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  1. Resources for Information | Approved Drugs

FDA D.I.S.C.O.: Osimertinib for Non-Small Cell Lung Cancer


FDA medical oncologists discuss the approval of osimertinib for EGFR mutation-positive non-small cell lung cancer.


Sanjeeve Bala: Welcome back to the D.I.S.C.O. Today’s Drug Information Soundcast in Clinical Oncology from FDA’s Oncology Center of Excellence discusses the recent approval of osimertinib, marketed as TAGRISSO.

Abhi Nair: Around 10 to 15 percent of patients with non-small cell lung cancer have an activating mutation in the epidermal growth factor receptor. These mutations are more common in women, patients of east-Asian descent, and never smokers. On today’s DISCO, we will discuss the approval of osimertinib for a specific subset of EGFR mutation-positive non-small cell lung cancers. Hi, I’m Abhi Nair, a medical oncologist at the Oncology Center of Excellence here at the FDA.

SB: And I am Sanjeeve Bala, a medical oncologist and acting clinical team leader at FDA. Most patients with EGFR-mutated non-small cell lung cancer are initially treated with first- and second-generation EGFR tyrosine kinase inhibitors, such as erlotinib, gefitinib, and afatinib. Unfortunately, within a year, most of these patients will develop disease that’s resistant to these first-line TKIs. About 60% of these patients have developed resistance through an additional EGFR mutation, at the locus known as T790M.

AN: The T790M mutation blocks the specific engagement of first- and second-generation TKIs with EGFR. Sanjeeve, tell us more about osimertinib and how this third-generation TKI overcomes tumor resistance.

SB: Abhi, osimertinib is an irreversible EGFR TKI designed to inhibit both EGFR sensitizing and EGFR T790M resistance mutations. It crosses the blood-brain barrier and is known to have activity against central nervous system lesions. Osimertinib was granted accelerated approval in 2015 for patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer after progression on or after EGFR TKI treatment.

AN: In order to change the accelerated approval of osimertinib to regular approval, confirmatory clinical data are required. Tell us about the new data.

SB: Regular approval was granted based on improvements in PFS in the AURA3 trial, in patients with EGFR T790M non-small cell lung cancer who progressed on prior EGFR TKI. They were randomized to osimertinib, 80 mg daily, or chemotherapy with platinum plus pemetrexed. The median PFS was 10.1 months in the osimertinib arm and 4.4 months in the chemotherapy arm. The overall response rate was 72% on osimertinib versus 31% for chemotherapy, and median durations of response were 9.7 months vs. 4.1 months for the two arms.

AN: Sanjeeve, brain metastases continue to be a devastating complication for patients with lung cancer. Did this trial also confirm the activity of osimertinib in the CNS lesions that you mentioned earlier?

SB: A group of patients with measureable CNS disease at baseline had an objective response rate of 57% in the CNS with a median duration that was not reached when treated with osimertinib, compared with 25% of patients treated with chemotherapy who had a median response duration of 5.7 months. This confirmed the CNS activity of osimertinib.

AN: Did patient eligibility for this trial require selection with a companion diagnostic device?

SB: Yes, Abhi. One of the key features of this approval was the new liquid biopsy companion diagnostic used to identify some patients for the trial, called the cobas® EGFR Mutation Test v2. This test, approved by FDA in September 2016, identifies cell-free DNA with the T790M mutation circulating in a patient’s plasma, which is useful when patients don’t have tumor tissue available for testing.

AN: So patients wouldn’t need to undergo tumor biopsies.

SB: That’s right. But because of the false-negative rate for this test, tumor biopsy is required for patients who have a negative circulating tumor DNA test. But it can spare a significant number of patients from undergoing an invasive procedure.

AN: That is a major advance. Now let’s talk about the relative toxicity of osimertinib. How did the safety signals of osimertinib compare with chemotherapy in this trial?

SB: Treatment with osimertinib produced some toxicities in over 20% of patients, including diarrhea, rash, nail bed disorders, dry skin, cough, nausea, and anorexia. Patients on the chemotherapy arm had a different toxicity profile that’s familiar to oncologists, and relatively more incidents of vomiting, stomatitis, constipation, and thrombocytopenia, for example.

AN: So there are safety trade-offs between the TKI and traditional cytotoxic chemotherapy, but they sound predictable and manageable. Are there any other key safety issues that a practicing oncologist should be alert for?

SB: Previously-identified significant adverse events with osimertinib include interstitial lung disease or pneumonitis, prolongation of the QTc interval, and changes in cardiac contractility. The current approval did not identify any new safety signals. Detailed safety information can be found in the package insert on the web at Drugs@FDA.

AN: Sanjeeve, tell us the three take-home points from this D.I.S.C.O.

SB: Sure, Abhi. The three main take away points are: Osimertinib is a new option for the second-line treatment of patients with non-small cell lung cancer harboring T790M mutations. It also demonstrated meaningful clinical efficacy in central nervous system metastases. And patients can be tested for the target mutation using the plasma-based companion diagnostic, but if that test is negative, they should have confirmatory tumor biopsy.

Detailed prescribing and safety information may be found in the package insert, available on the web at Drugs@FDA.

For a transcript with links to the FDA analysis, and the multidisciplinary team of FDA experts who conducted the review, visit our website at www.fda.gov/DISCO.

AN: Thank you Sanjeeve. Are there other FDA oncology drug approvals that you would like to hear about? Leave us your questions and comments on Twitter @FDAOncology and as always, we welcome your feedback. I’m Abhi Nair, thank you for tuning in to the D.I.S.C.O. today.

SB: And until next time at the D.I.S.C.O., I’m Sanjeeve Bala.


This Drug Information Soundcast in Clinical Oncology was developed by Abhilasha Nair, Sanjeeve Bala, Lauretta Odogwu, Gideon Blumenthal, Kirsten B. Goldberg, and Richard Pazdur, of the Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the Division of Drug Information was the sound producer.

Members of the Multi-Disciplinary Review and Evaluation team for this product application were:

Regulatory Project Manager: Ingrid Fan
Medical Officer Review: Luckson Mathieu, Lauretta Odogwu (Primary Reviewers); Erin Larkins (Medical Team Leader)
Statistical Review: Mallorie Fiero (Primary Reviewer); Lisa Rodriguez (Team Leader)
Pharmacology Toxicology Review: Shawna Weis (Primary Reviewer); Whitney Helms (Team Leader)
Clinical Pharmacology Review: Safaa Burns (Primary Reviewer); Jeanne Fourie Zirkelbach (Team Leader)
Pharmacometrics Review: Luning Zhuang (Primary Reviewer); Jiang Liu (Team Leader)
Office of Prescription Drug Products/ Division of Medical Policy Programs: Nazia Fatima (OPDP) and Sharon Mills (DMPP) (Primary Reviewers); Barbara Fuller (Team Leader for Patient Labeling, DMPP); LaShawn Griffiths (Associate Director for Patient Labeling, DMPP)
Office of Scientific Investigations: Lauren Iacono-Connor (Reviewer); Susan Thompson (Team Leader); Kassa Ayalew (Branch Chief)
Cross-Discipline Team Leader Review (incorporated into Medical Officer Review): Erin Larkins

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