Crizotinib--latest champion in the cancer wars?

Three articles in this issue of the Journal report on the therapeutic potential of a new kid on the kinase inhibitor block: crizotinib, an ATP-competitive inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase. Kwak et al.1 summarize a study involving patients with non–small-cell lung cancer who were enrolled in a phase 1 trial, starting in 2008, hot on the heels of a study in which cell lines derived from non–small-cell lung tumors were shown to be sensitive to NVP-TAE6842 and crizotinib (PF-02341066).3,4 From a cohort of 1500 patients with non–small-cell lung cancer, 82 (5.5%) were found to carry an ALK rearrangement on fluorescence in situ hybridization (FISH). The authors note that not all of these genetic rearrangements were confirmed as EML4-ALK,5 which suggests that other ALK fusions may be present, such as TFG-ALK6 and KIF5B-ALK.7 Although the best-studied ALK fusion is the nucleophosmin (NPM)-ALK protein found in lymphoma, it is reasonable to expect that a number of the signaling pathways activated by NPM-ALK will also be involved in transformation by variants such as EML4-ALK (Fig. 1). Most of the patients with non–small-cell lung cancer who carried the EML4-ALK translocation were nonsmokers and had adenocarcinomas. Even though more than 90% of these patients had undergone at least one previous line of therapy, the investigators observed a 57% response rate to crizotinib, according to Response Evaluation Criteria in Solid Tumors (RECIST), with a rate of disease control of 87% at 8 weeks. Although a control group was lacking in this study, these results compare very favorably with the reported 10% response with second-line chemotherapy. At a mean treatment duration of 6.4 months, 27 patients had stable disease, 46 had a partial response, and 1 had a complete response. All patients tested negative for amplification of MET, another target for crizotinib, which suggested that the therapeutic effect is through inhibition of ALK. These results raise the question of whether crizotinib will yield equally strong responses as the first therapeutic intervention or whether a combined approach will be more beneficial. At a rate of approximately 5% positivity for the ALK rearrangement, the number of potential patients for crizotinib therapy is substantial, approaching 10,000 annually in the United States alone. Clearly, with mutant epidermal growth factor receptor (EGFR), K-RAS, and ALK as important clinical determinants in this type of lung cancer, the use of genotyping as standard practice must be considered as a move toward personalized therapy. As with the kinase inhibitors already in use, such as imatinib and EGFR inhibitors, kinase inhibition frequently leads to the appearance of drug-resistance mutations within the target kinase itself. Although Kwak et al. do not address this issue, it is possible that in a number of ALKpositive patients who had a limited response in this study, such mutations may have developed either before or during treatment with crizotinib. This factor is clearly illustrated in a study by Choi et al.,10 who describe mutations in EML4-ALK that confer resistance to crizotinib. Their data support the independent appearance of mutations leading to C1156Y and L1196M coding changes in a patient with non–small-cell lung cancer who had an initial strong clinical response to