A novel ALK/EGFR (anaplastic lymphoma kinase/epidermal growth factor receptor) inhibitor—AP26113 (ARIAD Pharmaceuticals, Inc.)—achieved good responses in crizotinib-resistant and crizotinib-naive patients with non-small cell lung cancer (NSCLC) as well as radiographic regression of central nervous system (CNS) metastases in these patients. The results of the first-in-human phase 1/2 dose-finding study of AP26113 were presented by D. Ross Camidge, MD, University of Colorado, Denver, at the European Cancer Congress (ESMO/ECCO/ESTRO), held September 27- October 1, 2013, in Amsterdam, the Netherlands.
Half of all ALK-positive patients with NSCLC who develop crizotinib resistance become resistant in the brain, suggesting that crizotinib has inadequate CNS exposure. Systemic progression typically occurs later in the course of disease.
Phase 1 was a 3x3 dose escalation study in 30 to 60 patients with various advanced malignancies. In phase 2, there were 5 cohorts—4 with NSCLC (n = 85 total) and 1 with other cancers amenable to ALK inhibition (n = 20).
The identified dose of 180 mg/day was used in phase 2 initially, but some patients developed pulmonary symptoms at that level, which resolved with steroids over 1 week. The decision was made to use a step-up approach of 90 mg/day for the first week on drug, and then move to 180 mg/day, Camidge said.
Other adverse events included gastrointestinal disturbances, and these were mainly mild. Elevated liver enzymes were reported in 12% of patients. Treatment-emergent grade 3 or higher adverse events were reported in 2% to 4% of patients across all dose levels.
Objective response rate was 65%. Response rate in patients previously treated with crizotinib was 61%; all 3 crizotinib-naive patients responded (100%), 1 with a complete response.
Eight of 10 patients with CNS metastasis had radiographic evidence of regression, and this improvement lasted from 8 to 40 weeks.
Responses were seen in some patients with the T290M mutation who were treated with the drug. Among 12 treated patients with the T790M mutation, 5 had stable disease, 4 had progressive disease, and 3 discontinued the study before receiving treatment.
These data are preliminary. More experience is needed to determine if the drug will be an improvement on crizotinib. At least 2 other second-generation ALK inhibitors are in development, and these drugs also appear to achieve radiographic regression in CNS metastases.