December 2013, Vol 2, No 8
Second-Generation ALK Inhibitor Regresses CNS Metastasis in NSCLC
A novel ALK/EGFR inhibitor – AP26113 (ARIAD Pharmaceuticals) – achieved good responses in crizotinib-resistant and crizotinib-naive patients with non–small cell lung cancer (NSCLC) and achieved radiographic regression of central nervous system (CNS) metastases in these patients. These results from the first-in-human phase 1/2 dose-finding study of AP26113 were presented by D. Ross Camidge, MD, PhD, University of Colorado, Denver.
Half of all ALK-positive NSCLC patients 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 3×3 dose-escalation study in 30 to 60 patients with various advanced malignancies. Phase 2 had 5 cohorts – 4 with NSCLC (n=85 total) and 1 with other ALK-positive cancers (n=20).
The identified dose of 180 mg/day was used in phase 2 initially, but some patients developed pulmonary symptoms at that level; symptoms resolved with steroids tapered over 1 week. Because of the pulmonary symptoms on the higher dose, a step-up approach will be used in future studies, starting with 90 mg/day for the first week on drug, and then moving to 180 mg/day, Camidge said.
Other adverse events included mostly mild gastrointestinal disturbances. Elevated liver enzymes were noted in 12% of patients. Treatment-emergent grade 3 or higher adverse events were reported in 2% to 4% of 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-naive patients (1 had a complete response).
Eight of 10 patients with CNS metastasis had radiographic evidence of regression lasting from 8 to 40 weeks.
Responses were seen in some patients whose tumors expressed the T790M 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, Camidge emphasized. More experience is needed to determine if the new ALK inhibitor 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.
For the first time, a therapy – the antibody MPDL3280A (Genentech) – for non–small cell lung cancer (NSCLC) has achieved responses in both smokers and nonsmokers, including responses in tumors with squamous and adenocarcinoma histology. These results of a phase 1 study in patients with metastatic NSCLC were so encouraging [ Read More ]
Targeted therapy to the B-cell receptor (BCR) signaling is paying off in chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Two novel agents – the PI3K inhibitor idelalisib and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib – show great promise for these malignancies. These drugs have been studied in phase [ Read More ]