FDA Approves Tagrisso for Resistant NSCLC

Started by Leida, November 13, 2015
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Posted on
November 13, 2015
The FDA has approved Tagrisso (osimertinib, AZD9291) for patients with advanced EGFR T790M mutation positive non–small cell lung cancer (NSCLC) following prior therapy on a prior EGFR TKI, based on data from 411 patients from two single-arm studies.

In the first study, labeled AURA, the objective response rate with Tagrisso was 61 percent for those with previously treated EGFR T790M-mutant NSCLC (201 patients). In the second study, known as AURA2, the objective response rate was 57 percent among 210 patients, according to the FDA. Along with Tagrisso, the FDA also approved the cobas EGFR Mutation Test v2 as a companion diagnostic.

“Our understanding of the molecular basis of lung cancer and reasons these cancers become resistant to prior treatments is rapidly evolving,” Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval provides a new treatment for patients who test positive for the EGFR resistance mutation, T790M, and is based on substantial evidence from clinical trials that shows Tagrisso had a significant effect on reducing tumor size in over half of patients who were treated.”

In approximately 50 to 60 percent of cases, resistance to frontline EGFR inhibition is associated with the acquired EGFR T790M mutation, which the cobas EGFR Mutation Test v2 detects. This approval, which arrived three months ahead of schedule, marks the first for a treatment following a rebiopsy and molecular test, indicating a significant milestone for precision medicine.

“The approval of safe and effective companion diagnostic tests and drugs continue to be important developments in oncology,” Alberto Gutierrez, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, said in a statement. “The availability of the cobas EGFR Mutation Test v2 meets a need for the detection of this important EGFR gene mutation, which can alter treatment effectiveness.”

In the phase 2 AURA2 trial, 210 patients at a median age of 64 years with locally advanced or metastatic NSCLC received oral Tagrisso at 80 mg daily. All patients had tumors that tested positive for the T790M resistance mutation and all had progressed on an approved EGFR TKI. Patients had received a median of 1 prior therapy (ranging from one to two).

In an updated analysis presented at the 16th World Conference on Lung Cancer in September,1 the objective response rate with Tagrisso was 71 percent, with two complete responses. The stable disease rate of at least six weeks was 21 percent, for a disease control rate of 92 percent. The median duration of response was 7.8 months and median progression-free survival was 8.6 months.

In the AURA trial, 201 patients with a median age of 62 years received Tagrisso. Of patients enrolled, 30 percent were receiving Tagrisso as second-line therapy while 70% were treated in the third-line setting. Ninety-eight percent of tumors tested positive for T790M.

In updated data presented at World Conference on Lung Cancer,2 the objective response rate was 61 percent. The median duration of response was not reached at the time of the analysis and the median PFS was also not yet calculable. At this analysis, only a quarter of events had occurred.

In the data assessed by the FDA from both studies, 96 percent of responses were ongoing, with the duration of response ranging from 1.1 to 5.6 months. In an earlier dose escalation portion of the AURA study reported by the FDA, data for 63 patients were available for analysis. In this group, the ORR was 51 percent and the duration of response was 12.4 months.

In a combined analysis of the 411 patients in both trials, the FDA reported that the most commonly reported all-grade adverse events (AEs) were diarrhea (42 percent), rash (41 percent), dry skin (31 percent), nail toxicity (25 percent), eye disorders (18 percent), nausea (17 percent), decreased appetite (16 percent) and constipation (15 percent). These events were primary grade 1/2, with a low rate of AEs of at least grade 3. The most common AEs of at least grade 3 were pneumonia (2 percent) and pulmonary embolism (2 percent).

Across both studies dose reductions as a result of AEs were needed for 4.4 percent of patients. The most frequently reported AEs that led to a dose reduction or interruption were QTc prolongation (2 percent) and neutropenia (2 percent). Other AEs resulting in treatment discontinuation were interstitial lung disease or pneumonitis (2 percent) and cerebrovascular accident (1 percent). Fatal AEs occurred in 3.2 percent of patients and consisted of fourcases of pneumonitis, which were attributed to Tagrisso.

The time from the start of clinical trials to FDA approval for Tagrisso was just two and a half years. As it was developed, the agent received fast track and Breakthrough Therapy designations from the FDA, which helped to expedite its approval. Given this rapid development and approval under the FDA’s accelerated program, a full indication for Tagrisso is contingent on findings from confirmatory studies.

At this time, the phase 3 AURA3 study is comparing Tagrisso with platinum-based chemotherapy in patients with T790M-positive advanced NSCLC that has progressed following prior EGFR-TKI therapy. Findings from this 410-patient study are anticipated in December 2017. Other studies exploring combination strategies and earlier use of Tagrisso are being conducted.


  1. Mitsudomi T, Tsai C, Shepherd F, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 Phase II study. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1406.
  2. Yang JC, Ahn M, Ramalingam SS, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA study Phase II extension cohort. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 943.

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