Osimertinib in EGFR Inhibitor–Pretreated T790M-Positive Advanced NSCLC
In the phase II extension component of the phase I/II AURA trial, reported by Yang et al in the Journal of Clinical Oncology, osimertinib (Tagrisso) was found to be highly active in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor–pretreated T790M-positive advanced non–small cell lung cancer (NSCLC). The trial helped support the November 2015 Accelerated Approval of osimertinib in this setting.
Study Details
In the study, 201 patients from 46 study centers in Japan, the United States, South Korea, Australia, France, Germany, Spain, Italy, Taiwan, and the UK were treated with osimertinib at 80 mg once daily, with enrollment beginning in May 2014. Patients with asymptomatic stable central nervous system (CNS) metastases not requiring corticosteroids were allowed to enter the study.
Patients had a median age of 62 years, 66% were women, 57% were Asian and 38% white, 67% were never-smokers, 30% received osimertinib as second-line and 70% ≥ third-line treatment, and 98% had metastatic disease. The primary endpoint was objective response rate on independent radiology assessment.
Response Rate
The median treatment duration was 13.2 months at the time of data cutoff (November 2015). Among 198 evaluable patients, the objective response rate was 62% (95% confidence interval [CI] = 54%–68%), with a disease control rate of 90% (95% CI = 85%–94%). The median duration of response was 15.2 months (95% CI = 11.3 months to not calculable). Median progression-free survival was 12.3 months (95% CI = 9.5–13.8 months). At data cutoff, median follow-up for overall survival was 13.8 months. Median overall survival was not reached; 1-year overall survival was 79% (95% CI = 72%–84%).
Adverse Events
The most common adverse events considered at least possibly related to osimertinib treatment were diarrhea (43%, grade ≥ 3 in < 1%), rash (40%, grade ≥ 3 in < 1%), paronychia (31%, grade ≥ 3 in 0%), and dry skin (31%, grade 3 in 0%). Adverse events led to dose interruption in 21% of patients, dose reduction in 5%, and treatment discontinuation in 3% (due to interstitial lung disease in 7 of 9 patients). Interstitial lung disease (as a grouped term) occurred in eight patients (4%), including grade ≥ 3 events in six patients; three patients died of interstitial lung disease.
The investigators concluded: “In patients with [activating EGFR mutation] T790M advanced NSCLC who progress after EGFR-[tyrosine kinase inhibitor] treatment, osimertinib provides a high [objective response rate], encouraging [progression-free survival], and durable response.”
The study was supported by AstraZeneca.
James Chih-Hsin Yang, MD, PhD, of the National Taiwan University Hospital, is the corresponding author of the Journal of Clinical Oncology article.
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