In patients with EGFR T790M-positive non-small cell lung cancer (NSCLC) whose disease has progressed on first-line EGFR tyrosine kinase inhibitor (TKI) therapy, osimertinib demonstrated a statistically significant greater efficacy than platinum-pemetrexed chemotherapy. The results of the AURA3 study were presented in a Presidential Symposium during the World Lung Cancer Conference in Vienna, Austria (5-8 December 2016) and simultaneously published in NEJM.
Osimertinib is a potent, irreversible, EGFR TKI selective for both EGFR sensitising and T790M resistance mutations.
In an international, open-label, phase III trial, 419 patients with centrally confirmed (by cobas® EGFR Mutation Test) EGFR T790M-positive advanced NSCLC whose disease has progressed to first-line EGFR TKI therapy, were randomised 2:1 to osimertinib and pemetrexed plus carboplatin or cisplatin. Maintenance pemetrexed was allowed.
The study's primary endpoint was progression-free survival (PFS) evaluated by investigator assessment according to RECIST v1.1; sensitivity analysis was by blinded independent central review (BICR).
Baseline characteristics were generally balanced across treatment groups.
Median PFS with osimertinib was 10.1 months vs 4.4 months with platinum-pemetrexed, hazard ratio (HR) 0.30 (p < 0.001). The result was consistent with PFS analysis by BICR, HR 0.28 (p<0.001), 11.0 months vs 4.2 months.
Among 144 patients with metastases to the central nervous system (CNS), the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum-pemetrexed (8.5 months vs. 4.2 months; HR, 0.32).
The objective response rate was significantly improved with osimertinib (71%) compared to platinum-pemetrexed treatment (31%); odds ratio 5,39, p < 0.001. The median duration of response was 9.7 months with osimertinib and 4.1 months with platinum-pemetrexed.
The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib than with platinum therapy plus pemetrexed. The most common causally-related adverse events in the osimertinib group were diarrhoea and rash, while nausea and decreased appetite in the platinum-pemetrexed group.
The investigators concluded that in patients with EGFR T790M-positive advanced NSCLC following progression on EGFR-TKI treatment, including those with CNS metastases, osimertinib demonstrated a superior clinically-meaningful efficacy over platinum-pemetrexed, with a 70% reduction in the risk of disease progression, and a well-characterised safety profile, establishing a new standard of care for these patients.
Pooled data from two phase II trials on CNS response to osimertinib in patients with T790M-positive advanced NSCLC will be presented on 7 December 2016 at the same conference.
In November 2015, after a priority review, the US FDA granted accelerated approval to osimertinib for the treatment of metastatic EGFR T790M-positive NSCLC, as detected by an FDA-approved test, which has progressed on or after EGFR TKI therapy. The FDA approval made reference to two clinical trials, in which an EGFR T790M mutation was confirmed by a Cobas EGFR mutation test.
The European Medicines Agency gave a similar approval in February 2016 after two phase II studies (AURA extension and AURA2).
PL03.03 – V. Papadimitrakopoulou, YL Wu, M. Ahn, et al. Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3). Presented at 17th World Conference on Lung Cancer, Vienna, Austria.
Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. NEJM; Published online 6 December, 2016. DOI: 10.1056/NEJMoa1612674