Novel ALK-Inhibitor Active in NSCLC with Brain Metastasis

The novel targeted agent AP26113 shows strong anti-tumor activity in Xalkori® (crizotinib)-resistant and Xalkori-naïve patients with non-small cell lung cancer, including those with brain metastasis after treatment with Xalkori.

Lung cancer is the leading cause of cancer death in the U.S. and around the world, highlighting the importance of developing effective new approaches to treatment. Up to 7 percent of non-small cell lung cancers (NSCLC) have an abnormal version of the anaplastic lymphoma kinase (ALK) gene. Lung cancers with this abnormality typically occur in non-smokers. The abnormal gene contributes to the growth and development of cancer cells. Xalkori is another ALK-inhibitor used to treat NSCLC, but most patients will become resistant to it.

AP26113 is a novel targeted agent known as a tyrosine kinase inhibitor. It potently inhibits mutant activated forms of anaplastic lymphoma kinase (ALK+) and epidermal growth factor receptor (EGFRm), but does not inhibit native EGFR.

Researchers conducted a phase 1/2 open-label, multi-center study of AP26113—a 3×3 dose escalation study. Phase I explored a range of 30 to 300 mg/d and the dose of 180 mg/d orally was selected for further study. Phase II included five cohorts—four with NSCLC totaling 85 patients and another cohort of 20 patients with other ALK-positive tumors.

AP26113 was generally well tolerated. Common adverse events of all grades were nausea (38%), fatigue (34%), and diarrhea (32%); 12% had elevated liver enzymes. Treatment-emergent grade 3 or higher adverse events were reported in 2% to 4% across all dose levels, and included dyspnea, fatigue, diarrhea, hypoxia, and pneumonitis. Pulmonary events occurred early in 3/25 patients at the 180-mg/d level, but seemed to be rarer at lower doses. These events were responsive to drug interruption, some patients experienced resolution with continued dosing. Future studies will employ a step-up approach, initiating the drug at 90 mg/d for 7 days before moving up to 180 mg/d.

An objective response was observed in 22 (65%) of 34 ALK-positive NSCLC patients. The response rate in patients previously treated with Xalkori was 61%; all three Xalkori-naive patients responded (100%), one with a complete response. Eight of 10 patients (80%) with preexisting brain metastasis had radiographic evidence of regression, and ongoing improvements lasting more than 40 weeks were reported.

The researchers note that the data is immature, but 80 percent of patients remain on therapy after six months and there is a marked response in brain metastases.

The researchers concluded that AP26113 continues to exhibit antitumor activity in Xalkori-naive and Xalkori-resistant NSCLC and is active in ALK-positive brain metastasis, demonstrating responses of clinically meaningful duration.


Camidge DR, Bazhenova L, Salgia R, et al. Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies. 2013 European Cancer Congress. Abstract 3401.

Copyright © 2018 CancerConnect. All Rights Reserved.