Osimertinib in Advanced Non–Small-Cell Lung Cancer

For patients with advanced non-small cell
lung cancer and a mutation in the epidermal growth factor receptor (or EGFR), first line
treatment is with an EGFR tyrosine kinase inhibitor (an EGFR-TKI). Some patients initially have a good response
to this treatment but over time the cancer progresses in most. In up to 60% of patients who have a recurrence
of lung cancer, a point mutation in the gene coding region T790M has been identified. The presence of this mutation is associated
with reduced binding of the EGFR TKI therapy to the receptor, leading to less inhibition
and to cancer progression. Osimertinib is an oral, irreversible EGFR-TKI
that is selective for both EGFR and T790M resistance variants with activity against
metastases to the central nervous system. The international, open-label, AURA3
trial included 419 patients with T790M-positive advanced non-small cell lung cancer, who had
progression of cancer after prior treatment with EGFR-TKI therapy. 144 of the patients (34%) had asymptomatic
brain metastases. Patients were randomized to receive a daily
dose of osimertinib or intravenous platinum-pemetrexed chemotherapy every three weeks for 6 cycles,
followed by maintenance pemetrexed. The primary endpoint was investigator-assessed
median progression-free survival, which was 10.1 months in the osimertinib group, as compared
with 4.4 months among those treated with IV chemotherapy. The hazard ratio, 0.30 was statistically significant. A subgroup analysis of the patients with CNS
metastases showed a median progression-free survival of 8.5 months in the osimertinib
group, as compared with 4.2 months in the IV chemotherapy group. Patients in the osimertinib group had diarrhea,
rash and dry skin. Cases of severe myelotoxicity were less common
with osimertinib than with IV chemotherapy. The authors conclude that in patients with
T790M-positive advanced non-small cell lung cancer and prior EGFR-TKI therapy, treatment
with osimertinib resulted in significantly longer progression-free survival than did IV platinum-pemetrexed
chemotherapy. Full trial results are available at NEJM.org.