Osimertinib has demonstrated a statistically significant and clinically meaningful improvement in overall survival compared with standard first-generation EGFR tyrosine kinase inhibitors in patients with newly diagnosed <em>EGFR</em>-mutated non–small cell lung cancer, according to updated findings from the phase III FLAURA trial.
Jose Baselga, MD, PhD
Osimertinib (Tagrisso) has demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) compared with standard first-generation EGFR tyrosine kinase inhibitors (TKIs) in patients with newly diagnosedEGFR-mutated nonsmall cell lung cancer (NSCLC), according to updated findings from the phase III FLAURA trial.1
OS was a key secondary endpoint of the FLAURA trial, which had already met its primary endpoint of improvement in progression-free survival (PFS) in 2017.2The PFS benefit seen in the FLAURA trial led to theFDA approval of osimertinib as a frontline treatmentfor patients with NSCLC harboringEGFRmutations in 2018. These updated findings show that the third-generation, irreversible EGFR TKI also improves OS in this setting.
“Today’s positive results show that Tagrisso provides an unprecedented survival outcome versus previous standard-of-care EGFR TKIs, reaffirming Tagrisso as the first-line standard-of-care for EGFR-mutated metastatic NSCLC,” said José Baselga, MD, PhD, executive vice president, Oncology Research & Development, AstraZeneca, in a press release announcing the OS findings.
The company plans to present the full OS findings from FLAURA at an upcoming medical meeting.
The randomized, double-blind phase III trial enrolled 556 treatment-naïve patients withEGFR-positive locally advanced or metastatic NSCLC who were randomly assigned to receive either osimertinib (n = 279) or standard first-generation EGFR TKIs of erlotinib (Tarceva) or gefitinib (Iressa) (n = 277).2Patients received a daily oral therapy of osimertinib (80 mg), gefitinib (250 mg), or erlotinib (150 mg).
Patients with central nervous system (CNS) metastases were allowed to be included, but all patients in the trial had to haveEGFRexon 19 deletions or L858R mutations. CNS progression occurred in 6% of all patients treated with osimertinib compared with 15% of patients treated with erlotinib and gefitinib.
Median PFS with osimertinib was 18.9 months (95% CI, 15.2-21.4) with osimertinib compared with 10.2 months (95% CI, 9.6-11.1) for gefitinib or erlotinib (HR, 0.46; 95% CI, 0.37-0.57;P<.0001), demonstrating a 54% reduction in the risk of progression or death with osimertinib compared with standard therapy.
PFS benefits were also seen 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 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 patients without CNS involvement (n = 440), the median PFS was 19.1 months (95% CI, 15.2-23.5) for the osimertinib arm and 10.9 months (95% CI, 9.6-12.3) for the first-generation TKI arm (HR, 0.46; 95% CI, 0.36-0.59;P<.0001).
The objective response rate was 77% in the osimertinib arm compared with 69% in the standard TKI arm. The median duration of response with osimertinib was 17.6 months compared with 9.6 months for gefitinib or erlotinib.
According to earlier interim OS findings, at 25% maturity, the hazard ratio favored osimertinib at 0.63 (95% CI, 0.45-0.88;P= .0068).
The most common all-grade adverse events (AEs) with osimertinib were diarrhea (58%) and dry skin (32%), whereas diarrhea (57%) and dermatitis acneiform (48%) were the most common AEs in the control arm.
In the osimertinib group, 33.7% experienced a grade ≥3 AE versus 44.8% in the erlotinib and gefitinib group. Patients in the osimertinib group were less likely to stop treatment due to AEs (13.3% vs 18.1%).