AZD9291 Shows Promise in EGFR-Mutated NSCLC

A third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) known as AZD9291 showed promising clinical activity and progression-free survival (PFS) in a dose-escalation study of patients with advanced-stage, EGFR mutation–positive non–small-cell lung cancer (NSCLC). The study (abstract 8000) was presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting held May 29 to June 2 in Chicago.

“For patients with advanced-stage NSCLC whose tumors bear an EGFR mutation, EGFR TKIs are preferred over chemotherapy in the front-line setting,” said Suresh S. Ramalingam, MD, of Emory University School of Medicine in Atlanta. “However, regardless of the extent of initial response to EGFR TKIs, patients develop resistance to therapy.” This resistance is mediated by the T790M mutation in almost 60% of patients.

AZD9291 is a mutant-specific EGFR TKI selective for that T790M mutation. In the new trial, sequential cohorts of treatment-naïve patients were treated with 20 mg up through 240 mg of the drug. There were two predefined expansion cohorts, at 80-mg and 160-mg doses. Ramalingam presented results of those cohorts, with 30 patients in each.

The median follow-up overall was 9.6 months, and was slightly longer in the 80-mg group (11.0 months) than in the 160-mg group (8.5 months). Most patients were female, with an average age of 64 years; 43% of the cohort was Asian. There were 46 patients who were T790M-negative, five positive, and nine with unknown status.

Overall, 97% of the cohort received some clinical benefit from the drug as measured by either complete response, partial response, or stable disease. The overall response rate was 73%, with a slightly higher rate in the 160-mg group (83%) than the 80-mg group (63%).

Ramalingam said that the data are still too immature to estimate median PFS. The 12-month PFS, however, was 73% for 80-mg patients; the 9-month PFS rate in the 160-mg group was 78%.

All patients in the trial experienced some toxicity, and the 160-mg dose had slightly more grade 3 or higher adverse events. No adverse event in either group led to death. There were more adverse events leading to dose interruption in the 160-mg group (30%) than the 80-mg group (17%). The same was true for adverse events leading to dose reduction (43% vs 10%).

The discussant for the session, Gregory J. Riely, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, called the PFS data encouraging, but said it needs to mature before more firm conclusions can be made.

Ramalingam noted that a phase III study is underway comparing AZD9291 80 mg with standard of care.