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Clinical Studies

Association of immune-related adverse events with durvalumab efficacy after chemoradiotherapy in patients with unresectable Stage III non-small cell lung cancer

British Journal of Cancer (2024)Cite this article

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Abstract

Background

Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown.

Methods

In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid.

Results

Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31–11.38) compared with no irAEs and 11.58 (95% CI, 2.11–63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration.

Conclusions

The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid–treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.

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Fig. 1: Survival outcome according to immune-related adverse event (irAE) profiles in 8-week landmark analysis.
Fig. 2: Relation between the development of immune-related adverse events (irAEs) and baseline clinical features or tumour microenvironment (TME) profiles.

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Data availability

The data generated in this study are not publicly available as restricted by the study protocol due to the possibility that could compromise patient privacy or consent, but are possibly available upon reasonable request from the corresponding author.

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Acknowledgements

The authors thank all patients, their families, and the investigators who participated in this study; members of the WJOG Data Center (in particular, Koji Takeda, and Shinichiro Nakamura) for central data management and administrative support; and Haruka Yamaguchi, Yume Shinkai, Michiko Kitano, Mami Kitano, Shinji Kurashimo and Yoshihiro Mine of Kindai University Faculty of Medicine for technical support. Shunsuke Teraoka is currently an employee of AstraZeneca K.K.

Funding

This study was conducted by the West Japan Oncology Group (WJOG) Data Center with a research grant from AstraZeneca KK.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan

    Koji Haratani, Kazuhiko Nakagawa & Hidetoshi Hayashi

  2. Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Miyagi, Japan

    Atsushi Nakamura

  3. Division of Thoracic Oncology, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan

    Nobuaki Mamesaya

  4. Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Osaka, Japan

    Kenji Sawa

  5. Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan

    Yoshimasa Shiraishi

  6. Department of Respiratory Medicine, Tohoku University School of Medicine, Sendai, Miyagi, Japan

    Ryota Saito

  7. Division of Medical Oncology, Kishiwada City Hospital, Kishiwada, Osaka, Japan

    Junko Tanizaki

  8. Respiratory Medicine and Thoracic Oncology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan

    Yosuke Tamura

  9. Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Kobe, Hyogo, Japan

    Akito Hata

  10. Department of Respiratory Medicine, Iizuka Hospital, Iizuka, Fukuoka, Japan

    Kosuke Tsuruno

  11. Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan

    Tomohiro Sakamoto

  12. Internal Medicine III, Wakayama Medical University, Wakayama, Wakayama, Japan

    Shunsuke Teraoka & Nobuyuki Yamamoto

  13. Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan

    Masahide Oki

  14. Department of Respiratory Medicine, Saka General Hospital, Shiogama, Miyagi, Japan

    Hiroshi Watanabe

  15. Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan

    Takaaki Tokito

  16. Department of Respiratory Medicine, Itami City Hospital, Itami, Hyogo, Japan

    Kenji Nagata

  17. Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Hiroshima, Japan

    Takeshi Masuda

  18. Department of Pathology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan

    Yasushi Nakamura & Akihiko Ito

  19. Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan

    Kazuko Sakai & Kazuto Nishio

  20. Clinical Research Center, Kindai University Hospital, Osaka-Sayama, Osaka, Japan

    Yasutaka Chiba

Authors
  1. Koji Haratani
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  2. Atsushi Nakamura
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Contributions

K Haratani developed the hypothesis, designed the overall study concept, wrote the study protocol, provided clinical data and samples, supervised IHC experiments, performed FCM experiments, performed data analysis and interpreted the data, wrote the manuscript, and supervised the project. A Nakamura, N Mamesaya, K Sawa, Y Shiraishi, R Saito, J Tanizaki, Y Tamura, A Hata, K Tsuruno, T Sakamoto, S Teraoka, M Oki, H Watanabe, T Tokito, K Nagata and T Masuda provided clinical data and samples. Y Nakamura supervised IHC experiments and evaluated IHC staining. K Sakai performed genomic sequencing and processed genomic data. Y Chiba wrote the study protocol and supervised the statistical analysis. A Ito supervised IHC experiments, evaluated IHC staining, and provided administrative support. K Nishio, N Yamamoto, K Nakagawa and H Hayashi provided administrative support and supervised the project. All authors critically revised the manuscript for important intellectual content and approved the final version.

Corresponding author

Correspondence to Koji Haratani.

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Competing interests

K Haratani has received lecture fees or honoraria from AS ONE Corporation, Bristol-Myers Squibb Co. Ltd., MSD K.K., and Ono Pharmaceutical Co. Ltd.; and research funding from AstraZeneca K.K., and MSD K.K. A Nakamura has received lecture fees or honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Nippon Kayaku Co. Ltd., Novartis Pharma K.K., Taiho Pharmaceutical Co. Ltd., and Thermo Fisher Scientific Inc. K Sawa has received lecture fees or honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Kyowa Kirin Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Ono Pharmaceutical Co. Ltd., and Taiho Pharmaceutical Co. Ltd. Y Shiraishi has received lecture fees or honoraria from AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., and Taiho Pharmaceutical Co. Ltd.; and research funding from Chugai Pharmaceutical Co. Ltd. J Tanizaki has received lecture fees or honoraria from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Nihon Medi-Physics Co. Ltd., Nippon Kayaku Co. Ltd., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., and Taiho Pharmaceutical Co. Ltd. A Hata has received lecture fees or honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Nippon Kayaku Co. Ltd., Pfizer Inc., and Taiho Pharmaceutical Co. Ltd.; and research funding from MSD K.K., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co. Ltd., and AstraZeneca K.K. T Sakamoto has received lecture fees or honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Hisamitsu Pharmaceutical Co. Inc., Illumina K.K., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Merck KGaA, MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co., Ltd. S Teraoka has received lecture fees or honoraria from AstraZeneca K.K. Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Pfizer R&D Japan G.K., and Taiho Pharmaceutical Co. Ltd.; and advisory board fees from Pfizer R&D Japan G.K. S Teraoka is currently an employee of AstraZeneca K.K. M. Oki has received lecture fees or honoraria from AMCO Inc., AstraZeneca K.K., Canon Medical Systems Corporation., Chugai Pharmaceutical Co. Ltd., Fujifilm Toyama Chemical Co. Ltd., Kaneka Medix Corp., Merit Medical Japan K.K., Novartis Pharma K.K., Olympus Corporation, and Sanofi K.K.; and research funding from AbbVie Inc., AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Fujifilm Toyama Chemical Co. Ltd., GlaxoSmithKline K.K., Janssen Pharmaceutical K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Parxel International Corporation, Pfizer Japan Inc., and Sanofi K.K. Takaaki Tokito has received lecture fees or honoraria from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD K.K., Nippon Kayaku Co. Ltd., Novartis Pharma K.K., and Ono Pharmaceutical Co. Ltd. Takeshi Masuda has received lecture fees or honoraria from AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Kyowa Kirin Co. Ltd., MSD K.K., Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., and Taiho Pharmaceutical Co. Ltd.; and research funding from MSD K.K. Yasushi Nakamura has received consulting fees from LSI Medience Corporation., and Nikon Corporation.; and advisory fees from Agilent Technologies Inc. K Sakai has received lecture fees or honoraria from Chugai Pharmaceutical Co. Ltd., Hitachi Ltd., Life Technologies Corporation, Takeda Pharmaceutical Co. Ltd., and Yodosha Co. Ltd. Y Chiba has received lecture fees or honoraria from Chugai Pharmaceutical Co. Ltd. K. Nishio has received research funding from Clinical Research Support Center Kyushu, Eli Lilly Japan K.K., Hitachi Ltd., Nichirei Biosciences Inc., Nippon Boehringer Ingelheim Co. Ltd., North East Japan Study Group, Otsuka Pharmaceutical Co. Ltd., Sysmex Corporation, Thoracic Oncology Research Group and West Japan Oncology Group. N Yamamoto has received lecture fees or honoraria from Amgen Inc., AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Guardant Health Japan Corp., Janssen Pharmaceutical K.K., Kyorin Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., Merck kGaA, MIYARISAN Pharmaceutical Co,, MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Nippon Kayaku Co. Ltd., Novartis Pharma K.K., Ono Pfizer Japan Inc., Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Sanofi K.K., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., and TSUMURA & CO.; and advisory board fees from AstraZeneca K.K., Eli Lilly Japan K.K., and Takeda Pharmaceutical Co. Ltd.; and research funding from AbbVie Inc., Amgen Inc., Asahi Kasei Pharma Corporation, Astellas Pharma Inc., AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Nippon Kayaku Co. Ltd., Nobelpharma Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Pfizer Japan Inc., Sanofi K.K., Shionogi & Co. Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., TOSOH CORPORATION. and TSUMURA & CO. K. Nakagawa has received lecture fees or honoraria from AstraZeneca K.K., Amgen Inc., Bayer Yakuhin Ltd., Care Net Inc., Chugai Pharmaceutical Co. Ltd., CMIC Co. Ltd., CMIC ShiftZero K.K., Eli Lilly Japan K.K., Japan Clinical Research Operations, Kyowa Kirin Co. Ltd., Life Technologies Japan Ltd., Merck Biopharma Co. Ltd., Medical Mobile Communications Co. Ltd, Medical Review Co. Ltd., MSD K.K., Nikkei Business Publications Inc., Nippon Boehringer Ingelheim Co. Ltd., Nippon Kayaku Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co. Ltd., TAIYO Pharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., Yodosya Co. Ltd., and 3H Clinical Trial Inc.; and consulting fees from Eli Lilly Japan K.K., and Ono Pharmaceutical Co. Ltd.; and research funding from Amgen Inc., AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Covance Japan Inc., Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., EP-CRSU Co. Ltd., EPS Corporation, EPS International Co. Ltd., GlaxoSmithKline K.K., IQVIA Services JAPAN K.K., Janssen Pharmaceutical K.K., Japan Clinical Research Operations, Kissei Pharmaceutical Co. Ltd., Mebix Inc., Medical Research Support, MSD K.K., Mochida Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Nippon Kayaku Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., PAREXEL International Corp., PPD-SNBL K.K., PRA Health Sciences., Sanofi K.K., SRL Inc., SymBio Pharmaceuticals Limited., Syneos Health Clinical K.K., Sysmex Corporation., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd.; and has patents pending with Daiichi Sankyo Co. Ltd. H. Hayashi has received lecture fees or honoraria from Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Guardant health　Inc., Kyorin Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd., MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd., Shanghai Haihe Biopharm, Taiho Pharmaceutical Co. Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Co. Ltd.; and research funding from AbbVie Inc, Astellas Pharma Inc., AstraZeneca K.K., A2 Healthcare Corp., Bayer Yakuhin Ltd., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., CMIC ShiftZero K.K., Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., EP-CRSU Co. Ltd., EPS Corporation., EPS International Co. Ltd., GRITSONE ONCOLOGY INC., ICON Japan K.K., inVentiv Health Japan, IQVIA Services JAPAN K.K., Kissei Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd, Merck Biopharma Co. Ltd., Merck Serono Co. Ltd., MSD K.K., Linical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., PAREXEL International Corp., Pfizer Japan Inc., Pfizer R&D Japan G.K., SymBio Pharmaceuticals Limited., Quintiles Inc., Syneos Health, Taiho Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd. All other authors declare competing interests.

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Haratani, K., Nakamura, A., Mamesaya, N. et al. Association of immune-related adverse events with durvalumab efficacy after chemoradiotherapy in patients with unresectable Stage III non-small cell lung cancer. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02662-2

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