Pharmacological Class:
Tyrosine kinase inhibitor.

Active Ingredient(s):
Ceritinib 150mg; hard gel caps.

Company
Novartis Pharmaceuticals Corp
Indication(s):
Treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Not established for improvement in survival or disease-related symptoms.

Pharmacology:
Ceritinib inhibits 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.

Clinical Trials:
The efficacy of Zykadia was established in a multicenter, single-arm, open-label clinical trial (Study 1) involving 163 patients with metastatic ALK-positive NSCLC who progressed while receiving or were intolerant to crizotinib. All patients received Zykadia 750mg once daily. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.0 as eva luated by both investigators and a Blinded Independent Central Review Committee (BIRC). Duration of response (DOR) was an additional outcome measure.

Results showed that the overall response rate in patients with ALK-positive NSCLC who received prior crizotinib was 54.6% (95% CI: 47, 62) and 43.6% (95% CI: 36, 52) in the investigator (N=163) and BIRC assessment (N=163), respectively. Also, in the investigator assessment, 1.2% achieved a complete response while 53.4% achieved a partial response with a median DOR of 7.4 months (95% CI: 5.4, 10.1). In the BIRC assessment, 2.5% achieved a complete response while 41.1% achieved a partial response with a median DOR of 7.1 months (95% CI: 5.6, NE).

Legal Classification:
Rx

Adults:
Take on an empty stomach (at least 2 hours before or after a meal). 750mg once daily until disease progression or unacceptable toxicity. Discontinue if 300mg once daily not tolerated. Moderate-to-severe hepatic impairment: not established. Dose modifications: see full labeling.

Children:
Not established.

Warnings/Precautions:
Monitor for severe or persistent GI toxicity; if occurs, withhold until improved; resume at reduced dose. Monitor ALT/AST and total bilirubin once monthly, and more frequently if elevated transaminases develop; withhold then reduce dose, or permanently discontinue as clinically indicated. Congenital long QT syndrome; avoid. CHF, bradyarrhythmias, electrolyte abnormalities; monitor ECG, electrolytes periodically. Permanently discontinue if QTc prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or serious arrhythmia develop. Monitor HR and BP regularly; serum glucose and pulmonary symptoms as clinically indicated. Permanently discontinue if treatment-related interstitial lung disease (ILD)/pneumonitis, uncontrolled hyperglycemia, or life-threatening bradycardia occur. Pregnancy (Category D). Females of reproductive potential should use effective contraception during treatment and for at least 2 weeks after completion. Nursing mothers: not recommended.

Interaction(s)
Avoid concomitant strong CYP3A4 inhibitors (eg, ritonavir, macrolides, ketoconazole, nefazodone), grapefruit juice; if unavoidable, reduce ceritinib dose by 1/3. Avoid concomitant strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wor