Success for Crizotinib in ALK-Driven Cancer

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NEWS & ANALYSIS BIOBUSINESS BRIEFS TRIAL WATCH Success for crizotinib in ALK-driven cancer Data from an open-label Phase I trial of says. Indeed, a third publication by Butrynski crizotinib (PF-02341066), a small-molecule and colleagues reports a sustained partial inhibitor of the tyrosine kinases ALK response with crizotinib in a patient with and MET, have shown disease control inflammatory myofibroblastic tumour with rates of ~90% in patients with non-small an ALK translocation, indicating that ALK cell lung cancer (NSCLC) with oncogenic rearrangements define a molecular subgroup EML4–ALK gene rearrangements. of tumours that is susceptible to targeted As reported by Kwak and colleagues kinase inhibition (N. Engl. J. Med. 363, (N. Engl. J. Med. 363, 1693–1703; 2010), 1727–1733; 2010). 57% out of 82 mostly heavily pretreated The trial of crizotinib in NSCLC patients enrolled in the study had partial also illustrates how prospective tumour responses, including one complete response, genotyping can streamline drug development. and 33% had stable disease. “This is far The first reports of ALK inhibition better than the traditional response rates shrinking tumours in a targeted population of ~10% with conventional chemothera- of patients was made only 2 years after peutics,” says Hiroyuki Mano, a professor the first description of the EML4–ALK at the Graduate School of Medicine, rearrangement, and a Phase III trial has now University of Tokyo, Japan. “Also, considering started enrolment, only 2 years after the the relatively wide target-specificity of initiation of the Phase I trial. This contrasts crizotinib, the side effects of the compound with ~10 years from initially unsuccessful [mainly gastrointestinal] were mild and trials of epidermal growth factor receptor tolerable.” (EGFR) inhibitors in non-genotyped patients Oncogenic fusion genes consisting of with NSCLC to a randomized Phase III trial EML4 and ALK occur in ~3–5% of patients that showed the effectiveness of the EGFR with NSCLC, explains Mano, who is the inhibitor gefitinib (Iressa; AstraZeneca) in lead author of a second paper published patients with specific EGFR mutations. concomitantly that describes the first “Overall, these studies provide further resistance mutations to crizotinib proof that targeting essential tumour growth (N. Engl. J. Med. 363, 1734–1729; 2010). drivers results in marked efficacy,” notes Mano. In addition, ALK also directly participates in He speculates that ALK inhibitors might prove carcinogenesis through the fusion to NPM in to be the “imatinib of solid tumours”, referring anaplastic large cell lymphoma, and to TPM3 to the spectacular results achieved with (or TPM4) in inflammatory myofibroblastic imatinib (Gleevec; Novartis) in cancers tumours. Moreover, point mutations in ALK driven by the mutant BCR–ABL kinase. are likely to have a role in the pathogenesis With two resistance mutations in the kinase of neuroblastoma in children. “So, crizotinib domain of EML4–ALK already mapped, work and other ALK inhibitors should have on second-generation ALK inhibitors can substantial efficacy in such tumours,” he begin. 908 | DECEMBER 2010 | VOLUME 9 www.nature.com/reviews/drugdisc © 2010 Macmillan Publishers Limited. All rights reserved.

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