First-Line Alectinib Tops Crizotinib in ALK-Positive NSCLC

Alectinib yielded significantly prolonged progression-free survival compared with crizotinib in ALK-positive non–small-cell lung cancer (NSCLC) patients, according to results of the Japanese open-label phase III J-ALEX trial (abstract 9007). The results were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago.

“ALK gene rearrangements occur in approximately 4% to 5% of all Caucasian and Asian patients with advanced NSCLC,” said Hiroshi Nokihara, MD, PhD, of the National Cancer Center in Tokyo, who presented the study. “Alectinib is a potent, highly selective, CNS-active ALK inhibitor” with activity against ALK resistance mutations. Previous work has shown that alectinib has early and potent efficacy in ALK inhibitor-naive patient.

The study included 207 patients at 41 centers in Japan; patients were randomized to either alectinib 300 mg twice daily (103 patients) or to crizotinib 250 mg twice daily (104 patients), and treatment continued until disease progression or unacceptable toxicity. All patients had stage IIIB/IV or recurrent ALK-positive NSCLC.

After a planned interim analysis, the trial was stopped for efficacy, as an improvement in progression-free survival was already demonstrated. In the alectinib patients, the median progression-free survival was not reached, compared with 10.2 months in the crizotinib patients, yielding a hazard ratio of 0.34 (99.6826% CI, 0.17–0.71; P < .0001).

The investigator-assessed objective response rate was 85.4% with alectinib and 70.2% with crizotinib. A subgroup analysis showed alectinib offered better progression-free survival in all groups.

The only adverse event with a frequency above 30% in the alectinib patients was constipation, in 35% of patients. In the crizotinib patients, 74% had nausea, 73.1% had diarrhea, 57.7% had vomiting, 54.8% had visual disturbance, along with several other frequent adverse events. Grade 3 and 4 adverse events also occurred more frequently with crizotinib (51.9%) than with alectinib (26.2%), and there were no treatment-related deaths in either group. In the crizotinib group, 20.2% of patients discontinued the study drug due to adverse events, compared with 8.7% of alectinib patients.

“Based on these results, we believe alectinib is a new standard first-line therapy for ALK-positive NSCLC,” Nokihara said.

The discussant for the session, Shirish M. Gadgeel, MD, of the Karmanos Cancer Institute at Wayne State University in Detroit, said “J-ALEX suggests that a more potent ALK inhibitor can lead to greater clinical benefit.” He asked if a higher alectinib dose, or perhaps a different agent, could offer even greater inhibition and thus greater benefit. He also noted that alectinib carries substantial cost, at $12,500 for a single month of treatment.