Numerous different tyrosine kinases have been targeted in the treatment of cancer, many with a good deal of success, such as VEGF and EGFR. Another that is proving promising is the ALK (anaplastic lymphoma kinase) fusion gene, and Pfizer’s crizotinib has just received its first FDA approval in locally advanced or metastatic non-small cell lung cancers that express the abnormal form of this gene.1 In addition the drug was found to target another tyrosine kinase, known as Met, which can also be overexpressed in lung cancer. It is also in clinical trials for the treatment of a number of other solid tumours.
Several clinical trials have been reported. For example, in a Phase II trial, about 1,500 patients with NSCLC were screened for abnormalities in the ALK gene, and 82 were identified as potential responders to the drug.2 They were given 250mg oral doses twice a day on 28-day cycles, and nearly all saw some degree of tumour shrinkage. There were 46 confirmed partial responses, and one confirmed complete response, while a further 27 achieved stable disease.
Initial results of another Phase II trial also showed its promise in NSCLC.3 Patients were given 250mg doses of the drug twice a day continuously in three-week cycles. Most had undergone at least two prior chemotherapy regimens, and received a median nine weeks of treatment. Of the 76 patients evaluable for tumour response at this stage of the trial, 63 had target lesion shrinkage, and in 41 of these the shrinkage was greater than 30%. Seven had objective progression, while the most frequent treatment-related adverse events were nausea, vision disorders, vomiting and diarrhoea.
It is also being evaluated in other forms of cancer, and results of a small trial in anaplastic large cell lymphoma were recently announced.4 Four patients with ALK positive ALCL were given 250mg doses twice a day as part of a compassionate use named protocol trial; all were resistant to at least three lines of treatment. No steroids or antineo-plastic drugs were given alongside crizotinib. Three patients achieved a complete response, and the fourth a partial response. Trials continue.
references
1. J.J. Cui et al. J. Med. Chem. 2011, 54, 6342
2. E.L. Kwak et al. N. Engl. J. Med. 2010, 363, 1693
3. L. Crinò et al. J. Clin. Oncol. 2011, 29 (suppl.), Abst. 7514
4. E.M. Pogliani et al. J. Clin. Oncol. 2011, 29 (suppl.), Abst. e18507