CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non–Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3)

Abstract

Purpose In patients with epidermal growth factor receptor ( EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC), there is an unmet need for EGFR-tyrosine kinase inhibitors with improved CNS penetration and activity against CNS metastases, either at initial diagnosis or time of progression. We report the first comparative evidence of osimertinib CNS efficacy versus platinum-pemetrexed from a phase III study (AURA3; ClinicalTrials.gov identifier: NCT02151981) in patients with EGFR T790M-positive advanced NSCLC who experience disease progression with prior EGFR-tyrosine kinase inhibitor treatment. Methods Patients with asymptomatic, stable CNS metastases were eligible for enrollment and were randomly assigned 2:1 to osimertinib 80 mg once daily or platinum-pemetrexed. A preplanned subgroup analysis was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiological review. The CNS evaluable for response set included only patients with one or more measurable CNS lesions. The primary objective for this analysis was CNS objective response rate (ORR). Results Of 419 patients randomly assigned to treatment, 116 had measurable and/or nonmeasurable CNS lesions, including 46 patients with measurable CNS lesions. At data cutoff (April 15, 2016), CNS ORR in patients with one or more measurable CNS lesions was 70% (21 of 30; 95% CI, 51% to 85%) with osimertinib and 31% (5 of 16; 95% CI, 11% to 59%) with platinum-pemetrexed (odds ratio, 5.13; 95% CI, 1.44 to 20.64; P = .015); the ORR was 40% (30 of 75; 95% CI, 29% to 52%) and 17% (7 of 41; 95% CI, 7% to 32%), respectively, in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 3.24; 95% CI, 1.33 to 8.81; P = .014). Median CNS duration of response in patients with measurable and/or nonmeasurable CNS lesions was 8.9 months (95% CI, 4.3 months to not calculable) for osimertinib and 5.7 months (95% CI, 4.4 to 5.7 months) for platinum-pemetrexed; median CNS progression-free survival was 11.7 months and 5.6 months, respectively (hazard ratio, 0.32; 95% CI, 0.15 to 0.69; P = .004). Conclusion Osimertinib demonstrated superior CNS efficacy versus platinum-pemetrexed in T790M-positive advanced NSCLC.

Osimertinib in patients with T790M mutation‐positive, advanced non–small cell lung cancer: Long‐term follow‐up from a pooled analysis of 2 phase 2 studies

“…[6][7][8][9] Cancer March 15, 2019 Osimertinib is a central nervous system (CNS) active, third-generation EGFR-TKI that is selective for both EGFR-TKI-sensitizing (EGFRm) and EGFR T790M-resistance mutations. [10][11][12][13][14] In 2 phase 2 trials (the AZD9291 First Time in Patients Ascending Dose Study [AURA] extension study [clincialtrials. gov identifier NCT01802632] and the AURA2 study [NCT02094261]), osimertinib treatment in patients who had T790M-positive, advanced NSCLC and disease progression after prior EGFR-TKI therapy provided high objective response rates (ORRs) (62% and 70%, respectively) and prolonged median progression-free survival (PFS) (12.3 and 9.9 months, respectively).…”

New data highlighting the efficacy and safety outcomes of third‐generation EGFR‐TKI in NSCLC patients with rare EGFR mutations

“…Osimertinib is a third‐generation EGFR‐TKI that can selectively inhibit sensitizing mutations and Thr790Met mutation . At present, it is approved for the first‐line treatment of patients with metastatic NSCLC harboring EGFR Thr790Met mutations and specific Leu858Arg mutation .…”

Impact of Disease and Treatment Response in Drug–Drug Interaction Studies: Osimertinib and Simvastatin in Advanced Non‐Small Cell Lung Cancer

“…EGFR T790M mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system metastases. [4][5][6][7][8] Osimertinib 80 mg is approved for first-line treatment of patients with metastatic EGFRm NSCLC. [9][10][11] Osimertinib exhibits linear PK across the 20-240 mg dose range and once-daily administration leads to a threefold accumulation within 15 days.…”

“…Osimertinib is a third‐generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that potently and selectively inhibits both EGFR‐tyrosine kinase inhibitor‐sensitizing (EGFR mutant (EGFRm)) and EGFR T790M mutations and has demonstrated efficacy in non‐small cell lung cancer (NSCLC) central nervous system metastases . Osimertinib 80 mg is approved for first‐line treatment of patients with metastatic EGFRm NSCLC…”