Frontline Osimertinib Submitted for Japanese Approval in NSCLC

AstraZeneca has submitted a&nbsp;supplemental new drug application to Japan&#39;s&nbsp;Pharmaceuticals and Medical Devices Agency for the use of the&nbsp;third-generation, irreversible EGFR tyrosine kinase inhibitor osimertinib (Tagrisso) in the frontline treatment of patients with&nbsp;inoperable or recurrent <em>EGFR</em>-positive non&ndash;small cell lung cancer.

AstraZeneca has submitted a supplemental new drug application (sNDA) to Japan's Pharmaceuticals and Medical Devices Agency for the use of the third-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) in the frontline treatment of patients with inoperable or recurrentEGFR-positive non—small cell lung cancer (NSCLC).

The application was submitted based on results from the phase III FLAURA trial. In the study, frontline osimertinib reduced the risk of progression or death by 54% compared with the standard EGFR TKIs erlotinib (Tarceva) and gefitinib (Iressa) in patients with locally-advanced or metastaticEGFR-positive NSCLC.

In the double-blind FLAURA trial, 556 treatment-naïve patients withEGFR-positive locally advanced or metastatic NSCLC were randomly assigned to osimertinib (n = 279) or standard care with either erlotinib or gefitinib (n = 277). 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 of osimertinib, 250 mg of gefitinib, or 150 mg of erlotinib.

Median progression-free survival (PFS) was 18.9 months (95% CI, 15.2-21.4) for osimertinib compared with 10.2 months (95% CI, 9.6-11.1) for the control group, an 8.7-month improvement in median PFS (hazard ratio [HR], 0.46; 95% CI, 0.37-0.57;P<.0001). Improvements were seen in all prespecified subgroups, including patients with and without brain metastases

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 meaningful. There had been 58 deaths in the osimertinib arm and 83 in the control group.

The objective response rate with osimertinib was 80% compared with 76% for erlotinib and gefitinib (odds ratio, 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.

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 (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 most common any 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 like to discontinue treatment because of AEs (13.3% vs 18.1%).


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.