Ceritinib Granted Priority Review by the FDA in Frontline ALK+ NSCLC


Ceritinib has been granted a priority review by the FDA as a first-line treatment for patients with <em>ALK</em>-positive, metastatic NSCLC.

Vas Narasimhan, MD

Vas Narasimhan, MD

Ceritinib (Zykadia) has been granted a priority review by the FDA as a first-line treatment for patients withALK-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 FDA also granted frontline ceritinib a breakthrough therapy designation for use in patients withALK-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-na&iuml;ve patients with stage IIIB or IV ALK+ NSCLC to either 750 mg of oral ceritinib daily or standard chemotherapy (500 mg/m2of pemetrexed plus 75 mg/m2of 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&rsquo;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 withALK-positive NSCLC following treatment with the ALK inhibitor crizotinib (Xalkori).


de Castro G, Tan DS, Crin&ograve; 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.

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