Hiroyuki Yasuda1, Eiki Ichihara2, Jun Sakakibara-Konishi3, Yoshitaka Zenke4, Shinji Takeuchi5, Masahiro Morise6, Katsuyuki Hotta7, Mineyoshi Sato3, Shingo Matsumoto4, Azusa Tanimoto5, Reiko Matsuzawa6, Katuyuki Kiura2, Yuta Takashima3, Seiji Yano5, Junji Koyama6, Takahiro Fukushima1, Junko Hamamoto1, Hideki Terai1, Shinnosuke Ikemura8, Ryo Takemura9, Koichi Goto4, Kenzo Soejima10. 1. Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. 2. Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan. 3. Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Hokkaido, Japan. 4. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. 5. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa Japan. 6. Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan. 7. Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan. 8. Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Keio Cancer Center, School of Medicine, Keio University School of Medicine, Tokyo, Japan. 9. Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan. 10. Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan. Electronic address: ksoejima@cpnet.med.keio.ac.jp.
Abstract
OBJECTIVES: Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC. MATERIALS AND METHODS: From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy. RESULTS: Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC. CONCLUSIONS: Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.
OBJECTIVES: Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC. MATERIALS AND METHODS: From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy. RESULTS: Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC. CONCLUSIONS: Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.