Novartis today 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].

Novartis' Commitment to Lung Cancer
Novartis Oncology's research into targeted therapies has helped transform treatment approaches for patients living with mutation-driven lung cancers. Patients with a mutation-driven NSCLC may be candidates for treatment with targeted therapies[7].

Zykadia was one of the first medicines to be approved following FDA Breakthrough Therapy designation. It is currently indicated for the treatment of patients with ALK+ metastatic NSCLC who have progressed on or are intolerant to crizotinib. This indication was approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Zykadia was commercially available in the US less than three and a half years after the first patient entered a clinical trial.

Novartis continues its commitment to the global lung cancer community through ongoing studies of its marketed therapies as well as the exploration of investigational compounds that target genomic biomarkers in NSCLC.

About ASCEND-4
ASCEND-4 was a Phase III randomized, open-label, multicenter, global clinical trial to evaluate the safety and efficacy of Zykadia compared to standard chemotherapy, including maintenance, in adult patients with Stage IIIB or IV ALK+ advanced NSCLC who received no prior therapy for their advanced disease. Patients received Zykadia orally at 750 mg/daily or standard pemetrexed-based platinum doublet chemotherapy per label (pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin AUC 5-6) for 4 cycles followed by pemetrexed maintenance.

Of 376 patients, 189 (59 with brain metastases) were randomized to Zykadia and 187 (62 with brain metastases) to chemotherapy. Approximately 60% of patients with baseline brain metastases treated with Zykadia did not have prior radiation therapy, the current standard of treatment for baseline brain metastases. Among patients randomized to the chemotherapy arm, 105 (72%) of 145 received an ALK inhibitor as their first treatment after discontinuation of chemotherapy.

About Zykadia
Zykadia is an oral, selective inhibitor of anaplastic lymphoma kinase (ALK), a gene that can fuse with others to form an abnormal "fusion protein" that promotes the development and growth of certain tumors in cancers including non-small cell lung cancer (NSCLC). Zykadia is currently approved in over 64 countries worldwide.

About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world.

1. Soria JC, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomized, open-label Phase 3 study. The Lancet. 2017.
2. US Food and Drug Administration. Priority Review. Available at http://www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm. Accessed February 2, 2017.
3. US Food and Drug Administration. Fact Sheet: Breakthrough Therapies. Available at http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htm. Accessed February 6, 2017.
4. World Health Organization. Estimated number of deaths, both sexes, worldwide in 2012. World Health Organization. http://gco.iarc.fr/today/online-analysis-pie?mode=cancer&mode_population=continents&population=900&sex=0&cancer=11&type=1&statistic=0&prevalence=0&color_palette=default. Accessed on January 19, 2017.
5. World Health Organization. International Agency for Research on Cancer. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Lung Cancer. Available at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=lung. Accessed February 2, 2017.
6. Lovly, C., L. Horn, W. Pao. 2016. Molecular Profiling of Lung Cancer. My Cancer Genome. Available at https://www.mycancergenome.org/content/disease/lung-cancer/. Accessed February 7, 2017.
7. Riess JW, Wakelee, HA. Metastatic Non-Small Cell Lung Cancer Management: Novel Targets and Recent Clinical Advances. Clinical Advances in Hematology & Oncology. 2012; 10: 226-224.