AZD9291 for EGFR-Inhibitor–Resistant Non–Small-Cell Lung Cancer

Summary and Comment |
April 29, 2015

AZD9291 for EGFR-Inhibitor–Resistant Non–Small-Cell Lung Cancer

  1. Anne S. Tsao, MD

This EGFR inhibitor was highly active in patients who carried the EGFR T790M mutation.

  1. Anne S. Tsao, MD

AZD9291 is an oral, irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets mutated EGFR while sparing the wild-type EGFR. AZD9291 has activity in non–small-cell lung cancer (NSCLC) against the known T790M resistance mutation, which is often acquired after disease progression on earlier-generation EGFR TKIs.

Now, investigators have conducted an industry-supported phase I study to test the safety and effectiveness of AZD9219 in 253 patients with advanced mutated-EGFR NSCLC in whom resistance to EGFR TKIs had developed. Of these, 31 were included in the dose-escalation (from 20 to 240 mg once daily) portion of the study, and 222 were included in 5 dose-expansion cohorts, for which central determination of tumor EGFR T790M status was required.

No dose-limiting toxicity was reached in the dose-escalation portion of the trial. The most common toxicities were diarrhea in 47% of patients, rash in 40%, nausea in 22%, and anorexia in 21%. Grade 3 events occurred in 22% of patients, and serious treatment-related adverse events occurred in 6%. Six patients experienced possible pneumonitis, 6 had hyperglycemia, and 11 had QTc prolongation. Dose reduction was required by 7% of patients, and the discontinuation rate was 6%. For all patients, the overall response rate was 51%, and median progression-free survival (PFS) was 8.2 months. In 127 patients who carried the EGFR T790M mutation, the response rate was 61%, and median PFS was 9.6 months. In 61 patients who did not carry the mutation, the response rate was 21%, and median PFS was 2.8 months.

Comment

AZD9291 was highly active against EGFR T790M NSCLC and was well tolerated with low rates of dose reduction and discontinuation. AZD9291 has FDA breakthrough designation and will likely receive indication for the resistant T790M mutation. Understanding its unique toxicity profile and performing routine electrocardiograms and glucose checks will be necessary for patients taking this drug.

Editor Disclosures at Time of Publication

  • Disclosures for Anne S. Tsao, MD at time of publication Consultant / Advisory board Genetech; Roche; Medimmune; Novartis; Astellas; Boehringer-Ingelheim; Eli Lilly Speaker’s bureau Genetech; Roche; Medimmune; Novartis; Astellas; Boehringer-Ingelheim; Eli Lilly Grant / Research support Department of Defense; SWOG Leadership positions in professional societies American Medical Association (Member); American Association of Cancer Research (Member); American Society of Clinical Oncology (Member); AACR-Women in Cancer Research (Member); International Mesothelioma Interest Group (Member); SWOG (Member); International Association for the Study of Lung Cancer (Communications Committee Chair); American Radium Society (Chair); RTOG (Member)

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