Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2025 Jun 13;31(12):2317-2326.
doi: 10.1158/1078-0432.CCR-24-3532.

Randomized Phase III Study of EGFR Tyrosine Kinase Inhibitor and Intercalated Platinum-Doublet Chemotherapy for Non-Small Cell Lung Cancer Harboring EGFR Mutation

Shintaro Kanda  1 , Seiji Niho  2 , Takayasu Kurata  3 , Shogo Nomura  4 , Yosuke Kawashima  5 , Eiji Iwama  6 , Toshihide Yokoyama  7 , Yasutaka Watanabe  8 , Hiroshi Tanaka  9 , Yutaka Fujiwara  10 , Yoshitaka Zenke  11 , Koichi Azuma  12 , Hirokazu Taniguchi  13 , Ryo Toyozawa  14 , Yukio Hosomi  15 , Haruyasu Murakami  16 , Satoshi Hara  17 , Akihiro Bessho  18 , Nobuyuki Yamamoto  19 , Yuichiro Ohe  20
Affiliations
Clinical Trial

Randomized Phase III Study of EGFR Tyrosine Kinase Inhibitor and Intercalated Platinum-Doublet Chemotherapy for Non-Small Cell Lung Cancer Harboring EGFR Mutation

Shintaro Kanda et al. Clin Cancer Res. .

Abstract

Purpose: This study was performed to confirm the superiority in overall survival (OS) of EGFR tyrosine kinase inhibitor (TKI gefitinib or osimertinib) monotherapy versus EGFR TKI with intercalation of cisplatin plus pemetrexed as the first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSqNSCLC) harboring EGFR mutation.

Patients and methods: This was an open-label, multicenter, randomized phase III study. Patients with chemotherapy-naïve advanced or recurrent NSqNSCLC harboring EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were randomly assigned (1:1) to EGFR-TKI monotherapy or the EGFR TKI plus intercalated chemotherapy group. The primary endpoint was OS, and the secondary endpoints included progression-free survival (PFS).

Results: From December 2015 to October 2020, 501 patients were randomized. The EGFR TKI was changed from gefitinib to osimertinib in October 2018 (gefitinib cohort: n = 308 and osimertinib cohort: n = 193). There was no survival advantage in the EGFR TKI plus intercalated chemotherapy group; the median survival time of both groups was 48.0 months (HR, 0.985; 91.4% confidence interval, 0.796-1.219; one-sided P = 0.4496). The median PFS time was 12.0 months in the EGFR-TKI monotherapy group and 18.0 months in the EGFR TKI plus intercalated chemotherapy group (HR, 0.762; 95% confidence interval, 0.628-0.925; one-sided P = 0.003). The OS and PFS trends in both gefitinib and osimertinib cohorts were identical to those in the entire population.

Conclusions: The intercalation of cisplatin plus pemetrexed after the response to EGFR TKI improved PFS but not OS compared with EGFR TKI monotherapy as the first-line treatment for patients with advanced NSqNSCLC harboring EGFR mutation.

PubMed Disclaimer

Conflict of interest statement

S. Kanda reports grants from National Cancer Center Research and Development Funds and Japan Agency for Medical Research and Development Grants during the conduct of the study, as well as personal fees from AstraZeneca K.K., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Guardant Health AMEA, Kyowa Kirin Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd., outside the submitted work. S. Niho reports grants from AMED during the conduct of the study, as well as personal fees from AstraZeneca and Eli Lilly and Company outside the submitted work. T. Kurata reports grants and personal fees from MSD, AstraZeneca, Chugai, Ono Pharmaceutical, and Takeda, personal fees from Nippon Kayaku, Bristol Myers Squibb, Eli Lilly and Company, and Pfizer, and grants from Daiichi Sankyo, Boehringer Ingelheim, Janssen, Novartis, and Amgen outside the submitted work. S. Nomura reports grants and personal fees from AstraZeneca, Chugai Pharmaceutical, and MSD, as well as personal fees from Kyowa Hakko, Bayer, Asahi Kasei Pharma,, Takeda, Eli Lilly and Company, and Daiichi Sankyo outside the submitted work. Y. Kawashima reports personal fees from Taiho Pharmaceutical, Eli Lilly and Company, Life Technologies Japan Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca, and Kyowa Kirin Co., Ltd., outside the submitted work. E. Iwama reports personal fees from AstraZeneca and Chugai Pharmaceutical outside the submitted work. T. Yokoyama reports grants from AbbVie GK, Boehringer Ingelheim, Daiichi Sankyo, Delta-Fly Pharma, Janssen, and Parexel International, grants and personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, MSD, and Takeda, and personal fees from Eli Lilly and Company, Merck Biopharma, Nippon Kayaku, Novartis, Ono Pharmaceutical, and Pfizer outside the submitted work. H. Tanaka reports grants and personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, Ono Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Takeda Pharmaceutical, Taiho Pharmaceutical, Merck, Boehringer Ingelheim, Amgen, and Pfizer and personal fees from AbbVie, Eisai, Novartis, and Celltrion outside the submitted work. Y. Fujiwara reports grants from AbbVie, AnHeart Therapeutics, Astellas, Boehringer Ingelheim, Incyte, and Merck KGaA, grants and personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly and Company, Merck Sharp & Dohme, Novocure, and Taiho Pharmaceutical, and personal fees from Chiome Bioscience, Daiichi Sankyo, Merck Biopharma, Novartis, Micron, Nippon Kayaku, Ono Pharmaceutical, Pfizer, and Takeda outside the submitted work. Y. Zenke reports grants and personal fees from AstraZeneca, Guardant Health, and Daiichi Sankyo, personal fees from Bristol Myers Squibb, Ono Pharmaceutical, Boehringer Ingelheim, Takeda Pharmaceutical, Taiho Pharmaceutical, Eli Lilly and Company, Pfizer, Nippon Kayaku, Kyowa Kirin, MSD, and Janssen Pharma, and grants from Merck and Novocure outside the submitted work. K. Azuma reports personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, MSD, Ono Pharmaceutical, and Takeda Pharmaceutical outside the submitted work. R. Toyozawa reports grants from AbbVie, Amgen, AnHeart Therapeutics, Daiichi Sankyo, Eli Lilly and Company Japan, MSD, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical and personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly and Company Japan, MSD, Nippon Kayaku, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical, and Thermo Fisher Scientific outside the submitted work. Y. Hosomi reports personal fees from AstraZeneca, Eli Lilly and Company Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda, Eisai, Novartis, Pfizer, and MSD outside the submitted work. H. Murakami reports grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, and Taiho Pharmaceutical, grants from AbbVie, IQVIA, and Bayer, and personal fees from Eli Lilly and Company Japan, Takeda, Amgen, Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD, Pfizer, Novartis, Eisai, Nippon Kayaku, GAIA BioMedicine, and Kyowa Kirin outside the submitted work. A. Bessho reports grants and personal fees from AstraZeneca, Pfizer, and Chugai Pharmaceutical and personal fees from Eli Lilly and Company and Boehringer Ingelheim during the conduct of the study, as well as grants and personal fees from MSD and Ono Pharmaceutical and personal fees from Bristol Myers Squibb and Taiho Pharmaceutical outside the submitted work. N. Yamamoto reports grants and personal fees from AstraZeneca K.K., Amgen K.K., Eli Lilly and Company Japan K.K., AbbVie GK, Janssen Pharmaceutical K.K., Bristol Myers Squibb, Pfizer R&D Japan G.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., and Novartis Japan and personal fees from Guardant Health Japan Corp., as well as personal fees from Taiho Oncology, Inc., Tsumura & Co., Nippon Kayaku Co., Ltd., Merck Biopharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo, Inc., Takeda Pharmaceutical Co., Ltd., Terumo.co.jp., and KYORIN Pharmaceutical Co., Ltd., outside the submitted work. Y. Ohe reports grants from National Cancer Center and Japan Agency for Medical Research and Development during the conduct of the study, as well as personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Janssen, Eisai, Bristol Myers Squibb, Tsumura, and Boehringer Ingelheim, grants and personal fees from Amgen, and grants from Taiho Pharmaceutical outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
CONSORT diagram. Flowchart of patient disposition throughout the study, including randomization, eligibility, treatment, and follow-up.
Figure 2.
Figure 2.
Kaplan–Meier analysis of OS. A, ITT population. The 1-, 2-, 3-, 4-, and 5-year survival rates were 92.8%, 80.4%, 63.5%, 49.6%, and 36.9% in the control group and 94.4%, 81.7%, 69.9%, 49.9%, and 35.3% in the experimental group, respectively. B, Gefitinib cohort. The 1-, 2-, 3-, 4-, and 5-year survival rates were 91.5%, 78.4%, 59.5%, 46.3%, and 34.4% in the control group and 92.2%, 77.7%, 66.4%, 46.5%, and 32.9% in the experimental group, respectively. C, Osimertinib cohort. The 1-, 2-, and 3-year survival rates were 94.8%, 83.4%, and 69.8% in the control group and 97.9%, 88.3%, and 76.0% in the experimental group, respectively. D, Subgroup analysis of OS. ECOG, Eastern Clinical Oncology Group; Ex19del, EGFR exon 19 deletion; L858R, EGFR exon 21 L858 point mutation; NE; not estimable; PS, performance status.
Figure 3.
Figure 3.
Kaplan–Meier analysis of PFS. A, ITT population. The 1-, 2-, 3-, 4-, and 5-year PFS rates were 49.2%, 26.0%, 18.0%, 12.9%, and 7.8% in the control group and 67.0%, 39.8%, 24.1%, 11.9%, and 9.5% in the experimental group, respectively. B, Gefitinib cohort. The 1-, 2-, 3-, 4-, and 5-year PFS rates were 37.3%, 13.7%, 8.5%, 6.5%, and 4.0% in the control group and 59.5%, 32.7%, 15.7%, 7.2%, and 5.7% in the experimental group, respectively. C, Osimertinib cohort. The 1-, 2-, and 3-year PFS rates were 68.0%, 45.3%, and 32.2% in the control group and 79.0%, 51.4%, and 39.6% in the experimental group, respectively. D, Subgroup analysis of PFS. ECOG, Eastern Clinical Oncology Group; Ex19del, EGFR exon 19 deletion; L858R, EGFR exon 21 L858 point mutation; PS, performance status.
See this image and copyright information in PMC

References

    1. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113–25. - PubMed
    1. Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 2020;382:41–50. - PubMed
    1. Chmielecki J, Gray JE, Cheng Y, Ohe Y, Imamura F, Cho BC, et al. Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer. Nat Commun 2023;14:1070. - PMC - PubMed
    1. Hosomi Y, Morita S, Sugawara S, Kato T, Fukuhara T, Gemma A, et al. Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study. J Clin Oncol 2020;38:115–23. - PubMed
    1. Miyauchi E, Morita S, Nakamura A, Hosomi Y, Watanabe K, Ikeda S, et al. Updated analysis of NEJ009: gefitinib-alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated EGFR. J Clin Oncol 2022;40:3587–92. - PMC - PubMed

Publication types

MeSH terms