FDA Grants Frontline Osimertinib Priority Review for NSCLC

The FDA has granted a priority review to a supplemental new drug application (sNDA) for the use of osimertinib (Tagrisso) as a first-line treatment for patients with non—small cell lung cancer (NSCLC) whose tumors harbor EGFR mutations (exon 19 deletions or exon 21 [L858R] substitution mutations).

The sNDA is based on the phase III FLAURA study, in which frontline osimertinib reduced the risk of progression or death by 54% versus standard TKI therapy—erlotinib (Tarceva) or gefitinib (Iressa). In the double-blind study, the median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 12.5-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).

The FDA previously granted osimertinib a breakthrough therapy designation in this setting. Under the priority review, the FDA acts within 6 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 osimertinib (n = 279) or a standard TKI (erlotinib or gefitinib; n = 277). Patients with 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 osimertinib, 250 mg of gefitinib, or 150 mg of erlotinib.

The PFS benefit with osimertinib extended across all prespecified subgroups. In patients with CNS metastases (n = 116), the median PFS with osimertinib was 15.2 months (95% CI, 12.1-24.4) compared with 9.6 months (95% CI, 7.0-12.4) with standard therapy (HR, 0.47; 95% CI, 0.30-0.74; P = .0009). In those without CNS involvement (n = 440), the median PFS was 19.1 months (95% CI, 15.2-23.5) and 10.9 months (95% CI, 9.6-12.3), for osimertinib and the control arm, respectively (HR, 0.46; 95% CI, 0.36-0.59; P <.0001). Across all patients, CNS progression occurred in 6% treated with osimertinib versus 15% for erlotinib and gefitinib.

The objective response rate with osimertinib was 80% compared with 76% for erlotinib and gefitinib (odds ratio [OR], 1.28, 0.85-1.93; P = .2335). The median duration of response with osimertinib was 17.2 months versus 8.5 months in the comparator arm.

Medians had not yet been reached for overall survival, but at just 25% maturity, HR favored osimertinib at 0.63, a 37% reduction in the risk of death (95% CI, 0.45-0.88; P = .0068). 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 osimertinib arm and 83 in the control group.

The most common all-grade adverse events (AEs) were diarrhea (58%) and dry skin (32%) in the experimental group compared with diarrhea (57%) and dermatitis acneiform (48%) in the control group.

Overall, 33.7% of patients experienced a grade ≥3 AE in the osimertinib group compared with 44.8% for erlotinib and gefitinib. Patients in the osimertinib group were less likely to discontinue treatment because of AEs (13.3% vs 18.1%).

Osimertinib 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 osimertinib 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 osimertinib for patients with locally-advanced or metastatic EGFR mutation—positive NSCLC.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.