Osimertinib (Tagrisso), a third-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), received breakthrough therapy designation from the FDA for the first-line treatment of patients with EGFR-mutation–positive non–small-cell lung cancer (NSCLC), based on results from the phase 3 FLAURA trial, which included a doubling of progression-free survival (PFS).1,2
The EGFR TKIs currently available for the treatment of patients with EGFR-positive NSCLC—gefitinib (Iressa) and erlotinib (Tarceva)—block the cell-signaling pathways that spur tumor cell growth.1 Resistance to these agents, and the disease progression that comes along with it, is nevertheless common, with approximately half of patients developing the resistance mutation, EGFR T790M.1 Osimertinib goes a step further by targeting the secondary mutation.1 In addition, osimertinib shows clinical activity against central nervous system metastases, a need for the approximately 25% of patients with EGFR-positive NSCLC with brain metastases at diagnosis—a figure that increases to roughly 40% within 2 years of diagnosis.1
The double-blind, randomized, phase 3 FLAURA trial compared osimertinib with standard EGFR TKIs in 556 treatment-naïve patients with EGFR-positive (exon 19 deletion or L858R) advanced NSCLC across 30 countries.1,2 The researchers randomized patients in a 1:1 ratio to receive either 80 mg osimertinib once daily or a standard EGFR TKI (250 mg gefitinib once daily or 150 mg erlotinib once daily).2 The study’s primary end point was PFS, and secondary end points were overall survival (OS), duration of response (DOR), objective response rate (ORR), disease control rate, safety, and health-related quality of life.1,2
Osimertinib demonstrated significantly longer PFS, at 18.9 months, compared with standard EGFR TKIs, at 10.2 months (hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37-0.57; P <.001). ORRs were comparable between the 2 arms; 80% in patients receiving osimertinib and 76% for those receiving standard EGFR TKIs (odds ratio, 1.27; 95% CI, 0.85-1.90; P = .24).2 Osimertinib had more than double the DOR of standard EGFR TKIs (17.2 months [95% CI, 13.8-22.0] vs 8.5 months [95% CI, 7.3-9.8]).
Grade ≥3 adverse events occurred less frequently with osimertinib than with standard EGFR TKIs (34% vs 45%).2
Survival data were only 25% mature and OS had yet to be reached when lead investigator Suresh Ramalingam, MD, Deputy Director of the Winship Cancer Institute at Emory University, Atlanta, GA, presented the results at the 2017 ESMO Congress in September.3
“Interim overall survival data show a promising trend favoring osimertinib,” Dr Ramalingam said, adding, “Osimertinib should be considered a new standard of care for first-line therapy of EGFR mutation-positive NSCLC.”
The researchers concluded that osimertinib demonstrated superiority over standard EGFR TKIs as a first-line treatment for advanced NSCLC with EGFR mutations, with significantly longer PFS, lower incidence of serious adverse events, and a similar safety profile.2
1. Tagrisso granted breakthrough therapy designation by US FDA for the 1st-line treatment of patients with EGFR mutation-positive non-small cell lung cancer. October 9, 2017. www.astrazeneca.com/media-centre/press-releases/2017/tagrisso-granted-breakthrough-therapy-designation-by-us-fda-for-the-1st-line-treatment-of-patients-with-egfr-mutation-positive-non-small-cell-lung-cancer-09102017.html. Accessed January 27, 2018.
2. Soria JC, Ohe Y, Vansteenkiste J, et al; for the FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378:113-125.
3. Goodman A. ‘Clinically meaningful’ results with first-line osimertinib in EGFR-positive NSCLC. The ASCO Post. October 10, 2017. www.ascopost.com/issues/october-10-2017/clinically-
meaningful-results-with-first-line-osimertinib-in-egfr-positive-nsclc. Accessed January 27, 2018.