AZD9291 Effective in EGFR T790M-Positive NSCLC

Treatment with the third-generation EGFR inhibitor AZD9291 was found to be highly active in patients with EGFR T790M-mutated NSCLC following progression on prior therapy with an EGFR TKI.

Pasi A. Jänne MD, PhD

Treatment with the third-generation EGFR inhibitor AZD9291 was found to be highly active in patients withEGFR T790M-mutated non-small cell lung cancer (NSCLC) following progression on prior therapy with an EGFR TKI, according to findings from the phase I/II AURA study that were published inThe New England Journal of Medicine.

In most situations, theEGFR T790Mmutation is the mechanism of drug resistance to frontline EGFR inhibitors, such as erlotinib. All patients enrolled in the study were EGFR-positive and received prior treatment with an EGFR inhibitor. Of these individuals, 127 were found to have anEGFR T790Mmutation by central review.

Efficacy of AZD9291

“Although the data are still immature (30% maturity), the current median progression-free survival in patients with detectableEGFR T790Mis encouraging,” the authors of the study wrote. “EGFR T790Mhas been recognized as a prognostic biomarker, but our findings show that it is also a predictive biomarker for the efficacy of AZD9291.”In the study, AZD9291 was administered at doses ranging from 20 to 240 mg once daily in 253 patients. The overall response rate (ORR) in the full population with AZD9291 was 51% (95% CI, 45-58). In those withT790Mmutations, the ORR was 61% (95% CI, 52-70). In patients without theT790Mmutation, the ORR was 21% (95% CI, 12-34).

The median progression-free survival (PFS) was 9.6 months in those with EGFR T790M mutations (95% CI, 8.3 - not yet reached). InT790M-negative patients, the median PFS was 2.8 months (95% CI, 2.1-4.3).

Toxicity Defined

"One reason for the activity of AZD9291 in patients without detectable EGFR T790M may be a retreatment effect after a “holiday” from treatment with an EGFR tyrosine kinase inhibitor, as reported previously in some studies of gefitinib," the authors hypothesized.In a dose escalation portion of the study, 31 patients were treated without the occurrence of dose-limiting toxicity, suggesting that a maximum tolerated dose has not yet been identified.

Next Steps

Across all doses, adverse events were seen in 96% of patients. The most common adverse events observed in the study were diarrhea (47%), rash (40%), nausea (22%), and decreased appetite (21%). The majority of these side effects were lower-grade. The rate of grade 3-5 adverse events was low (<2%).Given the modest toxicity and high-level of activity with AZD9291, the authors of the study suggest that it could be combined with other treatments for NSCLC, including MET inhibitors.

"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," the researchers wrote.

Additionally, AZD9291 will continue to be explored as a single-agent, with the AURA study still enrolling (NCT01802632).

Jänne PA, Yang J C-H, Kim D-W, et al. AZD9291 in EGFR Inhibitor—Resistant Non–Small-Cell Lung Cancer.NEJM. 2015;372(5):1689-1699.