Tagrisso (osimertinib) was granted a Breakthrough Therapy Designation for the firstline treatment of patients who have metastatic EGFR
mutation-positive non-small cell lung cancer (NSCLC).
Tagrisso is a third-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) designed to inhibit both EGFR-sensitizing and EGFR T790M
-resistance mutations, with clinical activity against central nervous system (CNS) metastases. Frontline Tagrisso was associated with a 54 percent reduction in the risk of progression or death compared with standard therapy, according to phase 3 data from the FLAURA study presented at the 2017 ESMO Congress.
“The Breakthrough Designation acknowledges not only Tagrisso’s potential as a first-line standard of care in advanced EGFR
mutation-positive NSCLC, but also the significant need for improved clinical outcomes in this disease,” Sean Bohen, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said in a press release. “The results of the FLAURA trial have the potential to redefine clinical expectations and offer new hope for patients who currently have a poor prognosis.”
AstraZeneca submitted data from FLAURA to support its Biologics License Application (BLA). That double-blind trial evaluated Tagrisso versus standard-of-care EGFR TKI therapy with Tarceva (erlotinib) or Iressa (gefitinib) in treatment-naïve patients with locally-advanced or metastatic EGFR
Median progression-free survival (PFS) was 18.9 months, for Tagrisso compared with 10.2 months for the control group, an 8.7-month improvement in median PFS. Improvements were seen in all pre-specified subgroups, including patients with and without brain metastases
Medians had not yet been reached for overall survival, but at just 25 percent maturity, HR favored Tagrisso at 0.63, a 37 percent reduction in the risk of death. However, those results have not yet been shown to be meaningful. There had been 58 deaths in the Tagrisso arm and 83 in the control group.
In the double-blind trial, 556 treatment-naïve patients with EGFR-positive locally advanced or metastatic NSCLC were randomly assigned to Tagrisso (279 patients) or an existing TKI (277 patients). Patients with CNS metastases were allowed on the trial and all had exon 19 deletions or L858R
mutations. Daily oral therapy was given with 80 mg Tagrisso, 250 mg Iressa or 150 mg Tarceva.
The objective response rate (ORR) with Tagrisso was 80 percent compared with 76 percent for Tarceva and Iressa. The median duration of response with Tagrisso was 17.2 months versus 8.5 months in the comparator arm.
In patients with CNS metastases (116 patients), the median PFS with Tagrisso was 15.2 months compared with 9.6 months with standard therapy. In those without CNS involvement (440 patients), the median PFS was 19.1 and 10.9 months, for Tagrisso and the control arm, respectively. Across all patients, CNS progression occurred in 6 percent treated with Tagrisso versus 15 percent for Tarceva and Iressa.
The most common any grade adverse events (AEs) were diarrhea (58 percent) and dry skin (32 percent) in the experimental group compared with diarrhea (57 percent) and dermatitis acneiform (48 percent) in the control group.
Overall, 33.7 percent of patients experienced a grade 3 or higher AE in the Tagrisso group compared with 44.8 percent for Tarceva and Iressa. Patients in the Tagrisso group were less like to discontinue treatment because of AEs (13.3 percent vs 18.1 percent).
Tagrisso was initially granted an accelerated approval by the FDA in November 2015 followed by a full indication in March 2017 for pretreated patients with T790M
-positive NSCLC. The NCCN Clinical Practice Guidelines in Oncology recommended first-line Tagrisso for patients with locally-advanced or metastatic EGFR
mutation-positive NSCLC in September. The use of Tagrisso for the first-line treatment of patients with locally-advanced or metastatic EGFR
mutation-positive NSCLC is not yet FDA approved.