Many of the anticancer agents currently being developed are designed to have activity in tumour cells with specific mutations. One such drug is AstraZeneca’s osimertinib, which has recently been given accelerated approval in the US for non-small cell lung cancers that have the epidermal growth factor receptor, or EGFR, T790M mutation.1 The approval was given just over two and a half years after clinical trials began.
EGFR is a Type I receptor tyrosine kinase, and is involved in the modulation of cell differentiation. When it is overexpressed in cancer cells, this can increase its propensity to metastasise. Cancer cells can develop resistance to the first generation EGFR tyrosine kinase inhibitors within a year, and the T790M mutation – a threonine residue at position 790 replaced by methionine – is found in tumour cells isolated from at least half of these patients. Osimertinib has high potency and inhibitory activity against mutant EGFR phosphorylation in vitro. In addition, it has much lower activity in cell lines without this mutation.
In a proof of principle study, two patients with advanced NSCLC and this mutation showed benefit.2
The pivotal trial that led to its early approval was carried out in 253 patients with advanced EGFR inhibitor resistant NSCLC, who had radiologically confirmed disease progression after therapy with EGFR tyrosine kinase inhibitors.3 Subjects were given doses of 20 to 240mg of osimertinib once a day, 31 of them in dose escalation cohorts, and the remainder in five dose expansion cohorts. The overall objective tumour response rate was 51%, and of those 127 patients whose tumours had been shown to have developed the T790M mutation and were evaluable for response, the response rate was 61%. In a further evaluable 61 patients who did not have centrally detectable EGFR T790M, the response rate was substantially lower at 21%. The median progression-free survival was 9.6 months in those with the mutation, and 2.8 months for those without.
A randomised Phase III study comparing its activity with gefitinib or erlotinib in treatment-naïve patients with advanced NSCLC and the T790M mutation is underway.4
The drug also shows potential in combination with other targeted anticancer therapies. Preliminary results of a multi-arm Phase Ib trial have been reported, where the drug was given in combination with various other developmental agents from the AZ portfolio – the anti PD-L1 monoclonal antibody MEDI4736, the MET inhibitor AZD6094, or the MEK1/2 inhibitor selumetinib.5 Subjects with EGFR mutant lung cancer were given 80mg daily doses of osimertinib, and the second agent escalated from the dose below that being given as monotherapy in Phase II trials. At the point when preliminary data on 42 patients was reported, three partial responses had been observed with the MED4736 combination, two with the AZD6094 combination, and a further two in the selumetinib combination group.
References
1. M.R. Finlay et al. J. Med. Chem. 2014, 57, 8249
2. D.A. Cross et al. Caner Discov. 2014, 4, 1046
3. P.A. Jänne et al. N. Engl. J. Med. 2015, 372, 1689
4. S.S. Ramalingam et al. J. Clin. Oncol. 2015, 33 (suppl.), Abst. TPS 8102
5. P.A. Jänne et al. J. Clin Oncol. 2014, 32 (suppl.), Abst. 8009
