Amsterdam, The Netherlands—The novel ALK/EGFR inhibitor known as AP26113 achieved good responses in reducing brain metastases in patients with crizotinib (Xalkori)-resistant and crizotinib-nave non–small-cell lung cancer (NSCLC), as well as radiographic regression of central nervous system (CNS) metastases. These results of the first-in-human phase 1/2 dose-finding study of AP26113 were presented at the 2013 European Cancer Congress by David R. Camidge, MD, PhD, Director, Thoracic Oncology Clinical Program, University of Colorado Denver, Aurora.
“ALK-positive NSCLC came to prominence because of the marked activity of crizotinib. However, most, if not all, patients will become resistant to crizotinib,” Dr Camidge said.
Of the patients with ALK-positive NSCLC who develop crizotinib resistance, 50% showed resistance in the brain, suggesting that crizotinib has an inadequate CNS exposure: systemic disease progression typically occurs later in the course of the disease.
The phase 1 study was a 3 × 3 dose-escalation study that included up to 60 patients with different types of advanced malignancies.
The phase 2 study had 5 cohorts—4 groups with NSCLC (N = 85 total) and 1 group with other ALK-positive cancers (N = 20).
The identified dose of 180 mg daily was initially used in the phase 2 study, but some patients developed pulmonary symptoms at that level, which resolved with steroids that were tapered over 1 week.
Because of the pulmonary symptoms with the higher dose, a step-up approach will be used in future studies, starting with 90 mg daily for the first week, moving to 180 mg daily, Dr Camidge said.
Other adverse events included gastrointestinal disturbances, which were mainly mild; 12% of the patients had elevated liver enzymes. Treatment-emergent grade ≥3 adverse events were reported in 2% to 4% of the patients across all dose levels.
The objective response rate (ORR) was 65%. The ORR rate was 61% in patients previously treated with crizotinib and 100% in all 4 crizotinib-naïve patients (1 had a complete response).
Of the 10 patients with CNS metastases, 8 had radiographic evidence of regression, which lasted from 8 to 40 weeks.
Responses were seen in some patients whose tumors expressed the T290M mutation. Among 12 patients with the T790M mutation, 5 had stable disease, 4 had progressive disease, and 3 discontinued the study before going on treatment.
These data are preliminary, Dr Camidge emphasized, noting that of the patients in this study, “80% remain on therapy after 6 months, and we see marked responses in CNS metastases.” More experience is needed to determine if this novel ALK inhibitor will be an improvement on crizotinib. At least 2 other second-generation ALK inhibitors are in development, and these drugs also show radiographic regression in CNS metastases.
