Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: a multicenter phase II trial protocol (REAL study)

Taisuke Araki; Shintaro Kanda; Masamichi Komatsu; Kei Sonehara; Kazunari Tateishi; Munetake Takada; Akane Kato; Manabu Yamamoto; Kenichi Nishie; Mineyuki Hama; Toshihiko Agatsuma; Yumiko Kakizaki; Fumiaki Yoshiike; Akemi Matsuo; Tomoshige Chiaki; Kanae Samizo; Yoshiko Takagi; Maki Yamaura; Masayuki Hanaoka; Tomonobu Koizumi

doi:10.21037/tlcr-23-12

Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: a multicenter phase II trial protocol (REAL study)

Transl Lung Cancer Res. 2023 Jun 30;12(6):1320-1327. doi: 10.21037/tlcr-23-12. Epub 2023 Jun 15.

Authors

Taisuke Araki¹, Shintaro Kanda², Masamichi Komatsu¹, Kei Sonehara¹, Kazunari Tateishi¹, Munetake Takada³, Akane Kato⁴, Manabu Yamamoto⁵, Kenichi Nishie⁶, Mineyuki Hama⁷, Toshihiko Agatsuma⁸, Yumiko Kakizaki⁹, Fumiaki Yoshiike¹⁰, Akemi Matsuo¹¹, Tomoshige Chiaki¹², Kanae Samizo¹³, Yoshiko Takagi¹³, Maki Yamaura¹³, Masayuki Hanaoka¹, Tomonobu Koizumi²

Affiliations

¹ First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
² Department of Hematology and Medical Oncology, Shinshu University School of Medicine, Matsumoto, Japan.
³ Department of Respiratory Medicine, Jiseikai Aizawa Hospital, Matsumoto, Japan.
⁴ Department of Respiratory Medicine, Ina Central Hospital, Ina, Japan.
⁵ Department of Respiratory Medicine, Japanese Red Cross Society Nagano Hospital, Nagano, Japan.
⁶ Department of Respiratory Medicine, Iida Municipal Hospital, Iida, Japan.
⁷ Department of Respiratory Medicine, Japanese Red Cross Society Suwa Hospital, Suwa, Japan.
⁸ Department of Respiratory Medicine, Shinshu Ueda Medical Center, Ueda, Japan.
⁹ Lung Cancer and Respiratory Disease Center, Yamanashi Prefectural Central Hospital, Kofu, Japan.
¹⁰ Department of Respiratory Medicine, Nagano Municipal Hospital, Nagano, Japan.
¹¹ Department of Internal Medicine, Minami-Nagano Medical Center, Shinonoi General Hospital, Nagano, Japan.
¹² Department of Respiratory Medicine, Hokushin General Hospital, Nakano, Japan.
¹³ Shinshu University Hospital, Center for Clinical Research, Matsumoto, Japan.

Abstract

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and contributed to the development of precision medicine. Osimertinib is a standard first-line (1L) treatment for EGFR-mutated NSCLC and has demonstrated superior survival benefits over previous-generation TKIs. However, resistance to osimertinib is nearly inevitable, and subsequent treatment strategies remain unmet medical needs in this setting. Afatinib, a second-generation EGFR-TKI, exhibits activity against certain uncommon EGFR mutation types in the 1L setting. There are a few case reports on the efficacy of afatinib against EGFR-dependent resistance after osimertinib treatment, although these have not been prospectively investigated.

Methods: The present phase II, single-arm multicenter trial aims to verify the efficacy and safety of afatinib rechallenge after 1L osimertinib resistance. Patients (aged ≥20 years) with advanced or recurrent non-squamous NSCLC harboring drug-sensitive EGFR mutations (deletion of exon 19 or L858R) who were previously treated with 1L osimertinib and second-line chemotherapy other than TKIs are considered eligible. Undergoing next-generation sequence-based comprehensive genomic profiling is one of the key inclusion criteria. The primary endpoint is the objective response rate; the secondary endpoints are progression-free survival, overall survival, and tolerability. Thirty patients will be recruited in December 2023.

Discussion: The results of this study may promote incorporating afatinib rechallenge into the treatment sequence after 1L osimertinib resistance, a setting in which concrete evidence has not been yet established.

Registration: UMIN Clinical Trial Registry: UMIN000049225.

Keywords: Non-small cell lung cancer (NSCLC); afatinib; epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI); osimertinib; rechallenge.