FDA Grants Frontline Alectinib Priority Review for ALK-Positive NSCLC

Sandra Horning, MD

The FDA has granted a priority review to a supplemental new drug application (sNDA) for alectinib (Alecensa) for the frontline treatment of patients with ALK-positive locally advanced or metastatic non—small cell lung cancer (NSCLC), according to Genentech (Roche), the manufacturer of the second-generation ALK inhibitor.

The agency is scheduled to issue a final ruling by November 30, 2017. Alectinib was previously approved for patients with metastatic ALK-positive NSCLC who have progressed on or are intolerant to crizotinib (Xalkori).

The frontline sNDA is based on findings from the phase III ALEX and J-ALEX studies. Compared with crizotinib, alectinib improved progression-free survival (PFS) by 53% (hazard ratio [HR], 0.47; 95% CI, 0.34-0.65; P <.0001) in the ALEX study and by 62% (HR, 0.38; 95% CI, 0.25-0.55; P <.0001) in the J-ALEX trial.

“Phase III results showed Alecensa reduced the risk of disease worsening by more than half compared to the current standard of care and lowered the risk of tumors spreading to or growing in the brain by more than 80%,” Sandra Horning, MD, Genentech chief medical officer and head of Global Product Development, said in a press release. “We are working closely with the FDA to bring this medicine as an initial treatment for people with ALK-positive NSCLC as soon as possible.”

In the ALEX trial, researchers at 161 locations in 31 countries randomly assigned treatment-naïve patients to twice daily dosages of 600 mg of alectinib (n = 152) or 250 mg of crizotinib (n = 151). Investigator-reported median PFS, the study’s primary endpoint, was 11.1 months (95% CI, 9.1-13.1) with crizotinib and had not been reached (95% CI, 17.7 to not reached) in the alectinib arm. Median PFS, as determined by an independent review committee, was 25.7 months (95% CI, 19.9 to not reached) in the alectinib arm versus 10.4 months (95% CI, 7.7-14.6) in the crizotinib arm (HR, 0.50; 95% CI, 0.36-0.70; P<.0001).

Alectinib reduced the risk for progression in the CNS by 84% compared with crizotinib (HR, 0.16; 95% CI, 0.10-0.28; P <.0001). The 12-month cumulative rate of CNS progression for people with or without existing CNS metastases at baseline was 9.4% (95% CI, 5.4-14.7) in the alectinib arm and 41.4% (95% CI, 33.2-49.4) for crizotinib.

In the 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 300 mg of alectinib twice-daily (n = 103) or 250 mg of crizotinib twice-daily (n = 104). 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 randomly assigned 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 median duration of follow-up was 12.0 months in the alectinib arm and 12.2 months in the crizotinib arm.

In the subgroup of patients with brain metastases at baseline, alectinib reduced the risk for CNS progression by 49% (HR, 0.51; 95% CI, 0.16-1.64). In patients who did not have brain metastases at baseline, alectinib reduced the risk for CNS progression by 81% (HR, 0.19; 95 CI, 0.07-0.53).

Alectinib was associated with fewer serious adverse events (AEs) in both studies. In ALEX, 41% of patients assigned to alectinib experienced grade ≥3 AEs compared with 50% in the crizotinib group. Additionally, AEs leading to discontinuation (11% vs 13%), dose reduction (16% vs 21%), and dose interruption (19% vs 25%) were all lower with alectinib.

In the J-ALEX trial, the rate of grade 3/4 AEs in the crizotinib arm was 57% compared with 32% in the alectinib group. As in ALEX, patients assigned to alectinib were less likely to experience discontinuation (11% vs 23%) and dose interruption (29% vs 64%).

Alectinib previously received an FDA breakthrough therapy designation as a frontline treatment for patients with ALK-positive NSCLC.

FDA grants Genentech’s Alecensa priority review for initial treatment of people with ALK-positive lung cancer. Genentech. Available at: http://bit.ly/2u67edG. Accessed August 3, 2017.