The ALK/ROS1 Inhibitor PF-06463922 Has Potency across Resistant ALK Mutants

Anaplastic lymphoma kinase (ALK) is activated in non–small cell lung cancers (NSCLC) by various point mutations or gene fusions and has been clinically targeted by small-molecule inhibitors, including crizotinib and the second-generation ALK inhibitors ceritinib and alectinib. However, many patients with NSCLC who initially respond to these ALK inhibitors relapse and develop brain metastases, often due to the acquisition of secondary resistant ALK mutations and poor brain penetrance of the inhibitors, demonstrating the need to identify more potent ALK inhibitors. Zou, Friboulet, Kodack, and colleagues compared the potency and in vivo efficacy of PF-06463922, a next-generation ATP-competitive, selective ALK/ROS1 inhibitor, to that of crizotinib, ceritinib, and alectinib. In vitro, PF-06463922 was more potent than existing ALK inhibitors against wild-type ALK, clinically relevant resistant ALK mutants, and EML4–ALK mutant fusions, resulting in inhibition of ALK-dependent cell growth and induction of apoptosis. In subcutaneous ALK fusion–driven xenograft models, PF-06463922 induced >95% inhibition of ALK phosphorylation and tumor regression at a relatively low dose. Significantly, PF-06463922 induced the regression of crizotinib-resistant tumors, including those harboring the highly resistant ALK^G1202R mutation. Furthermore, in ALK fusion–driven intracranial tumor models, PF-06463922 exhibited superior potency against brain metastases compared with crizotinib and alectinib, resulting in dose-dependent regression of intracranial tumors and prolonged survival, suggesting that PF-06463922 has enhanced brain penetrance. Finally, PF-06463922 was well tolerated at all doses and had little toxicity in preclinical studies. In summary, these findings suggest that the potent antitumor activity against known clinically acquired ALK mutations, safety profile, and superior central nervous system penetrance of PF-06463922 make it a strong candidate for treating ALK-driven lung cancers as a single agent and possibly in combination with other ALK inhibitors and/or other agents to overcome or prevent relapse.

Zou HY, Friboulet L, Kodack DP, Engstrom LD, Li Q, West M, et al. PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical models. Cancer Cell 2015;28:70–81.

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