AZD9291 Demonstrates Efficacy in Resistant EGFR-Positive NSCLC

Pasi A. Jänne, MD, PhD

The highly selective EGFR inhibitor AZD9291 demonstrated an overall response rate (ORR) of 64% without inducing dose-limiting toxicities in patients with metastatic non-small cell lung cancer (NSCLC) who harbor an acquiredEGFR T790Mresistance mutation.

Based on these promising findings, the FDA granted AZD9291 a breakthrough therapy designation for the treatment of patients withEGFR T790Mmutation-positive metastatic NSCLC following progression on a prior EGFR inhibitor. Results from the phase I dose-escalation study and the announcement of the new designation were presented by Pasi A. Jänne, MD, PhD, the director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, during a press briefing in advance of the 2014 ASCO Annual Meeting.

"Most patients unfortunately develop acquired resistance to EGFR inhibitors, and 60% of the time, this resistance is associated with a secondaryEGFRmutation known asEGFR T790M," Jänne said during the briefing. "In this study, AZD9291 exhibited no dose-limiting toxicities and a non-tolerated or maximum-tolerated dose was not defined. The promising results from this phase I study warrant further investigation of the activity of AZD9291 and additional clinical development is ongoing."

In the phase I study, 199 patients withEGFR-mutant NSCLC received treatment with AZD9291 at 5 doses ranging from 20 to 240 mg. The median age of patients was 60, 65% were Asian, and 32% were Caucasian. Patients with stable brain metastases were not excluded from the study.

Responses by RECIST criteria were observed at all dose levels, including patients with brain metastases. In all evaluable patients treated with the drug (n = 177), the overall response rate (ORR) was 51%. In patients with confirmedT790Mresistance mutations (n = 89), the ORR was 64% (95% CI; 53%-74%) and the disease control rate was 96%. In patients without theT790Mmutations (n = 43), the ORR was 23% (95% CI; 12%-39%).

The median duration of response had not been reached at the time of the analysis, with the longest duration of response being >8 months.

"Drug resistance has been the bane of chemotherapy treatment of cancers for decades. Efforts to understand drug resistance—how it is acquired and how to overcome that—have been very difficult to break through," Peter P. Yu, MD, ASCO President-Elect, said during the presentation. "However, here we have a molecularly targeted therapy—so bringing the new science understanding of cancer biology to bear—which has identified a mutation that drives this form of lung cancer."

AZD9291 is an irreversible inhibitor ofEGFRandT790Mmutations with a reduced affinity for wild-type EGFR. As a result, the rate of skin rash with the treatment was considerably lower than experienced with earlier EGFR inhibitors. In the study, the most common adverse events were primarily low-grade diarrhea (30%), rash (24%), and nausea (17%).

"The rash was mostly mild in nature and diarrhea was also mild," Jänne noted during his presentation.

Grade 3/4 adverse events occurred in 16% of patients, with 6 requiring a dose reduction. Over the course of the trial, 7 patients discontinued treatment as a result of side effects. There were 5 reports of interstitial lung disease, most of which occurred with a 160-mg dose of AZD9291 (n = 4) and were resolved without fatalities.

"As the newer treatments fine-tune and hone their targets, we are seeing less toxicity," Yu said during the briefing. "In this study, two of the major limiting toxicities of the first-generation drugs, diarrhea and rash, were seen less frequently and were milder."

Earlier results from the phase I study of AZD9291 were presented at the 2013 European Cancer Congress. At this point, 27 patients had received treatment with AZD9291 at 20, 40, and 80 mg doses. At the lowest dose, partial responses were confirmed in 33% of patients.

Once activity was observed, the study, labeled AURA, was expanded to enroll an additional 299 patients (N = 498) withEGFRmutation-positive NSCLC. A once daily 80-mg dose of the oral agent AZD9291 was selected for this portion of the study. The primary outcome measure is focused on safety, tolerability, and efficacy.

A separate open-label phase II study has been initiated to explore the 80 mg dose of AZD9291 specifically in patients withT790M-positive metastatic NSCLC following progression on a prior EGFR inhibitor. The target enrollment for this study is 442 patients and the primary endpoint is ORR.

Pasi AJ, Ramalingam, SS, Yang CHJ, et al. Clinical activity of the mutant selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor resistant non-small cell lung cancer (NSCLC).J Clin Oncol. 2014;(suppl; abstr 8009).

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