Another kinase target that has gained a lot of attention is ALK, or anaplastic lymphoma kinase
Another kinase target that has gained a lot of attention is ALK, or anaplastic lymphoma kinase. The genetic mutation that expresses the rearranged form of gene is particularly common in non-smokers who develop non small cell lung cancer. While NSCLC is the most common lung cancer type, accounting for up to 90% of all lung cancers, only somewhere between 2 and 7% of these are thought to have the ALK gene rearrangements that enhances cancer cell growth.
One drug that works at this target, Pfizer’s crizotinib, is already on the market for the treatment of NSCLC. However, cancers with this gene have a habit of developing resistance to crizotinib via further mutations. Another ALK inhibitor, ceritinib, is being developed by Novartis. Preclinical studies indicated that it may be able to overcome four out of six identified crizotinib resistance mutations, and it also showed a higher antitumour potency in vitro.1 Unlike crizotinib, however, ceritinib does not hit another common kinase anticancer target, Met.
Extremely promising early results have already been achieved in NSCLC patients. In a Phase I trial in 59 patients with advanced NSCLC with genetic alterations to ALK were given ceritinib in doses of 50mg to 750mg once a day in an escalation phase.2 They then continued at the maximum tolerated dose. Toxic events that limited the amount of drug that could be tolerated included vomiting, diarrhoea, dehydration, hypophosphataemia and elevated aminotransferase levels.
Subsequently, a further 71 patients were added to the trial in an expansion phase, at the established maximum tolerated dose of 750mg. The overall response rate for those who received at least 400mg doses of the drug was 58%, and of the 80 patients who had previously been treated with crizotinib, the response rate was almost as good, at 56%. Responses were seen in patients with a variety of different resistance mutations in ALK, and also in those with no detectable mutations. The median progression-free survival for those receiving at least 400mg doses was seven months.
Phase II trials are now under way to further establish its safety and efficacy. In one of these, an open label, single arm study, patients who had received between one and three lines of cytotoxic chemotherapy, including a platinum therapy, and had progressed on crizotinib as their most recent therapy, are being given 750mg daily doses of the drug.3 Two Phase III trials have also been initiated, also in patients with ALK+ NSCLC.
1. L. Friboulet et al. Cancer Discov. 2014, Mar 27, e-pub ahead of print
2. A.T. Shaw et al. N. Engl. J. Med. 2014, 370, 1189
3. A.T. Shaw et al. J. Clin. Oncol. 2013, 31 (suppl.), Abst. TPS 8119