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Alectinib May Constitute New Frontline Treatment for ALK-Positive NSCLC

Alectinib, an oral ALK inhibitor recently approved for the treatment of advanced ALK-positive non–small cell lung cancer (NSCLC) after crizotinib failure, significantly improved progression-free survival (PFS) compared with crizotinib in the frontline setting, according to data from a head-to-head open-label phase 3 Japanese study.

In December 2015, the FDA granted accelerated approval to alectinib in patients with advanced NSCLC whose disease progressed on crizotinib or who were intolerant to crizotinib.

Results from the J-ALEX study that compared the 2 ALK inhibitors were presented by Hiroshi Nokihara, MD, PhD, at the 2016 ASCO Annual Meeting.

“Based on these results, we believe that alectinib is the new standard first-line therapy for ALK-positive NSCLC,” said Dr Nokihara, from the National Cancer Center Hospital in Tokyo, Japan.

In J-ALEX, 207 Japanese patients with ALK-positive advanced or recurrent NSCLC who were ALK inhibitor–naive were randomized to alectinib 300 mg twice daily or crizotininb 250 mg twice daily. Treatment continued until disease progression or unacceptable toxicity.

At baseline, a higher proportion of patients randomized to crizotinib had brain metastases compared with those randomized to alectinib (27.9% vs 13.6%). Otherwise, baseline characteristics were similar between the groups. Although the investigators sought to determine optimal first-line therapy, approximately one-third of patients in each arm had 1 prior line of chemotherapy.

The findings reported here came from a prespecified interim analysis, with a duration of follow-up of 12.0 months in the alectinib arm and 12.2 months in the crizotinib arm.

As assessed by the investigators, the overall response rate (ORR) was 85.4% in the alectinib arm and 70.2% in the crizotinib arm. When assessed by independent review, ORR was 91.6% in the alectinib arm, consistent with phase 1/2 data of alectinib, and 78.9% in the crizotinib arm.

The primary end point, median PFS as assessed by independent review, was significantly superior with alectinib. The median PFS had not yet been reached at the time of data analysis in the arm receiving alectinib, said Dr Nokihara, but he noted that the lower 95% confidence interval was 20.3 months. Median PFS in crizotinib-treated patients was 10.2 months, for a hazard ratio (HR) of 0.34 (P <.0001) in favor of alectinib.

In the subgroup of patients with brain metastases at baseline, the HR for PFS with alectinib versus crizotinib was 0.08 (95% CI, 0.01-0.61).

In addition to a superior effect on PFS, the percentage of patients who experienced grade 3/4 adverse events was lower in the alectinib arm versus the crizotinib arm (26.2% vs 51.9%), and the percentage who discontinued study treatment because of adverse events was also lower (8.7% vs 20.2%). Interruptions to treatment for adverse events also occurred with less frequency with alectinib (29.1% vs 74.0%).

In the alectinib arm, the only adverse event that occurred with >30% frequency was constipation. In the crizotinib arm, nausea, diarrhea, vomiting, visual disturbance, dysgeusia, constipation, and ALT and AST elevations each occurred in >30% of patients.

Eight patients in each arm withdrew due to inter­stitial lung disease. In the crizotinib arm, 5 patients also discontinued because of impaired hepatic function, and 4 discontinued following an increase in ALT.

In addressing whether alectinib should now be considered the new frontline standard in ALK-positive NSCLC based on J-ALEX, discussant Shirish M. Gadgeel, MD, gave a cautious “yes.”

The superior efficacy and toxicity profile with alectinib are persuasive, said Dr Gadgeel, Professor, Karmanos Cancer Institute/Wayne State University, Detroit, MI, 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.”

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