On May 26, 2017, ceritinib (Zykadia) was granted regular approval for treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by a U.S. Food and Drug Administration–approved test.^1,2 In 2014, the drug received accelerated approval for patients with ALK-positive metastatic NSCLC whose disease had progressed on or who were intolerant of crizotinib (Xalkori). 

Supporting Efficacy Data 

THE CURRENT approval is based on the finding of improved progression-free survival with ceritinib in the phase III ASCEND-4 trial.^2,3 All patients had evidence of ALK rearrangement on the VENTANA ALK (D5F3) test in central laboratory testing. In the trial, 376 previously untreated patients were randomized to receive ceritinib at 750 mg orally once daily until disease progression (n = 189) or platinum-pemetrexed (Alimta) chemotherapy (n = 187) consisting of pemetrexed (500 mg/m2) with either cisplatin (75 mg/ m2) or carboplatin (AUC = 5–6) on day 1 of every 21-day cycle for up to 4 cycles followed by pemetrexed maintenance therapy. 

Overall, the median age of patients was 54 years (range = 22–81 years, 22% ≥ 65 years), 57% were female, 54% were white, 42% were Asian, and 2% were black, regions were Europe for 53%, Asia Pacific for 42%, and South America for 5%, 97% had adenocarcinoma, 61% had never smoked, and 32% had brain metastasis at screening. 

 Median progression-free survival was 16.6 months (95% confidence interval [CI] = 12.6–27.2 months) in the ceritinib group vs 8.1 months (95% CI = 5.8–11.1 months) in the chemotherapy group on a blinded independent review (hazard ratio [HR] = 0.55, P < .0001). Confirmed objective response rates were 73% vs 27%, and the median duration of response was 23.9 months (95% CI = 16.6 months to not estimable) vs 11.1 months (95% CI = 7.8–16.4 months). Overall survival data are immature. 

In 28 ceritinib patients and 27 chemotherapy patients with measurable central nervous system lesions at baseline, confirmed overall intracranial response rate was 57% vs 22%, and median duration of response was 16.6 months (95% CI = 8.1 months to not estimable) and not estimable (95% CI = 1.5 months to not estimable). 

How It Works 

CERITINIB IS an inhibitor of ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor, and ROS1 kinases, with greatest activity against ALK. It has been shown to inhibit autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells in in vitro and in vivo assays. It inhibits proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and exhibits dose-dependent inhibition of EML4-ALK–positive NSCLC xenograft growth in animal models. It also exhibits dose-dependent antitumor activity at clinically relevant concentrations in mice with EML4-ALK–positive NSCLC xenografts with demonstrated resistance to crizotinib. 

How It Is Used 

THE RECOMMENDED DOSE of ceritinib is 750 mg once daily until disease progression or unacceptable toxicity. Dose reductions for adverse reactions are sequentially to 600, 450, and 300 mg once daily, with the drug being discontinued if the 300-mg dose is not tolerated. 

Treatment should be withheld for lipase or amylase level increase to > 2 times the upper limit of normal (ULN), severe or intolerable nausea, vomiting, or diarrhea, persistent hyperglycemia > 250 mg/dL, QTc interval > 500 msec on 2 separate measurements, symptomatic non–life threatening bradycardia, clinically significant bradycardia requiring intervention or life-threatening bradycardia in patients taking a concomitant medication known to cause bradycardia or hypotension , and alanine transaminase (ALT) or aspartate transaminase (AST) level elevation > 5 times ULN with bilirubin level elevation ≤ 2 times ULN; upon recovery, treatment can be restarted with a 150-mg dose reduction. 

Treatment should be permanently discontinued for inadequate control of hyperglycemia, any grade treatment-related interstitial lung disease/pneumonitis, QTc interval prolongation with torsade de pointes or polymorphic ventricular tachycardia or signs/ symptoms of serious arrhythmia, life-threatening bradycardia in patients not taking medication known to cause bradycardia or hypotension, and ALT or AST level elevation > 3 times ULN with bilirubin level elevation > 2 times ULN in the absence of cholestasis or hemolysis. 

Concomitant use of strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, telithromycin [Ketek], nefazodone, grapefruit/grapefruit juice) should be avoided. If use of these inhibitors cannot be avoided, the ceritinib dose should be reduced by approximately one-third, rounded to the nearest multiple of the 150-mg dosage strength, during concomitant treatment; ceritinib can be resumed at the former dose after discontinuation of the CYP3A inhibitor. Concomitant use of strong CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, and St. John’s wort) should be avoided. 

Safety Profile 

IN THE PHASE III trial, the median duration of exposure to ceritinib was 18 months. The most common adverse events of any grade in the ceritinib group were diarrhea (85% vs 11% in chemotherapy group), nausea (69% vs 55%), vomiting (67% vs 36%), fatigue (45% vs 49%), and abdominal pain (40% vs 13%); the most common grade 3 or 4 adverse events were fatigue (7% vs 6%), diarrhea (4.8% vs 1.1%), abdominal pain (3.7% vs 0%), weight loss (3.7% vs 0.6%), and prolonged QT interval (2.6% vs 0.6%). Additional clinically significant adverse events occurring in ≥ 2% of ceritinib patients were vision disorder (4%), bradycardia (4%), interstitial lung disease/pneumonitis (2%), hepatotoxicity (2%), and renal failure (2%). The most common grade 3 or 4 laboratory abnormalities were increased gamma-glutamyl transferase (GGT; 49% vs 10%), increased ALT level (34% vs 3.4%), increased AST level (21% vs 2.3%), increased alkaline phosphatase level (12% vs 1.7%), hyperglycemia (10% vs 10%), increased amylase level (8% vs 4.5%), and increased lipase level (6% vs 0.6%). 

Serious adverse events occurred in 38% of the ceritinib group, with the most common being pneumonia (4%), pleural effusion (4%), vomiting (4%), nausea (3%), dyspnea (3%), hyperglycemia (3%), AST level increased (2%), lung infection (2%), and pericardial effusion (2%). Adverse events led to ceritinib dose interruption in 77% of patients and dose reduction in 66%, with the most common causes being ALT level increased (48%), AST level increased (34%), vomiting (15%), blood creatinine level increased (14%), GGT level increased (13%), diarrhea (13%), and nausea (13%). Adverse events led to treatment discontinuation in 12%, with the most common causes (≥ 1%) being blood creatinine level increased (2.1%), amylase level increased (1.1%), and lipase level increased (1.1%). Adverse events led to death in four patients, due to myocardial infarction, respiratory tract infection, pneumonitis, and an unknown cause. 

Ceritinib carries warnings/precautions for severe or persistent gastrointestinal toxicity, hepatotoxicity, interstitial lung disease/ pneumonitis, QT interval prolongation, hyperglycemia, bradycardia, pancreatitis, and embryofetal toxicity. Liver tests should be performed at least monthly. Electrocardiograms and electrolytes should be monitored in patients with congestive heart failure, bradyarrhythmia, electrolyte abnormalities, and in those taking medications known to prolong the QTc interval. Glucose should be monitored and antihyperglycemic medications initiated or optimized as necessary. Heart rate and blood pressure should be monitored regularly. Lipase and amylase levels should be monitored prior to treatment and periodically thereafter as clinically indicated. ■

REFERENCES 

1. U.S. Food and Drug Administration: FDA broadens ceritinib indication to previously untreated ALK-positive metastatic NSCLC. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560873.htm. Accessed January 8, 2018. 

2. Zykadia (ceritinib) capsules prescribing information, Novartis Pharmaceuticals Corporation, May 2017. Available at www.accessdata.fda.gov/drugsatfda_ docs/label/2017/205755s009lbl.pdf. Accessed January 8, 2018. 

3. Soria JC, Tan DSW, Chiari R, et al: First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 study. Lancet 389:917-929, 2017.