Novel Selective ALK Inhibitor Demonstrates Good Activity in Advanced NSCLC
Crizotinib (Xalkori), a multitargeted receptor tyrosine kinase inhibitor, is the only agent currently available for treating ALK-rearranged non–small cell lung cancer (NSCLC). CH5424802 is a novel selective oral ALK inhibitor with activity in tumor cell lines harboring ALK alterations, including those with mutations associated with resistance to crizotinib. As reported in Lancet Oncology, a Japanese phase I-II study (AF-100JP) conducted by Takashi Seto, MD, and colleagues showed a high response rate with CH5424802 in ALK inhibitor–naive patients with ALK-rearranged NSCLC.
Study Details
Eligible patients had histologically or cytologically confirmed advanced or metastatic ALK-rearranged stage IIIB, IV, or recurrent NSCLC and ECOG performance status of 0 or 1. Patients had to have received two or more previous chemotherapy regimens for the phase I portion of the study and one or more for the phase II portion.
In the phase I portion, 24 patients received escalated doses of CH5424802 from 20 mg to 300 mg in 21-day cycles, with all patients completing at least two cycles of treatment. No dose-limiting toxicities or adverse events of grade 4 were observed up to the 300 mg twice daily dose, with this dose subsequently being tested in the phase II portion of the study.
High Response Rate
In the phase II portion of the study, 46 patients received 300 mg twice daily in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. Of the 46 patients, 43 (93.5%) had objective response (two with complete response) and 1 (2.2%) had stable disease on independent review committee assessment. No patients had progressive disease, with two having unknown response due to early withdrawal from the study. All patients had a reduction in tumor size of more than 30%. Response to treatment was rapid, with partial response being achieved by 65% of patients within 3 weeks (first cycle) and by 87% patients within 6 weeks (second cycle). The study is ongoing, with 40 patients (87%) remaining on treatment as of the data cutoff. The median treatment duration as of the data cutoff was greater than 7 months (range 1-11 months) with a median follow-up of 7.6 months.
Adverse Events
The most common treatment-related adverse events were dysgeusia (30%), increased AST (28%), increased bilirubin (28%), increased blood creatinine (26%), rash (26%), constipation (24%), and increased ALT (22%). Treatment-related grade 3 adverse events consisted of decreased neutrophil count in 4% of patients, increased blood creatine phosphokinase in 4%, increased bilirubin in 2%, rash in 2%, and increased ALT in 2%; there were no grade 4 adverse events. According to the investigators, rash was clinically unlike that seen with epidermal growth factor receptor tyrosine kinase inhibitors.
Serious adverse events occurred in five patients (11%), consisting of brain edema, radius fracture, tumor hemorrhage, sclerosing cholangitis, and allergic alveolitis. Four patients (9%) discontinued treatment due to brain edema, tumor hemorrhage, interstitial lung disease, and sclerosing cholangitis, all of which were considered treatment-related except for brain edema. Overall, 22 patients (48%) had treatment interrupted due to adverse events, with none requiring dose reduction.
The investigators concluded, “Based on the results of the present study, CH5424802 could be an effective and safe option for the treatment of ALK-rearranged NSCLC. Further studies to confirm the efficacy of the drug and to assess its activity in patients resistant to crizotinib are ongoing.”
Chugai Pharmaceutical Co, Ltd, provided funding for the study.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
