Anne S. Tsao, MD reviewing Mok TS et al. N Engl J Med 2016 Dec 6.

The EGFR inhibitor osimertinib is superior to chemotherapy and should be considered the standard of care for this population.

The T790M epidermal growth factor receptor (EGFR) mutation confers resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). Such resistance arises in close to 60% of non–small-cell lung cancer (NSCLC) patients with sensitive EGFR mutations. A recent phase I study showed that the EGFR inhibitor osimertinib (AZD9291) was highly active in EGFR T790M-mutated patients with EGFR-inhibitor–resistant NSCLC (NEJM JW Oncol Hematol Jul 2015 and N Engl J Med 2015; 372:1689).

To confirm these findings, the investigators conducted an industry-funded, international, open-label, randomized phase III trial (AURA3) comparing the effectiveness of osimertinib versus chemotherapy with platinum-pemetrexed in 419 NSCLC EGFR-mutated patients with T790M-positive disease. Patients were randomized 2:1 to receive osimertinib or intravenous pemetrexed plus either carboplatin or cisplatin every 3 weeks for up to six cycles, followed by optional maintenance pemetrexed.

Median progression-free survival (PFS; the primary endpoint) was superior with osimertinib versus chemotherapy (10.1 vs. 4.4 months; hazard ratio, 0.30; P<0.001), as were 6-month PFS (69% vs. 37%) and objective response rate (71% vs. 31%; odds ratio, 5.39; P<0.001). Osimertinib improved survival across all subgroups of patients (HR, <0.50), especially among patients with the 144 patients with central nervous system metastases (8.5 vs 4.2 months, HR, 0.32). Osimertinib had less grade 3 or higher toxicity than chemotherapy (23% vs. 47%).

CITATION(S):

Mok TS et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med 2016 Dec 6; [e-pub].

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