Osimertinib in Pretreated T790M-Positive Advanced Non–Small-Cell Lung Cancer: AURA Study Phase II Extension Component

Abstract

Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ≥ 3, < 1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.

Optimizing outcomes in EGFR Mutation-Positive Nsclc: Which Tyrosine Kinase Inhibitor and When?

“…In the Phase I part, the response rate for osimertinib was 61%, with a median PFS of 9.6 months among patients who had centrally confirmed EGFR T790M [8]. These results were confirmed in the Phase II AURA extension, in patients with EGFR TKI-pretreated EGFR T790M-positive disease, where the response rate was reported as 62% and median PFS was 12.3 months [7]. Similarly, in the AURA2 study in patients who had progression on previous EGFR TKI therapy, the response rate was 70% [37].…”

“…The predominant mechanism of resistance appears to be acquisition of EGFR T790M, occurring in 50-70% of patients [6,7]. The third-generation EGFR TKIs were developed to target this mechanism, showing high potency for T790M and EGFR TKI-sensitizing mutations, although the pharmacological potency for the common Del19/L858R mutations is lower with osimertinib than secondgeneration EGFR TKIs [35,36].…”

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

“…Osimertinib was recently approved by the US Food and Drug Administration for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR-TKI therapy. Osimertinib clinical activity has been demonstrated in the treatment of patients with EGFR mutant NSCLC after progression on a previous EGFR-TKI owing to the EGFR T790M mutation in the ongoing AURA (NCT01802632) and AURA2 (NCT02094261) studies (Jänne et al, 2015a,b;Mitsudomi et al, 2015;Yang et al, 2015). Preclinical data suggest that osimertinib is principally metabolized by cytochrome P450 (CYP3A4) and produces at least two circulating active metabolites: AZ5104 and AZ7550 (Cross et al, 2014;Planchard et al, 2014).…”

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

“…Data from the AURA phase II extension component confirms the high activity of osimertinib at 80 mg oncedaily in patients with EGFRm NSCLC progressing after EGFR-TKI treatment and who harbor T790M mutation (8). Among 198 evaluable patients, the ORR was 62%, DCR was 90%, and median duration of response (DoR) was 15.2 months.…”