Novel ALK Inhibitor Shows Promise Against Brain Metastasis in NSCLC

Bonnie Gillis
Published Online: Monday, September 30, 2013
D. Ross Camidge, MD, PhD, associate professor and director of the Thoracic Oncology Clinical Program at the University of Colorado, Denver

D. Ross Camidge, MD, PhD

The first-in-human phase I/II dose-finding study of a novel ALK/EGFR inhibitor called AP26113 (Ariad Pharmaceuticals) demonstrated promising results in both crizotinib-resistant and crizotinib-naïve patients with non-small cell lung cancer (NSCLC). Notably, AP26113 was effective in reducing brain metastases.
 
The data were presented during the 2013 European Cancer Congress, held September 27 through October 1 in Amsterdam, the Netherlands.   
 
“ALK-positive NSCLC came to prominence because of the marked activity of crizotinib [the first ALK inhibitor to be FDA-approved for ALK-positive NSCLC]. However, most if not all patients will become resistant to crizotinib,” explained lead author D. Ross Camidge, MD, PhD, associate professor and director of the Thoracic Oncology Clinical Program at the University of Colorado, Denver.
 
Half of all patients who develop resistance become resistant in the brain, he continued, suggesting inadequate central nervous system (CNS) exposure. Systemic progression is usually a later event, mediated through diverse mechanisms.
 
The phase I study was a 3+3 dose escalation study in 30-60 patients with various advanced malignancies—with the exception of leukemia—who were refractory to standard treatment, or for whom no standard treatment existed. For phase II, there were five cohorts: four with NSCLC who had ALK gene arrangement or mutated EGFR (n=85 total) and one with other cancers amenable to ALK inhibition (n=20).
 
In phase I, the dose of 180 mg/day was selected for use in phase II. The range of dosing explored was 30-300 mg/day, with most patients ending up on 180 mg/day, Camidge said.
 
Adverse events included gastrointestinal disturbances, mainly mild. Twelve percent of participants experienced elevation of liver enzymes. Treatment-emergent grade 3 or higher adverse events were reported in 2%-4% of patients across all dose levels. Pulmonary adverse events were seen in 3/25 patients at the 180 mg/day level. These events were characterized by shortness of breath, oxygen desaturation, chest tightness, and fever, and were reversible and responsive to drug interruption. Tapered-dose steroids were used to resolve symptoms over one week, and patients restarted the drug at 90 mg/day without further pulmonary symptoms, Camidge said.
 
In the future, a step-up approach will be pursued, with patients receiving 90 mg/day for seven days before moving up to 180 mg.
 
The objective response rate (ORR) to the drug was 65%. The response rate in patients previously treated with crizotinib was 61%; all three crizotinib-naïve patients responded (100%), one 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.
 
Twelve patients with the T790M mutation were treated; five had stable disease, four had progressive disease, and three discontinued the study before going on treatment.
 
“The data are immature,” Camidge acknowledged, “but 80% remain on therapy after six months, and we see a marked response in CNS metastases.”
 
Formal discussant of this trial, Frances Shepherd, MD, FRCPC, professor of Medicine at the University of Toronto School of Medicine and senior staff physician at Princess Margaret Hospital in Toronto, Canada, said that the response in brain metastasis is an attractive feature of AP26113.
 
She said that two other second-generation ALK inhibitors are in development: LDK378 (Novartis) and ASP3026 (Astellas Pharma), and that both have sparked responses in brain metastasis.
Going forward, the question will be how to incorporate such drugs into practice and their potential uses sequentially, in combination with other drugs, and with chemotherapy.


Camidge DR, Bazhenova L, Salgia R, et al. Update results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies. Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 3401.

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