FDA Approves Osimertinib for EGFR T790M-Positive NSCLC

Nov 13, 2015

The FDA has granted an accelerated approval to osimertinib for patients with advanced EGFR T790M mutation positive non–small cell lung cancer following prior therapy on a prior EGFR TKI.

Richard Pazdur, MD

The FDA has granted an accelerated approval to osimertinib (Tagrisso, AZD9291) for patients with advanced EGFR T790M mutation-positive non—small cell lung cancer (NSCLC) following progression on a prior EGFR TKI, based on data from 411 patients in two single-arm studies.

In the first study, labeled AURA, the objective response rate (ORR) with osimertinib was 61% for those with EGFR T790M-mutant NSCLC. In the second trial, known as AURA2, the ORR was 57%, according to the FDA. Along with osimertinib, 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, MD, 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% of cases, resistance to frontline EGFR inhibition is associated with the acquired EGFR T790M mutation, which the cobas EGFR Mutation Test v2 detects. Osimertinib's approval, which arrived 3 months ahead of schedule, is the first for a treatment following a rebiopsy and molecular testing, marking a significant milestone in the move toward precision medicine.

“The approval of safe and effective companion diagnostic tests and drugs continue to be important developments in oncology,” Alberto Gutierrez, PhD, 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 II AURA2 trial, 210 patients at a median age of 64 years with locally advanced or metastatic NSCLC received oral osimertinib 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 (range, 1-2).

In an updated analysis presented at the 2015 World Conference on Lung Cancer (WCLC),1 the ORR with osimertinib was 71%, with 2 complete responses. The stable disease rate at ≥6 weeks was 21%, for a disease control rate of 92%. The median duration of response was 7.8 months (95% CI, 7.1-NR). The median progression-free survival (PFS) was 8.6 months (95% CI, 8.3-9.7).

In the AURA trial, 201 patients at a median age of 62 years received osimertinib. Of patients enrolled, 30% were receiving osimertinib 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 from WCLC,2 the ORR was 61% (95% CI, 54-68). 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% 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% and the duration of response was 12.4 months.

“The accelerated approval of Tagrisso highlights its clinical promise for a targeted group of patients and gives healthcare providers an important new option,” Pasi A Jänne MD, PhD, director, Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, said in a statement. “In the AURA clinical studies, Tagrisso has demonstrated compelling early efficacy and tolerability in patients with EGFR mutated, T790M metastatic non—small cell lung cancer. This treatment has the potential to become the standard of care for patients living with EGFR mutated, T790M non—small cell lung cancer.”

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%), rash (41%), dry skin (31%), nail toxicity (25%), eye disorders (18%), nausea (17%), decreased appetite (16%), and constipation (15%). These events were primary grade 1/2, with a low rate of grade ≥3 AEs. The most common grade ≥3 AEs were pneumonia (2%) and pulmonary embolism (2%).

Across both studies dose reductions as a result of AEs were needed for 4.4% of patients. The most frequently reported AEs that led to a dose reduction or interruption were QTc prolongation (2%) and neutropenia (2%). Other AEs resulting in treatment discontinuation were interstitial lung disease or pneumonitis (2%) and cerebrovascular accident (1%). Fatal AEs occurred in 3.2% of patients and consisted of 4 cases of pneumonitis, which were attributed to osimertinib.

“The FDA approval of Tagrisso marks an important milestone for lung cancer patients who urgently need new treatment options,” Pascal Soriot, chief executive officer of AstraZeneca, the company developing the osimertinib, said in a statement. “As we advance our comprehensive lung cancer portfolio, we have the opportunity to treat greater numbers of patients across all stages of this disease through precision medicines, immunotherapies and novel combinations.”

The time from the start of clinical trials to FDA approval for osimertinib 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 osimertinib is contingent on findings from confirmatory studies.

At this time, the phase III AURA3 study is comparing osimertinib 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 (NCT02151981). Other studies exploring combination strategies and earlier use of osimertinib 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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