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.
Ramalingam SS, Yang JC, Lee CK, Kurata T, Kim DW, John T, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol 2017 Aug 25 [Epub ahead of print].
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