EGFR-V834L combined with L858R mutation reduced afatinib sensitivity and associated to early recurrence in lung cancer

Nanao Terada; Hayato Koba; Shigeki Nanjo; Hideharu Kimura; Akihiro Nishiyama; Taro Yoneda; Takayuki Takeda; Hiroki Shirasaki; Koichi Nishi; Takashi Sone; Tadaaki Yamada; Koichi Takayama; Kazuhiko Shibata; Hiroki Matsuoka; Toshiyuki Kita; Kazuhiro Nagata; Yuichi Tambo; Noriyuki Ohkura; Johsuke Hara; Kazuo Kasahara; Shinji Kohsaka; Hiroyuki Mano; Seiji Yano

doi:10.21037/tlcr-24-471

EGFR-V834L combined with L858R mutation reduced afatinib sensitivity and associated to early recurrence in lung cancer

Transl Lung Cancer Res. 2024 Nov 30;13(11):3067-3082. doi: 10.21037/tlcr-24-471. Epub 2024 Nov 28.

Authors

Nanao Terada^#¹, Hayato Koba^#¹, Shigeki Nanjo^#¹, Hideharu Kimura¹, Akihiro Nishiyama², Taro Yoneda³, Takayuki Takeda^{4

5}, Hiroki Shirasaki⁶, Koichi Nishi⁷, Takashi Sone⁷, Tadaaki Yamada⁸, Koichi Takayama⁸, Kazuhiko Shibata⁹, Hiroki Matsuoka¹⁰, Toshiyuki Kita¹¹, Kazuhiro Nagata¹², Yuichi Tambo¹, Noriyuki Ohkura¹, Johsuke Hara¹, Kazuo Kasahara^{1

13}, Shinji Kohsaka¹⁴, Hiroyuki Mano¹⁴, Seiji Yano^{1

2

15}

Affiliations

¹ Department of Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan.
² Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
³ Department of Respiratory Medicine, Komatsu Municipal Hospital, Komatsu, Japan.
⁴ Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan.
⁵ Department of Internal Medicine, Uji-Tokushukai Medical Center, Uji, Japan.
⁶ Department of Respiratory Medicine, Fukui-ken Saiseikai Hospital, Fukui, Japan.
⁷ Department of Respiratory Medicine, Ishikawa Prefectural Central Hospital, Kanazawa, Japan.
⁸ Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
⁹ Department of Medical Oncology, Kouseiren Takaoka Hospital, Takaoka, Japan.
¹⁰ Department of Internal Medicine, Keiju Medical Center, Nanao, Japan.
¹¹ Department of Respiratory Medicine, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan.
¹² Department of Internal Medicine, Koseikai Takeda Hospital, Kyoto, Japan.
¹³ Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
¹⁴ Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
¹⁵ Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.

^# Contributed equally.

Abstract

Background: The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is widely used as a first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC). However, there is no established treatment for osimertinib resistance, so second-generation afatinib is an alternative treatment option. The purpose of this study was to elucidate gene alterations associated with afatinib efficacy and resistance by analyzing cell-free DNA (cfDNA) obtained from patients with EGFR-mutated NSCLC.

Methods: This study was conducted as a prospective clinical trial in patients with EGFR-mutated NSCLC at multiple institutions. We analyzed plasma cfDNA from the patients treated with afatinib as the first-line therapy.

Results: Paired specimens were obtained before and at the time of resistance to afatinib treatment, and specimens only at afatinib resistance were obtained from 22 and 18 patients, respectively. In plasma cfDNA from the 22 cases, driver EGFR mutations were detected in 13 cases (59.1%), and the compound V834L mutation was detected in two cases in cis with EGFR-L858R mutation. The median progression-free survival (mPFS) was remarkably shorter in patients with V834L than in all 22 cases (4.2 vs. 9.2 months). Moreover, we detected V834L and T790M combined with EGFR-L858R in the cfDNA from one patient resistant to afatinib. Preclinical experiments using EGFR-L858R, with or without V834L, in Ba/F3 cells revealed that V834L with L858R conferred resistance to low concentrations of EGFR-TKIs, including afatinib and osimertinib. In three cases of EGFR-L858R+V834L, other co-mutations, including TP53, CTNNB1, and RB1, were detected either before or after afatinib resistance.

Conclusions: These results suggested that V834L cooperates with other coexisting mutations to influence the therapeutic efficacy of EGFR-TKIs.

Keywords: Co-mutation; cell-free DNA (cfDNA); epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI); liquid biopsy; resistance.