Kazuhiko Nakagawa1, Edward B Garon2, Takashi Seto3, Makoto Nishio4, Santiago Ponce Aix5, Luis Paz-Ares5, Chao-Hua Chiu6, Keunchil Park7, Silvia Novello8, Ernest Nadal9, Fumio Imamura10, Kiyotaka Yoh11, Jin-Yuan Shih12, Kwok Hung Au13, Denis Moro-Sibilot14, Sotaro Enatsu15, Annamaria Zimmermann16, Bente Frimodt-Moller17, Carla Visseren-Grul18, Martin Reck19. 1. Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan. Electronic address: nakagawa@med.kindai.ac.jp. 2. David Geffen School of Medicine at University of California Los Angeles, Translational Research in Oncology US Network, Los Angeles, CA, USA. 3. National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. 4. Department of Thoracic Medical Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan. 5. Hospital Universitario 12 de Octubre, H12O-CNIO Lung Cancer Clinical Research Unit, Universidad Complutense and Ciberonc, Madrid, Spain. 6. Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 7. Samsung Medical Center, Division of Hematology and Oncology, Sungkyunkwan University School of Medicine, Seoul, South Korea. 8. Department of Oncology, University of Turin, Azienda ospedaliero-universitaria San Luigi, Orbassano, Italy. 9. Department of Medical Oncology, Catalan Institute of Oncology, and Clinical Research in Solid Tumors group, Oncobell, l'Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet, Barcelona, Spain. 10. Osaka International Cancer Institute, Osaka, Japan. 11. National Cancer Center Hospital East, Kashiwa, Japan. 12. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. 13. Queen Elizabeth Hospital, Kowloon, Hong Kong. 14. Grenoble University Hospital, Grenoble, France. 15. Eli Lilly Japan KK Kobe, Kobe, Japan. 16. Eli Lilly and Company, Indianapolis, IN, USA. 17. Eli Lilly and Company, Copenhagen, Denmark. 18. Lilly Oncology, Utrecht, Netherlands. 19. LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.
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.
RCT Entities:
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.
Authors: Helena A Yu; Luis G Paz-Ares; James Chih-Hsin Yang; Ki Hyeong Lee; Pilar Garrido; Keunchil Park; Joo-Hang Kim; Dae Ho Lee; Huzhang Mao; Sameera R Wijayawardana; Ling Gao; Rebecca R Hozak; Bo H Chao; David Planchard Journal: Clin Cancer Res Date: 2020-10-12 Impact factor: 12.531
Authors: Monique B Nilsson; Jacqulyne Robichaux; Matthew H Herynk; Tina Cascone; Xiuning Le; Yasir Elamin; Sonia Patel; Fahao Zhang; Li Xu; Limei Hu; Lixia Diao; Li Shen; Junqin He; Xiaoxing Yu; Petros Nikolinakos; Pierre Saintigny; Bingliang Fang; Luc Girard; Jing Wang; John D Minna; Ignacio I Wistuba; John V Heymach Journal: J Thorac Oncol Date: 2020-12-09 Impact factor: 15.609