Lung tumours are genetically heterogenous and show mutations in a number of different oncogenes, many of which are kinases. The success of inhibitors of the epidermal growth factor receptor in inhibiting non small cell lung cancers (NSCLC) that exhibit oncogenic EGFR mutations suggests that selective kinase inhibition may be effective in treating tumours with particular mutations.

The anaplastic lymphoma kinase gene (ALK) has been shown to be mutated in many cancers including NSCLC, in which tumour the activating mutation is a fusion of this kinase with the gene EML4. Researchers headed by a group based at the Massachusetts General Hospital Cancer Center have now shown in a Phase I clinical trial* that crizotinib, an orally available ALK inhibitor developed by Pfizer, Inc., can cause tumour shrinkage or stable disease in a subset of NSCLC patients known to exhibit the EML4-ALK fusion mutation.

The researchers screened tumour samples from about 1500 patients with non small cell lung cancer using fluorescence in situ hybridisation, and identified eighty-two EML4-ALK positive patients with stable disease who were also otherwise eligible to enter the clinical trial. These patients were, in general, younger than NSCLC patients without the rearrangement, and were significantly less likely to be smokers; seventy-two (96%) had been diagnosed with adenocarcinomas. Doses were escalated from 50 mg once daily to 300 mg twice daily and the maximum tolerated dose established at 250 mg twice daily; patients continued to receive the drug until their tumours progressed or side effects became intolerable. Patients were evaluated for safety every two weeks during the first two chemotherapy cycles and every four weeks afterwards.

After six months’ treatment, the overall response rate was 57% (47 patients), classified into one full and 46 partial responses. A further 27 patients had stable disease, and almost all the patients with responses or stable disease were continuing to receive the drug. The only side effects reported frequently were mild gastrointestinal disturbances. These positive results indicate that, in NSCLC patients with the EML4-ALK rearrangement, selective inhibitors of this kinase may be more effective than standard chemotherapy and, more generally, that prospective genotyping can be beneficial in selecting cancer patients for treatment regimens or clinical trials.