On April 29, 2014, the U. S. Food and Drug Administration granted accelerated approval to ceritinib (ZYKADIA, Novartis Pharmaceuticals Corporation) for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) with disease progression on or who are intolerant to crizotinib.
On March 6, 2013, FDA granted ceritinib breakthrough therapy designation based on preliminary evidence of clinical activity in patients with metastatic ALK-positive NSCLC previously treated with crizotinib.
The approval of ceritinib was based on the results of a multicenter, single-arm, open-label clinical trial enrolling a total of 163 patients with metastatic, ALK-positive, NSCLC who had progressed on or were intolerant to crizotinib. All patients received ceritinib at a dose of 750 mg once daily.
The primary endpoint supporting approval was objective response rate (ORR) according to RECIST v1.0 as evaluated by both investigator and a Blinded Independent Central Review Committee (BIRC). Duration of response (DOR) was also assessed.
The median age of patients was 52 years. The majority of patients were female (54%), and White (66%), never or former smoker (97%), had ECOG Performance Status 0 or 1 (87%) and adenocarcinoma histology (93%). Nearly all patients (91%) had disease progression on previous crizotinib and 84% had received two or more prior therapies for metastatic disease. Sites of extra-thoracic metastasis included brain (60%), liver (42%), and bone (42%).
The trial results demonstrated durable responses of large magnitude with an ORR of 44% (95% CI: 36, 52) and DOR of 7.1 months based on BIRC-determined tumor assessments. The analysis by investigator assessment showed similar results with an ORR of 55% (95% CI: 47, 62) and DOR of 7.4 months.
The safety evaluation of ceritinib was based on 255 patients with ALK-positive tumors (246 patients with NSCLC and 9 patients with other cancers) who received ceritinib at a dose of 750 mg once daily. The most common adverse reactions (greater than or equal to 25%) were diarrhea, nausea, transaminitis, vomiting, abdominal pain, fatigue, decreased appetite and constipation. The most common CTCAE Grade 3-4 adverse reactions (greater than or equal to 5%) were diarrhea, fatigue, transaminitis, hyperglycemia, hypophosphatemia, increased lipase levels, and anemia. Additional serious adverse reactions include interstitial lung disease and QT prolongation.
The recommended dose of ceritinib is 750 mg orally once daily on an empty stomach until disease progression or unacceptable toxicity. Approximately 60% of patients initiating treatment at the recommended dose required at least one dose reduction.
Full prescribing information is available at:
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and 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) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).