Ceritinib

Ceritinib is an orally administered targeted anticancer medicine belonging to the class of anaplastic lymphoma kinase, or ALK, tyrosine kinase inhibitors. ALK is a receptor tyrosine kinase involved in cellular signaling, and genetic rearrangements involving ALK can produce abnormal signaling that promotes the growth and survival of cancer cells. Ceritinib inhibits ALK activity and also has activity against certain ALK mutations that can contribute to resistance to earlier ALK-directed treatment. By suppressing abnormal ALK signaling, ceritinib can reduce the proliferation and survival of ALK-driven tumor cells. It is available as an oral tablet and is administered once daily with food. Its principal clinical role is the treatment of adults with ALK-positive advanced or metastatic non-small cell lung cancer. Ceritinib became clinically important as a second-generation ALK inhibitor that provided a treatment option for patients whose disease had progressed during or after treatment with crizotinib and subsequently demonstrated activity in previously untreated ALK-positive disease. Ceritinib also has activity against cancer involving the central nervous system, which is relevant because brain metastases can occur in ALK-positive non-small cell lung cancer.

Ceritinib was developed as a next-generation selective ALK inhibitor to address ALK-driven non-small cell lung cancer, including disease that had become resistant to earlier ALK inhibition. The molecule was evaluated in the ASCEND clinical development program, which included studies in previously treated and treatment-naive patients with ALK-rearranged non-small cell lung cancer. The United States Food and Drug Administration granted accelerated approval for ceritinib on April 29, 2014, for patients with metastatic ALK-positive non-small cell lung cancer who had progressed on or were intolerant to crizotinib. The U.S. indication was subsequently expanded to include adults with metastatic ALK-positive non-small cell lung cancer as detected by an FDA-approved test. The European Medicines Agency granted conditional marketing authorization for ceritinib on May 6, 2015, for adults with advanced ALK-positive non-small cell lung cancer previously treated with crizotinib; the authorization was converted to full approval on July 26, 2017. In India, CDSCO oncology committee records document regulatory review of ceritinib 150 mg capsules and subsequent package-insert activity. The ASCEND-4 phase 3 study supported the use of ceritinib in previously untreated ALK-positive advanced disease, while ASCEND-5 evaluated ceritinib in patients previously treated with chemotherapy and crizotinib.

Ceritinib is used for adults with advanced or metastatic non-small cell lung cancer whose tumors are positive for an ALK rearrangement. In the United States, treatment selection requires confirmation of ALK-positive status using an FDA-approved diagnostic test. Ceritinib may be used as systemic targeted therapy and is administered as a single anticancer agent rather than as a conventional cytotoxic chemotherapy combination. Clinical development established activity both in patients previously treated with crizotinib and in patients receiving ALK-directed treatment earlier in the course of advanced disease. In the European Union, the authorized indication specifically covers adults with advanced ALK-positive non-small cell lung cancer previously treated with crizotinib. Treatment decisions should take into account prior ALK-directed therapy, disease progression, central nervous system involvement, overall clinical status, and the applicable local regulatory indication.

Ceritinib is administered orally once daily with food. The currently recommended adult dosage is 450 mg once daily with food. Tablets should be swallowed whole and should not be crushed or chewed. Treatment is generally continued until disease progression or unacceptable toxicity. Dose interruption or reduction may be required when clinically significant adverse reactions occur, particularly gastrointestinal toxicity, hepatotoxicity, or other treatment-related abnormalities. Earlier clinical studies used higher doses, including 750 mg once daily under fasting conditions, but the recommended regimen was subsequently established as 450 mg once daily with food because food increases drug exposure and this regimen provides an appropriate balance between exposure and tolerability. Patients should take ceritinib consistently according to the prescribed schedule, and treatment should be modified only under appropriate medical supervision.

Common side effects of ceritinib include diarrhea, nausea, vomiting, abdominal pain, decreased appetite, fatigue, weight loss, constipation, headache, and changes in liver enzyme levels. Hyperglycemia and increased pancreatic enzyme levels may also occur. Gastrointestinal effects can be prominent, particularly during treatment initiation, and may affect hydration and nutritional intake. Laboratory abnormalities involving alanine aminotransferase and other liver enzymes are also relatively frequent. Patients should report persistent diarrhea, repeated vomiting, significant abdominal discomfort, unusual fatigue, changes in appetite, or other worsening symptoms so that supportive treatment and appropriate dose modification can be considered.

Important serious risks associated with ceritinib include severe or persistent gastrointestinal toxicity, hepatotoxicity, interstitial lung disease or pneumonitis, QT interval prolongation, bradycardia, hyperglycemia, pancreatitis, and severe hypersensitivity reactions. Liver injury can be clinically significant and may require treatment interruption, dose reduction, or permanent discontinuation depending on severity. New or worsening cough, difficulty breathing, fever, or other respiratory symptoms require evaluation for interstitial lung disease or pneumonitis. Ceritinib may prolong the QT interval and can affect heart rate, particularly in patients with relevant cardiovascular risk factors or when combined with other medicines that affect cardiac conduction. Hyperglycemia can occasionally become severe, particularly in patients with diabetes or other metabolic risk factors. Pancreatic enzyme elevations and pancreatitis require clinical monitoring, particularly when abdominal symptoms occur.

Before initiating ceritinib, ALK-positive status should be confirmed using an appropriate validated diagnostic test. Baseline assessment should include liver function, pancreatic enzymes, blood glucose, electrolyte levels, cardiac history, and review of concomitant medications. Liver function tests should be monitored regularly, particularly during the first months of therapy. Electrocardiographic monitoring and assessment of electrolytes may be appropriate in patients with cardiac risk factors or when medicines capable of prolonging the QT interval are used. Ceritinib is metabolized primarily through CYP3A, and strong CYP3A inhibitors or inducers can substantially affect ceritinib exposure and should generally be avoided or managed according to prescribing recommendations. Ceritinib can also affect the exposure of certain medicines through inhibition of CYP3A and other metabolic or transporter pathways. Patients with diabetes or impaired glucose regulation may require closer blood-glucose monitoring. Pregnancy and breastfeeding considerations should also be reviewed because ceritinib may cause fetal harm and breastfeeding is generally not recommended during treatment.

Prescribers should confirm ALK positivity before treatment and review previous ALK inhibitor exposure, disease progression pattern, central nervous system involvement, baseline liver function, pancreatic enzymes, blood glucose, and cardiovascular risk. The 450 mg once-daily regimen should be administered with food according to current prescribing recommendations rather than using older fasting regimens from early clinical trials. Pharmacists should carefully screen the medication list for strong CYP3A inhibitors or inducers, QT-prolonging medicines, and other drugs whose exposure may be affected by ceritinib. Patients should be counselled about taking the medicine consistently with food, maintaining hydration, and promptly reporting persistent diarrhea, vomiting, jaundice, severe abdominal pain, new respiratory symptoms, palpitations, fainting, or marked changes in blood glucose. Regular laboratory monitoring is particularly important for hepatic, pancreatic, and metabolic abnormalities, while treatment interruption or dose modification should follow the severity-specific recommendations in the current prescribing information.