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The FDA granted regular approval to ceritinib 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.

FDA; NSCLC. FDA; NSC... - Click to enlarge in new windowFDA; NSCLC. FDA; NSCLC

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 percent 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 percent (95% CI: 66%, 79%) and 27 percent (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, assessed by a BIRC neuro-radiologist, was 57 percent (95% CI: 37%, 76%) in the ceritinib arm and 22 percent (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 percent of patients treated with ceritinib. Adverse reactions leading to ceritinib discontinuation occurred in 12 percent. Adverse reactions that led to ceritinib discontinuation in 1 percent or more of patients were increased creatinine, increased amylase, and increased lipase. Dose interruption due to adverse reactions occurred in 77 percent of ceritinib-treated patients, while dose reductions were required in 66 percent.


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.


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.