AZD9291 Produces Strong Responses in EGFR-Mutated NSCLC

Roxanne Nelson

September 14, 2015

DENVER -- An investigational third-generation tyrosine kinase inhibitor (TKI) showed strong and consistent response rates across three studies in both treatment-naïve and pretreated patients with advanced non–small cell lung cancer (NSCLC) that harbored specific mutations.

Confirmed objective response rates ranged from 61% to 75%.

These data were presented here at the 16th World Conference on Lung Cancer (WCLC) and are from the AURA phase 1 trial first-line cohort and two AURA phase 2 studies conducted in pretreated patients.

AZD9291 (AstraZeneca Pharmaceuticals LP) is an oral, potent, irreversible EGFR TKI that is selective for EGFR tyrosine kinase inhibitor–sensitizing mutations and the T790M resistance mutation.

The EGFR T790M mutation confers resistance to treatment with first-generation EGFR inhibitors, such as erlotinib (Tarceva, Osi Pharmaceuticals, Inc) and gefitinib (Iressa, AstraZeneca Pharmaceuticals LP) or the second-generation EGFR inhibitor afatinib (Gilotrif, Boehringer Ingelheim Pharmaceuticals, Inc), making the disease difficult to treat.

Studies are assessing this agent as both a first-line agent and for use in patients who have developed or have shown resistance to other treatments. "Conceptually, what we all struggle with is, should we develop the sequential model -- start with one inhibitor, develop resistance, and move on to another," said Pasi Jänne, MD, PhD, director of the Lower Center for Thoracic Oncology at the Dana-Farber Cancer Institute, Boston, Massachusetts, and an investigator in several AZD929 studies being presented at the meeting.

"Or should we put our best weapon first," he told Medscape Medical News, "take the one that can overcome all resistance mechanisms first and use it up front."

Another important issue is that agents such as AZD9291 are better tolerated than erlotinib and afatinib in terms of dermatologic side effects. "That means it will be easier to use it as a building block for combination regimens," said Dr Jänne. "It's harder to do that with erlotinib and afatinib because of their toxicities, but it will be easier with this agent. There are already ongoing phase 1 trials looking at that."

"For advanced cancers, I don't think we are going to get cures with single agents, but maybe we will with combinations or series of combinations," he added. "And early data suggest that there are agents that can be combined together."

High Response in the First-Line Setting

In the AURA phase 1 trial, updated data were presented for the use of AZD9291 as a first-line therapy for patients with EGFRm-positive advanced NSCLC.

In this treatment-naïve group, AZD9291 "demonstrated encouraging clinical activity and a manageable tolerability profile," according to Dr. Jänne, who presented the study on behalf of study author Suresh S. Ramalingam, MD, chief of thoracic oncology and director of medical oncology, Emory University School of Medicine, Atlanta, who wasn't able to attend.

The confirmed objective response rate was 75% (95% confidence interval [CI], 62% to 85%), and the longest duration of response at the time of data cutoff was ongoing at 18 months.

"Seventy-two percent of patients remain alive and progression-free at 12 months," he told attendees, "and this has prompted the initiation of the phase 3 FLAURA study, comparing AZD9291 at the 80-mg dose vs current standard of care EGFR TKIs for treatment-naïve patients, and the study is currently enrolling."

In this expansion cohort, 60 patients received AZD9291 at 80 or 160 mg/day in sequential dose groups. Central testing revealed several EGFR mutation subtypes, including L858R (40%), exon 19 deletion (37%), other EGFR-sensitizing mutations (3%), and T790M (8%).

At data cutoff, 52 patients in the cohort remained on treatment.

The disease control rate was 97% for both cohorts. Two patients experienced a complete response (both were in the 160-mg dose group). In addition, 43 patients had a partial response, 13 had stable disease, and only two experienced disease progression (both in the 80-mg group).

For duration of response and progression-free survival, Dr Jänne noted that the data are still relatively immature. "For progression-free survival, it is only at 35% maturity, and in the total population of patients, the lower limit of the 95% confidence interval is 13.7 months," he said. "The maximum for the two different dose levels is 19.2 months."

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," Dr Jänne said. "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 the treatment, it may in fact work even better."

"And I think we are getting hints of that," he said. "But this is an exciting area in this field, because they are better tolerated than erlotinib or afatinib, so it would be great to able to start with this, but we'll see how the data evolve."

Continuing Efficacy and Tolerability

The AURA clinical program also included two phase 2 studies, AURA 2 and AURA extension cohort, that evaluated the efficacy and safety of the compound in patients with EGFRm advanced NSCLC and with positive T790M status, who had progressed after treatment with EGFR tyrosine kinase inhibitors. Although still preliminary, in both of these studies, AZD9291 also showed an efficacy and tolerability profile that is consistent with previously reported data, Dr Janne pointed out.

The AURA extension trial, which is a continuation of a phase 1 dose-escalation study, included 201 patients who received the 80-mg once-daily dose of AZD9291.

The overall response rate was 61% (95% CI, 54% to 68%), but the median duration of response and median progression-free survival have not yet reached maturity.

There were no complete responses, 122 (61%) partial responses, 58 patients with stable disease (29%), and 19 (10%) with progressive disease.

"The disease control rate was 91%," said lead author James Chih-Hsin Yang, MD, director, Department of Oncology and Department of Medical Research, National Taiwan University Hospital, Taipei City, who presented the findings. "Only a few patients had progressive disease as their best response."

But although progression-free survival has not reached maturity, "the curve shows there is a very long progression-free survival, up to 12 months of follow-up," he said.

Consistent results were observed in the third study, the AURA2, a global, open-label, single-arm phase 2 study. As in the AURA extension trial, all participants tested positive for T790M, as well as other EGFR mutations, including Ex19del (65%), L858R (32%), others (3%).

In this study, AZD9291 showed a 71% objective response rate. There were two complete responses and 139 partial responses. The stable disease rate at 6 weeks or longer was 21%, for a disease control rate of 92%.

The 71% response rate is "somewhat higher than you saw in the AURA extension trial," said lead investigator Tetsuya Mitsudomi, MD, PhD, chief of thoracic surgery at Aichi Cancer Center Hospital, in Nagoya, Japan.

The median progression-free survival was 8.6 months (38% maturity), and the median duration of response was 7.8 months (27% maturity).

"AZD9291 has demonstrated a positive clinical benefit across two phase 2 studies with encouraging duration of response and progression-free survival data," he noted. "A longer follow-up is needed to fully characterize these efficacy outcomes."

The AURA3 trial, which is currently ongoing, features AZD9291 vs platinum-based doublet chemotherapy in patients with EGFRm- and T790M-positive advanced NSCLC who have disease progression after prior tyrosine kinase therapy, added Dr Mitusdomi. The planned enrollment is 410 patients.

In all three studies, there was predominance of female and Asian patients, and in the phase 2 trials, the majority were also never-smokers (67% and 76%, respectively).

The safety profile of AZD9291 in these studies was in line with that already reported for this agent. In the AURA first-line cohort, the most common all-cause adverse events of any grade across different dose groups included rash (grouped terms) (77% all grades, 2% grade ≥3) and diarrhea (73% all grades, 3% grade ≥3).

These events were also reported as the most common in the two AURA phase 2 studies: for the AURA extension -- rash, 40% all grades, 1% grade ≥3; diarrhea, 45% all grades, 1% grade ≥3; and for AURA2 -- rash, 42% all grades, 1% grade ≥3; and diarrhea, 39% all grades, 1% grade ≥3.

Available as Soon as Possible

In a discussion of all three papers, Martin Reck, MD, PhD, from the Department of Thoracic Oncology at the Lung Clinic Grosshansdorf, Germany, noted that there are several interesting points that were seen in the presentations.

"We have seen confirmed efficacy in pretreated patients," he said. "As far as tolerability, due to the mechanism of these drugs, these compounds seem to be very well tolerated, so we typically do not the side effects of the first-generation TKIs," he said.

As for using this agent as first-line therapy, it is still unclear how effective it is in untreated patients. "But that question will be answered by the first-line FLAURA trial," he said.

Dr Reck added that "impressive efficacy" has been observed in pretreated patients. "But there are questions about efficacy in T790M-negative patients, and we do see responses in about 20% to 30% of these patients."

But in the end, he summarized, "I would say that these drugs should become available as soon as possible."

According to the manufacturer, marketing authorization applications for AZD9291 for the treatment of EGFRm T790M mutation-positive NSCLC have been submitted to the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other regulatory authorities. The FDA has already granted priority review to AZD9291, and the drug has also been granted accelerated assessment by the EMA.

All three trials were sponsored by AstraZeneca. Dr Yang, Dr Mitsudomi, Dr Ramalingam, and Dr Reck have disclosed relationships with industry, including AstraZeneca, the manufacturer of AZD9291.

16th World Conference on Lung Cancer (WCLC). Presented September 8, 2015. Abstract Mini 16.06, 16.07, 16.08 presented September 9, 2015.

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