FDA Grants Osimertinib Full Approval for EGFR T790M-Positive NSCLC

March 31, 2017

The FDA on March 30, 2017, granted full approval to osimertinib for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC.

Clinicians now have a new treatment to offer patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC).

The US Food and Drug Administration (FDA) on March 30, 2017, granted full approval to osimertinib (Tagrisso, AstraZeneca Pharmaceuticals) for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

Osimertinib, which is a third-generation EGFR TKI drug, received accelerated approval this past November for this indication based on an overall response rate (ORR) of 59% among 411 patients in two single-arm clinical trials (AURA2). The current approval is based on AURA3, a randomized, multicenter, open-label, active-controlled trial conducted in patients with metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first-line EGFR TKI therapy.

AURA3 required all patients to have EGFR T790M mutation-positive NSCLC identified by the cobas EGFR mutation test performed in a central laboratory. The trial randomized 419 patients, and 279 patients received osimertinib 80 mg orally once daily and 140 received platinum-based doublet chemotherapy.

The trial demonstrated an improvement in investigator-assessed progression-free survival (PFS), with a hazard ratio of 0.30. The estimated median PFS was 10.1 months in the osimertinib arm compared to 4.4 months in the chemotherapy arm. Confirmed ORR was 65% in the osimertinib arm and 29% in the chemotherapy arm, according to investigator assessment. The estimated median response durations were 11 months in the osimertinib and 4.2 months in the chemotherapy arm.

“The data show very strong improvement in PFS/ORR, including brain mets. The crossover design prevents achievement of OS [overall survival] difference, but it would really not be ethical to not offer osimertinib at chemo progression based on the earlier RR 59%,” Igor Puzanov, MD, professor of oncology at Roswell Park Cancer Institute, Buffalo, told OncoTherapy Network.

In patients with measurable central nervous system (CNS) lesions on baseline brain scans, the confirmed CNS ORR was estimated to be 57% in the osimertinib arm and 25% in the chemotherapy arm. Overall survival data are not yet available.

“The T790M EGFR mutation is the leading cause of resistance after first-line EGFR targeted therapy in NSCLC and osimertinib targets this difficult to treat group, for which standard anti-PD-1 therapies work less well, possibly due to the low mutation burden in majority of patients,” said Puzanov.  

The most common adverse reactions (occurring in at least 20% of patients) were diarrhea, rash, dry skin, nail toxicity, and fatigue. Serious adverse reactions were evaluated in 833 patients receiving osimertinib. The most serious adverse reactions were interstitial lung disease/pneumonitis (3.5%), QTc interval prolongation (0.7%), cardiomyopathy (1.9%), and keratitis (0.7%).

“The side effect profile seems tolerable and in line with previous anti-EGFR therapies. Therefore, I find osimertinib to be a welcome addition to our armamentarium to fight cancer in this rare molecular subgroup of patients,” Puzanov said.