In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On December 11, 2015, alectinib (Alecensa) was granted accelerated approval for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non–small cell lung cancer (NSCLC) whose disease has progressed on or who are intolerant of crizotinib (Xalkori).1,2 Most patients had received prior systemic chemotherapy.
Supporting Efficacy Data
The approval was based on two multicenter single-arm open-label trials in patients with metastatic ALK rearrangement–positive NSCLC who had had disease progression on or were intolerant to the ALK inhibitor crizotinib (studies 1 and 2). All patients received alectinib at 600 mg twice daily.
The major efficacy outcome measure was objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as evaluated by independent review committee and by investigator. Additional outcome measures included duration of response, central nervous system (CNS) objective response rate, and CNS duration of response.
Study 12,3 was conducted in North America and enrolled 87 patients. Patients had a median age of 54 years (18% aged ≥ 65 years), 84% were white and 8% Asian, 55% were female, 90% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 100% were never or former smokers, 99% had stage IV disease, 94% had adenocarcinoma, and 74% had prior chemotherapy. The most common sites of extrathoracic metastasis were CNS (60%, of whom 65% had received CNS radiation), lymph nodes (43%), bone (36%), and liver (34%).
Study 22,4 was conducted internationally and enrolled 138 patients. Median age was 52 years old (10% aged ≥ 65 years), 67% were white and 26% Asian, 56% were female, 91% had an ECOG performance status of 0 or 1, 98% were never or former smokers, 99% had stage IV disease, 96% had adenocarcinoma, and 80% had prior chemotherapy. The most common sites of extrathoracic metastasis included CNS (61%, of whom 73% had received CNS radiation), bone (51%), lymph nodes (38%), and liver (30%).
In study 1, the objective response rate was 38% (95% confidence interval [CI] = 28%–49%) by independent review committee and 46% (95% CI = 35%–57%) by investigator. In study 2, the objective response rate was 44% (95% CI = 36%–53%) by independent review committee and 48% (95% CI = 39%–57%) by investigator. The median duration of response on independent review committee assessment was 7.5 months in study 1 and 11.2 months in study 2 after median durations of follow-up of 4.8 months and 10.9 months; median durations of response on investigator assessment were not estimable and 7.8 months. In a pooled analysis of 51 patients with baseline measurable CNS lesions, the CNS objective response rate was 61% (95% CI = 46%–74%), and the median duration of response was 9.1 months (95% CI = 5.8 months to not estimable).
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 who have had disease progression 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 are as follows. For alanine transaminase (ALT) or aspartate transaminase (AST) elevation > 5 times upper limit of normal with total bilirubin ≤ 2 times upper limit of normal, treatment should be withheld until recovery to baseline or < 3 times limit of normal and then resumed at reduced dose. Treatment should be permanently discontinued for ALT or AST elevation > 3 times limit of normal with total bilirubin elevation > 2 times limit of normal in the absence of cholestasis or hemolysis. For total bilirubin elevation > 3 times limit of normal, treatment should be withheld until recovery to baseline or to < 1.5 times limit of normal and then resumed at reduced dose.
Treatment should be permanently discontinued for any grade treatment-related interstitial lung disease/
For symptomatic bradycardia, treatment should be withheld until recovery to asymptomatic bradycardia or to heart rate ≥ 60 beats per minute. 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 heart rate ≥ 60 beats per minute; if no contributing concomitant medication is identified or if contributing concomitant medications are not discontinued or dose-modified, alectinib can be resumed at reduced dose upon recovery to asymptomatic bradycardia or to heart rate ≥ 60 beats per minute.
For bradycardia (< 60 beats per minute) 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 reduced dose upon recovery to asymptomatic bradycardia or to heart rate ≥ 60 beats per minute, 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 limit of normal and resumed at the same dose for elevation > 5 times limit of normal and withheld until recovery to baseline or to < 2.5 times limit of normal and then resumed at reduced dose for elevations > 10 times limit of normal or second occurrence of elevation > 5 times limit of normal.
No dose adjustment is recommended for patients with mild or moderate renal impairment or mild hepatic impairment. Safety has not been evaluated in patients with severe renal impairment or moderate or severe hepatic impairment.
Among the 253 patients in the two phase II trials, median duration of exposure to alectinib was 9.3 months, with 67% of patients having exposure > 6 months and 40% > 1 year. The most common adverse events of any grade were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common grade 3 or 4 adverse event was dyspnea (3.6%; all others in < 2%).
The most common laboratory abnormalities of any grade were anemia (56%), elevated AST (51%), elevated alkaline phosphatase (47%), and elevated creatine phosphokinase (43%). The most common grade 3 or 4 abnormalities were elevated ALT (4.8%), lymphopenia (4.6%), elevated creatine phosphokinase (4.6%), and hypokalemia (4.0%). Interstitial lung disease/pneumonitis was observed in 0.4% of patients and severe myalgia in 1.2%.
Serious adverse events occurred in 19%, with the most frequent being pulmonary embolism (1.2%), dyspnea (1.2%), and hyperbilirubinemia (1.2%). Adverse events led to dose reduction in 23%, with the most common causes of reduction or interruption being elevated bilirubin (6%), elevated creatine phosphokinase (4.3%), elevated ALT (4.0%), elevated AST (2.8%), and vomiting (2.8%).
Adverse events led to treatment discontinuation in 6%, with the most common causes being hyperbilirubinemia (1.6%), increased ALT (1.6%), and increased AST (1.2%). Fatal adverse events occurred in 2.8%, including one case each of hemorrhage and intestinal perforation attributed to alectinib.
Alectinib carries warnings/precautions for hepatotoxicity, interstitial lung disease/pneumonitis, bradycardia, severe myalgia/creatine phosphokinase elevation, and embryofetal toxicity. Liver tests should be monitored every 2 weeks during the first 2 months of treatment and then periodically during treatment. 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. Women of reproductive potential must be advised of potential risk to a fetus and to use effective contraception. ■
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).