FDA Approves Ceritinib for Frontline ALK+ NSCLC

The FDA has approved ceritinib (Zykadia) for the treatment of patients with ALK-positive, metastatic non—small cell lung cancer (NSCLC), according to Novartis, the manufacturer of the second-generation ALK inhibitor.

Patients’ ALK-positive status must be determined by an FDA-approved test.

The approval is based on findings from the phase III ASCEND-4 trial, in which ceritinib reduced the risk of disease progression or death by 45% compared with standard chemotherapy. The median progression-free survival (PFS) benefit favoring ceritinib was 8.5 months (HR, 0.55; 95% CI, 0.42-0.73; P <.0001).

“Today’s approval represents the next step in the development of Zykadia as a treatment option for ALK-positive metastatic NSCLC, bringing this important medication to a patient population where a need still exists,” Bruno Strigini, CEO, Novartis Oncology, said in a statement. “At Novartis, we are tireless in our pursuit of developing novel medicines to treat lung cancer, and the first-line approval of Zykadia for ALK-positive metastatic NSCLC illustrates our commitment to cancer patients.”

The open-label phase III ASCEND-4 trial randomized 376 treatment-naïve patients with stage IIIB or IV ALK+ NSCLC to either 750 mg of oral ceritinib daily or standard chemotherapy (500 mg/m² of pemetrexed plus 75 mg/m² of cisplatin or carboplatin AUC 5-6), including pemetrexed maintenance. Patients were enrolled at 203 locations cross 31 countries. The median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy.

Beyond reaching the study’s primary endpoint of PFS, ceritinib also improved key secondary outcome measures, including objective response rate (ORR) and duration of response. Median PFS by RECIST v1.1 criteria was 16.6 months (95% CI, 12.6-27.2) compared with 8.1 months (95% CI, 5.8-11.1) with chemotherapy.

The ORR with ceritinib was higher at 72.5% compared with 26.7% in the chemotherapy group. The median duration of response was 23.9 months versus 11.1 months, respectively.

The overall intracranial response rate in patients with measurable brain metastases was 57% (95% CI, 37-76) in the ceritinib arm versus 22% (95% CI, 9-42) in the chemotherapy cohort.

Crossover from chemotherapy to ceritinib was allowed at disease progression; 80 patients crossed over, which could possibly impact overall survival (OS). OS data were immature at the interim analysis.

The most frequently reported all-grade adverse events included diarrhea (85% with ceritinib vs 11% with chemotherapy), nausea (69% vs 55%), vomiting (67% vs 36%), ALT increase (91% vs 65%), AST increase (86% vs 58%), gamma-glutamyltransferase increase (84% vs 67%), decreased appetite (34% vs 32%), blood alkaline phosphate increase (81% vs 47%), and fatigue (45% vs 49%).

The FDA granted ceritinib an accelerated approval in April 2014 for the treatment of patients with ALK-positive advanced NSCLC previously treated with crizotinib (Xalkori). Today's FDA action also converts that second-line approval into a full approval.

de Castro G, Tan DS, Crinò L, et al. First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4). Presented at: Presented at: 17th World Lung Cancer Conference, the Annual Meeting of the International Association for the Study of Lung Cancer (IASLC); December 4-7, 2016; Vienna, Austria.