FDA Gives Zykadia a Priority Review for Frontline Lung Cancer Treatment

Zykadia (ceritinib) was granted a priority review by the Food and Drug Administration (FDA) to be used as a frontline treatment for 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 3 ASCEND-4 trial, in which Zykadia reduced the risk of disease progression or death by 45 percent compared with standard chemotherapy. The median progression-free survival (PFS) benefit favoring Zykadia was 8.5 months.

The FDA also granted frontline Zykadia a breakthrough therapy designation for use in patients with ALK-positive NSCLC and brain metastases. Under the priority review, the application for frontline ceritinib will be reviewed within six months of submission, instead of the standard 10-month timeframe.

"We are committed to advancing our understanding of mutation-driven lung cancer, where there continues to be significant unmet need," Vas Narasimhan, M.D., global head of drug development and chief medical officer, Novartis, said in a statement. "Today's priority review of Zykadia for newly diagnosed patients with ALK+ metastatic NSCLC, including breakthrough therapy designation for those with brain metastases, brings us closer to delivering the right treatment to the right patient at the right time."

The open-label phase 3 ASCEND-4 trial randomized 376 treatment-naïve patients with stage 3B or 4 ALK+ NSCLC to either 750 mg of oral Zykadia 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 Zykadia and 26.9 weeks for chemotherapy.

Beyond reaching the study’s primary endpoint of PFS, Zykadia 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 compared with 8.1 months with chemotherapy.

The ORR with Zykadia was higher at 72.5 percent compared with 26.7 percent 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 with Zykadia versus 8.3 months with chemotherapy. In patients with brain metastases, the median PFS was 10.7 months versus 6.7 months, respectively.

Crossover from chemotherapy to Zykadia 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 percent with Zykadia vs 11 percent with chemotherapy), nausea (69 percent vs 55 percent), vomiting (66 percent vs 36 percent), ALT increase (60 percent vs 22 percent), AST increase (53 percent vs 19 percent), gamma-glutamyltransferase increase (37 percent vs 10 percent), decreased appetite (34 percent vs 31 percent), blood alkaline phosphate increase (29 percent vs 5 percent) and fatigue (29 percent vs 30 percent).

Ceritinib was previously approved by the FDA in April 2014 for patients with ALK-positive NSCLC following treatment with the ALK inhibitor Xalkori (crizotinib).