Purpose Osimertinib, a third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI), has demonstrated substantial clinical benefit in patients with non-small-cell lung cancer (NSCLC) who were resistant to early-generation EGFR-TKIs and had acquired a T790M mutation. The aim of our study was to identify the mechanisms underlying resistance to osimertinib and to correlate them with clinical outcomes. Methods We retrospectively analyzed patients with advanced NSCLC who received osimertinib for T790M-mutated acquired resistance to prior EGFR-TKIs between March 1, 2017 and December 31, 2018. Patients with paired molecular data of preosimertinib and after resistance development, which were not confirmed with small-cell lung cancer (SCLC) transformation, were included in the molecular analysis set. Results Of 49 patients evaluated in the molecular analysis set, 24 patients maintained T790M mutation, while 25 patients exhibited T790M-loss. Molecular modifications were identified in 27 of 49 patients including EGFR acquired mutations (C797S, C796S, G796S, V802I, V834L, E758D and G724S), non-EGFR-dependent mutations (PIK3CA, ALK, BRAF, KRAS and TP53), EGFR amplification and MET amplification. At data cutoff, median progression-free survival (PFS) was 9.3 months in the T790M-retain group compared with 7.8 months in T790M-loss patients (P = 0.053). Median PFS was significantly longer in patients with EGFR-dependent resistance mechanism (13.5 months) than in those with alternative pathway activation (8.2 months; P = 0.012). Conclusions The study revealed heterogeneous mechanisms of resistance to osimertinib in advanced NSCLC patients and their association with clinical outcomes. Patients who maintained T790M mutation or with EGFR-dependent resistance mechanism had longer clinical outcome benefits.

Objectives Central nervous system (CNS) metastases are very common in patients with non-small-cell lung cancer (NSCLC). We aimed to explore the clinical impact of osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), on CNS metastases in patients with advanced NSCLC in real-world setting. Methods Patients with advanced NSCLC who received osimertinib after progression of early-generation EGFR-TKIs and CNS metastases on baseline brain scan were retrospectively collected. Primary outcomes were disease control rate (DCR) and progression-free survival (PFS), and secondary objectives were objective response rate (ORR), time to tumor response, median best percentage change from baseline in CNS target lesion (TL) size and safety.

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BRAF mutation is an oncogenic driver gene in non-small cell lung cancer (NSCLC) with low frequency. The data of patients with NSCLC harboring BRAF mutations is rare. We conducted a retrospective multicenter study in Chinese patients with NSCLC harboring BRAF mutations between Jan 2017 and Jul 2019. A total of 65 patients treated in 22 centers were included, 54 harbored BRAF-V600E mutation and 11 had non-V600E mutations, including K601E, G469S, G469V, G469A, G596R, G466R, and T599dup. Of 18 patients with early-stage disease at diagnosis and underwent a resection, the median disease-free survival (DFS) was 43.2, 18.7, and 10.1 months of stage I, II, and IIIA patients, respectively. In 46 patients with advanced-stage disease at data cutoff, disease control rate (DCR), and progression-free survival (PFS) of first-line anti-BRAF targeted therapy was superior than chemotherapy in patients harboring BRAF-V600E mutation (DCR, 100.0 vs. 70.0%, P = 0.027; median PFS, 9.8 vs. 5.4 months, P = 0.149). Of 30 V600E-mutated patients who received anti-BRAF therapy during the course of disease, median PFS of vemurafenib, dabrafenib, and dabrafenib plus trametinib was 7.8, 5.8, and 6.0 months, respectively (P = 0.970). Median PFS were similar between V600E and non-V600E patients (5.4 vs. 5.4 months, P = 0.825) to first-line chemotherapy. Nine patients were treated with checkpoint inhibitors, with median PFS of 3.0 months. Our data demonstrated the clinical benefit of anti-BRAF targeted therapy in Chinese NSCLC patients harboring BRAF-V600E mutation. The value of immunotherapy and treatment selection among non-V600E population needs further study.

Background The third-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) osimertinib has become the standard treatment for patients with pretreated EGFR -mutated non-small cell lung cancer (NSCLC) who acquire the T790M resistance mutation. However, no standard treatment after osimertinib failure has been established. Objective This study was undertaken to explore the clinical resistance modality upon failure of osimertinib therapy and to assess post-progression treatments in a real-world setting. Patients and Methods Medical data were retrospectively collected in our cancer center of patients with advanced NSCLC treated between 1 March 2017 and 1 July 2018, and who developed resistance to osimertinib. Results A total of 65 patients were analyzed. Clinical resistance modality varied among patients: 15 (23.1%) with local progression, 29 (44.6%) with gradual progression, and 21 (32.3%) with dramatic progression. Most patients experienced intrathoracic progression only (40/65, 61.5%), while ten (15.4%) cases presented intracranial failure only. Upon progressive disease, 20 patients (30.8%) received subsequent chemotherapy, and showed a trend for longer median overall survival (OS) than in those receiving a non-chemotherapy regimen (25.0 vs. 11.8 months, p = 0.106). Thirty-nine patients (60.0%) continued osimertinib beyond progression with a median post-progression treatment duration of 4.1 months. No significant difference in median OS was seen between patients who continued osimertinib and those who discontinued osimertinib (18.9 vs. 15.1 months, p = 0.802). In subgroup analyses, OS was improved in patients who experienced dramatic progression and were treated with chemotherapy, but data were immature for patients with local or gradual progression. Conclusions Chemotherapy could be an effective option after osimertinib failure in unselected patients.