Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.

Abstract

BACKGROUND:

Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC).

METHODS:

In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival.

RESULTS:

The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%).

CONCLUSIONS:

Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).

• Authors: Jean-Charles Soria, Yuichiro Ohe, Johan Vansteenkiste, Thanyanan Reungwetwattana, Busyamas Chewaskulyong, Ki Hyeong Lee, Arunee Dechaphunkul, Fumio Imamura, Naoyuki Nogami, Takayasu Kurata, Isamu Okamoto, Caicun Zhou, Byoung Chul Cho, Ying Cheng, Eun Kyung Cho, Pei Jye Voon, David Planchard, Wu-Chou Su, Jhanelle E Gray, Siow-Ming Lee, Rachel Hodge, Marcelo Marotti, Yuri Rukazenkov, Suresh S Ramalingam, FLAURA Investigators
• Journal: The New England journal of medicine (N Engl J Med) Vol. 378 Issue 2 Pg. 113-125 (01 11 2018) ISSN: 1533-4406 [Electronic] United States
• PMID: 29151359 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Acrylamides
• Aniline Compounds
• Antineoplastic Agents
• Piperazines
• Protein Kinase Inhibitors
• Quinazolines
• osimertinib
• Erlotinib Hydrochloride
• ErbB Receptors
• Protein-Tyrosine Kinases
• Gefitinib

Topics

• Acrylamides
• Adult
• Aged
• Aged, 80 and over
• Aniline Compounds
• Antineoplastic Agents (adverse effects, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, mortality)
• Disease-Free Survival
• Double-Blind Method
• ErbB Receptors (genetics)
• Erlotinib Hydrochloride (therapeutic use)
• Female
• Gefitinib
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (drug therapy, genetics, mortality)
• Male
• Middle Aged
• Mutation
• Piperazines (adverse effects, therapeutic use)
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Quinazolines (therapeutic use)
• Survival Rate