Osimertinib As First-Line Treatment of EGFR Mutation–Positive Advanced Non–Small-Cell Lung Cancer

Abstract

Purpose The AURA study ( ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naïve patients to examine clinical activity and safety of osimertinib (an epidermal growth factor receptor [EGFR] -tyrosine kinase inhibitor selective for EGFR-tyrosine kinase inhibitor sensitizing [ EGFRm] and EGFR T790M resistance mutations) as first-line treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC). Patients and Methods Sixty treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily (30 patients per cohort). End points included investigator-assessed objective response rate (ORR), progression-free survival (PFS), and safety evaluation. Plasma samples were collected at or after patients experienced disease progression, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), to investigate osimertinib resistance mechanisms. Results At data cutoff (November 1, 2016), median follow-up was 19.1 months. Overall ORR was 67% (95% CI, 47% to 83%) in the 80-mg group, 87% (95% CI, 69% to 96%) in the 160-mg group, and 77% (95% CI, 64% to 87%) across doses. Median PFS time was 22.1 months (95% CI, 13.7 to 30.2 months) in the 80-mg group, 19.3 months (95% CI, 13.7 to 26.0 months) in the 160-mg group, and 20.5 months (95% CI, 15.0 to 26.1 months) across doses. Of 38 patients with postprogression plasma samples, 50% had no detectable circulating tumor DNA. Nine of 19 patients had putative resistance mechanisms, including amplification of MET (n = 1); amplification of EGFR and KRAS (n = 1); MEK1, KRAS, or PIK3CA mutation (n = 1 each); EGFR C797S mutation (n = 2); JAK2 mutation (n = 1); and HER2 exon 20 insertion (n = 1). Acquired EGFR T790M was not detected. Conclusion Osimertinib demonstrated a robust ORR and prolonged PFS in treatment-naïve patients with EGFRm advanced NSCLC. There was no evidence of acquired EGFR T790M mutation in postprogression plasma samples.

Osimertinib as first-line treatment of EGFR mutant advanced non-small-cell lung cancer

“…Ramalingam and colleagues report the results of these two cohorts of patients in the Journal of Clinical Oncology in August 2017 (12). This is the first full publication reporting the anticancer activity and safety of osimertinib as first-line treatment in patients in these two expansion cohorts of the phase I component of AURA trial (12). With median follow-up of 19.1 months the confirmed ORR was 67% in the 80-mg cohort and 87% in the 160-mg cohort.…”

“…Osimertinib was tested at two dose levels of 80 or 160 mg once daily and a total of 60 treatment-naïve patients were enrolled with 30 patients in each cohort. Ramalingam and colleagues report the results of these two cohorts of patients in the Journal of Clinical Oncology in August 2017 (12). This is the first full publication reporting the anticancer activity and safety of osimertinib as first-line treatment in patients in these two expansion cohorts of the phase I component of AURA trial (12).…”

“…In an analysis of 216 patients included in the AURA phase I trial in whom both central tumor and plasma samples for diagnostic comparison were available, plasma genotyping using BEAMing technology had a sensitivity of 82-86% for sensitizing mutations and 70% for T790M mutation (14). In the two expansion cohorts of 60 treatment naïve patients, 40% had EGFR exon 19 deletion mutation, 42% exon 21 L858R mutation, and five patients had de novo EGFR T790M confirmed by central laboratory tissue genotyping at study entry (12). Plasma genotyping identified two additional de novo T790M patients.…”

“…The data from these two expansion cohorts of the phase I component of AURA trial (12) further support the recommended 80 mg once daily dose in view of the similar PFS observed with the 80-and 160-mg treatment groups and the better tolerability of the 80-mg dose with fewer dose reductions, lower frequency of skin disorders, nail side effects, and diarrhea compared with the 160-mg dose consistent with data from later-line patients treated with osimertinib in the AURA phase I study (7,13). The approval of the 80-mg dose was also based on pharmacokinetic analyses showing the 80 mg dose ensured exposure levels that are greater than those observed for the 20 or 40 mg dose, which had also demonstrated clinical activity in the AURA phase I study.…”

“…The approval of the 80-mg dose was also based on pharmacokinetic analyses showing the 80 mg dose ensured exposure levels that are greater than those observed for the 20 or 40 mg dose, which had also demonstrated clinical activity in the AURA phase I study. In the AURA study, circulating cell-free tumor DNA (ctDNA) extracted from baseline plasma samples was genotyped using the beads, emulsions, amplification, and magnetics (BEAMing) digital polymerase chain reaction (PCR) (Sysmex Inostics Inc., Mundelein, IL, USA) for three EGFR mutations: exon 19 deletion, L858R, and T790M (12). With central tissue genotyping (cobas; Roche Molecular Diagnostics, Pleasanton, CA, USA) as a reference, high sensitivity and specificity were observed with plasma genotyping using BEAMing digital PCR (14).…”