Osimertinib is now the new standard of care for patients with EGFR T790M–positive NSCLC following disease progression after first-line EGFR tyrosine kinase therapy. These results underscore the need for us to look for the T790M mutation in patients [for whom first-line therapy fails].— Vassiliki A. Papadimitrakopoulou, MD
For patients with epidermal growth factor receptor (EGFR) T790M–positive non–small cell lung cancer (NSCLC), osimertinib (Tagrisso) demonstrated clinically superior efficacy over pemetrexed (Alimta) plus a platinum agent, with a 70% reduction in the risk of disease progression, according to the results of the AURA3 study, presented by Vassiliki A. Papadimitrakopoulou, MD, at the International Association for the Study of Lung Cancer (IASLC) 17th World Conference on Lung Cancer in Vienna.1
The study results were simultaneously published in The New England Journal of Medicine.2 (Watch future issues of The ASCO Post for a Journal Spotlight and accompanying commentary on the publication.)
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are widely used as front-line therapy in patients with NSCLC, but the EGFR T790M point mutation leads to resistance to clinically available anti-EGFR agents. Osimertinib is an oral, irreversible, third-generation EGFR-targeted tyrosine kinase inhibitor, selective for both EGFR-sensitizing and T790M-resistance mutations.
Forty percent of Asian patients and 15% of Western patients with advanced NSCLC present with an EGFR mutation in their tumor. “Invariably, all patients will progress after standard front-line therapy with an EGFR tyrosine kinase inhibitor, and in 60% of cases, the tumor will harbor the T790M mutation,” said Dr. Papadimitrakopoulou, Professor of Medicine in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.
AURA3 is the first randomized, phase III study to compare an EGFR T790M–selective agent (osimertinib) against platinum-based doublet chemotherapy in patients with centrally confirmed EGFR T790M–positive advanced NSCLC whose disease had progressed on first-line therapy. “Osimertinib is the new standard of care for these patients,” she reported.
A total of 419 patients with locally advanced or metastatic NSCLC were randomized 2:1 to osimertinib at 80 mg orally daily (n = 279) or to standard-care pemetrexed at 500 mg/m2 plus either carboplatin at AUC5 or cisplatin at 75 mg/m2 every 3 weeks, for up to 6 cycles, with maintenance pemetrexed allowed.
The primary endpoint was progression-free survival by investigator assessment. One key secondary endpoint was blinded independent central review–assessed progression-free survival. Patients were allowed to continue therapy post progression if they continued to demonstrate clinical benefit.
Patient characteristics and demographics were well balanced between the two treatment arms. The majority of patients in both arms were female, and two-thirds were Asian, as per normal epidemiologic distribution. Central nervous system (CNS) metastases were present in 33% of the osimertinib arm and 36% of the control arm, and 96% of patients in both treatment groups had received only 1 prior line of therapy. “Concurrent with mutation to T790M was exon 19 deletion, as is expected for the majority of patients,” she noted.
Progression-Free Survival Improvement
Patients treated with osimertinib had a 5.7-month improvement in median progression-free survival. Median progression-free survival was 10.1 months with osimertinib vs 4.4 months with standard platinum/pemetrexed treatment (hazard ratio [HR] = 0.30, P < .001). Analysis by central review was consistent with investigator assessment, Dr. Papadimitrakopoulou reported.
The hazard ratios favoring osimertinib for progression-free survival in all predefined subgroups were similarly impressive, as all were less than 0.50, she said. The hazard ratios were 0.32 for Asians and 0.48 for non-Asians; they were 0.32 for patients with brain metastases compared to 0.40 in patients without brain metastases.
Median progression-free survival for patients with CNS metastases on osimertinib was 8.5 months, compared to 4.2 months for platinum/pemetrexed. For patients without CNS metastases, median progression-free survival in the osimertinib arm was 10.8 months, compared to 5.6 months for chemotherapy.
A statistically superior and durable objective response rate was seen in the osimertinib arm when compared to standard of care: 71% vs 31%, respectively. Median duration of response on osimertinib was 9.7 months, vs 4.1 months for chemotherapy. Patients in the osimertinib cohort also suffered fewer grade 3 or higher adverse events (6%) than those in the pemetrexed group (34%). The more commonly reported toxicities in the osimertinib arm were diarrhea, rash, dry skin, and paronychia, whereas in the chemotherapy arm, nausea, fatigue, anemia, neutropenia, and constipation were most commonly reported. Fatal adverse events were observed in 1% of each treatment arm.
“Osimertinib demonstrated benefit in all subgroups examined and, notably, for patients with and without CNS metastases,” said Dr. Papadimitrakopoulou. “Osimertinib is now the new standard of care for patients with EGFR T790M–positive NSCLC following disease progression after first-line EGFR tyrosine kinase therapy. These results underscore the need for us to look for the T790M mutation in patients [for whom first-line therapy fails].” ■
Disclosure: Dr. Papadimitrakopoulou reported no potential conflicts of interest.
1. Papadimitrakopoulou V, Wu YL, Ahn M, et al: Randomized phase III study of osimertinib vs platinum-pemetrexed for EGFR T790M-positive advanced NSCLC (AURA3). International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer. Abstract PL03.03. Presented December 6, 2016.
Clearly this is a positive study, and the median progression-free survival and hazard ratio are amazing. It makes me think osimertinib is like a time machine that takes the patient back to the first line.— Tetsuya Mitsudomi, MD
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