FDA Grants Osimertinib Breakthrough Therapy Designation for First-Line NSCLC

Sean Bohen, MD, PhD

Sean Bohen, MD, PhD

Osimertinib (Tagrisso) has been granted Breakthrough Therapy Designation by the FDA for the first-line treatment of patients with metastaticEGFRmutation-positive non-small cell lung cancer (NSCLC).

Osimertinib is a third-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) designed to inhibit both EGFR-sensitizing andEGFR T790M-resistance mutations, with clinical activity against central nervous system (CNS) metastases. Frontline osimertinib was associated with a 54% reduction in the risk of progression or death compared with standard therapy, according to phase III 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 advancedEGFRmutation-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 osimertinib versus standard-of-care EGFR TKI therapy with erlotinib (Tarceva) or gefitinib (Iressa) in treatment-naïve patients with locally-advanced or metastaticEGFRmutation-positive NSCLC.

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 pre-specified 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.

In the double-blind trial, 556 treatment-na&iuml;ve patients with EGFR-positive locally advanced or metastatic NSCLC were randomly assigned to osimertinib (n = 279) or an existing TKI (n = 277). Patients with CNS metastases were allowed on the trial and all had exon 19 deletions orL858Rmutations. Daily oral therapy was given with 80 mg osimertinib, 250 mg gefitinib, or 150 mg erlotinib.

The objective response rate (ORR) 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.

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 &ge; 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%).

Osimertinib was initially granted an accelerated approval by the FDA in November 2015 followed by a full indication in March 2017 for pretreated patients withT790M-positive NSCLC. The NCCN Clinical Practice Guidelines in Oncology recommended first-line osimertinib for patients with locally-advanced or metastaticEGFRmutation-positive NSCLC in September. The use of osimertinib for the first-line treatment of patients with locally-advanced or metastaticEGFRmutation-positive NSCLC is not yet FDA approved.

Reference:

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.