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Osimertinib Approved by FDA as First-Line Treatment for Patients with EGFR+ NSCLC

Jason M. Broderick
Published Online:1:12 PM, Thu April 19, 2018

Suresh S. Ramalingam, MD
Osimertinib (Tagrisso) has been approved by the FDA as a frontline treatment for patients with non-small cell lung cancer (NSCLC) who have tumors harboring EGFR mutations (either exon 19 deletions or exon 21 L858R substitution mutations). This approval is based off results from a recent phase III study.

The FLAURA study found that frontline osimertinib reduced the risk of progression or death by 54% compared to standard TKI therapy of either erlotinib (Tarceva) or gefitinib (Iressa). 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, 15.2-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001), according to the results of this double-blind study.

“The approval of osimertinib in the first-line setting represents a major advance in the treatment of patients with EGFR mutations and a significant change in the treatment paradigm. Osimertinib provides robust improvements in progression-free survival with no unexpected safety signals compared to the previous generation of EGFR inhibitors,” said Suresh S. Ramalingam, lead investigator and director of medical oncology at Emory University’s Winship Cancer Institute.

There were 556 treatment-naïve patients with EGFR-positive locally advanced or metastatic NSCLC in the trial, each randomly assigned to a treatment of osimertinib (n = 279) or the standard TKI (erlotinib or gefitinib; n = 277). The trial allowed patients with CNS metastases, while all patients in the trial had exon 19 deletions or L858R mutations. Patients received a daily oral therapy of osimertinib (80 mg), gefitinib (250 mg), or erlotinib (150 mg).

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

There was an objective response of 77% in the osimertinib arm versus 69% in the erlotinib and gefitinib arms. Investigators also noted a 17.6 month median duration of response with osimertinib compared to 9.6 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.

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

In the osimertinib group, 33.7% experienced a grade ≥3 AE versus 44.8% in the erlotinib and gefitinib groups. Patients in the osimertinib group were less likely to stop treatment due to AEs (13.3% vs 18.1%).

Osimertinib, a third-generation, irreversible EGFR TKI, is designed to inhibit both EGFR-sensitizing and EGFR T790M-resistance mutations, with clinical activity against CNS metastases.

Osimertinib was granted an accelerated approval by the FDA 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. The NCCN Clinical Practice Guidelines in Oncology recommended frontline osimertinib for patients with locally-advanced or metastatic EGFR mutation–positive NSCLC in September 2017.
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.

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