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Osimertinib Approved in Europe for EGFR T790M-Mutant NSCLC

Silas Inman @silasinman
Published: Wednesday, Feb 03, 2016

Dr. Matthew Peters

Matthew Peters, MD

The European Commission (EC) has granted a conditional marketing authorization to osimertinib (Tagrisso, AZD9291) for patients with locally advanced or metastatic EGFR T790M mutation-positive non–small cell lung cancer (NSCLC), regardless of prior treatment with EGFR TKI. The EC noted in its approval that the EGFR T790M alteration could be detected using either tumor or blood testing.

The approval was based on data from two phase II studies and one phase I expansion study, which together investigated osimertinib in 474 patients with NSCLC. In the phase II AURA and AURA2 trials, the objective response rate (ORR) with osimertinib was 66% and median progression-free survival (PFS) was 9.7 months.

“Patients with common sensitizing EGFR mutations and the separate T790M have disappointing responses to standard treatments," Matthew Peters, MD, professor of Respiratory Medicine at Macquarie University Hospital, said in a statement. “Testing for the T790M status of lung cancer patients, using either a tumor sample or a simple blood test, and directing patients towards a medication such as osimertinib that is specifically designed for their pattern of mutations, offers greater prospects for durable treatment outcomes.”

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 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 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 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. Overall, 96% of responses were ongoing, with the duration of response ranging from 1.1 to 5.6 months.

In earlier data from the phase I AURA expansion trial, 63 patients were treated with osimertinib at various doses. In this group, the ORR was 51% and the duration of response was 12.4 months. In updated data released at the time of the approval, the ORR with osimertinib was 62%, median PFS was 11 months, and the duration of response was 9.7 months.

In the combined phase II studies, the most frequently observed all-grade adverse events were diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%); however, the majority of these events were grade 1/2. Overall, there were no incidences of grade 3/4 dry skin or nail toxicity, and 1% or less of patients had grade 3/4 diarrhea or rash.

“It is an exciting time in the care of patients with lung cancer," said Peters. “The ability to precisely characterize patients who have different types of lung cancer based on genetic mutations, and predict their response to targeted treatments, offers a more accurate and efficient approach to lung cancer care."

Adding to these results, other studies have explored osimertinib in various settings. In another phase I expansion study, 60 treatment-naive patients received osimertinib at 80 or 160 mg per day in sequential dosing groups. The median age of patients was 63.5 years. The primary EGFR mutation subtypes were L858R (40%), exon 19 deletion (37%), and T790M (8%).
In data presented at WCLC,3 the ORR was 75% (95% CI, 62-85). At this analysis, the longest duration of response was 18 months. The 12-month PFS rate with osimertinib was 72% in the frontline setting (95% CI, 58-82).
“Osimertinib defines a new generation of targeted EGFR-TKI treatments, and the European Commission’s expedited approval reflects the importance of this innovative medicine for addressing the needs of patients with lung cancer who have the T790M mutation," Sean Bohen, executive vice president, Global Medicines Development and Chief Medical Officer at AstraZeneca, said in a statement. "We are now building on our understanding of the clinical activity of osimertinib to explore its full potential in patients with EGFRm lung cancer in multiple treatment settings.”
The EC decision followed a positive opinion by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency in December 2015. In the Unite States, the FDA approved osimertinib in November 2015. An application for the drug is still pending in Japan, and other regulatory filings are anticipated worldwide, according to AstraZeneca, the company developing the drug.
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.
  3. Ramalingam SS, Yang JC-H, Lee CK, et al. AZD9291 in Treatment-Naïve EGFRm Advanced NSCLC: AURA First-Line Cohort. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1232.

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