Novartis Gains Priority Review for Zykadia - Drug Discovery and Development

Novartis announced that the US Food and Drug Administration (FDA) accepted the Company’s supplemental New Drug Application (sNDA) for filing, and granted Priority Review for the expanded use of Zykadia (ceritinib) as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. The FDA also granted Breakthrough Therapy designation to Zykadia for the first-line treatment of patients with ALK+ metastatic NSCLC with metastases to the brain.

“We are committed to advancing our understanding of mutation-driven lung cancer, where there continues to be significant unmet need,” said Vas Narasimhan, Global Head Drug Development and Chief Medical Officer, Novartis. “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 sNDA submission for first-line use of Zykadia is based on the primary analysis of ASCEND-4, a global Phase III, randomized, open-label, multicenter clinical trial which evaluated safety and efficacy of Zykadia compared to platinum-based chemotherapy, including maintenance, in adult patients with Stage IIIB or IV ALK+ NSCLC. The study was conducted at 134 clinical trial sites across 28 countries, and randomized across 376 patients. The study found:

Patients treated with first-line Zykadia had a median progression-free survival (PFS) of 16.6 months (95% confidence interval [CI]: 12.6, 27.2), compared to 8.1 months (95% CI: 5.8, 11.1) for patients treated with standard first-line pemetrexed-platinum chemotherapy with pemetrexed maintenance. A 45% risk reduction in PFS was obtained in the Zykadia arm compared to the chemotherapy arm (hazard ratio [HR] = 0.55, [95% CI: 0.42, 0.73; one-sided p value <0.001])[1].
In a pre-specified analysis of patients receiving Zykadia without brain metastases at screening, patients experienced a median PFS of 26.3 months (95% CI: 15.4, 27.7), compared with 8.3 months (95% CI: 6.0, 13.7) among patients treated with chemotherapy (HR = 0.48 [95% CI: 0.33, 0.69])[1].
In a pre-specified analysis of patients receiving Zykadia with brain metastases at baseline, the median PFS was 10.7 months (95% CI: 8.1, 16.4) in the Zykadia group versus 6.7 months (95% CI: 4.1, 10.6) in the chemotherapy group (HR = 0.70 [95% CI: 0.44, 1.12])[1]. Intracranial overall response rate (ORR) (72.7%, [95% CI: 49.8, 89.3]) is consistent with whole body ORR (72.5% [95% CI: 65.5, 78.7]).

The most common adverse events (AEs) occurring in more than 25% of Zykadia patients were diarrhea (85% vs. 11% with chemotherapy), nausea (69% vs. 55% with chemotherapy), vomiting (66% vs. 36% with chemotherapy), ALT increase (60% vs. 22% with chemotherapy), AST increase (53% vs. 19% with chemotherapy), gamma-glutamyltransferase increase (37% vs. 10% in chemotherapy), decreased appetite (34% vs. 31% with chemotherapy), blood alkaline phosphate increase (29% vs. 5% with chemotherapy) and fatigue (29% vs. 30% with chemotherapy).

FDA grants Priority Review to applications for drugs that treat serious conditions and, if approved, would provide a significant improvement in treatment safety or efficacy[2]. For applications granted priority review, FDA is to take action within 6 months of submission instead of 10 months under standard review timelines.

Breakthrough Therapy designation is intended to expedite the development and review of drugs that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement on at least one clinically significant endpoint over an available therapy[3]. Novartis has received 13 Breakthrough Therapy designations to date, underscoring the company’s ongoing commitment to developing innovative therapies for rare diseases or underserved cancer patients. This latest designation is for the first-line treatment of patients with ALK+ NSCLC with brain metastases and is the second Breakthrough Therapy designation for Zykadia.

Worldwide, lung cancer causes more deaths than colon, breast and prostate cancer combined[4], and an estimated 1.8 million new cases of lung cancer are diagnosed each year[5]. Among those patients with NSCLC, the most common type of lung cancer, 3-7% are ALK-positive[6].