Bruno Strigini, CEO
The EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of 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.
The priority review 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 <.001).
The positive opinion will now be reviewed by the European Commission (EC) and a final approval decision for use in the European Union (EU) is expected in about 2 months.
“Novartis is committed to bringing targeted treatment options to more patients living with lung cancer who may benefit from them,” Bruno Strigini, CEO, Novartis Oncology, said in a statement. “Today, we've taken an important step towards fulfilling that commitment with the potential approval of Zykadia as a first-line treatment option for those in the EU diagnosed with ALK-positive advanced NSCLC.”
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.
Among patients without brain metastases at screening, the median PFS was 26.3 months (95% CI, 15.4-27.7) with ceritinib versus 8.3 months (95% CI, 6.0-13.7) with chemotherapy (HR, 0.48; 95% CI, 0.33-0.69). In patients with brain metastases, the median PFS was 10.7 months (95% CI, 8.1-16.4) versus 6.7 months (95% CI, 4.1-10.6), respectively (HR, 0.70; 95% CI, 0.44-1.12).
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 (AEs) included diarrhea (85% with ceritinib vs 11% with chemotherapy), nausea (69% vs 55%), vomiting (66% vs 36%), ALT increase (60% vs 22%), AST increase (53% vs 19%), gamma-glutamyltransferase increase (37% vs 10%), decreased appetite (34% vs 31%), blood alkaline phosphate increase (29% vs 5%), and fatigue (29% vs 30%).
Ceritinib is approved in the EU for the treatment of patients with ALK-positive advanced NSCLC previously treated with crizotinib (Xalkori). In the United States, ceritinib was approved by the FDA in April 2014 for use in the same second-line setting. The FDA granted a priority review to ceritinib in February 2017 as a first-line treatment for patients with ALK-positive, metastatic NSCLC.
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.