AZD9291 Updates Encouraging for Treatment-Resistant NSCLC

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Pasi Jänne, MD, PhD

Suresh S. Ramalingam, MD

James Chih-Hsin Yang, MD

Tetsuya Mitsudomi, MD, PhD

At the 16th World Conference on Lung Cancer, several studies showed consistent activity with the investigational third-generation inhibitor AZD9291 in patients with advanced non–small cell lung cancer (NSCLC) that is resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Confirmed objective response rates ranged from 61% to 75% in three AURA trials.

AZD9291 is a potent oral, irreversible EGFR tyrosine kinase inhibitor that is selective for EGFR-activating mutations and the T790M resistance mutation. The T790M mutation confers resistance to treatment with first-generation EGFR inhibitors, such as erlotinib and gefitinib (Iressa) and the second-generation tyrosine kinase inhibitor afatinib (Gilotrif).

Studies are assessing AZD9291 for use in the first-line setting and beyond. The question is whether to use agents sequentially, as patients develop resistance, or perhaps start with a stronger drug—one that seems less likely to cause resistance, like this one—upfront, researchers indicated. AZD9291 also appears to provoke less skin toxicity than current agents, which suggests its potential for combining with other agents.

First-Line, High Response Rate

Pasi Jänne, MD, PhD, Director of the Lower Center for Thoracic Oncology at Dana-Farber Cancer Institute, Boston, presented an update of the phase I first-line AURA trial,1 noting that in treatment-naive patients, AZD9291 “demonstrated encouraging clinical activity and a manageable tolerability profile.” Suresh S. Ramalingam, MD, of Emory University School of Medicine in Atlanta, was the study’s first author.

The patients were found to have several EGFR-mutation subtypes, including L858R (40%), exon 19 deletion (37%), other EGFR-sensitizing mutations (3%), and T790M (8%). Patients received 80 mg or 160 mg of AZD9291.

After 12.3 months of follow-up, the confirmed objective response rate was 75%, with some responses ongoing at 18 months. The disease-control rate was 97%. A total of 72% of patients remained alive and progression-free at 12 months.

“This has prompted the initiation of the phase III FLAURA study, comparing AZD9291 at the 80-mg dose vs the current standard-of-care EGFR tyrosine kinase inhibitors for treatment-naive patients,” Dr. Jänne said.

The data in the first-line setting are still relatively immature, Dr. Jänne said. “For progression-free survival, it is only at 35% maturity.” Although the median progression-free survival has not yet been reached, “if you look at the curves, the lower limit of the 95% confidence interval for progression-free survival was about 12 to 13 months, which is higher than we normally see the medians for EGFR inhibitors…”. He added, “That part is incredibly exciting because, as you move an effective therapy that works in patients that have developed resistance and give it early on in treatment, it may in fact work even better.”

Phase II Studies

Two phase II studies that are part of the AURA clinical program were also presented: the AURA extension and AURA2 cohorts. They evaluated AZD9291 in patients with EGFR-mutated, T790M-mutation–positive advanced NSCLC who progressed after EGFR tyrosine kinase inhibitor treatment.

The AURA extension trial is a continuation of a phase I dose-escalation study of 201 patients receiving AZD9291 80 mg once daily.2 The findings were reported by James Chih-Hsin Yang, MD, ­Director of the Departments of Oncology and Medical Research, National Taiwan University Hospital in Taipei City.

The overall response rate was 61% (all partial responses), and the disease-control rate was 91%, with “only a few patients having progressive disease as their best response,” he said. Although the median duration of response and median progression-free survival have not yet reached maturity, Dr. Yang indicated, “The curve shows there is a very long progression-free survival in up to 12 months of follow-up.”

Findings were similar in AURA2, a global, open-label, single-arm phase II trial of 210 patients with T790M mutations.3 The response rate was 71%, including two complete responses. The disease-control rate was 92%, and median progression-free survival was 8.6 months, but the follow-up is not mature, Tetsuya ­Mitsudomi, MD, PhD, Professor, Division of Thoracic Surgery, Kinki University, Japan, said.

“AZD9291 has demonstrated a positive clinical benefit across two phase II studies, with encouraging duration of response and progression-free survival. A longer follow-up is needed…,” Dr. Mitsudomi said.

The ongoing phase III AURA3 trial is evaluating AZD9291 vs a platinum-based doublet in patients with T790M-positive advanced NSCLC who progress after tyrosine kinase inhibitor treatment. The planned enrollment is 410 patients. ■

Disclosure: Dr. Jänne has been a consultant for AstraZeneca, Roche Genentech, Pfizer, and Merrimack, owns stock in Gatekeeper Pharmaceuticals, and has received postmarketing royalties from Dana-Farber Cancer Institute–owned intellectual property on EGFR mutations licensed to Lab Corp. Dr. Ramalingam serves on advisory boards for AstraZeneca, Genentech, Boehringer Ingelheim, and Clovis. Dr. Yang serves on advisory boards for Boehringer Ingelheim, Lilly, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Merck, Bayer, and Clovis Oncology and has received research support from Boehringer Ingelheim. Dr. Mitsudomi has received grants/research support from AstraZeneca, Pfizer, Chugai, Taiho, and Boehringer Ingelheim, has been a consultant for AstraZeneca, Pfizer, Chugai, Novartis, Boehringer Ingelheim, Kyowa Hakko-Kirin, MSD, and Clovis, and has received honoraria from AstraZeneca, Pfizer, Chugai, Taiho, and Boehringer Ingelheim.


1. Ramalingam S, et al: World Conf on Lung Cancer. Abst MINI16.07. Sept 8, 2015.

2. Yang J C-H, et al: World Conf on Lung Cancer. Abst MINI16.06. Sept 8, 2015.

3. Mitsudomi T, et al: World Conf on Lung Cancer. Abst MINI16.08. Sept 8, 2015.

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