AZD9291, a Novel Mutation-Selective EGFR Inhibitor, May Overcome EGFR-TKI Resistance

June 2014, Vol 5, No 5

Chicago, IL—AZD9291, a novel mutation-selective tyrosine kinase inhibitor (TKI), may become a treatment option for patients with advanced, EGFR-mutated non–small-cell lung cancer (NSCLC) that has progressed with standard EGFR inhibitors, according to results of a phase 1 study presented at the 2014 American Society of Clinical Oncology (ASCO) meeting and highlighted at a press briefing.

These results demonstrated excellent safety and promising efficacy in patients with NSCLC and acquired resistance to EGFR-targeted TKIs in patients with the T790M mutation.

So far, no dose-limiting toxicity and no maximum-tolerated dose have been identified.

The US Food and Drug Admin­istration has granted AZD9291 a breakthrough therapy designation for the treatment of patients with EGFR-positive NSCLC that has progressed with currently available EGFR-targeted TKI therapy.

ASCO President-Elect Peter P. Yu, MD, Director, Cancer Research, Palo Alto Medical Foundation, CA, said that the issue of drug resistance is important to understand for all cancers, but it is difficult to overcome resistance. Dr Yu was particularly pleased that the knowledge about the mechanism of drug resistance (ie, the presence of the T790M mutation) led to designing a TKI to overcome that resistance.

Targeted TKIs for EGFR-Mutated NSCLC
“The greater precision [of AZD9291] appears to have reduced the toxicity rendered to normal tissues that presumably do not express this mutation,” Dr Yu commented.

EGFR mutations were the first biomarker for lung cancer that led to the development of EGFR-targeted therapies. Currently, the TKIs erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif) are approved for the treatment of patients with EGFR-mutated NSCLC.

Patients will respond to these drugs, but most will acquire resistance to EGFR-targeted TKIs within 10 to 14 months. Approximately 60% of patients who become resistant to one of these TKIs have a secondary EGFR mutation known as T790M.

The exciting finding from this phase 1 study is that AZD9291 appears to be effective in patients with the T790M mutation, and it is much less toxic than the currently approved TKIs, explained lead investigator Pasi A. Jänne, MD, PhD, Director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston.

Study Details
In the open-label, multicenter, phase 1 AZD9291 First Time in Patients Ascending Dose Study (AURA), patients were assigned to 1 of 5 dosing cohorts at doses ranging from 20 mg daily to 240 mg daily. These cohorts were not preselected according to T790M status.

A total of 5 expansion cohorts were preselected according to T790M status. As of January 2014, 199 patients were enrolled. No dose-limiting toxicity was identified at doses of 20 mg to 240 mg daily, and no maximum-tolerated dose was defined.

Adverse events included grade 1 diarrhea (30%), rash (24%), and nausea (17%). Grade 3 or 4 adverse events occurred in 16% of patients; 6 patients (3%) required dose reductions, and 7 patients discontinued treatment as a result of adverse events. There were 5 reports of interstitial lung disease that responded to treatment, and investigators are exploring this side effect further.

The overall response rate in all evaluable patients was 51%. The overall response rate was higher in cancers with the T790M mutation: 64% in mutation-positive patients versus 23% in mutation-negative patients.

Overall disease control was 96% in mutation-positive patients (85 of 89 patients). The longest duration of response was 8 months, and responses were seen across all dose levels.

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