FDA Broadens Ceritinib Indication to Previously Untreated ALK-Positive Metastatic NSCLC
On May 26, 2017, the U.S. Food and Drug Administration (FDA) granted regular approval to ceritinib (Zykadia®, Novartis Pharmaceuticals Corp.) for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
In April 2014, ceritinib received accelerated approval for patients with ALK-positive metastatic NSCLC whose disease has progressed or who are intolerant to crizotinib based on a blinded independent review committee (BIRC)-assessed overall response rate (ORR) of 44% among 163 patients in a single-arm trial.
The current approval is based on data from ASCEND-4, a randomized, multicenter, open-label, active-controlled trial conducted in patients with untreated ALK-positive NSCLC. All patients were required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3) test performed through central laboratory testing.
ASCEND-4 randomized 376 patients (1:1) to receive either ceritinib (n=189) 750 mg orally once daily until disease progression or platinum-pemetrexed doublet chemotherapy (n=187). Patients in the chemotherapy arm received 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.
ASCEND-4 randomized 376 patients (1:1) to receive either ceritinib (n=189) 750 mg orally once daily until disease progression or platinum-pemetrexed doublet chemotherapy (n=187). Patients in the chemotherapy arm received 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.
In patients with measurable central nervous system (CNS) lesions on baseline brain scans, the confirmed overall intracranial response rate (OIRR), assessed by BIRC neuro-radiologist, was 57% (95% CI: 37%, 76%) in the ceritinib arm and 22% (95% CI 9%, 42% in the chemotherapy arm. The median CNS response duration was 16.6 months (95% CI: 8.1, NE) and not estimable (95% CI: 1.5, NE) in the ceritinib and chemotherapy arms, respectively.
The most common adverse reactions (occurring in at least 25% of ceritinib-treated patients in ASCEND-4) were diarrhea, nausea, vomiting, fatigue, abdominal pain, decreased appetite, and cough. Serious adverse reactions occurred in 38% of patients treated with ceritinib. Adverse reactions leading to ceritinib discontinuation occurred in 12%. Adverse reactions that led to ceritinib discontinuation in 1% or more of patients were increased creatinine, increased amylase, and increased lipase. Dose interruption due to adverse reactions occurred in 77% of ceritinib-treated patients, while dose reductions were required in 66%.
The recommended ceritinib dose is 750 mg orally once daily, to be taken at least 1 hour before or at least 2 hours after a meal.
Full prescribing information is available (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205755s009lbl.pdf).
FDA previously granted ceritinib Breakthrough Therapy Designation for the first-line treatment of ALK-positive metastatic NSCLC with metastases to the brain. The application was granted Priority Review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics (http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf).
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