FDA Approves Tagrisso Ahead of Schedule for Advanced NSCLC

The FDA has granted an accelerated approval for Tagrisso (osimertinib) to treat patients with advanced non–small cell lung cancer (NSCLC) positive the EGFR T790M mutation and whose disease worsened following a prior EGFR TKI.

Richard Pazdur, MD

The FDA has granted an accelerated approval for Tagrisso (osimertinib) to treat patients with advanced non—small cell lung cancer (NSCLC) positive for the EGFR T790M mutation and whose disease worsened following a prior EGFR TKI.

The approval was based on data from two single-arm studies. In the first, labeled AURA, the objective response rate (ORR) with Tagrisso was 61% for those with previously treated EGFR T790M-mutant NSCLC. In the second study, known as AURA2, the ORR was 57%, according to the FDA. Along with Tagrisso, the FDA also approved the cobas EGFR Mutation Test v2 as a companion diagnostic.

“Our understanding of the molecular basis of lung cancer and reasons these cancers become resistant to prior treatments is rapidly evolving,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval provides a new treatment for patients who test positive for the EGFR resistance mutation, T790M, and is based on substantial evidence from clinical trials that shows Tagrisso had a significant effect on reducing tumor size in over half of patients who were treated.”

Patients with EGFR-mutant NSCLC often respond to EGFR inhibitors, such as gefitinib, erlotinib and afatinib. In approximately 50% to 60% of cases, resistance is associated with the presence of the acquired EGFR T790M mutation, which the cobas EGFR Mutation Test v2 detects. This approval, which arrived several months ahead of schedule, marks the first for a drug following a rebiopsy and new mutational test, marking a milestone in precision medicine.

“The approval of safe and effective companion diagnostic tests and drugs continue to be important developments in oncology,” Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, said in a statement. “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.”

The phase II AURA2 trial enrolled 210 patients at a median age of 64 years with locally advanced or metastatic NSCLC following progression on an approved EGFR TKI. All patients had tumors that tested positive for the T790M resistance mutation. Tagrisso was administered at 80 mg once daily.

Asians accounted for almost two thirds of the patients, and three fourths of the cohort had never smoked. Tumor histology was adenocarcinoma in 96% of cases. The patients had received a median of one prior therapy (range, 1-9). The primary endpoint of the study was ORR.

In an updated analysis presented at the 2015 World Conference on Lung Cancer (WCLC),1 the ORR with Tagrisso was 71%, with 2 complete responses. The stable disease rate at ≥6 weeks was 21%, for a disease control rate of 92%. The median duration of response was 7.8 months (95% CI, 7.1-NR). The median progression-free survival (PFS) was 8.6 months (95% CI, 8.3-9.7).

Grade ≥3 adverse events occurred in 29% of patients, including drug-related events in 11%. The rate of discontinuation prompted by adverse events was 3%. One death was considered attributable to a drug-related adverse event.

The most common adverse events (any grade) were diarrhea (39%), dry skin (25%), rash (23%), nausea (16%), and paronchia, constipation, pruritus, and fatigue (15% each). Of those events, only diarrhea occurred at grade ≥3 severity and affected two patients. With respect to specific adverse events of interest, interstitial lung disease occurred in 2% of patients (1% grade ≥3), hyperglycemia in 1%, and QT prolongation in 5% (2% grade ≥3).

References:

1. Mitsudomi T, Tsai C, Shepherd F, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 Phase II study. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1406.

2. Yang JC, Ahn M, Ramalingam SS, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA study Phase II extension cohort. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 943.