On April 18, 2018, AstraZeneca announced that the U.S. Food and Drug Administration (FDA) has approved the targeted therapy Osimertinib for the first-line treatment of patients with metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Eligible patients must be confirmed—via an FDA-approved test—to have either an EGFR exon 19 deletion mutation or an exon 21 L858R mutation. This approval is based on results from the Phase III FLAURA clinical trial; the data were presented at the 2017 Annual Meeting of the European Society for Medical Oncology (ESMO) and subsequently published in *The New England Journal of Medicine*.
Key Statements
Dave Fredrickson, Executive Vice President of AstraZeneca’s Oncology Business Unit, stated: "The approval of Osimertinib for first-line treatment marks a major milestone for both patients and the company. The drug demonstrated an unprecedented median progression-free survival benefit across all pre-specified patient subgroups—including those with or without central nervous system metastases—offering the potential to extend survival for more patients while simultaneously inhibiting tumor progression or spread."
Dr. Suresh S. Ramalingam, Principal Investigator of the FLAURA trial and Director of the Winship Cancer Institute of Emory University, noted: "The first-line approval of Osimertinib represents a major breakthrough in the treatment of EGFR-mutated lung cancer and will significantly alter the treatment paradigm. Compared to previous-generation EGFR inhibitors, Osimertinib achieved a significant improvement in progression-free survival without introducing any new safety concerns."
Safety Data
The safety profile of Osimertinib in the FLAURA trial was consistent with findings from previous studies:
1. Tolerability: Overall tolerability was good.
2. Incidence of Grade 3 or Higher Adverse Events (AEs): The incidence was 34% in the Osimertinib arm, which was lower than the 45% observed in the control arm. 3. Common Adverse Reactions (≥20%): Diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), fatigue (21%), and decreased appetite (20%).
Global Approval Progress and Indication Expansion
1. Current U.S. Indications
Previously approved as a second-line treatment for patients with metastatic EGFR-mutation-positive NSCLC whose tumors have been confirmed by an FDA-approved test to harbor the EGFR T790M resistance mutation (i.e., patients who have progressed following first-line EGFR-TKI therapy).
2. 2017 Accelerated Approval Pathway
Granted "Breakthrough Therapy" and "Priority Review" designations by the FDA for use as a first-line treatment.
3. Global Regulatory Updates
Applications for the first-line treatment indication are currently under review in the EU and Japan, with approval anticipated in the second half of 2018.
4. Brazil: First to Approve
Based on data from the FLAURA trial, Osimertinib was the first to be approved globally—on April 16, 2018—for the first-line treatment of metastatic EGFR-mutation-positive NSCLC.
Osimertinib: Mechanism of Action
1. Third-Generation Irreversible EGFR-TKI
Simultaneously inhibits both EGFR-sensitizing mutations (e.g., Exon 19 deletion/L858R) and the T790M resistance mutation; demonstrates clinical activity against central nervous system (CNS) metastases.
2. Global Approval Status
The 40 mg/80 mg once-daily oral tablet formulation has been approved for the first-line treatment indication in the U.S. and Brazil, and is approved in over 75 countries—including the U.S., EU, Japan, and China—for the second-line treatment of advanced NSCLC harboring the EGFR T790M mutation.
3. U.S. Approval History
Received accelerated approval from the FDA for second-line treatment in 2015; received full approval in March 2017 based on data from the Phase III AURA3 trial.
