Patients with non–small cell lung cancer (NSCLC) whose tumors have the ALK gene rearrangement usually respond to the drug crizotinib (Xalkori), with a median duration of response of approximately 10 months. In a study reported by Shirish Gadgeel, MD, of Karmanos Cancer Institute in Detroit, and colleagues at the International Association for the Study of Lung Cancer’s 15th World Conference on Lung Cancer, alectinib showed promising tumor activity in patients with ALK-positive NSCLC who were refractory to crizotinib. Alectinib is a potent ALK inhibitor recently granted Breakthrough Therapy designation by the FDA.1
Phase I Study
In a phase I dose-escalation study, alectinib was administered to 37 patients with ALK-positive NSCLC that had progressed on crizotinib and chemotherapy. The primary endpoint was dose-limiting toxicity, with secondary endpoints of efficacy, safety, and pharmacokinetic analyses. The ALK inhibitor was administered orally at doses ranging from 300 to 900 mg twice-daily until lack of clinical benefits.
Researchers found promising tumor activity with alectinib. In the 37 patients who received a therapeutic dose (≥ 460 mg twice daily), alectinib demonstrated an overall response rate of 59.5%. Median progression-free survival had not been reached after over 5 months of follow-up. No dose-limiting toxicities were observed up to the highest dose tested (900 mg twice-daily), and only one patient required dose modification due to grade 2 fatigue.
Effect on Brain Metastases
In addition, alectinib showed significant shrinkage of brain metastases,2 with only 4 of the 21 patients who were enrolled with preexisting brain metastases having discontinued treatment due to disease progression. Activity against brain metastases was observed as early as the third week of treatment, and the investigators noted that alectinib could “potentially replace or delay the need of brain radiation in ALK-positive NSCLC patients.” ■
Disclosure: Dr. Gadgeel reported no potential conflicts of interest.
1. Gadgeel S, Ou SH, Chiappori A, et al: A phase I dose escalation study of a new ALK inhibitor, CH542480202, in ALK+ non-small cell lung cancer patients who have failed crizotinib. Abstract O16.06. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.
2. Ou SH, Gadgeel S, Chiappori AA, et al: Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer patients in an ongoing phase I/II study. Abstract O16.07. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.