On November 6, 2017, alectinib (Alecensa) received regular approval for treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non–small cell lung cancer
(NSCLC), as detected by a U.S. Food and Drug Administration–approved test.^1,2

Supporting Efficacy Data

Approval was based on the findings of the open-label phase III ALEX trial, in which 303 patients with ALK-positive disease who had not received prior systemic therapy for metastatic disease were randomized to receive oral alectinib at 600 mg twice daily (n = 152) or oral crizotinib (Xalkori) at 250 mg twice daily (n = 151).^2,3 Patients were required to have evidence of ALK rearrangement identified by the VENTANA ALK (D5F3) CDx Assay on central laboratory testing.

Median progression-free survival assessed by a blinded independent review committee was 25.7 months (95% confidence interval [CI] = 19.9 months to not estimable) in the alectinib group vs 10.4 months (95% CI = 7.7–14.6 months) in the crizotinib group (hazard ratio = 0.53, P < .0001). The incidence of disease progression in the central nervous system (CNS) as the first site of disease progression, alone or concurrent with systemic disease progression, was 12% in the alectinib group vs 45% in the crizotinib group. Objective response rates were 79% vs 72%; 64% vs 36% of responders had a response duration ≥ 12 months. Among 43 patients with measurable CNS lesions, CNS response rates were 81% vs 50%; 59% vs 36% of responders had a CNS response duration ≥ 12 months.

How It Works

Alectinib is a tyrosine kinase inhibitor targeting ALK and RET. In preclinical studies, alectinib inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT and decreased tumor-cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations. The major active metabolite of alectinib, M4, showed similar in vitro potency and activity. Alectinib and M4 showed in vitro and in vivo activity against multiple mutant forms of the ALK enzyme, including mutations found in NSCLC tumors in patients whose disease has progressed on crizotinib. Alectinib resulted in antitumor activity and prolonged survival in mouse models with tumors carrying ALK fusions, including models with intracranial implanted ALK-driven tumor cell lines.

How It Is Used

The recommended dose of alectinib is 600 mg orally twice daily with food until disease progression or unacceptable toxicity. Permissible stepwise dose reductions are to 450 mg and 300 mg twice daily, with treatment being discontinued if the latter dose is not tolerated.

Recommended dose modifications follow. For alanine transaminase (ALT) or aspartate transaminase (AST) elevation > five times the upper limit of normal (ULN) with total bilirubin ≤ two times ULN, treatment should be withheld until recovery to baseline or < three times ULN and then resumed at a reduced dose. Treatment should be permanently discontinued for ALT or AST elevation > three times ULN, with total bilirubin elevation > two times ULN in the absence of cholestasis or hemolysis. For total bilirubin elevation > 3 times ULN, treatment should be withheld until recovery to baseline or to < 1.5 times ULN and then resumed at a reduced dose.

Treatment should be permanently discontinued for any grade treatment-related interstitial lung disease/pneumonitis.

For symptomatic bradycardia, treatment should be withheld until recovery to asymptomatic bradycardia or to a heart rate ≥ 60 beats per minute (bpm). If a contributing concomitant medication is identified and discontinued or dose-adjusted, alectinib can be resumed at the previous dose upon recovery to asymptomatic bradycardia or to a heart rate ≥ 60 bpm; if no contributing concomitant medication is identified or if contributing concomitant medications are not discontinued or dose-modified, alectinib can be resumed at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate ≥ 60 bpm.

For bradycardia with life-threatening consequences or for which urgent intervention is indicated, alectinib should be permanently discontinued if there is no contributing concomitant medication; if a contributing concomitant medication is identified and discontinued or dose-adjusted, alectinib can be resumed at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate ≥ 60 bpm, with frequent monitoring as clinically indicated. Alectinib should be permanently discontinued for recurrence.

For creatine phosphokinase elevations, treatment should be withheld until recovery to baseline or to ≤ 2.5 times ULN and resumed at the same dose for elevation > 5 times ULN and withheld until recovery to baseline or to < 2.5 times ULN and then resumed at a reduced dose for elevations > 10 times ULN or a second occurrence of elevation > 5 times ULN.

For grade 3 renal impairment, treatment should be withheld until serum creatinine recovers to ≤ 1.5 times ULN and then resumed at a reduced dose. Treatment should be permanently discontinued for grade 4 renal impairment.

Safety Profile

In the ALEX trial, the most common adverse events of any grade (≥ 20%) in the alectinib group were constipation (34% vs 33% in the crizotinib group), fatigue (26% vs 23%), myalgia (23% vs 4%), and edema (22% vs 34%); the most common adverse event in the crizotinib group were nausea (48%), diarrhea (45%), and vomiting (38%). Grade ≥ 3 adverse events occurred in 41% of the alectinib group, with the most common being renal impairment (3.9%) and fatigue (1.3%). The most common grade 3 or 4 laboratory abnormalities were anemia (7.0%), increased ALT (6.0%), and increased creatine phosphokinase (2.8%).

Serious adverse events occurred in 28% of alectinib patients, with the most common being pneumonia (4.6%) and renal impairment (3.9%). Adverse events led to a dose reduction in 16% of patients, dose interruption in 19%, and permanent treatment discontinuation in 11%; the most common causes of treatment discontinuation were renal impairment (2.0%), hyperbilirubinemia (1.3%), increased ALT (1.3%), and increased AST (1.3%). Adverse events led to death in 3.3% of patients, including renal impairment in two patients and sudden death, cardiac arrest, and pneumonia in one patient each.

Alectinib carries warnings/precautions for hepatotoxicity, interstitial lung disease/pneumonitis, renal impairment, bradycardia, severe myalgia/creatine phosphokinase elevation, and embryofetal toxicity. Liver tests should be monitored every 2 weeks during the first 3 months of treatment and then once a month and as clinically indicated. Heart rate and blood pressure should be regularly monitored. Creatine phosphokinase should be assessed every 2 weeks during the first month of treatment and in patients reporting unexplained muscle pain, tenderness, or weakness.

REFERENCES

1. U.S. Food and Drug Administration: Alectinib approved for (ALK) positive metastatic non-small cell lung cancer (NSCLC). Available at www.fda.gov/Drugs/InformationOnDrugs/-ApprovedDrugs/ucm584082.htm. Accessed November 21, 2017.

2. Alecensa (alectinib) capsules prescribing information, Genentech, Inc, November 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/208434s003lbl.pdf. Accessed November 21, 2017.

3. Peters S, Camidge DR, Shaw AT, et al: Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 377:829-838, 2017.