Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced [NSCLC] in whom disease had progressed during first-line EGFR-[tyrosine kinase inhibitor] therapy.— Tony S. Mok, MD, and colleagues
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In the phase III AURA3 trial reported in The New England Journal of Medicine by Tony S. Mok, MD, of the Chinese University of Hong Kong, and colleagues, osimertinib (Tagrisso) significantly improved progression-free survival vs platinum/pemetrexed (Alimta) among patients with epidermal growth factor receptor (EGFR) T790M–positive non–small cell lung cancer (NSCLC) progressing during first-line EGFR tyrosine kinase inhibitor therapy.1 Osimertinib is an EGFR tyrosine kinase inhibitor that is selective for both EGFR tyrosine kinase inhibitor–sensitizing and T790M resistance mutations.
In this open-label international trial, 419 patients were enrolled from 126 sites between August 2014 and September 2015 and were randomized 2:1 to receive oral osimertinib at 80 mg once daily (n = 279) or intravenous pemetrexed at 500 mg/m2 plus either carboplatin at AUC5 or cisplatin at 75 mg/m2 every 3 weeks for up to 6 cycles; maintenance pemetrexed was allowed. Randomization was stratified for Asian vs non-Asian race. The primary endpoint was investigator-assessed progression-free survival. A protocol amendment in December 2014 permitted crossover to osimertinib treatment in patients in the platinum/pemetrexed group after objective disease progression.
For the osimertinib vs platinum-pemetrexed groups: median age was 62 vs 63 years; 62% vs 69% were female; 65% vs 66% were Asian and 32% vs 32% were white; 68% vs 67% had no history of smoking; 95% vs 99% had metastatic disease and 33% vs 36% had central nervous system (CNS) metastases; in addition to T790M, EGFR mutations included exon 19 deletion in 68% vs 62% and exon 21 L858R in 30% vs 32%; 96% vs 96% had received one prior therapy for advanced disease; and previous EGFR tyrosine kinase inhibitor treatment consisted of gefitinib (Iressa) in 59% vs 62%, erlotinib (Tarceva) in 34% vs 35%, and afatinib (Gilotrif) in 7% vs 3%.
Median follow-up was 8.3 months. Median progression-free survival was 10.1 months in the osimertinib group vs 4.4 months in the platinum/pemetrexed group (hazard ratio [HR] = 0.30, P < .001, adjusted for Asian vs non-Asian race). On blinded independent central review, median progression-free survival was 11.0 months vs 4.2 months (adjusted HR = 0.28, P < .001).
Hazard ratios for progression-free survival (all < 0.50) significantly favored osimertinib in all predefined subgroups. Median progression-free survival was 8.5 months vs 4.2 months (HR = 0.32, 95% confidence interval [CI] = 0.21–0.49) in patients with CNS metastases. Hazard ratios were 0.34 (95% CI = 0.24–0.46) among patients with EGFR exon 19 deletion, 0.46 (95% CI = 0.30–0.71) among those with EGFR L858R mutation, 0.32 (95% CI = 0.24–0.44) among Asian patients, and 0.48 (95% CI = 0.32–0.75) among non-Asian patients. Among patients with tumor and plasma T790M-positive status, median progression-free survival was 8.2 months vs 4.2 months (HR = 0.42, 95% CI = 0.29–0.61).
The objective response rate was 71% vs 31% (odds ratio = 5.39, P < .001). Median response duration was 9.7 months vs 4.1 months. Data on overall survival were not mature at the time of the report. At data cutoff, death had occurred in 13% of the osimertinib group and 19% of the platinum/pemetrexed group.
The most common adverse events of any grade were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%) in the osimertinib group and nausea (49%), decreased appetite (36%), constipation (35%), and anemia (30%) in the platinum/pemetrexed group. Adverse events of grade ≥ 3 occurred in 23% vs 47%; none occurred in > 1% of the osimertinib group, and neutropenia and anemia (both 12%) were the most common in the platinum/pemetrexed group. Interstitial lung disease–like adverse events occurred in 4% vs 1%, and prolongation of the QT interval occurred in 4% vs 1%.
Adverse events led to discontinuation of treatment in 7% vs 10%. Fatal adverse events occurred in four patients in the osimertinib group (respiratory failure in two, pneumonitis in one, and ischemic stroke in one) and in one patient in the platinum/pemetrexed group (hypovolemic shock).
The investigators concluded: “Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced [NSCLC] (including those with CNS metastases) in whom disease had progressed during first-line EGFR-[tyrosine kinase inhibitor] therapy.” ■
Disclosure: The study was funded by AstraZeneca. For full disclosures of the study authors, visit www.nejm.org.
The AURA3 study confirms the fundamental role of EGFR T790M testing in patients with acquired EGFR tyrosine kinase inhibitor resistance in order to plan subsequent treatment.— Geoffrey R. Oxnard, MD
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The AURA3 study—reported by Mok and colleagues and...