FDA OKs Osimertinib for Specific Non-Small-Cell Lung Cancers

Nick Mulcahy

November 13, 2015

The US Food and Drug Administration (FDA) today granted accelerated approval for osimertinib (Tagrisso, AstraZeneca), previously known as AZD9291, for the treatment of a specific type of advanced non-small-cell lung cancer.

The oral therapy is approved for patients whose tumors have an epidermal-growth factor receptor (EGFR) T790M mutation and who have progressed after treatment with another EGFR-blocking therapy.

Osimertinib, the first drug approved for these patients, is a third-generation tyrosine kinase inhibitor (TKI). It is expected that a similar agent, rociletinib (Clovis Oncology), will be available soon.

Approval was granted on the basis of "substantial evidence from clinical trials that shows osimertinib had a significant effect on reducing tumor size in over half of patients who were treated," Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA Center for Drug Evaluation and Research, said in a press statement

"Our understanding of the molecular basis of lung cancer and reasons these cancers become resistant to prior treatments is rapidly evolving," he added.

The FDA also approved the first companion diagnostic test (cobas EGFR Mutation Test v2) to detect the T790M "resistance" mutation. The newly approved version of the test adds this mutation to the clinically relevant mutations detected by the original (v1) test.

"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," said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health at the FDA Center for Devices and Radiological Health.

An investigator involved in pivotal clinical trials of this drug discussed clinical circumstances for its use earlier this year. Resistance to first-line EGFR inhibitors happens "virtually in everybody," said Pasi Jänne, MD, PhD, director of the Lower Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston. "In the majority of cases [60%], this is mediated by the T790M mutation."

The new drug will therefore be a boon to clinicians treating patients with EGFR-positive disease that has responded to first-line EGFR inhibitors — such as erlotinib (Tarceva, OSI Pharmaceuticals), gefitinib (Iressa, AstraZeneca), and afatinib (Gilotrif, Boehringer Ingelheim) — but then progressed, he said.

Until the emergence of the new third-generation TKIs, it was not clear what treatment to offer next, Dr. Jänne said.

"We now have a good treatment strategy for these patients," he told Medscape Medical News.

The FDA approval of AZD9291 was granted on the basis of data from the two AURA phase 2 studies (AURA extension and AURA2). In these two multicenter, single-group studies, involving a total of 411 patients in this setting, 57% of patients in the first study and 61% of patients in the second study experienced a complete or partial reduction in tumor size. Thus, the FDA is approving the drug based on a surrogate — the objective response rate.

Continued approval "may be contingent upon further confirmatory studies," according to the FDA.

Clinical data on osimertinib were published in the New England Journal of Medicine earlier this year, and presented at the 16th World Conference on Lung Cancer in September.

Third-generation EGFR inhibitors such as osimertinib are much better tolerated than the earlier EGFR inhibitors, Dr. Jänne noted, because they are more specific for mutated vs wild-type EGFR than the earlier drugs. In particular, there is less skin toxicity and diarrhea than with the earlier drugs.

The most common adverse events were generally mild to moderate, the manufacturer notes.

Table. Common Adverse Events

Event All Grades, % Grade 3/4, %
Diarrhea 42.0 1.0
Rash 41.0 0.5
Dry skin 31.0 0.0
Nail toxicity 25.0 0.0


The AZD9291 tolerability profile showed that no individual severe adverse events of grade 3 or higher occurred at a rate of 3.5% or above, according to a company press statement.

There are no contraindications for AZD9291. Warnings and precautions include interstitial lung disease, QT interval prolongation, cardiomyopathy, and embryofetal toxicity.

The FDA granted AstraZeneca breakthrough therapy designation, priority review, and orphan drug designation for osimertinib.

Dr. Jänne reports receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceuticals, Pfizer, Merrimack Pharmaceuticals, and Clovis Oncology; receiving lecture fees from Roche; and owning stock in Gatekeeper Pharmaceuticals.


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