The sNDA is based on the phase 3 FLAURA study, in which frontline Tagrisso reduced the risk of progression or death by 54 percent versus standard TKI therapy— Tarceva (erlotinib) or Iressa (gefitinib). In the double-blind study, the median progression-free survival (PFS) was 10.2 months for standard therapy and 18.9 months with Tagrisso.
The FDA previously granted Tagrisso a breakthrough therapy designation in this setting. Under the priority review, the FDA acts within six months of receiving a supplemental application, rather than the standard 10 months.
In the FLAURA trial, 556 treatment-naïve patients with EGFR-positive locally advanced or metastatic NSCLC were randomly assigned to Tagrisso (279 patients) or a standard TKI (Tarceva or Iressa; 277 patients). Patients with central nervous sytem (CNS) metastases were allowed on the trial and all patients had exon 19 deletions or L858R mutations. Daily oral therapy was given with 80 mg of Tagrisso, 250 mg of Iressa, or 150 mg of Tarceva.
The PFS benefit with Tagrisso extended across all prespecified subgroups. 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 months 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 objective response rate 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.
Medians had not yet been reached for overall survivaal, 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 statistically significant. At the time of the analysis, there had been 58 deaths in the Tagrisso arm and 83 in the control group.
The most common all-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 likely to discontinue treatment because of AEs (13.3 percent vs 18.1 percent).
Tagrisso is a third-generation, irreversible EGFR TKI designed to inhibit both EGFR-sensitizing and EGFR T790M-resistance mutations, with clinical activity against CNS metastases.
The FDA granted Tagrisso an accelerated approval in November 2015 followed by a full indication in March 2017 for patients with EGFR T790M–positive NSCLC whose disease progressed on or after EGFR TKI therapy. In September 2017, the NCCN Clinical Practice Guidelines in Oncology recommended first-line Tagrisso for patients with locally-advanced or metastatic EGFR mutation–positive NSCLC.