyilkan, Ozgur; Henning, Ivo; Popat, Sanjay; Hatcher, Olivia; Mileham, Kathryn; Acoba, Jared; Garon, Edward; Jung, Gabriel; Raj, Moses; Martin, William; Dakhil, Shaker.

In: The Lancet Oncology, Vol. 20, No. 12, 12.2019, p. 1655-1669.

Research output: Contribution to journalArticle

Nakagawa, K, Garon, EB, Seto, T, Nishio, M, Ponce Aix, S, Paz-Ares, L, Chiu, CH, Park, K, Novello, S, Nadal, E, Imamura, F, Yoh, K, Shih, JY, Au, KH, Moro-Sibilot, D, Enatsu, S, Zimmermann, A, Frimodt-Moller, B, Visseren-Grul, C, Reck, M, Chu, Q, Cortot, A, Pujol, JL, Fabre, E, Lamour, C, Bischoff, H, Kollmeier, J, Kimmich, M, Engel-Riedel, W, Hammerschmidt, S, Schütte, W, Syrigos, K, Ho, JCM, Au, KH, Ardizzoni, A, Pasello, G, Gregorc, V, Del Conte, A, Galetta, D, Takahashi, T, Kumagai, T, Hotta, K, Goto, Y, Hosomi, Y, Sakai, H, Takiguchi, Y, Kim, YH, Kurata, T, Yamaguchi, H, Daga, H, Okamoto, I, Satouchi, M, Ikeda, S, Kasahara, K, Atagi, S, Azuma, K, Aoe, K, Horio, Y, Yamamoto, N, Tanaka, H, Watanabe, S, Nogami, N, Ozaki, T, Koyama, R, Hirashima, T, Kaneda, H, Tomii, K, Fujita, Y, Seike, M, Nishimura, N, Kato, T, Ichiki, M, Saka, H, Hirano, K, Nakahara, Y, Sugawara, S, Kim, SW, Min, YJ, Lee, HW, Kang, JH, An, HJ, Lee, KH, Kim, JS, Lee, GW, Lee, SY, Alexandru, A, Udrea, AA, Juan-Vidal, Ó, Nadal-Alforja, E, Gil-Bazo, I, Ponce-Aix, S, Rubio-Viqueira, B, Alonso Garcia, M, Felip Font, E, Fuentes Pradera, J, Coves Sarto, J, Lin, MC, Su, WC, Hsia, TC, Chang, GC, Wei, YF, Su, J, Cicin, I, Goksel, T, Harputluoglu, H, Ozyilkan, O, Henning, I, Popat, S, Hatcher, O, Mileham, K, Acoba, J, Garon, E, Jung, G, Raj, M, Martin, W & Dakhil, S 2019, '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', The Lancet Oncology, vol. 20, no. 12, pp. 1655-1669. https://doi.org/10.1016/S1470-2045(19)30634-5
Nakagawa, Kazuhiko ; Garon, Edward B. ; Seto, Takashi ; Nishio, Makoto ; Ponce Aix, Santiago ; Paz-Ares, Luis ; Chiu, Chao Hua ; Park, Keunchil ; Novello, Silvia ; Nadal, Ernest ; Imamura, Fumio ; Yoh, Kiyotaka ; Shih, Jin Yuan ; Au, Kwok Hung ; Moro-Sibilot, Denis ; Enatsu, Sotaro ; Zimmermann, Annamaria ; Frimodt-Moller, Bente ; Visseren-Grul, Carla ; Reck, Martin ; Chu, Quincy ; Cortot, Alexis ; Pujol, Jean Louis ; Fabre, Elizabeth ; Lamour, Corinne ; Bischoff, Helge ; Kollmeier, Jens ; Kimmich, Martin ; Engel-Riedel, Walburga ; Hammerschmidt, Stefan ; Schütte, Wolfgang ; Syrigos, Konstantinos ; Ho, James Chung Man ; Au, Kwok Hung ; Ardizzoni, Andrea ; Pasello, Giulia ; Gregorc, Vanessa ; Del Conte, Alessandro ; Galetta, Domenico ; Takahashi, Toshiaki ; Kumagai, Toru ; Hotta, Katsuyuki ; Goto, Yasushi ; Hosomi, Yukio ; Sakai, Hiroshi ; Takiguchi, Yuichi ; Kim, Young Hak ; Kurata, Takayasu ; Yamaguchi, Hiroyuki ; Daga, Haruko ; Okamoto, Isamu ; Satouchi, Miyako ; Ikeda, Satoshi ; Kasahara, Kazuo ; Atagi, Shinji ; Azuma, Koichi ; Aoe, Keisuke ; Horio, Yoshitsugu ; Yamamoto, Nobuyuki ; Tanaka, Hiroshi ; Watanabe, Satoshi ; Nogami, Naoyuki ; Ozaki, Tomohiro ; Koyama, Ryo ; Hirashima, Tomonori ; Kaneda, Hiroyasu ; Tomii, Keisuke ; Fujita, Yuka ; Seike, Masahiro ; Nishimura, Naoki ; Kato, Terufumi ; Ichiki, Masao ; Saka, Hideo ; Hirano, Katsuya ; Nakahara, Yasuharu ; Sugawara, Shunichi ; Kim, Sang We ; Min, Young Joo ; Lee, Hyun Woo ; Kang, Jin Hyoung ; An, Ho Jung ; Lee, Ki Hyeong ; Kim, Jin Soo ; Lee, Gyeong Won ; Lee, Sung Yong ; Alexandru, Aurelia ; Udrea, Anghel Adrian ; Juan-Vidal, Óscar ; Nadal-Alforja, Ernest ; Gil-Bazo, Ignacio ; Ponce-Aix, Santiago ; Rubio-Viqueira, Belén ; Alonso Garcia, Miriam ; Felip Font, Enriqueta ; Fuentes Pradera, Jose ; Coves Sarto, Juan ; Lin, Meng Chih ; Su, Wu Chou ; Hsia, Te Chun ; Chang, Gee Chen ; Wei, Yu Feng ; Su, Jian ; Cicin, Irfan ; Goksel, Tuncay ; Harputluoglu, Hakan ; Ozyilkan, Ozgur ; Henning, Ivo ; Popat, Sanjay ; Hatcher, Olivia ; Mileham, Kathryn ; Acoba, Jared ; Garon, Edward ; Jung, Gabriel ; Raj, Moses ; Martin, William ; Dakhil, Shaker. / 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. In: The Lancet Oncology. 2019 ; Vol. 20, No. 12. pp. 1655-1669.
@article{c65646af98fa4c4ca7177e82612623de,
title = "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",
abstract = "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.",
author = "Kazuhiko Nakagawa and Garon, {Edward B.} and Takashi Seto and Makoto Nishio and {Ponce Aix}, Santiago and Luis Paz-Ares and Chiu, {Chao Hua} and Keunchil Park and Silvia Novello and Ernest Nadal and Fumio Imamura and Kiyotaka Yoh and Shih, {Jin Yuan} and Au, {Kwok Hung} and Denis Moro-Sibilot and Sotaro Enatsu and Annamaria Zimmermann and Bente Frimodt-Moller and Carla Visseren-Grul and Martin Reck and Quincy Chu and Alexis Cortot and Pujol, {Jean Louis} and Elizabeth Fabre and Corinne Lamour and Helge Bischoff and Jens Kollmeier and Martin Kimmich and Walburga Engel-Riedel and Stefan Hammerschmidt and Wolfgang Sch{\"u}tte and Konstantinos Syrigos and Ho, {James Chung Man} and Au, {Kwok Hung} and Andrea Ardizzoni and Giulia Pasello and Vanessa Gregorc and {Del Conte}, Alessandro and Domenico Galetta and Toshiaki Takahashi and Toru Kumagai and Katsuyuki Hotta and Yasushi Goto and Yukio Hosomi and Hiroshi Sakai and Yuichi Takiguchi and Kim, {Young Hak} and Takayasu Kurata and Hiroyuki Yamaguchi and Haruko Daga and Isamu Okamoto and Miyako Satouchi and Satoshi Ikeda and Kazuo Kasahara and Shinji Atagi and Koichi Azuma and Keisuke Aoe and Yoshitsugu Horio and Nobuyuki Yamamoto and Hiroshi Tanaka and Satoshi Watanabe and Naoyuki Nogami and Tomohiro Ozaki and Ryo Koyama and Tomonori Hirashima and Hiroyasu Kaneda and Keisuke Tomii and Yuka Fujita and Masahiro Seike and Naoki Nishimura and Terufumi Kato and Masao Ichiki and Hideo Saka and Katsuya Hirano and Yasuharu Nakahara and Shunichi Sugawara and Kim, {Sang We} and Min, {Young Joo} and Lee, {Hyun Woo} and Kang, {Jin Hyoung} and An, {Ho Jung} and Lee, {Ki Hyeong} and Kim, {Jin Soo} and Lee, {Gyeong Won} and Lee, {Sung Yong} and Aurelia Alexandru and Udrea, {Anghel Adrian} and {\'O}scar Juan-Vidal and Ernest Nadal-Alforja and Ignacio Gil-Bazo and Santiago Ponce-Aix and Bel{\'e}n Rubio-Viqueira and {Alonso Garcia}, Miriam and {Felip Font}, Enriqueta and {Fuentes Pradera}, Jose and {Coves Sarto}, Juan and Lin, {Meng Chih} and Su, {Wu Chou} and Hsia, {Te Chun} and Chang, {Gee Chen} and Wei, {Yu Feng} and Jian Su and Irfan Cicin and Tuncay Goksel and Hakan Harputluoglu and Ozgur Ozyilkan and Ivo Henning and Sanjay Popat and Olivia Hatcher and Kathryn Mileham and Jared Acoba and Edward Garon and Gabriel Jung and Moses Raj and William Martin and Shaker Dakhil",
year = "2019",
month = "12",
doi = "10.1016/S1470-2045(19)30634-5",
language = "English",
volume = "20",
pages = "1655--1669",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "12",

}

TY - JOUR

T1 - Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY)

T2 - a randomised, double-blind, placebo-controlled, phase 3 trial

AU - Nakagawa, Kazuhiko

AU - Garon, Edward B.

AU - Seto, Takashi

AU - Nishio, Makoto

AU - Ponce Aix, Santiago

AU - Paz-Ares, Luis

AU - Chiu, Chao Hua

AU - Park, Keunchil

AU - Novello, Silvia

AU - Nadal, Ernest

AU - Imamura, Fumio

AU - Yoh, Kiyotaka

AU - Shih, Jin Yuan

AU - Au, Kwok Hung

AU - Moro-Sibilot, Denis

AU - Enatsu, Sotaro

AU - Zimmermann, Annamaria

AU - Frimodt-Moller, Bente

AU - Visseren-Grul, Carla

AU - Reck, Martin

AU - Chu, Quincy

AU - Cortot, Alexis

AU - Pujol, Jean Louis

AU - Fabre, Elizabeth

AU - Lamour, Corinne

AU - Bischoff, Helge

AU - Kollmeier, Jens

AU - Kimmich, Martin

AU - Engel-Riedel, Walburga

AU - Hammerschmidt, Stefan

AU - Schütte, Wolfgang

AU - Syrigos, Konstantinos

AU - Ho, James Chung Man

AU - Au, Kwok Hung

AU - Ardizzoni, Andrea

AU - Pasello, Giulia

AU - Gregorc, Vanessa

AU - Del Conte, Alessandro

AU - Galetta, Domenico

AU - Takahashi, Toshiaki

AU - Kumagai, Toru

AU - Hotta, Katsuyuki

AU - Goto, Yasushi

AU - Hosomi, Yukio

AU - Sakai, Hiroshi

AU - Takiguchi, Yuichi

AU - Kim, Young Hak

AU - Kurata, Takayasu

AU - Yamaguchi, Hiroyuki

AU - Daga, Haruko

AU - Okamoto, Isamu

AU - Satouchi, Miyako

AU - Ikeda, Satoshi

AU - Kasahara, Kazuo

AU - Atagi, Shinji

AU - Azuma, Koichi

AU - Aoe, Keisuke

AU - Horio, Yoshitsugu

AU - Yamamoto, Nobuyuki

AU - Tanaka, Hiroshi

AU - Watanabe, Satoshi

AU - Nogami, Naoyuki

AU - Ozaki, Tomohiro

AU - Koyama, Ryo

AU - Hirashima, Tomonori

AU - Kaneda, Hiroyasu

AU - Tomii, Keisuke

AU - Fujita, Yuka

AU - Seike, Masahiro

AU - Nishimura, Naoki

AU - Kato, Terufumi

AU - Ichiki, Masao

AU - Saka, Hideo

AU - Hirano, Katsuya

AU - Nakahara, Yasuharu

AU - Sugawara, Shunichi

AU - Kim, Sang We

AU - Min, Young Joo

AU - Lee, Hyun Woo

AU - Kang, Jin Hyoung

AU - An, Ho Jung

AU - Lee, Ki Hyeong

AU - Kim, Jin Soo

AU - Lee, Gyeong Won

AU - Lee, Sung Yong

AU - Alexandru, Aurelia

AU - Udrea, Anghel Adrian

AU - Juan-Vidal, Óscar

AU - Nadal-Alforja, Ernest

AU - Gil-Bazo, Ignacio

AU - Ponce-Aix, Santiago

AU - Rubio-Viqueira, Belén

AU - Alonso Garcia, Miriam

AU - Felip Font, Enriqueta

AU - Fuentes Pradera, Jose

AU - Coves Sarto, Juan

AU - Lin, Meng Chih

AU - Su, Wu Chou

AU - Hsia, Te Chun

AU - Chang, Gee Chen

AU - Wei, Yu Feng

AU - Su, Jian

AU - Cicin, Irfan

AU - Goksel, Tuncay

AU - Harputluoglu, Hakan

AU - Ozyilkan, Ozgur

AU - Henning, Ivo

AU - Popat, Sanjay

AU - Hatcher, Olivia

AU - Mileham, Kathryn

AU - Acoba, Jared

AU - Garon, Edward

AU - Jung, Gabriel

AU - Raj, Moses

AU - Martin, William

AU - Dakhil, Shaker

PY - 2019/12

Y1 - 2019/12

N2 - 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.

AB - 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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U2 - 10.1016/S1470-2045(19)30634-5

DO - 10.1016/S1470-2045(19)30634-5

M3 - Article

C2 - 31591063

AN - SCOPUS:85075654442

VL - 20

SP - 1655

EP - 1669

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 12

ER -