The ALK inhibitor alectinib was highly active and well-tolerated in patients with ALK-rearranged, crizotinib-refractory, advanced non–small-cell lung cancer.
The ALK inhibitor alectinib was highly active and well-tolerated in patients with ALK-rearranged, crizotinib-refractory, advanced non–small-cell lung cancer (NSCLC), according to results of a phase II trial.
In this trial, 138 patients with crizotinib-refractory ALK-positive NSCLC were treated with alectinib; 122 of these patients were evaluable for response, and 61% had central nervous system (CNS) metastases at baseline. The results were published in the Journal of Clinical Oncology.
“Almost all patients invariably experience progression on crizotinib, and approximately 40% of the patients with ALK-rearranged NSCLC develop CNS metastases as an initial site of progression,” wrote study authors led by Sai-Hong Ignatius Ou, MD, PhD, of the Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine in Orange, California. Alectinib is approximately five times as potent an ALK inhibitor as crizotinib, and can inhibit most of the acquired ALK resistance mutations to crizotinib.
The objective response rate (ORR) was 50%, which met the primary endpoint of the study, and the median duration of response was 11.2 months. Among only those patients who had previously been treated with chemotherapy (96 patients; 79%), the ORR was lower, at 45%. The disease control rate in the full cohort was 79%, and 77% in the prior chemotherapy group.
Among only the 26 chemotherapy-naÃ¯ve patients deemed response-evaluable, the ORR was 69%. At the time of data cutoff, 67% of responses were ongoing.
The median progression-free survival (PFS) in the study was 8.9 months. The chemotherapy-naÃ¯ve patients again fared better, with a median PFS of 13.0 months. Twenty-four of the 138 patients had died at the point of data cutoff.
Among the 61 patients with CNS metastases at baseline, most (64%) received CNS radiation more than 6 months before starting alectinib therapy. Of the 35 patients with measurable CNS lesions at baseline, the CNS ORR was 57%; 7 of those patients had a CNS complete response.
Alectinib was generally well-tolerated, with a low incidence of grade 3 and 4 adverse events (AEs). The most common treatment-related AEs were constipation (33%), fatigue (26%), and peripheral edema (25%). A total of 29 patients (21%) had a dose reduction and/or interruption, usually because of laboratory abnormalities. The mean duration of treatment interruption was 10 days. Four patients died as a result of AEs, though only one of those was considered possibly related to alectinib.
“The development of resistance to crizotinib is a major barrier to the successful long-term treatment of patients with ALK-rearranged NSCLC,” the authors wrote. They noted that alectinib is currently being studied in a randomized trial comparing it with crizotinib in treatment-naÃ¯ve patients. “The clinically meaningful ORR and duration of response in patients with crizotinib-resistant disease and the sustained CNS response reported from this study, as well as the good tolerability profile, support the additional development of this promising new ALK inhibitor.”