AZD9291 Shows Promising Response in T790M-Mutated NSCLC

Pasi A. Jänne MD, PhD

Treatment with AZD9291 at 80 mg per day elicited a response in 66% of patients with EGFR T790M-positive non—small cell lung cancer (NSCLC), according to investigator-assessed findings from the phase I AURA study presented at the 2015 European Lung Cancer Conference.

In the updated analysis of patients with EGFR T790M-positive NSCLC, the median duration of response has not yet been reached, although data are still immature. The longest duration of response was >8 months and the immature median progression-free survival (PFS) was 10.9 months with the 80 mg dose AZD9291, according to investigator-assessed criteria. An independent review of the data for the 80 mg cohort found an objective response rate (ORR) of 54%. The duration of response was 12.4 months and the PFS was 13.5 months.

“There are few treatment options currently available for patients with advanced EGFR-mutated non—small cell lung cancer who experience disease progression due to a second mutation known as T790M,” principal investigator Pasi A. Jänne MD, PhD, director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, said in a statement. “Management is usually limited to chemotherapy or rechallenge with EGFR tyrosine kinase inhibitors. As AURA continues to mature, and the trend in progression-free survival and durable clinical response is maintained, this may support the potential for AZD9291 as a future treatment option for advanced EGFR-mutated NSCLC.”

AZD9291 is an irreversible inhibitor of EGFR T790M mutations. In about 60% of patients with NSCLC, resistance to first-generation EGFR inhibition has been associated with an acquired mutation in EGFR T790M.

In 2013, AZD9291 was granted a breakthrough therapy designation for the treatment of patients with EGFR T790M-positive NSCLC, based on earlier data from the AURA trial. The company developing the drug, AstraZeneca, expects to submit a new drug application to the FDA within the next few months.

Included in the analysis of the ongoing phase I AURA study were 283 patients with EGFR-mutant advanced NSCLC who received treatment with AZD9291 at 5 doses ranging from 20 to 240 mg once daily. T790M-positive tumors were found in 163 of these patients.

Patients included in the study were a median age of 60 years old, and 62% were female; 61% were Asian and 31% were Caucasian. AZD9291 was administered to patients with advanced NSCLC who were experiencing disease progression after treatment with an EGFR inhibitor.

At all dose levels, the ORR was 59% for patients with EGFR T790M-positive tumors. The ORR was 23% in patients with T790M-negative tumors.

In patients treated with the 80 mg dose of AZD9291, the most common adverse events of any grade were rash which occurred in 38% of patients (0% grade ≥3) and diarrhea in 36% of patients (1% grade ≥3). Grade 3/4 treatment-related adverse events occurred in 14% of patients.

In all patients treated with AZD9291 at all doses, diarrhea was reported by 50% and rash by 46%. The most common adverse events were primarily low-grade. Grade 3/4 treatment-related adverse events occurred in 17% of patients.

“We are committed to developing novel medicines that address the significant unmet need in lung cancer by focusing on the genetic drivers underlying the disease,” said Antoine Yver, Head of Oncology, Global Medicines Development, AstraZeneca, the company developing the drug. “We are on track for a regulatory submission of AZD9291 in the United States in the second quarter of this year.”

In addition to the AURA trial, AZD9291 is also being investigated as a first-line therapy for patients with EGFR-mutated NSCLC. Additionally, the therapy is under exploration in combination with MEDI4736, an anti-PD-L1 immunotherapy, and with the MEK inhibitors selumetinib and AZD6094 in NSCLC. Initial data from these combination studies will be presented at the 2015 ASCO Annual Meeting.

“Our extensive clinical research program is also investigating the potential of AZD9291 in earlier disease and in combination with other pipeline assets, including immuno-oncology molecules,” Yver said. “With this comprehensive approach, our goal is to develop a broad range of potential treatment options for patients with EGFR mutation positive non-small cell lung cancer.”

Jänne PA, Ahn M, Kim D, et al. A phase I study of AZD9291 in patients with EGFR-TKI-resistant advanced NSCLC — updated progression-free survival and duration of response data. Presented at: European Lung Cancer Conference; April 15-18, 2015; Geneva, Switzerland. Abstract LBA3.