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Randomized Controlled Trial
. 2022 Jan;45(1):45-64.
doi: 10.1007/s40264-021-01127-2. Epub 2021 Dec 20.

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

Ernest Nadal  1 , Hidehito Horinouchi  2 , Jin-Yuan Shih  3 , Kazuhiko Nakagawa  4 , Martin Reck  5 , Edward B Garon  6 , Yu-Feng Wei  7 , Jens Kollmeier  8 , Bente Frimodt-Moller  9 , Emily Barrett  10 , Olga Lipkovich  11 , Carla Visseren-Grul  12 , Silvia Novello  13
Affiliations
Randomized Controlled Trial

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

Ernest Nadal et al. Drug Saf. 2022 Jan.

Abstract

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.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Treatment-emergent adverse events occurring in ≥ 20% of patients in the RAM + ERL arm in RELAY. ERL erlotinib, PBO placebo, RAM ramucirumab
Fig. 2
Fig. 2
Serious adverse events reported in two or more patients in the RAM + ERL arm in RELAY. ERL erlotinib, PBO placebo, RAM ramucirumab
Fig. 3
Fig. 3
Treatment-emergent adverse events of special interest in RELAY. ERL erlotinib, PBO placebo, RAM ramucirumab
Fig. 4
Fig. 4
Number of patients experiencing adverse events of special interest (all grades) over time in RELAY: a hypertension, b proteinuria, c bleeding/hemorrhage, d hepatic events, e dermatitis, and f diarrhea. The frequencies of selected adverse events across treatment cycles were plotted by treatment arm using a stacked bar chart, where each bar represents one cycle and comprises four mutually exclusive groups: patients without events and patients with events of maximum grades 1, 2, or ≥ 3 in a given cycle. Plots are presented by treatment arm. ERL erlotinib, PBO placebo, RAM ramucirumab
Fig. 4
Fig. 4
Number of patients experiencing adverse events of special interest (all grades) over time in RELAY: a hypertension, b proteinuria, c bleeding/hemorrhage, d hepatic events, e dermatitis, and f diarrhea. The frequencies of selected adverse events across treatment cycles were plotted by treatment arm using a stacked bar chart, where each bar represents one cycle and comprises four mutually exclusive groups: patients without events and patients with events of maximum grades 1, 2, or ≥ 3 in a given cycle. Plots are presented by treatment arm. ERL erlotinib, PBO placebo, RAM ramucirumab
Fig. 5
Fig. 5
Any-grade treatment-emergent adverse events leading to ramucirumab or placebo dose adjustment in three or more patients in the RAM + ERL arm in RELAY. ERL erlotinib, PBO placebo, RAM ramucirumab
Fig. 6
Fig. 6
Any-grade treatment-emergent adverse events leading to erlotinib dose adjustment in three or more patients in the RAM + ERL arm in RELAY. ERL erlotinib, PBO placebo, RAM ramucirumab
Fig. 7
Fig. 7
Any-grade treatment-emergent adverse events leading to treatment discontinuation in two or more patients in the RAM + ERL arm in RELAY. ERL erlotinib, PBO placebo, RAM ramucirumab
Fig. 8
Fig. 8
Bleeding/hemorrhage, pulmonary hemorrhage, and hepatic events reported in RELAY. ERL erlotinib, PBO placebo, RAM ramucirumab
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