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. 2025 Jun 16:17:17588359251344010.
doi: 10.1177/17588359251344010. eCollection 2025.

Ramucirumab and erlotinib combination as first-line treatment for advanced or recurrent non-small cell lung cancer harboring EGFR Exon21 L858R mutation: a multicenter retrospective observational cohort study in Japan (REAL-SPEED)

Masashi Ishihara  1 , Takahisa Kawamura  2 , Yukiko Namba  3 , Yuki Takeyasu  4 , Yukihiro Hasegawa  5 , Yuki Sato  6 , Yoshiki Negi  7 , Tomohiro Oba  8 , Toshiyuki Sumi  9 , Hirokuni Hirata  10 , Hidemitsu Funabashi  11 , Yuko Oya  12 , Hajime Kikuchi  13 , Naoko Katsurada  14 , Takeshi Nakatani  15 , Keiko Tanimura  16 , Taku Nakagawa  17 , Naoya Takeda  18 , Takahiro Asami  19 , Osamu Honjo  20 , Hiromi Nagashima  21 , Takumi Yamaura  22 , Norihiko Hata  23 , Miyako Kitazono  24 , Naoya Nishioka  25 , Akihiro Tamiya  26 , Yuichi Sakamori  27 , Ryota Shigaki  28 , Kyoichi Kaira  29 , Ryoichi Honda  30 , Takashi Matsui  31 , Eriko Suzuki  32 , Kentaro Ito  33 , Kojiro Otsuka  34 , Naoto Takase  35 , Yusuke Murakami  36 , Kazuhiko Matsuno  37 , Sumito Inoue  38 , Akira Kisohara  39 , Sojiro Kusumoto  40 , Hiroe Aoshima  41 , Yumiko Kakizaki  42 , Akihito Kubo  43 , Akito Hata  44 , Nobuhisa Ishikawa  45 , Kosuke Hamai  46 , Nobuhiro Kanaji  47 , Toshihiro Misumi  48 , Noriyuki Matsutani  49 , Nobuhiko Seki  50
Affiliations

Ramucirumab and erlotinib combination as first-line treatment for advanced or recurrent non-small cell lung cancer harboring EGFR Exon21 L858R mutation: a multicenter retrospective observational cohort study in Japan (REAL-SPEED)

Masashi Ishihara et al. Ther Adv Med Oncol. .

Abstract

Background: EGFR L858R mutation is associated with poorer efficacy of EGFR-tyrosine kinase inhibitors (TKIs) than EGFR Ex19del in patients with non-small cell lung cancer (NSCLC). However, ramucirumab (RAM) + erlotinib (ERL) therapy exhibited comparable efficacy between patients with L858R mutation and Ex19del mutation (median progression-free survival (PFS): 19.6 vs 19.4 months) in the RELAY study, with favorable PFS for both gene mutations at 19.4 months in the Japanese subset. Meanwhile, the FLAURA study revealed shorter PFS with osimertinib (OSI) for L858R mutation than Ex19del mutation, with poorer PFS in the Japanese subset than in the overall population. The treatment discontinuation rates of RAM + ERL and OSI in Japanese patients were 18% and 29%, respectively. Consequently, RAM + ERL may exhibit superior efficacy and safety in Japanese patients with the L858R mutation.

Objectives: To evaluate the therapeutic efficacy and safety of RAM + ERL as a first-line treatment for advanced or recurrent NSCLC harboring the L858R mutation in Japanese patients.

Design: A multicenter, noninterventional, retrospective cohort study.

Methods and analysis: This study will involve patients with advanced or recurrent NSCLC (ECOG PS score 0-2) with L858R mutation who received RAM + ERL between November 1, 2020 and August 31, 2023, with the planned sample size of 200 patients. The primary endpoint is time to treatment failure, and the secondary endpoints are overall survival, PFS, PFS2, time to discontinuation of any EGFR-TKI, time to failure of strategy, objective response rate, disease control rate, and safety. Exploratory endpoints are effects of ERL and RAM on PD-L1 expression and neutrophil-to-lymphocyte ratio.

Discussion: To the best of our knowledge, this is the first retrospective study focusing on L858R mutations associated with the RELAY regimen, providing the corresponding real-world data.

Trial registration: UMIN Clinical Trials Registry identifier: UMIN000052047.

Keywords: L858R; erlotinib; non-small cell lung cancer; ramucirumab.

PubMed Disclaimer

Conflict of interest statement

M.I. received personal fees as honoraria from AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, and Daiichi Sankyo. T.S. received personal fees as honoraria from AstraZeneca, Boehringer Ingelheim, Ono Pharmaceutical, and Sanofi. Y.O. received personal fees as honoraria from AstraZeneca, Eli Lilly, and Chugai Pharmaceutical. H.K. received personal fees as honoraria from AstraZeneca. A.T. received grants from AstraZeneca, Daiichi Sankyo, Taiho Pharmaceutical, and BeiGene, and personal fees as honoraria from Eli Lilly, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, and MSD. K.Kaira received research funding and personal fees as honoraria from AstraZeneca, and personal fees as honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol-Myers Squibb. K.Ito received research funding and personal fees as honoraria from Ono Pharmaceutical and MSD, and personal fees as honoraria from Chugai Pharmaceutical and Eli Lilly. K.Otsuka received personal fees as honoraria from AstraZeneca and GlaxoSmithKline. S.Inoue received grants from Chugai Pharmaceutical and personal fees as honoraria from AstraZeneca. A.Hata received personal fees as honoraria from AstraZeneca, MSD, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer, and Eli Lilly. K.Hamai received personal fees as honoraria from AstraZeneca. N.Seki received research funding and personal fees as honoraria from Eli Lilly, Ono Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical, Nippon Kayaku, Pfizer, and Daiichi Sankyo, research funding from Eisai and Shionogi, and personal fees as honoraria from AstraZeneca, MSD, Bristol-Myers Squibb, Novartis, and Kyowa Kirin. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1.
Figure 1.
Schematic of ramucirumab plus erlotinib as a first-line treatment for advanced or recurrent non-small cell lung cancer with EGFR Exon21 L858R mutation (REAL-SPEED). BSC, best supportive care; TKI, tyrosine kinase inhibitor.
Figure 2.
Figure 2.
Differences between TTF and PFS. Upper: 1st-line Tx (RAM + ERL) was discontinued due to AE despite non-PD, and 2nd-line treatment was initiated. Lower: 1st-line Tx (RAM + ERL) was PD, and 2nd-line therapy was initiated. AE, adverse event; ERL, erlotinib; PD, progressive disease; PFS, progression-free survival; RAM, ramucirumab; TTF, time to treatment failure; Tx, therapy.
See this image and copyright information in PMC

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