Tagrisso approved for EGFR T790M mutation positive NSCLC patients
In another win for lung cancer patients, the Food and Drug Administration today granted accelerated approval to Tagrisso (Osimertinib or AZD9291 manufactured by AstraZeneca) this morning for patients whose disease has progressed on EGFR-targeted therapies, and whose tumors express a specific mutation in EGFR- the T790M mutation. Tagrisso is the first drug to be approved for EGFR T790M acquired treatment resistance mutation, with a few other similar compounds in the pipeline, such as Rociletinib (CO1686, manufactured by Clovis Oncology).
Companion Diagnostic: The FDA also approved a companion diagnostic test, the Cobas EGFR Mutation Test Version 2 (marketed by Roche Molecular Systems), to detect the EGFR T790M mutation targeted by Tagrisso. This is an updated version of the companion diagnostic that now tests for the T790M mutation, in addition to the other clinically relevant EGFR mutations detected by Version 1.
Quick Bench-to-Bedside Turnaround: Tagrisso entered the first human trials in 2013, and made its way from the bench to patient bedside in a unusually short time of 2.5 years. This quick progress and accelerated patient access to the therapeutic has been made possible in large part due to the FDA’s new program of providing special designations to promising experimental compounds. The FDA granted Tagrisso “breakthrough”, “priority” and “orphan drug” designations that accelerated its approval process and getting it to patients quicker. Tagrisso was approved under the agency’s “accelerated approval” program, which allows the approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. Today’s approval was based on the tumor response rate and duration of response seen with Tagrisso in two single arm phase 2 clinical trials, that allowed the drug to be approved three months ahead of schedule.
Mechanism of Action: Approximately, 10-15% of all non-small cell lung cancer (NSCLC) patients have mutations in EGFR (Epidermal Growth Factor Receptor). Most of these patients respond to therapy targeted to these mutations, such as erlotinib (Tarceva) or gefitinib (Iressa). Unfortunately, most EGFR mutation-positive patients develop resistance to these first-line targeted therapies, as their tumors find bypass mechanisms to avoid the targeted drugs and continue to grow. This drug resistance that is acquired upon exposure to front-line EGFR targeted therapies may be caused by a variety of new mutations that arise in these tumors such as the EGFR T790 mutation that arises in over 60% of these patients. So far, there have been no FDA approved drugs for these patients whose tumors stop responding to first-line EGFR targeted therapies. The FDA approval of Tagrisso today changes that. Tagrisso or AZD9291 is an EGFR TKI (tyrosine kinase inhibitor) designed to inhibit both the activating, sensitizing mutations in EGFR as well as the acquired resistance mutation, T790M.
Clinical Trials: Today’s approval of Tagrisso is based on the safety and efficacy data from two phase two clinical trials (AURA extension and AURA2) in 411 non-small cell lung cancer patients whose tumors had the EGFR T790M mutation upon disease progression post-treatment with EGFR-targeted therapies. Tagrisso demonstrated 57% and 61% objective response rates (a measure of tumor shrinkage) in the first and second clinical trial respectively, i.e. 57% and 61% patients in the two trials achieved partial or complete reduction in their tumor size.
Dosage: 80mg tablets, once daily.
Side Effects: The most common side effects of Tagrisso are diarrhea, skin and nail conditions such as dry skin, rash and infection or redness around the fingernails. Tagrisso may cause serious side effects, including inflammation of the lungs and injury to the heart. It also may cause harm to a developing fetus.
Ongoing studies: Continued approval for Tagrisso in the non-small cell lung cancer EGFR T790M mutation-positive patients is contingent upon further confirmatory studies that are ongoing. Tagrisso is being evaluated in a randomized Phase 3 study, AURA3, designed to study the safety and efficacy of the agent versus platinum-doublet chemotherapy in patients with EGFR T790M positive, locally advanced or metastatic NSCLC patients whose disease has progressed following treatment with EGFR-directed targeted therapies. AZD9291 is also being investigated in the adjuvant setting and in the metastatic first-line setting, including in patients with brain metastases, as well as in combination with other compounds.
It is a hopeful period for lung cancer patients, with several promising experimental compounds in the pipeline and 3 new drugs approved just in past few weeks! We can now march more confidently towards the era of precision medicine, with an entire arsenal of molecularly targeted drugs for lung cancer patients that come with their FDA-approved companion diagnostics.