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Survival benefit of using pemetrexed for EGFR mutation-positive advanced non-small-cell lung cancer in a randomized phase III study comparing gefitinib to cisplatin plus docetaxel (WJTOG3405)

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Abstract

Background

Pemetrexed is common cytotoxic chemotherapy among non-squamous non-small cell lung cancer (non-Sq-NSCLC) patients; however, among epidermal growth factor receptor (EGFR)-positive lung cancer, there is no clear evidence to support the efficacy of sequential treatment with pemetrexed.

Material and methods

We performed a post-hoc analysis of subsequent chemotherapies among 144 patients who received the post-protocol treatment in the phase III trial WJTOG 3405 comparing gefitinib to cisplatin plus docetaxel, and analyzed the effect of pemetrexed on overall survival (OS).

Results

Patients with treatment including pemetrexed exhibited significantly longer OS in comparison to those without pemetrexed; the median OS in the pemetrexed + and pemetrexed– patients were 40.7 months and 28.0 months, respectively (0.55 of HR [95% CI: 0.38–0.80, p = 0.0020]). On the other hand, other treatments, including docetaxel, TS-1 and paclitaxel showed no significant impact on OS. The multivariate analysis with a time-dependent Cox proportional hazards model showed that treatment including pemetrexed, as well as PS 0 and post-operative recurrence, were independent predictors of a good prognosis. Moreover, among patients who received at least four lines of prior treatment, pemetrexed + treatment also significantly prolonged OS in comparison to pemetrexed– treatment (median OS pemetrexed + vs. pemetrexed–: 44.4 months vs. 32.6 months; HR: 0.55 [95% CI: 0.31–0.94, p = 0.0290]).

Conclusions

Sequential treatment including pemetrexed against EGFR-mutated NSCLC might be associated with a better outcome. It was considered that pemetrexed should be administered without fail as a sequential treatment to improve the prognosis of EGFR-mutated NSCLC as well as like EGFR-tyrosine kinase inhibitors.

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Availability of data and materials

All data are available from the corresponding author.

Abbreviations

95% CI:

95% Confidence Interval

EGFR:

Epidermal growth factor receptor

HR:

Hazard ratio

non-Sq-NSCLC:

Non-squamous-non-small cell lung cancer

OS:

Overall survival

PS:

WHO performance status

TKIs:

Tyrosine kinase inhibitors

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Acknowledgements

We appreciate patients, their families, all investigators and the staff of the West Japan Oncology Group Data Center who were engaged in the WJTOG 3405 study.

Funding

This work was supported by the West Japan Oncology Group (WJOG): a non-profit organization supported by unrestricted donations from members of WJOG, citizens, and pharmaceutical companies (no grant numbers are applicable).

Author information

Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Naoki Haratake

  2. Department of Thoracic Oncology, National Hospital Organization, Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, 811-1395, Japan

    Naoki Haratake & Takashi Seto

  3. Department of Biostatistics, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan

    Mototsugu Shimokawa

  4. Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata, Japan

    Hiroshige Yoshioka

  5. Internal Medicine III, Wakayama Medical University Hospital, Wakayama, Japan

    Nobuyuki Yamamoto

  6. Department of Medical Oncology, Kindai University Hospital, Osaka-Sayama, Japan

    Kazuhiko Nakagawa

  7. Division of Thoracic Surgery, Department of Surgery, Kindai University Hospital, Osaka-Sayama, Japan

    Tetsuya Mitsudomi

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  1. Naoki Haratake
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Corresponding author

Correspondence to Takashi Seto.

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Conflict of interest

Naoki Haratake reports personal fees from Eli Lilly Japan K.K., personal fees from AstraZeneca, personal fees from Chugai Pharmaceutical Co. Ltd, outside the submitted work. Mototsugu Shimokawa has stated that they have no conflict of interest. Takashi Seto has received grants and personal fees from Chugai Pharmaceutical, grants and personal fees from Daiichi Sankyo, grants and personal fees from Eli Lilly Japan, grants and personal fees from MSD, grants and personal fees from Novartis Pharma, grants and personal fees from Pfizer Japan, grants and personal fees from Takeda Pharmaceutical, grants from Abbvie, grants from Kissei Pharmaceutical, grants from LOXO Oncology, grants from Merck Biopharma, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from Covidien Japan, personal fees from Kyowa Hakko Kirin, personal fees from Mochida Pharmaceutical, personal fees from Nippon Boehringer Ingelheim, personal fees from Ono Pharmaceutical, personal fees from Taiho Pharmaceutical, personal fees from Thermo Fisher Scientific, personal fees from Precision Medicine Asia. Hiroshige Yoshioka reports personal fees from Chugai Pharmaceutical Co. Ltd, personal fees from Eli Lilly Japan K.K., personal fees from AstraZeneca K.K, personal fees from Boehringer Ingelheim Japan Inc, personal fees from Pfizer Japan Inc., personal fees from TAIHO PHARMACEUTICAL CO., LTD., personal fees from MSD K.K., personal fees from Delta Fly Pharma, personal fees from Nippon Kayaku, personal fees from Novartis pharmaceuticals k.k, personal fees from Otsuka Pharmaceutical Co., Ltd., outside the submitted work. Nobuyuki Yamamoto reports personal fees from AstraZeneca, personal fees from MSD K.K., personal fees from ONO PHARMACEUTICAL CO., LTD., personal fees from Thermo Fisher Scientific, personal fees from DAIICHI SANKYO CO., grants and personal fees from TAIHO PHARMACEUTICAL CO., LTD., personal fees from Takeda Pharmaceutical CO., LTD., grants and personal fees from Chugai Pharmaceutical CO., LTD., personal fees from Eli Lilly Japan K.K., grants and personal fees from Boehringer-Ingelheim, personal fees from Novartis, personal fees from Pfizer Inc., personal fees from Bristol-Myers Squibb, personal fees from NIPPON KAYAKU, personal fees from GlaxoSmithKline K.K., personal fees from Sanofi K.K., personal fees from Hisamitsu Pharmaceutical Co.Inc, personal fees from Merk biopharma, grants from Tosoh Life Science Research Laboratory, outside the submitted work. Kazuhiko Nakagawa reports grants and personal fees from AstraZeneca K.K., grants and personal fees from Astellas Pharma Inc., grants and personal fees from MSD K.K., grants, personal fees and other from Ono Pharmaceutical Co., Ltd., grants and personal fees from Nippon Boehringer Ingelheim Co., Ltd., grants and personal fees from Novartis Pharma K.K., grants, personal fees and other from Pfizer Japan Inc., grants and personal fees from Bristol Myers Squibb Company, grants, personal fees and other from Eli Lilly Japan K.K., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Daiichi Sankyo Co., Ltd., grants and personal fees from Merck Serono Co., Ltd./ Merck Biopharma Co., Ltd., during the conduct of the study; personal fees from Clinical Trial Co., Ltd., personal fees from MEDICUS SHUPPAN, Publishers Co., Ltd., personal fees from Care Net, Inc, personal fees from Reno. Medical K.K., personal fees and other from KYORIN Pharmaceutical Co., Ltd., personal fees from Medical Review Co., Ltd., personal fees from Roche Diagnostics K.K., personal fees from Bayer Yakuhin, Ltd, personal fees from Medical Mobile Communications co., Ltd, personal fees from 3H Clinical Trial Inc., personal fees from Nichi-Iko Pharmaceutical Co., Ltd., grants, personal fees and other from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from SymBio Pharmaceuticals Limited., personal fees from NANZANDO Co., Ltd., personal fees from YODOSHA CO., LTD., personal fees from Nikkei Business Publications, Inc, personal fees from Thermo Fisher Scientific K.K., personal fees from YOMIURI TELECASTING CORPORATION., personal fees from Nippon Kayaku Co., Ltd., grants and personal fees from AbbVie Inc, grants from inVentiv Health Japan, grants from ICON Japan K.K., grants from GRITSONE ONCOLOGY.INC, grants from PAREXEL International Corp., grants from Kissei Pharmaceutical Co., Ltd., grants from EPS Corporation., grants from Syneos Health., grants from Pfizer R&D Japan G.K., grants from A2 Healthcare Corp., grants from Quintiles Inc. / IQVIA Services JAPAN K.K., grants from EP-CRSU CO., LTD., grants from Linical Co., Ltd., grants from Eisai Co., Ltd., grants from CMIC Shift Zero K.K., grants from Kyowa Hakko Kirin Co., Ltd, grants from Bayer Yakuhin, Ltd, grants from EPS International Co., Ltd,., grants from Otsuka Pharmaceutical Co., Ltd., outside the submitted work. Tetsuya Mitsudomi has received grants and personal fees from AstraZeneca, grants and personal fees from Eli-Lilly, during the conduct of the study; grants and personal fees from Boehringer-Ingeleheim, grants and personal fees from Chugai, grants and personal fees from Ono, personal fees from BMS, grants and personal fees from MSD, personal fees from Pfizer, grants and personal fees from Taiho, personal fees from Amgen, personal fees from Novartis, personal fees from Merck Biopharma, personal fees from Takeda, personal fees from Ddaiichi-Sankyo, outside the submitted work.

Ethical approval and consent to participate

All patients provided their written informed consent before study registration, and the study protocol was approved by the institutional ethics committee of each participating institution. The study was undertaken in accordance with the Declaration of Helsinki. All authors gave their final approval for the version to be published.

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Supplementary Information

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10147_2022_2193_MOESM1_ESM.pdf

Supplementary Figure 1. Kaplan–Meier estimates of overall survival in patients with treatment including pemetrexed + platinum doublet (Panel A), pemetrexed-monotherapy (Panel B) HR, hazard ratio; 95% CI, 95% confidence interval; PEM, pemetrexed. Supplementary file1 (PDF 68 KB)

Supplementary file2 (DOCX 16 KB)

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Haratake, N., Shimokawa, M., Seto, T. et al. Survival benefit of using pemetrexed for EGFR mutation-positive advanced non-small-cell lung cancer in a randomized phase III study comparing gefitinib to cisplatin plus docetaxel (WJTOG3405). Int J Clin Oncol 27, 1404–1412 (2022). https://doi.org/10.1007/s10147-022-02193-x

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