New data from an interim analysis of the head-to-head, open-label, phase 3, Japanese study J-ALEX show that alectinib (Alecensa) significantly improved progression-free survival (PFS) compared with crizotinib (Xalkori) in the frontline setting, said Hiroshi Nokihara, MD, PhD, of the National Cancer Center Hospital, Tokyo, Japan.
“Based on these results, we believe that alectinib is the new standard first-line therapy for ALK-positive NSCLC,” Dr Nokihara said at ASCO 2016.
Alectinib, an oral anaplastic lymphoma kinase (ALK) inhibitor, was approved in December 2015 for advanced, ALK-positive non–small-cell lung cancer (NSCLC) that progressed after crizotinib therapy.
Overall, 207 Japanese patients with advanced or recurrent NSCLC and ALK mutation who had never received an ALK inhibitor were randomized to alectinib 300 mg twice daily or to crizotinib 250 mg twice daily, with a follow-up of 12 months in the alectinib group and 12.2 months in the crizotinib group. Treatment continued until disease progression or unacceptable toxicity. The primary end point was median PFS.
At baseline, 27.9% of patients in the crizotinib group had brain metastases compared with 13.6% in the alectinib group; other baseline characteristics were similar between the 2 groups. Although the study investigated the optimal first-line therapy for patients with NSCLC and ALK mutation, approximately 33% of patients in each group had received 1 line of chemotherapy.
Alectinib Outperforms Crizotinib in the First-Line Setting
The investigator-assessed overall response rate (ORR) was 85.4% in the alectinib group compared with 70.2% in the crizotinib group. When assessed by an independent review, the ORR was 91.6% in the alectinib group versus 78.9% in the crizotinib group.
The median PFS was significantly superior with alectinib versus crizotinib: at the time of data analysis, the median PFS had not been reached in the alectinib group, but the lower 95% confidence interval was 20.3 months. The median PFS with crizotinib was 10.2 months, with a hazard ratio (HR) of 0.34 (P <.001) in favor of alectinib.
In the subgroup of patients with brain metastases at baseline, the HR for PFS was 0.08 with alectinib versus crizotinib.
In addition to a superior PFS, 26.2% of patients in the alectinib group had grade 3 or 4 adverse events versus 51.9% in the crizotinib group, and 8.7% of patients discontinued the study because of adverse events in the alectinib group versus 20.2% in the crizotinib group. Furthermore, treatment interruption because of adverse events was less common with alectinib (29.1%) than with crizotinib (74.0%).
The only adverse event reported in >30% of patients in the alectinib group was constipation; nausea, diarrhea, vomiting, visual disturbance, dysgeusia, constipation, elevation in alanine aminotransferase (ALT) levels, and elevation in aspartate aminotransferase levels each occurred in >30% of patients.
Overall, 8 patients in each treatment group withdrew from the study because of interstitial lung disease. In the crizotinib group, 5 patients discontinued treatment because of impaired hepatic function, and 4 patients discontinued treatment after an increase in ALT levels.
Addressing whether alectinib therapy should now be considered the new frontline standard in ALK-positive NSCLC based on the J-ALEX study, discussant Shirish M. Gadgeel, MD, Leader of the Thoracic Oncology Multidisciplinary Team, Karmanos Cancer Center, Detroit, MI, gave a cautious “yes.”
The superior efficacy and toxicity profile with alectinib are persuasive, said Dr Gadgeel, but “there’s clearly a note of caution in that these results are based on an interim analysis, though planned, and we still await the results of the global ALEX study.”