Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer

Abstract

Background: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown.

Methods: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival.

Results: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%).

Conclusions: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).

Figure 1 (facing page).. Duration of Progression-free Survival, According to Subgroup.

Shown are Kaplan–Meier estimates of the duration of progression-free survival as assessed by investigators in the intention-to-treat population (Panel A), in patients with central-nervous-system (CNS) metastases (Panel B), and in patients with EGFR T790M–positive status in both tumor and plasma (Panel C). The tick marks indicate censored data. Progression events that occurred after two or more missed visits (i.e., 14 weeks) after the last assessment were censored at the last assessment, according to Response Evaluation Criteria in Solid Tumors. CI denotes confidence interval.

Figure 2.. Subgroup Analyses of Progression-free Survival.

A hazard ratio of less than 1 indicates a lower risk of progression in the osimertinib group. The Cox proportional-hazards model includes randomized treatment, the subgroup covariate of interest, and the treatment according to subgroup interaction. The size of the circles is proportional to the number of events. Overall population analyses are presented from both a Cox proportional-hazards model and the primary analysis (U and V statistics from a log-rank test stratified according to race). If there were fewer than 20 events in any subgroup, then the analysis was not performed. The shaded area indicates the 95% CI for the overall hazard ratio (all patients). NC denotes could not be calculated.