AURA3

When a lung cancer driven by an EGFR mutation stops responding to a first- or second-generation inhibitor, about half the time the reason is a second mutation, T790M, in the gatekeeper position of the kinase. Osimertinib was designed to bind that residue covalently while sparing wild-type EGFR. AURA3 randomised 419 patients whose disease had progressed on first-line EGFR inhibition and whose tumour carried T790M 2:1 to osimertinib 80 mg daily or to pemetrexed with carboplatin or cisplatin every three weeks for up to six cycles, with maintenance pemetrexed allowed.

Median progression-free survival was 10.1 months with osimertinib against 4.4 months with chemotherapy (hazard ratio 0.30, 95 percent confidence interval 0.23 to 0.41), including in patients with central nervous system metastases.

AURA3 confirmed the accelerated approval osimertinib had received in 2015 and established the practice of re-biopsying, or testing plasma for, the resistance mutation at progression. FLAURA then moved osimertinib to first line, which removed most of the T790M population: the mutation arises under pressure from the older drugs, and when they are not used, it is not selected for.