In a phase II trial reported in The Lancet Oncology, Glenwood Goss, MD, of The Ottawa Hospital Cancer Centre, University of Ottawa, and colleagues found that osimertinib produced a high response rate in EGFR tyrosine kinase inhibitor–pretreated EGFR Thr790Met (T790M)–positive advanced non–small cell lung cancer (NSCLC). Osimertinib is an EGFR tyrosine kinase inhibitor selective for EGFR tyrosine kinase inhibitor–sensitizing mutations and the EGFR T790M resistance mutation. The study supported the accelerated approval of osimertinib in this indication in November 2015.
In the study, 199 evaluable patients with stage IIIB/IV EGFR T790M–positive NSCLC progressing after previous EGFR tyrosine kinase inhibitor therapy received osimertinib at 80 mg orally once daily. Treatment could continue beyond disease progression if clinical benefit was observed. Patients with asymptomatic stable central nervous system (CNS) metastases not requiring steroids were eligible for the study. The primary endpoint was objective response on blinded independent central review. The study is ongoing, and patients are still receiving treatment. As of data cutoff in November 2015, 122 patients (58%) remained on treatment.
Response Rate and Toxicity
Median duration of follow-up was 13.0 months. Objective response was observed in 140 patients (70%, 95% confidence interval [CI] = 64%–77%) of 199 patients, including a confirmed complete response in 6 patients (3%). Median duration of response was 11.4 months (95% CI = 9.0 months to not calculable). The proportion of patients remaining in response was 76% at 6 months, 59% at 9 months, and 48% at 12 months. Median progression-free survival was 9.9 months, with rates of 71% at 6 months, 56% at 9 months, and 44% at 12 months.
The most common grade 3 or 4 adverse events were pulmonary embolism (3%); prolonged QT interval (2%); decreased neutrophil count (2%); and anemia, dyspnea, hyponatremia, increased alanine transaminase, and thrombocytopenia (1% each). Adverse events led to dose reduction in 3% and treatment discontinuation in 5% (due to pneumonitis in 2 patients). Serious adverse events occurred in 25% patients, with 5% considered possibly related to treatment. Adverse events led to death in seven patients, with one (due to interstitial lung disease) considered possibly related to treatment.
The investigators concluded: “Osimertinib showed clinical activity with manageable side effects in patients with EGFR Thr790Met-positive NSCLC. Therefore, osimertinib could be a suitable treatment for patients with EGFR Thr790Met-positive disease who have progressed on an EGFR tyrosine-kinase inhibitor.”
The study was funded by AstraZeneca.