Alectinib Improves PFS, CNS Responses in Crizotinib-Treated ALK+ NSCLC

April 30, 2018
Dave Levitan

Alectinib offered significantly improved outcomes over standard chemotherapy in patients with ALK-positive non–small-cell lung cancer who had progressed on crizotinib therapy.

Alectinib offered significantly improved outcomes over standard chemotherapy in patients with advanced/metastatic ALK-positive non–small-cell lung cancer (NSCLC) who had progressed on or were intolerant to crizotinib therapy, according to a new randomized trial. Alectinib also yielded more central nervous system (CNS) responses in those with CNS disease.

“Most ALK-positive NSCLC patients who receive first-line crizotinib progress within 1 year, often because of insufficient disease control in the CNS,” wrote study authors led by Jürgen Wolf, MD, of University Hospital Cologne in Germany. Ceritinib is currently approved for those patients, but the agent is associated with significant side effects. “Thus, a high unmet medical need exists for these patients.”

The ALUR trial randomized 107 patients to receive either alectinib (72 patients) or standard chemotherapy (pemetrexed or docetaxel; 35 patients). The trial was conducted in 13 countries in Europe and Asia; results were published in Annals of Oncology.

The median progression-free survival (PFS) was 9.6 months with alectinib, compared with 1.4 months with chemotherapy, for a hazard ratio (HR) of 0.15 (95% CI, 0.08–0.29; P < .001). A multivariate analysis adjusting for baseline factors confirmed the result, with an HR of 0.16 (95% CI, 0.09–0.30; P < .01). The PFS advantage was noted across subgroups divided by age, sex, baseline CNS metastases, prior radiotherapy, and other stratification factors.

At baseline, 71.0% of the full cohort had CNS disease (50 alectinib patients, 26 chemotherapy patients). The CNS response rate was significantly better with alectinib, at 54.2%, compared with 0% in the chemotherapy group (P < .001). The time to CNS progression was longer with alectinib, with a cause-specific HR of 0.14 (95% CI, 0.06–0.36).

Following disease progression, 24 chemotherapy patients (70.6%) crossed over and received alectinib. At the time of data cutoff, the overall survival data remained immature, with an HR of 0.89 (95% CI, 0.35–2.24).

The incidence of all-grade adverse events was similar between the two treatment arms. Adverse events that occurred more frequently with alectinib than with chemotherapy included constipation, dyspnea, and increased blood bilirubin; the adverse events that occurred more commonly with chemotherapy included fatigue, nausea, alopecia, and others. Grade 3 or higher events were reported in 27.1% of alectinib patients and in 41.2% of chemotherapy patients; 5.7% of alectinib patients and 8.8% of chemotherapy patients had an adverse event that led to drug discontinuation.

“Our data support the efficacy and tolerability of alectinib, and demonstrate that alectinib shows clinically relevant superiority to chemotherapy for extra- and intracranial disease in patients who have been pretreated with crizotinib and [chemotherapy],” the authors concluded. “Alectinib has a more favorable therapeutic index than ceritinib, suggesting its preferential use in this setting.”

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