Osimertinib-induced DNA resistance mutations in cerebrospinal fluid of epidermal growth factor receptor-mutated non-small-cell lung carcinoma patients developing leptomeningeal metastases: Osimertinib Resistance Analysis-leptomeningeal metastases study.

Diagnosis and treatment of leptomeningeal metastases (LM) in epidermal growth factor receptor mutation-positive (EGFRm +) non-small-cell lung carcinoma (NSCLC) is challenging. We aimed to identify resistance mechanisms (RM) to osimertinib in cerebrospinal fluid (CSF) and plasma. EGFRm + patients with new or progressive LM during osimertinib were enrolled. NGS Ampliseq was performed on DNA isolated from CSF. Patients were prescribed osimertinib dose escalation (DE, 160 mg QD) following lumbar puncture. Clinical and radiological response was evaluated 4 weeks after osimertinib DE. Twenty-eight patients were included. The driver mutation was identified in 93% of CSF samples (n = 26). Seven (27%) harbored ≥1 RM. Twenty-five patients (89%) were prescribed osimertinib DE. Four weeks afterwards, symptoms improved in 5 patients, stabilized in 9 and worsened in 11 patients. Twenty-one (84%) patients underwent MR imaging. Four showed radiological improvement, 14 stabilization, and 3 worsening. In 27% of patients, an RM was found in CSF ctDNA, none of which are targetable at the time of writing, and the clinical efficacy of osimertinib DE seems limited. There is much to gain in diagnostic as well as therapeutic strategies in EGFRm + NSCLC LM.

van der Wel JWT ，Boelens MC ，Jebbink M ，Smulders SA ，Maas KW ，Luitse MJA ，Compter A ，Boltjes RPB ，Sol N ，Monkhorst K ，van den Broek D ，Smit EF ，de Langen AJ ，Brandsma D ... -  《-》

Osimertinib after definitive chemoradiotherapy in unresectable stage III epidermal growth factor receptor-mutated non-small-cell lung cancer: analyses of central nervous system efficacy and distant progression from the phase III LAURA study.

Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here. Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints. Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo. Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC.

Lu S ，Ahn MJ ，Reungwetwattana T ，Özgüroğlu M ，Kato T ，Yang JC ，Huang M ，Fujiki F ，Inoue T ，Quang LV ，Sriuranpong V ，Vicente D ，Fuentes C ，Chaudhry AA ，Poole L ，Armenteros Monterroso E ，Rukazenkov Y ，van der Gronde T ，Ramalingam SS ... -  《-》

Combined analysis of circulating tumor DNA and tumor tissue to overcome osimertinib resistance (OSIRIS); the second line osimertinib cohort.

Osimertinib resistance inevitably occurs in EGFR mutated NSCLC. We aimed to identify resistance mechanisms (RM) using paired plasma and tumor samples in patients that progressed on 2nd/3rd line osimertinib. From 09 - 2019 to 02 - 2021, 51 patients were enrolled. Plasma sequencing used AVENIO Expanded Panel (research use only), tumor biopsies underwent DNA and RNA sequencing and histological evaluation. Sequencing was regarded successful when the driver mutation was confirmed with a variant allele frequency of ≥0.10%. Concordance between modalities was calculated for the driver mutation and RMs covered in both modalities. The Molecular Tumor Board formulated a treatment advice. The driver mutation was detected in 42/51 plasma samples (82%) and in 50/51 tumor samples (98%), concordance rate was 80%. In 41/51 (80%) patients ≥1 RM was identified. Thirty-two RMs covered in both modalities were found in plasma (61.5%), 39 in tumor (75%), nineteen in both. RM concordance rate was 36.5%. Combined analysis of plasma and tumor samples post 2nd/3rd line osimertinib identifies additional RMs regardless of the comparative approach used. Plasma sequencing identified 61.5% of RMs, tumor analysis identified 75%. Combined, they provide a superior overview of osimertinib resistance, enabling more tailored treatment options.

van der Wel JWT ，Jebbink M ，van den Broek D ，Steinbusch LC ，Theelen WSME ，Ruiter G ，Buikhuisen W ，Burgers JA ，Baas P ，Vermeulen M ，van der Noort V ，Hashemi SMS ，Bosch LJW ，Monkhorst K ，Smit EF ，Boelens MC ，de Langen AJ ... -  《-》

Cardiac Events and Survival in Patients With EGFR-Mutant Non-Small Cell Lung Cancer Treated With Osimertinib.

Lin CY ，Chang WT ，Su PL ，Kuo CW ，Yang J ，Lin CC ，Lin SH ... -  《JAMA Network Open》

Impact of First-Line Osimertinib and Other EGFR-Tyrosine Kinase Inhibitors on Overall Survival in Untreated Advanced EGFR-Mutated Non-small Cell Lung Cancer in Japan: Updated Data from TREAD Project 01.

Hibino M ，Imamura Y ，Shimoyama R ，Fukui T ，Fukai R ，Iwase A ，Tamura Y ，Chihara Y ，Okabe T ，Uryu K ，Okuda T ，Taguri M ，Minami H ... -  《-》