FDA Grants Ceritinib Priority Review in Frontline ALK+ NSCLC

Vas Narasimhan, MD, global head of drug development and chief medical officer, Novartis

Vas Narasimhan, MD

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

UPDATE 5/26/2017: FDA Approves Ceritinib for Frontline ALK+ NSCLC

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 FDA also granted frontline ceritinib 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 6 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, MD, 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 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 was previously approved by the FDA in April 2014 for patients with ALK-positive NSCLC following treatment with the ALK inhibitor crizotinib (Xalkori).

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.