PMID- 34928484
OWN - NLM
STAT- MEDLINE
DCOM- 20220421
LR  - 20231213
IS  - 1179-1942 (Electronic)
IS  - 0114-5916 (Print)
IS  - 0114-5916 (Linking)
VI  - 45
IP  - 1
DP  - 2022 Jan
TI  - RELAY, Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib in Patients with 
      Untreated, Epidermal Growth Factor Receptor Mutation-Positive, Metastatic 
      Non-Small-Cell Lung Cancer: Safety Profile and Manageability.
PG  - 45-64
LID - 10.1007/s40264-021-01127-2 [doi]
AB  - INTRODUCTION: RELAY was a global, double-blind, placebo-controlled phase III 
      study that demonstrated superior progression-free survival (PFS) for ramucirumab 
      plus erlotinib (RAM + ERL) versus placebo plus erlotinib (PBO + ERL) in the 
      first-line treatment of patients with epidermal growth factor receptor (EGFR) 
      exon 19 deletion or exon 21 (L858R) mutation-positive, metastatic non-small-cell 
      lung cancer (NSCLC). OBJECTIVE: This article provides an in-depth analysis of the 
      safety profile of RAM + ERL versus PBO + ERL observed in RELAY. METHODS: Eligible 
      patients met these criteria: stage IV NSCLC; EGFR exon 19 deletion or exon 21 
      substitution (L858R) mutation; Eastern Cooperative Oncology Group performance 
      status 0 or 1; and no central nervous system metastases. Patients were randomized 
      (1:1) to receive erlotinib 150 mg/day orally plus either ramucirumab 10 mg/kg 
      intravenously or matching placebo once every 2 weeks, until disease progression 
      or unacceptable toxicity. The primary endpoint was PFS. Safety was evaluated 
      based on reported treatment-emergent adverse events (AEs) and clinical laboratory 
      assessments. RESULTS: The safety population comprised 446 patients (221 in 
      RAM+ERL arm; 225 in PBO + ERL arm) who received at least one dose of study drug 
      between January 2016 and February 2018. The overall incidence of grade >/= 3 AEs 
      was higher with RAM + ERL than with PBO + ERL, primarily driven by grade 3 
      hypertension. Grade >/= 3 dermatitis acneiform and diarrhea were also reported more 
      frequently in the RAM + ERL arm. The increased incidence of AEs with RAM + ERL 
      was easily detected through routine monitoring and managed through dose 
      adjustments and appropriate supportive care. CONCLUSION: This in-depth safety 
      analysis from RELAY supports that RAM + ERL, irrespective of the increased 
      incidence of AEs, does not affect a patient's ability to benefit from treatment. 
      CLINICAL TRIAL REGISTRATION NUMBER: NCT02411448.
CI  - (c) 2021. The Author(s).
FAU - Nadal, Ernest
AU  - Nadal E
AUID- ORCID: 0000-0002-9674-5554
AD  - Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain. 
      esnadal@iconcologia.net.
FAU - Horinouchi, Hidehito
AU  - Horinouchi H
AD  - National Cancer Center Hospital, Tokyo, Japan.
FAU - Shih, Jin-Yuan
AU  - Shih JY
AD  - National Taiwan University Hospital, Taipei City, Taiwan.
FAU - Nakagawa, Kazuhiko
AU  - Nakagawa K
AD  - Faculty of Medicine, Kindai University, Osaka, Japan.
FAU - Reck, Martin
AU  - Reck M
AD  - LungenClinic, Airway Research Center North, German Center for Lung Research, 
      Grosshansdorf, Germany.
FAU - Garon, Edward B
AU  - Garon EB
AD  - David Geffen School of Medicine at UCLA/Translational Research in Oncology-US 
      Network, Santa Monica, CA, USA.
FAU - Wei, Yu-Feng
AU  - Wei YF
AD  - E-Da Cancer Hospital, I-Shou University, Kaohsiung City, Taiwan.
FAU - Kollmeier, Jens
AU  - Kollmeier J
AD  - Helios Klinikum Emil von Behring, Berlin, Germany.
FAU - Frimodt-Moller, Bente
AU  - Frimodt-Moller B
AD  - Eli Lilly and Company, Copenhagen, Denmark.
FAU - Barrett, Emily
AU  - Barrett E
AD  - Eli Lilly and Company, Bracknell, UK.
FAU - Lipkovich, Olga
AU  - Lipkovich O
AD  - Eli Lilly and Company, Indianapolis, IN, USA.
FAU - Visseren-Grul, Carla
AU  - Visseren-Grul C
AD  - Lilly Oncology, Utrecht, Netherlands.
FAU - Novello, Silvia
AU  - Novello S
AD  - Department of Oncology, University of Turin, A.O.U. San Luigi Gonzaga, Turin, 
      Italy.
LA  - eng
SI  - ClinicalTrials.gov/NCT02411448
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20211220
PL  - New Zealand
TA  - Drug Saf
JT  - Drug safety
JID - 9002928
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics
MH  - ErbB Receptors/genetics
MH  - Erlotinib Hydrochloride/adverse effects
MH  - Humans
MH  - *Lung Neoplasms/drug therapy/genetics
MH  - Mutation
MH  - Ramucirumab
PMC - PMC8763844
COIS- EN has received research grants from Bristol Myers Squibb, Merck Serono, Roche, 
      and Pfizer; advisory board fees from Bristol Myers Squibb, Merck Sharp & Dohme, 
      Roche, Amgen, Pfizer, Eli Lilly and Company, Takeda, Sanofi, Bayer, AstraZeneca, 
      and Merck Serono; and lecturing/presentation/writing payments from Bristol Myers 
      Squibb, Merck Sharp & Dohme, Roche, Amgen, Pfizer, Eli Lilly and Company, Takeda, 
      Bayer, AstraZeneca, and Boehringer Ingelheim. HH has received lecture fees, 
      honoraria, or other fees from Eli Lilly and Company, AstraZeneca, Merck Sharp & 
      Dohme, Ono, and Bristol Myers Squibb and research grants from Merck Sharp & 
      Dohme, Chugai, Ono, Bristol Myers Squibb, AstraZeneca, Daiichi Sankyo, Novartis, 
      and Genomic Health. JYS has served as an advisory board member for AstraZeneca, 
      Roche, Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, 
      Chugai Pharma, Ono Pharmaceutical, Takeda, CStone Pharmaceuticals, Janssen, and 
      Bristol Myers Squibb; has received speaking honoraria from AstraZeneca, Roche, 
      Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai 
      Pharma, Ono Pharmaceutical, and Bristol Myers Squibb; and has received a research 
      grant from Roche. KN has received grants and personal fees from AstraZeneca K.K., 
      Astellas Pharma, Merck Sharp & Dohme K.K., Ono Pharmaceutical, Nippon Boehringer 
      Ingelheim, Novartis Pharma K.K., Pfizer Japan, Bristol Myers Squibb, Eli Lilly 
      Japan K.K., Chugai Pharmaceutical, Daiichi Sankyo, and Merck Serono; personal 
      fees from Medicus Shuppan, Publishers Co., Ltd, Care Net, Reno, Kyorin, Roche 
      Diagnostics K.K., Bayer Yakuhin, Medical Mobile Communications Co., 3H Clinical 
      Trial, Nanzando, Yodosha, Nikkei Business Publications, Thermo Fisher Scientific 
      K.K., Yomiuri Telecasting Corporation, Nippon Kayaku, and Nichi-Iko 
      Pharmaceutical; grants and personal fees from Takeda Pharmaceutical, Taiho 
      Pharmaceutical, SymBio Pharmaceuticals, and AbbVie; and grants from inVentiv 
      Health Japan, Icon Japan K.K., Gritstone Oncology, Parexel International, Kissei 
      Pharmaceutical, EPS Corporation, Syneos Health, Pfizer R&D Japan G.K., A2 
      Healthcare, Quintiles Inc/IQVIA Services Japan K.K., EP-CRSU, Linical, Eisai, 
      CMIC Shift Zero K.K., Kyowa Hakko Kirin, Bayer Yakuhin, EPS International, and 
      Otsuka Pharmaceutical. MR has received personal fees from Amgen, AstraZeneca, 
      Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly and Company, Merck, Merck 
      Sharp & Dohme, Novartis, Pfizer, Roche, and Samsung. EBG has received grants from 
      AstraZeneca, Dynavax, Eli Lilly and Company, Genentech, Iovance, Mirati and Neon; 
      grants and personal fees from Bristol Myers Squibb, EMD Serono, Merck, and 
      Novartis; and personal fees from ABL, Boehringer Ingelheim, Dracen, Eisai, GSK, 
      Sanofi, Shionogi, and Xilio. Y-FW has no conflicts of interest that are directly 
      relevant to the content of this article. JK has served as an advisory board 
      member for, without receiving any personal fees from, Roche Pharma, Boehringer 
      Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Takeda, Astra Zeneca, 
      Amgen, and Eli Lilly and Company. BFM, EB, OL, and CVG are employees of and own 
      stock in Eli Lilly and Company. SN has received speaker bureau/advisor personal 
      fees from Amgen, AstraZeneca, Boehringer, Beigene, Merck Sharp & Dohme, Roche, 
      Sanofi, Novartis, Takeda, and Pfizer.
EDAT- 2021/12/21 06:00
MHDA- 2022/04/22 06:00
PMCR- 2021/12/20
CRDT- 2021/12/20 12:29
PHST- 2021/10/17 00:00 [accepted]
PHST- 2021/12/21 06:00 [pubmed]
PHST- 2022/04/22 06:00 [medline]
PHST- 2021/12/20 12:29 [entrez]
PHST- 2021/12/20 00:00 [pmc-release]
AID - 10.1007/s40264-021-01127-2 [pii]
AID - 1127 [pii]
AID - 10.1007/s40264-021-01127-2 [doi]
PST - ppublish
SO  - Drug Saf. 2022 Jan;45(1):45-64. doi: 10.1007/s40264-021-01127-2. Epub 2021 Dec 
      20.