NEW ALK INHIBITORS FOR CRIZOTINIB RESISTANT NSCLC

In the phase I portion of a phase I/II study reported in The Lancet Oncology, Gadgeel et al found that the novel ALK inhibitor alectinib showed activity against systemic disease and brain metastases in patients with non–small cell lung cancer (NSCLC) resistant to the ALK inhibitor crizotinib (Xalkori). Alectinib exhibits in vitro activity against both wild-type and mutated ALK, including mutations that confer resistance to crizotinib. An alectinib dose of 600 mg twice daily has been moved forward to phase II testing.

Study Details

In the study, 47 patients with ALK-mutant NSCLC who progressed on (n = 46) or were intolerant of (n = 1) crizotinib received oral alectinib 300 mg to 900 mg twice daily during the dose-escalation phase. Central nervous system (CNS) metastases were present at baseline in 21 patients. Seventy percent of all patients and 72% of those with CNS metastases had received at least two prior lines of chemotherapy.

Response Rates

At a median follow-up of 126 days, 44 patients were evaluable for activity. Objective response was observed in 24 patients (55%), with confirmed complete response in 1 (2%), confirmed partial response in 14 (32%), and unconfirmed partial response in 9 (20%); 16 patients (36%) had stable disease and 4 (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had objective response, including 6 (29%) with complete response (3 confirmed) and 5 (24%) with partial response (4 confirmed); 8 (38%) had stable disease and 2 (10%) had progressive disease.

Toxicity

The most common adverse events of any grade were fatigue (30%, all grade 1 or 2), myalgia (17%, all grade 1 or 2), and peripheral edema (15% grade 1 or 2, 2% grade 3). Dose-limiting toxicities occurred in two patients at the 900-mg dose, consisting of grade 3 headache in one and grade 3 neutropenia in one. The most common grade 3 or 4 adverse events were increased gamma-glutamyl transpeptidase (4%), neutropenia (4%), and hypophosphatemia (4%). Grade 4 serious adverse events occurred in 3 patients (6%), consisting of acute renal failure, pleural effusion, and pericardial effusion, and brain metastasis; none were considered related to alectinib treatment.

The investigators concluded: “Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2.”

Sai-Hong Ignatius Ou, MD, of University of California Irvine School of Medicine, is the corresponding author for The Lancet Oncology article.

The study was funded by Chugai Pharmaceuticals and F Hoffmann La-Roche. For full disclosures of the study authors, visit www.thelancet.com.