Daichi Fujimoto1, Hiroaki Akamatsu2, Takeshi Morimoto3, Kazushige Wakuda4, Yuki Sato5, Yoshitaka Kawa6, Toshihide Yokoyama7, Motohiro Tamiya8, Ryota Hiraoka9, Naoki Shingu10, Hideki Ikeda11, Akihiro Tamiya12, Masaki Kanazu13, Eisaku Miyauchi14, Satoru Miura15, Masaaki Yanai16, Makiko Yomota17, Ryotaro Morinaga18, Takashi Yokoi19, Akito Hata20, Hidekazu Suzuki21, Hirotaka Matsumoto22, Shinya Sakata23, Naoki Furuya24, Yuhei Harutani25, Ichiro Nakachi26, Ayumu Otsuki27, Shinya Uematsu28, Satoshi Hara29, Keiki Yokoo30, Takeya Sugimoto2, Nobuyuki Yamamoto2. 1. Internal Medicine III, Wakayama Medical University, Wakayama, Japan. Electronic address: daichi@wakayama-med.ac.jp. 2. Internal Medicine III, Wakayama Medical University, Wakayama, Japan. 3. Department of Clinical Epidemiology, Hyogo College of Medicine, Nishinomiya, Japan. 4. Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan. 5. Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan. 6. Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan. 7. Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan. 8. Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan. 9. Department of Respiratory Medicine, National Hospital Organization Himeji Medical Center, Himeji, Japan. 10. Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan. 11. Department of Respirology, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Respiratory Medicine, Kimitsu Chuo Hospital, Kisarazu, Japan. 12. Department of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan. 13. Department of Thoracic Oncology, National Hospital Organization Osaka Toneyama Medical Center, Toyonaka, Japan. 14. Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. 15. Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan. 16. Division of Respiratory Medicine and Rheumatology, Faculty of Medicine, Tottori University, Yonago, Japan. 17. Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan. 18. Department of Thoracic Medical Oncology, Oita Prefectural Hospital, Oita, Japan. 19. Department of Thoracic Oncology, Hyogo College of Medicine, Hyogo, Japan. 20. Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Kobe, Japan. 21. Department of Thoracic Malignancy, Osaka Habikino Medical Center, Habikino, Japan. 22. Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan. 23. Department of Respiratory Medicine, Kumamoto University Hospital, Kumamoto, Japan. 24. Division of Respiratory Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan. 25. Department of Respiratory Medicine, National Hospital Organization Minami Wakayama Medical Center, Tanabe, Japan. 26. Department of Respiratory Medicine, Saiseikai Utsunomiya Hospital, Utsunomiya, Japan. 27. Department of Pulmonology, Kameda Medical Center, Chiba, Japan. 28. Department of Respiratory Medicine, Osaka Red Cross Hospital, Osaka, Japan. 29. Department of Respiratory Medicine, Itami City Hospital, Itami, Japan. 30. Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo, Japan.
Abstract
PURPOSE: This study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT). PATIENTS AND METHODS: We conducted a multicentre, retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT. RESULTS: In total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% [95% confidence interval: 2.3%-3.5%]). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non-small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months. CONCLUSION: HT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients.
PURPOSE: This study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT). PATIENTS AND METHODS: We conducted a multicentre, retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT. RESULTS: In total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% [95% confidence interval: 2.3%-3.5%]). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non-small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months. CONCLUSION: HT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients.