Prospective exosome-focused translational research for afatinib (EXTRA) study of patients with nonsmall cell lung cancer harboring EGFR mutation: an observational clinical study

Saori Takata; Kei Morikawa; Hisashi Tanaka; Hidetoshi Itani; Masashi Ishihara; Kazuya Horiuchi; Yasuhiro Kato; Shinnosuke Ikemura; Hideyuki Nakagawa; Yoshiro Nakahara; Yoshitaka Seki; Akihiro Bessho; Nobumasa Takahashi; Kentaro Hayashi; Takeo Endo; Kiyoshi Takeyama; Toshiya Maekura; Nagio Takigawa; Akikazu Kawase; Makoto Endoh; Kenji Nemoto; Kazuma Kishi; Kenzo Soejima; Yusuke Okuma; Kenichi Yoshimura; Daisuke Saigusa; Yae Kanai; Koji Ueda; Akira Togashi; Noriyuki Matsutani; Nobuhiko Seki

doi:10.1177/17588359231177021

Prospective exosome-focused translational research for afatinib (EXTRA) study of patients with nonsmall cell lung cancer harboring EGFR mutation: an observational clinical study

Ther Adv Med Oncol. 2023 Jun 5:15:17588359231177021. doi: 10.1177/17588359231177021. eCollection 2023.

Authors

Saori Takata¹, Kei Morikawa², Hisashi Tanaka³, Hidetoshi Itani⁴, Masashi Ishihara⁵, Kazuya Horiuchi⁶, Yasuhiro Kato⁷, Shinnosuke Ikemura⁸, Hideyuki Nakagawa⁹, Yoshiro Nakahara¹⁰, Yoshitaka Seki¹¹, Akihiro Bessho¹², Nobumasa Takahashi¹³, Kentaro Hayashi¹⁴, Takeo Endo¹⁵, Kiyoshi Takeyama¹⁶, Toshiya Maekura¹⁷, Nagio Takigawa¹⁸, Akikazu Kawase¹⁹, Makoto Endoh²⁰, Kenji Nemoto²¹, Kazuma Kishi²², Kenzo Soejima⁸, Yusuke Okuma⁷, Kenichi Yoshimura²³, Daisuke Saigusa²⁴, Yae Kanai²⁵, Koji Ueda²⁶, Akira Togashi²⁷, Noriyuki Matsutani²⁸, Nobuhiko Seki²⁹

Affiliations

¹ Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, Japan.
² Division of Respiratory Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.
³ Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, Aomori, Japan.
⁴ Department of Respiratory Medicine, Ise Red Cross Hospital, Mie, Japan.
⁵ Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
⁶ Respiratory Disease Center, Showa University Northern Yokohama Hospital, Kanagawa, Japan.
⁷ Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
⁸ Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan.
⁹ Department of Respiratory Medicine, National Hospital Organization Hirosaki Hospital, Aomori, Japan.
¹⁰ Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan.
¹¹ Department of Internal Medicine, The Jikei University Daisan Hospital, Tokyo, Japan.
¹² Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan.
¹³ Department of General Thoracic Surgery, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.
¹⁴ Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
¹⁵ Department of Respiratory Medicine, National Hospital Organization Mito Medical Center, Ibaraki, Japan.
¹⁶ Department of Respiratory Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
¹⁷ Department of Respiratory Medicine, Hoshigaoka Medical Center, Osaka, Japan.
¹⁸ Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan.
¹⁹ First Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan.
²⁰ Department of Thoracic Surgery, Yamagata Prefectural Central Hospital, Yamagata, Japan.
²¹ Department of Respiratory Medicine, National Hospital Organization, Ibarakihigashi National Hospital, Ibaraki, Japan.
²² Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, Tokyo, Japan.
²³ Department of Biostatistics, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.
²⁴ Laboratory of Biomedical and Analytical Sciences, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan.
²⁵ Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
²⁶ Project for Realization of Personalized Cancer Medicine, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
²⁷ Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.
²⁸ Department of Surgery, Teikyo University Hospital, Mizonokuchi, Kanagawa, Japan.
²⁹ Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.

Abstract

Background: The exosome-focused translational research for afatinib (EXTRA) study is the first trial to identify novel predictive biomarkers for longer treatment efficacy of afatinib in patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) via a comprehensive association study using genomic, proteomic, epigenomic, and metabolomic analyses.

Objectives: We report details of the clinical portion prior to omics analyses.

Design: A prospective, single-arm, observational study was conducted using afatinib 40 mg/day as an initial dose in untreated patients with EGFR mutation-positive NSCLC. Dose reduction to 20 mg every other day was allowed.

Methods: Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated.

Results: A total of 103 patients (median age 70 years, range 42-88 years) were enrolled from 21 institutions in Japan between February 2017 and March 2018. After a median follow-up of 35.0 months, 21% remained on afatinib treatment, whereas 9% had discontinued treatment because of AEs. The median PFS was 18.4 months, with a 3-year PFS rate of 23.3%. The median afatinib treatment duration in patients with final doses of 40 (n = 27), 30 (n = 23), and 20 mg/day (n = 35), and 20 mg every other day (n = 18) were 13.4, 15.4, 18.8, and 18.3 months, respectively. The median OS was not reached, with a 3-year OS rate of 58.5%. The median OS in patients who did (n = 25) and did not (n = 78) receive osimertinib during the entire course of treatment were 42.4 months and not reached, respectively (p = 0.654).

Conclusions: As the largest prospective study in Japan, this study confirmed favorable OS following first-line afatinib in patients with EGFR mutation-positive NSCLC in a real-world setting. Further analysis of the EXTRA study is expected to identify novel predictive biomarkers for afatinib.

Trial registration: UMIN-CTR identifier (UMIN000024935, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_his_list.cgi?recptno=R000028688.

Keywords: EGFR–TKI; afatinib; biomarker; exosome; nonsmall-cell lung cancer; omics.