Osimertinib Approved by FDA for EGFR T790M-Positive NSCLC

November 13, 2015
Silas Inman

The FDA has given osimertinib (Tagrisso, AZD9291) an accelerated approval for treatment of patients with advanced EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) following progression on a prior EGFR TKI.

Richard Pazdur, MD

The FDA has given osimertinib (Tagrisso, AZD9291) an accelerated approval for treatment of patients with advancedEGFR T790Mmutation-positive non—small cell lung cancer (NSCLC) following progression on a prior EGFR TKI, based on data from two single-arm studies.

In the first study, labeled AURA, the objective response rate (ORR) with osimertinib was 61% for those with previously treatedEGFR T790M-mutant NSCLC (n = 201). In the second study, labeled AURA2, the ORR was 57% among 210 patients, according to the FDA. The agency also approved the cobas EGFR Mutation Test v2 as a companion diagnostic alongside osimertinib.

This approval marks the first for a drug following a rebiopsy and new mutational test, marking a milestone in precision medicine.

Patients withEGFR-mutant NSCLC often respond to EGFR inhibitors like gefitinib, erlotinib and afatinib. In approximately 50% to 60% of cases, resistance is associated with the presence of the acquiredEGFR T790Mmutation, which the cobas EGFR Mutation Test v2 detects.

“Our understanding of the molecular basis of lung cancer and reasons these cancers become resistant to prior treatments is rapidly evolving,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement. “This approval provides a new treatment for patients who test positive for theEGFRresistance 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.”

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. Osimertinib 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),1the ORR with osimertinib was 71%, with two complete responses. The stable disease rate at ≥6 weeks was 21%, for a disease control rate of 92%.

After a median follow-up of 6.7 months, the median progression-free survival (PFS) was 8.6 months. The median duration of response was 7.8 months (27% maturity).

“The approval of safe and effective companion diagnostic tests and drugs continue to be important developments in oncology,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, in a statement. “The availability of the cobas EGFR Mutation Test v2 meets a need for the detection of this importantEGFRgene mutation, which can alter treatment effectiveness.”

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

The most common AEs (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.