What is crizotinib?
Crizotinib is a small molecule tyrosine kinase inhibitor.
How does crizotinib work?
A small population of patients with non-small cell lung cancer (NSCLC) have mutations in anaplastic lymphoma kinase (ALK) or ROS1. Crizotinib is a targeted small molecule that effectively inhibits kinase activity associated with ALK and ROS1 mutated cells.
What is this approved for?
Crizotinib is indicated for patients with metastatic NSCLC with ALK or ROS1-positive disease as detected by an FDA-approved test.
What is the basis for this approval?
A clinical trial of crizotinib versus chemotherapy was completed in 343 patients with treatment-naïve ALK-positive metastatic NSCLC. Crizotinib 250 mg by mouth twice daily was compared to pemetrexed and carboplatin chemotherapy. Progression-free survival was a median of 10.9 months with crizotinib versus 7.0 months with chemotherapy, correlating to a hazard ratio of 0.45 favoring crizotinib (p<0.001). This was associated with an overall tumor response rate of 74 percent with crizotinib versus 45 percent with chemotherapy (p<0.001) (N Engl J Med 2014;371:2167-2177).
A pilot study of 50 patients with NSCLC ROS1 rearrangment reported the use of crizotinib 250 mg by mouth twice daily. The independent response reviews reported 66 percent overall response rates associated with a median duration of response of 18.3 months. Further trials in patients with this molecular abnormality are ongoing; however, since the FDA approval, the use of crizotinib for ROS1 rearrangements has become standard practice (N Engl J Med 2014;371:1963-1971).
How do you administer this drug?
Crizotinib therapy is continuous with initial dosing recommendations at 250 mg orally twice daily. Dose reductions are recommended for grade 3 and 4 toxicities in patients after resolution of the toxicities.
Are there any premedications needed?
No premedications are typically required. However, crizotinib is considered moderate-high emetic potential and, with common side effects such as nausea and vomiting reported, antiemetic therapy is prudent for many patients. Antiemetics may be used as needed or scheduled medication based on patient tolerance and response.
What are the common side effects associated with crizotinib (> or = 10%)?
Crizotinib is associated with the following toxicities in more than 25 percent of patients on therapy. Patients may experience gastrointestinal issues such as nausea, diarrhea, vomiting, constipation, and decreased appetite. Additional constitutional symptoms such as fatigue may occur. Patients may experience vision disorders, dizziness, and neuropathy. Other side effects include edema, elevated transaminases, and upper respiratory infection.
What are the uncommon side effects associated with crizotinib (less than 10%)?
Serious but uncommon side effects include hepatotoxicity (fatal in 0.1%), interstitial lung disease (2.9%), QT interval prolongation (2.1%), bradycardia, and severe visual loss (0.2%); often further medical evaluation is needed if these toxicities occur and reevaluation of continued therapy is warranted.
Are there any important drug interactions I should be aware of?
Crizotinib is metabolized through the CYP3A4 pathway. Avoid using crizotinib with concurrent CYP3A4 inducers and inhibitors. Use with other CYP3A4 substrates should be used with caution.
How do I adjust the dose in the setting of renal insufficiency?
Patients with renal impairment, indicated by creatinine clearance < 30 mL/min, should be dose reduced to 250 mg orally once daily. This recommendation is appropriate for patients who are not on dialysis.
How do I adjust the dose in the setting of hepatic insufficiency?
Crizotinib has not been studied in patients with hepatic impairment; currently no recommendations exist for dose adjustment.
Crizotinib may be taken with or without food. Capsules should be swallowed whole. If vomiting occurs after a dose, take the next scheduled dose as planned.
Discontinuation of therapy due to side effects was seen in approximately 8.2 percent of patients in clinical trials. Dose reductions due to adverse events was seen in approximately 6.4 percent of patients.
For female patients taking crizotinib who are of child-bearing potential, contraception is recommended during therapy and for 45 days following discontinuation of therapy. For male patients, barrier contraception is recommended during therapy and for 90 days following discontinuation.
What should my patients know about crizotinib?
Patients should seek medical attention for:
- Symptoms of shortness of breath, slow heart rate, or changes in vision
What else should I know about crizotinib?
Advise patients of the need for the following:
- Periodic monitoring of blood counts, liver function tests, and EKG
- Ophthalmologic examinations may be needed
- Avoid becoming pregnant while on this medication
What useful links are available regarding crizotinib?
Any ongoing clinical trials related to crizotinib?
Clinical trials involving crizotinib are being conducted in several settings including ROS1 NSCLC, in combination with pembrolizumab for ALK-positive NSCLC, and in combination with dasatinib for glioma, as well as several other cancer types. More information can be found online at https://clinicaltrials.gov.
J. ANDREW SKIRVIN, PHARMD, BCOP, is Associate Clinical Professor, Northeastern University, School of Pharmacy, Boston. RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor.
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