Abstract
Osimertinib achieved objective responses in 77% of patients with treatment-naïve NSCLC.
Major finding: Osimertinib achieved objective responses in 77% of patients with treatment-naïve NSCLC.
Mechanism: Putative resistance mutations and amplifications, but not EGFR T790M, were detectable in ctDNA.
Impact: Osimertinib warrants further investigation for the treatment of treatment-naïve patients with NSCLC.
The selective EGFR tyrosine kinase inhibitor (TKI) osimertinib is active against EGFR-TKI–sensitizing mutations (EGFRm) and the EGFR T790M mutation, which promotes resistance to other EGFR-TKIs. Thus, osimertinib is indicated for patients with metastatic non–small cell lung cancer (NSCLC) who have progressed on other EGFR-TKI therapies. Osimertinib has been shown to delay the development of resistance in EGFRm tumors in preclinical studies, but has not been investigated as a first-line treatment in patients with NSCLC. Ramalingam and colleagues evaluated the safety and activity of osimertinib in 60 treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC as part of the open-label, phase I AURA trial. The patients were enrolled in two cohorts receiving either 80 mg or 160 mg of osimertinib daily. End points included objective response rate, duration of response, progression-free survival, and safety evaluation. The overall objective response rate was 77% (67% in the 80 mg group and 87% in the 160 mg group) and the disease control rate was 97% across doses. The median progression-free survival was 20.5 months across doses, and the median duration of response was 18 months across doses. Post-progression plasma samples were obtained from 38 patients, 19 (50%) of whom had no detectable circulating tumor DNA (ctDNA). Genetic alterations potentially involved in resistance were detected in ctDNA from 9 of 19 patients, including amplifications of MET, EGFR, and KRAS; mutations in MEK1, KRAS, PIK3CA, and JAK2; an insertion in HER2; and EGFR C797S mutations. The EGFR T790M mutation was not detected. The safety profile of osimertinib was consistent with previous reports, and 62% of patients experienced grade 3 or greater adverse events. The 80 mg dose was better tolerated. Collectively, these findings support further investigation of osimertinib as first-line therapy in patients with EGFRm NSCLC and suggest potential mechanisms of resistance independent of EGFR T790M mutations.
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