Abstract
The ALK inhibitor CH5424802 is well tolerated and active in patients with ALK-rearranged NSCLC.
Major finding: The ALK inhibitor CH5424802 is well tolerated and active in patients with ALK-rearranged NSCLC.
Approach: The safety and activity of CH5424802 were evaluated in a single-arm phase I–II trial.
Impact: CH5424802 may be more effective than crizotinib for patients with ALK-rearranged NSCLC.
Gene fusions involving anaplastic lymphoma kinase (ALK) have been implicated as oncogenic drivers and therapeutic targets in non–small cell lung cancer (NSCLC). Treatment with crizotinib, a small-molecule receptor tyrosine kinase inhibitor that targets ALK, MET, and ROS1 and is approved for use in ALK-rearranged NSCLC, is associated with improved survival; however, resistance often develops, in part via ALK mutations. Seto and colleagues assessed the safety and antitumor activity of CH5424802 (RO5424802), an orally available, highly selective ALK inhibitor that is active against ALK fusions and resistant ALK mutations in vitro, as a potential therapeutic alternative. Patients with advanced ALK-rearranged NSCLC who had not previously been treated with ALK inhibitors were enrolled in a single-arm phase I–II study. In the phase I portion, no dose-limiting toxicities or grade 4 adverse events were detected at any dose, and high plasma drug concentrations were achieved. The primary endpoint of the phase II portion was the proportion of patients who experienced an objective response; among 46 patients treated with the highest tested dose from the phase I trial, the objective response rate was 93.5%, including 41 (89.1%) partial responses, 2 (4.3%) complete responses, and prolonged disease control in patients with brain metastases. Rapid reductions in tumor size of greater than 30% were detected within 3 to 6 weeks, and 87% of patients currently remain on treatment. CH5424802 was well tolerated, as treatment-related side effects were generally minor; grade 3 adverse events occurred in 26% of patients but did not necessitate dose reduction. Although additional studies are necessary to investigate the efficacy of this drug in crizotinib-resistant tumors, these findings show that CH5424802 has potent antitumor activity and suggest that this inhibitor may be more effective than crizotinib in ALK-rearranged NSCLC.
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