Alectinib Approved by FDA for Frontline Treatment of ALK-Positive NSCLC

Alectinib (Alecensa) has received FDA approval for the frontline treatment of patients with ALK-positive metastatic non—small cell lung cancer (NSCLC), Genentech (Roche), the manufacturer of the second-generation ALK inhibitor, announced today.

The approval is primarily based on findings from the phase III ALEX study, which showed alectinib improved progression-free survival (PFS) by 47% compared with crizotinib (hazard ratio [HR], 0.53; 95% CI, 0.38-0.73;P<.0001), as assessed by an independent review panel.

In addition to granting this new indication, the FDA has also converted alectinib&rsquo;s accelerated approval for patients withALK-positive NSCLC who have progressed on crizotinib to a full approval.

&ldquo;Our goal is to develop medicines that have the potential to significantly improve upon the standard of care,&rdquo; Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, said in a statement. &ldquo;In our pivotal study, Alecensa significantly extended the time that people lived without their disease worsening compared to crizotinib and also showed a marked reduction in the risk of their cancer spreading to the brain.&rdquo;

In the ALEX trial, researchers at 161 locations in 31 countries randomly assigned treatment-na&iuml;ve patients to twice daily dosages of 600 mg of alectinib (n = 152) or 250 mg of crizotinib (n = 151). 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.

The overall response rate (ORR) with alectinib was 79% (95% CI, 72-85) versus 72% (95% CI, 64-79) with crizotinib (P= .1652). The complete response rates were 13% versus 6%, respectively, and the partial response rate was 66% in both arms.

Eighty-two percent of patients receiving alectinib had a response duration &ge;6 months, with 64% and 37%, having response durations &ge;12 months and &ge;18 months, respectively. The corresponding rates in the crizotinib arm were 57%, 36%, and 14%.

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.

The CNS ORR was 81% (95% CI, 58-95) in the alectinib arm versus 50% (95% CI, 28-72) in the crizotinib arm. The complete response rates were 38% versus 5%, respectively. CNS response duration was 12 months or longer in 59% of the crizotinib group versus 36% of the alectinib group.

Alectinib was associated with fewer serious adverse events (AEs). In ALEX, 41% of patients assigned to alectinib experienced grade &ge;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.

A separate phase III study, the Japanese phase III J-ALEX trial, also demonstrated the benefit of crizotinib inALK-positive NSCLC. In J-ALEX, 207 Japanese patients withALK-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).

The median PFS was 25.9 months in the alectinib arm versus 10.2 months in the crizotinib arm (HR, 0.38; 95% CI, 0.26-0.55;P<.0001). Among patients without brain metastases at baseline, alectinib reduced the risk of progression in the CNS by 81% (HR, 0.19; 95% CI, 0.07-0.53) and in patients with brain metastases at baseline, alectinib reduced the risk of CNS progression by 49% (HR, 0.51; 95% CI, 0.16-1.64).

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

Reference:

FDA Approves Genentech&rsquo;s Alecensa (Alectinib) as First-Line Treatment for People with Specific Type of Lung Cancer. Genentech. Available at: http://bit.ly/2zmLda7. Accessed November 6, 2017.