Chia-Chi Lin1, Jin-Yuan Shih2, Chong-Jen Yu2, Chao-Chi Ho2, Wei-Yu Liao2, Jih-Hsing Lee3, Tzu-Hsiu Tsai2, Kang-Yi Su4, Min-Shu Hsieh5, Yih-Leong Chang5, Ya-Ying Bai1, Derek De-Rui Huang6, Kenneth S Thress7, James Chih-Hsin Yang8. 1. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. 2. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. 3. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. 4. Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan. 5. Department of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan. 6. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. 7. Translational Sciences, Oncology, IMED Biotech Unit, AstraZeneca, Boston, MA, USA. 8. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: chihyang@ntu.edu.tw.
Abstract
BACKGROUND: Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). We assessed outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation who were treated with osimertinib, a third-generation EGFR TKI, after previous treatment failure with one or more other EGFR TKIs. METHODS: Eligible patients had been enrolled at one centre in the AURA study, had shown resistance to a previous EGFR TKI, and had EGFR-activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma. Patients took 20-240 mg osimertinib per day until disease progression or development of intolerable side-effects. Plasma samples were collected every 6 weeks and tumour tissue biopsy was done at study entry and was optional after disease progression. We tested samples for resistance mechanisms, including EGFR-activating, Thr790Met, and Cys797Ser mutations, and assessed associations with overall survival, progression-free survival, and survival after disease progression. FINDINGS: Of 71 patients enrolled in AURA, 53 were eligible for this analysis. Median progression-free survival was 11·1 months (95% CI 8·4-13·9) and overall survival was 16·9 months (11·7-29·1). 47 patients had disease progression. Median overall survival after osimertinib progression was 5·4 months (95% CI 4·1-10·0). Plasma samples were available for 40 patients after disease progression. 12 (30%) of these had the Thr790Met mutation (four of whom also had Cys797Ser mutations). Patients without detectable EGFR-activating mutations in plasma before treatment had the best overall and post-progression survival (22·4 months, 95% CI 15·6-not reached, and 10·8 months, 7·2-not reached, respectively). Loss of the Thr790Met mutation but presence of EGFR-activating mutations in plasma were associated with the shortest progression-free survival (median 2·6 months, 95% CI 1·3-not reached). In 22 post-progression tumour samples, we found one squamous cell and two small-cell transformations. We detected Thr790Met in nine (50%) of 18 samples, Cys797Ser in two (17%) of 12, cMET amplification in five (50%) of ten, BRAF mutation in one (8%) of 13, and KRAS mutation in one (8%) of 13. INTERPRETATION: Heterogeneous resistance mechanisms developed in patients receiving osimertinib. Differences in resistance mechanisms might dictate future development strategies for osimertinib in clinical trials. FUNDING: AstraZeneca, Taiwan Ministry of Science and Technology.
BACKGROUND: Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). We assessed outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation who were treated with osimertinib, a third-generation EGFR TKI, after previous treatment failure with one or more other EGFR TKIs. METHODS: Eligible patients had been enrolled at one centre in the AURA study, had shown resistance to a previous EGFR TKI, and had EGFR-activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma. Patients took 20-240 mg osimertinib per day until disease progression or development of intolerable side-effects. Plasma samples were collected every 6 weeks and tumour tissue biopsy was done at study entry and was optional after disease progression. We tested samples for resistance mechanisms, including EGFR-activating, Thr790Met, and Cys797Ser mutations, and assessed associations with overall survival, progression-free survival, and survival after disease progression. FINDINGS: Of 71 patients enrolled in AURA, 53 were eligible for this analysis. Median progression-free survival was 11·1 months (95% CI 8·4-13·9) and overall survival was 16·9 months (11·7-29·1). 47 patients had disease progression. Median overall survival after osimertinib progression was 5·4 months (95% CI 4·1-10·0). Plasma samples were available for 40 patients after disease progression. 12 (30%) of these had the Thr790Met mutation (four of whom also had Cys797Ser mutations). Patients without detectable EGFR-activating mutations in plasma before treatment had the best overall and post-progression survival (22·4 months, 95% CI 15·6-not reached, and 10·8 months, 7·2-not reached, respectively). Loss of the Thr790Met mutation but presence of EGFR-activating mutations in plasma were associated with the shortest progression-free survival (median 2·6 months, 95% CI 1·3-not reached). In 22 post-progression tumour samples, we found one squamous cell and two small-cell transformations. We detected Thr790Met in nine (50%) of 18 samples, Cys797Ser in two (17%) of 12, cMET amplification in five (50%) of ten, BRAF mutation in one (8%) of 13, and KRAS mutation in one (8%) of 13. INTERPRETATION: Heterogeneous resistance mechanisms developed in patients receiving osimertinib. Differences in resistance mechanisms might dictate future development strategies for osimertinib in clinical trials. FUNDING: AstraZeneca, Taiwan Ministry of Science and Technology.
Authors: Adam J Schoenfeld; Joseph M Chan; Daisuke Kubota; Hiroki Sato; Hira Rizvi; Yahya Daneshbod; Jason C Chang; Paul K Paik; Michael Offin; Maria E Arcila; Monika A Davare; Ujwal Shinde; Dana Pe'er; Natasha Rekhtman; Mark G Kris; Romel Somwar; Gregory J Riely; Marc Ladanyi; Helena A Yu Journal: Clin Cancer Res Date: 2020-01-07 Impact factor: 12.531
Authors: Xiuning Le; Sonam Puri; Marcelo V Negrao; Monique B Nilsson; Jacqulyne Robichaux; Theresa Boyle; J Kevin Hicks; Katherine L Lovinger; Emily Roarty; Waree Rinsurongkawong; Ming Tang; Huiying Sun; Yasir Elamin; Lara C Lacerda; Jeff Lewis; Jack A Roth; Stephen G Swisher; J Jack Lee; William N William; Bonnie S Glisson; Jianjun Zhang; Vassiliki A Papadimitrakopoulou; Jhanelle E Gray; John V Heymach Journal: Clin Cancer Res Date: 2018-09-18 Impact factor: 12.531