Identifying ALK rearrangements as a cancer target in patients with lung cancer led to the development and FDA approval of crizotinib (Xalkori) to treat ALK-positive non–small cell lung cancer (NSCLC). Several second-generation ALK inhibitors are in development, and these agents appear to work in ALK-positive NSCLC, including brain metastasis.

At the recent European Cancer Congress, a study was presented showing that a novel ALK/EGFR inhibitor called AP26113 had robust antitumor activity in crizotinib-resistant and crizotinib-naive NSCLC patients, including those with brain metastasis after crizotinib treatment.

“Most if not all patients with NSCLC will become resistant to crizotinib, and half of those who are resistant have brain metastasis,” explained lead author D. Ross Camidge, MD, PhD, Associate Professor and Director of the Thoracic Oncology Clinical Program at University of Colorado, Denver.

Study Details

The first-in-human phase I/II trial of AP26113 was a 3×3 dose escalation study in 30 to 60 patients with various advanced malignancies refractory to other therapies or with no available standard or curative therapy. There were five cohorts in phase II—four with NSCLC totaling 85 patients and another cohort of 20 patients with other ALK-positive tumors. In phase I, a range of 30 to 300 mg/d was explored, and the dose of 180 mg/d orally was selected for further study.

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, which occurred early in 3/25 patients at the 180-mg/d level and seemed to be rarer at lower doses, were responsive to drug interruption, although resolution, despite continued dosing, was also reported. 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.

Tapered dose steroids were used to resolve symptoms over 1 week, and patients restarted the drug at 90 mg/d without further pulmonary symptoms, he said. 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.

Marked Response

Response was determined by serial computed tomography scans using RECIST criteria. An objective response was observed in 22 (65%) of 34 ALK-positive NSCLC patients. The response rate in patients previously treated with crizotinib was 61%; all three crizotinib-naive patients responded (100%), one with a complete response.

Eight of 10 patients (80%) with preexisting CNS metastasis had radiographic evidence of regression, and ongoing improvements lasting more than 40 weeks were reported.

In vitro, at 30- to 50-fold higher concentrations than those required to hit ALK, the drug also hits common activating and resistance mutations in EGFR. Of 12 patients with the T790M EGFR mutation who were evaluable for response, 5 had stable disease, 4 had progressive disease, and 3 discontinued the study before going on treatment.

“The data are immature,” Dr. Camidge acknowledged, “but 80% remain on therapy after 6 months, and we see a marked response in CNS metastases. The updated results of this ongoing phase I/II study show that AP26113 continues to exhibit antitumor activity in crizotinib-naive and crizotinib-resistant NSCLC and is active in ALK-positive brain metastasis, demonstrating responses of clinically meaningful duration.” ■

Disclosure: Dr. Camdige reported no potential conflicts of interest.

Reference

1. Camidge DR, Bazhenova L, Salgia R, et al: 2013 European Cancer Congress. Abstract 3401. Presented September 28, 2013.