AZD9291 Shows Durable Responses in Patients With EGFR-Positive Lung Cancers
A clinical trial of the EGFR inhibitor AZD9291 in patients with advanced non–small cell lung cancer (NSCLC) who had disease progression after previous treatment with EGFR tyrosine kinase inhibitors has found that the drug was highly active—achieving a 95% disease control rate—in patients with the EGFR T790M mutation. The median progression-free survival was 9.6 months in the EGFR T790M–positive patients, and 2.8 months in EGFR–negative patients. Why the drug is less effective in patients whose cancers lacked the T790M mutation is unclear. The study by Jänne et al is published in The New England Journal of Medicine.
Study Methodology
A total of 253 patients were enrolled in the study. The researchers administered AZD9291 at doses of 20 mg to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors.
The study included dose-escalation cohorts and dose-expansion cohorts; prestudy tumor biopsies were required for central determination of EGFR T790M status in the expansion cohorts. Patients were assessed for safety, pharmacokinetics, and efficacy.
Study Results
Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI] = 45%–58%). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI = 52%–70%). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI = 12%–34%). The median progression-free survival was 9.6 months (95% CI = 8.3 to not reached) in EGFR T790M–positive patients and 2.8 months (95% CI = 2.1–4.3) in EGFR T790M–negative patients.
“Previously, if a patient became resistant to kinase inhibitors like [erlotinib] they were treated with chemotherapy,” said Pasi Jänne, MD, PhD, Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute and first author of the study, in a statement. “Now, there is this option, and the beautiful part is they don’t have the side effects of [erlotinib]—this drug is better tolerated.”
“The activity of AZD9291 coupled with its safety profile may provide the opportunity to evaluate combination treatment strategies, including with MET inhibitors, to further improve clinical outcomes in patients with resistance to EGFR tyrosine kinase inhibitors,” concluded the study authors.
Dr. Jänne is the corresponding author for The New England Journal of Medicine article.
Funding for this study was provided by Astra Zeneca. For full disclosures of the study authors, visit www.nejm.org.
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