FDA broadens ceritinib indication to previously untreated ALK-positive metastatic NSCLC

On May 26, 2017, the U.S. Food and Drug Administration 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 (NCT01828099), 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 demonstrated an improvement in progression-free survival (PFS) as assessed by BIRC, with a hazard ratio (HR) of 0.55 (95% CI: 0.42, 0.73, p-value <0.0001). The estimated median PFS was 16.6 months (95% CI: 12.6, 27.2) in the ceritinib arm and 8.1 months (95% CI: 5.8, 11.1) in the chemotherapy arm. Confirmed ORR, was 73% (95% CI: 66%, 79%) and 27% (95% CI: 21%, 34%) in the ceritinib and chemotherapy arms, respectively. Estimated median response durations were 23.9 months (95% CI: 16.6, not estimable [NE]) and 11.1 months (95% CI: 7.8, 16.4) in the ceritinib and chemotherapy arms, respectively. Overall survival data are immature.

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 at: Highlights of Prescribing Information ZYKADIA.

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.

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).

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