Alectinib Beats Crizotinib in Frontline ALK+ NSCLC ALEX Trial

Sandra Horning, MD

Alectinib (Alecensa) reduced the risk of disease progression or death compared with crizotinib (Xalkori) as a frontline treatment for patients with ALK-positive non—small cell lung cancer (NSCLC), according to findings from the phase III ALEX trial.

The much-anticipated ALEX findings are the confirmatory data for the December 2015 FDA accelerated approval of alectinib as a treatment for patients with metastatic ALK-positive NSCLC following progression on crizotinib. Genentech (Roche), the developer of the second-generation ALK inhibitor alectinib, plans to present the ALEX results at an upcoming medical meeting and submit the data to the FDA and other global regulatory agencies.

ALEX is now the second phase III trial in which alectinib has bested crizotinib in frontline ALK-positive NSCLC. Alectinib improved progression-free survival (PFS) by 66% versus crizotinib in the Japanese open-label phase III J-ALEX study, which was presented at the 2016 ASCO Annual Meeting. Alectinib previously received an FDA breakthrough therapy designation as a frontline treatment for patients with ALK-positive NSCLC.

“Our goal is to transform the standard of care and we are excited to share these results with the lung cancer community,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Roche, said in a statement. “As part of its breakthrough therapy designation, we hope to bring Alecensa as an initial treatment for people with ALK-positive NSCLC as soon as possible and will discuss these data with global health authorities.”

The open-label phase III ALEX study (NCT02075840) randomized 303 treatment-naive patients with ALK-positive NSCLC in a 1:1 ratio to alectinib or crizotinib. PFS was the primary endpoint of the study, which was conducted at 161 locations across 31 countries. Secondary outcome measures included time to CNS progression, objective response rate, duration of response, overall survival, quality of life, and safety. According to Genentech, adverse event (AE) data in ALEX were similar to previous alectinib trials, with no new safety signals.

In the phase III J-ALEX study, 207 Japanese patients with ALK-positive advanced or recurrent NSCLC who had not been previously treated with an ALK inhibitor were randomized to alectinib at 300 mg twice daily or crizotinib at 250 mg twice daily. Treatment was continued until disease progression or unacceptable toxicity.

Baseline characteristics were well balanced between the groups, with the exception that a higher proportion of patients randomized to crizotinib had brain metastases by independent review compared with those randomized to alectinib (27.9% vs 13.6%, respectively). About one-third of patients in each arm had received 1 line of chemotherapy before entry. The duration of follow-up was 12.0 months in the alectinib arm and 12.2 months in the crizotinib arm.

The primary endpoint, median PFS as assessed by independent review, was significantly improved with alectinib. Median PFS not reached in the alectinib arm, with a lower confidence interval of 20.3 months, compared with a median PFS of 10.2 months in the crizotinib arm (HR, 0.34; P <.0001). In the subgroup of patients with brain metastases at baseline, the hazard ratio for the primary endpoint with alectinib versus crizotinib was 0.08 (95% CI, 0.01-0.61).

Objective response rates as determined by investigators were 85.4% in the alectinib group and 70.2% in the crizotinib group. As assessed by independent review, ORR was 91.6% in the alectinib arm and 78.9% in the crizotinib arm.

Grade 3/4 AEs occurred with greater frequency in the crizotinib arm compared with the alectinib arm (51.9% vs 26.2%, respectively). Discontinuation of study drug due to AEs occurred more frequently in the crizotinib arm compared with the alectinib arm (20.2% vs 8.7%, respectively), as did dose interruption due to AEs (74.0% vs 29.1%, respectively).

ALEX is the second positive phase III alectinib trial that Genentech has reported this month. The company recently announced that in the phase III ALUR study, alectinib significantly improved PFS compared with chemotherapy in patients with ALK-positive NSCLC who had progressed following treatment with platinum-based chemotherapy and crizotinib.

Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study. Presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago. Abstract 9008.