Osimertinib for EGFR T790M – Positive Lung Cancer

Advanced non-small cell lung cancer is a major goal for the development of target therapies. At the moment, several therapies have been approved or are in the clinical trials stage. The assessment of their potential benefits is based on the mutation status of genes such as EGFR, ALK, ROS1 and others.

International guidelines advise that the patients with non-small cell lung cancer should be tested for mutations in the EGFR (epidermal growth factor receptor) gene. The percentage of mutant patients in European is about 10-15% according to various sources, and they are considered to be suitable for EGFR tyrosine kinase inhibitor therapies as a first line of the treatment.

Despite the initial strong tumor response, after an average of 9 to 13 months of the beginning of the treatment, the disease began to progress. In about 60% of the cases, a T790M (p.Thr790Met) point mutation in the gene was found and it was associated with resistance to initial therapy with first or second generation tyrosine kinase inhibitors.

Osimertinib is a third generation tyrosine kinase inhibitor, suitable for patients with EGFR mutations, but especially for patients with secondary T790M resistance mutation after target therapy treatment. In Phase I of the AURA clinical trial, a response to osimertinib therapy was observed in 61% of the patients and an average progression-free duration of 9.6 months. Two follow-up studies confirm this data. Based on the results, the US Food and Drug Administration approved the therapy and in early 2016 it was approved also in Europe.

The clinical trials for the therapy are ongoing. In a randomized, Phase III clinical trial, 419 patients with T790M positive advanced non-small cell lung cancer who had progression following first-line treatment with tyrosine kinase inhibitors were enrolled. In a 2:1 ratio they receive either osimertinib or pemetrexed intravenously combined with carboplatin or cisplatin every 3 weeks up to 6 cycles.

The results showed that the progression-free duration of osimertinib was significantly longer than that of platinum therapies (10.1 vs. 4.4 months). For 144 patients with central nervous system metastases, the progression-free survival was also longer for osimertinib-treated patients than for those receiving platinum therapy and pemetrexed – 8.5 versus 4.2 months, respectively. Patients with side effects of level 3 or higher with osimertinib were 23% and platinum and pemetrexed 47%.

The results of this clinical trial indicate that osimertinib has a significantly greater efficacy than platinum therapy combined with pemetrexed in patients with T790M – positive advanced non-small cell lung cancer who have a progression following first-line treatment with tyrosine kinase inhibitors.

References: T.S. Mok, Y.-L. Wu, M.-J. Ahn, M.C. Garassino, H.R. Kim, S.S. Ramalingam, F.A. Shepherd, Y. He, H. Akamatsu, W.S.M.E. Theelen, C.K. Lee, M. Sebastian, A. Templeton, H. Mann, M. Marotti, S. Ghiorghiu, and V.A. Papadimitrakopoulou, for the AURA3 Investigators; Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer; 2016, N Engl J Med 2017;376:629-40. DOI: 10.1056/NEJMoa1612674