Novartis receives positive CHMP opinion for first-line use of Zykadia® in ALK-positive advanced non-small cell lung cancer (NSCLC)

NovartisNovartis announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of expanding the use of Zykadia® (ceritinib) to include the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive. If approved, Zykadia will provide a new treatment option for previously untreated and newly diagnosed patients with ALK-positive advanced NSCLC.

"Novartis is committed to bringing targeted treatment options to more patients living with lung cancer who may benefit from them," said Bruno Strigini, CEO, Novartis Oncology. "Today, we've taken an important step towards fulfilling that commitment with the potential approval of Zykadia as a first-line treatment option for those in the EU diagnosed with ALK-positive advanced NSCLC."

The positive CHMP opinion was based on results from the ASCEND-4 study, a randomized, open-label, global Phase III trial. The study showed that patients treated with first-line Zykadia experienced a 45% reduction in the risk of disease progression compared to patients treated with standard first-line pemetrexed-platinum chemotherapy with pemetrexed maintenance (hazard ratio [HR] = 0.55 [95% CI: 0.42, 0.73])[1]. The median progression-free survival (PFS) was 16.6 months (95% confidence interval [CI]: 12.6, 27.2) for patients receiving Zykadia compared to 8.1 months (95% CI: 5.8, 11.1) for patients in the chemotherapy arm of the study[1].

Additionally, patients receiving Zykadia without brain metastases at baseline 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 in the chemotherapy arm (HR = 0.48 [95% CI: 0.33, 0.69])[1]. Among patients 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]. Of these patients, 59% did not receive prior brain radiotherapy[1]. The high intracranial overall response rate (ORR) (72.7% [95% CI: 49.8, 89.3]) was consistent with whole body ORR (72.5% [95% CI: 65.5, 78.7])[1].

The CHMP recommendation will now be reviewed by the European Commission (EC), which holds the authority to approve medicines for the European Union (EU). The EC typically follows the CHMP recommendation and typically issues an approval decision within two months, applicable to all 28 European Union member states plus Iceland, Lichtenstein, and Norway. Earlier this year, the US Food and Drug Administration (FDA) granted Zykadia Breakthrough Therapy designation for first-line treatment of patients with ALK-positive NSCLC with metastases to the brain. The application for first-line use of Zykadia is under Priority Review by the FDA.

Novartis Commitment to Lung Cancer
Worldwide, lung cancer causes more deaths than colon, breast and prostate cancer combined, and an estimated 1.8 million new cases of lung cancer are diagnosed each year[3],[4]. Among patients with NSCLC, roughly 25% have an actionable mutation that may be targeted with available therapies[5]-[8]. To determine that treatment, medical organizations recommend biomarker testing for patients with lung cancer[9].

Over the past decade, Novartis Oncology's research has supported the evolution of treatment approaches for patients living with mutation-driven types of lung cancer. The company continues its commitment to the global lung cancer community through ongoing studies, 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-positive 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 (pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin AUC 5-6) for four 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.

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), GGT 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)[1].

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 69 countries worldwide. Please visit www.NovartisOncology.com/news/product-portfolio/zykadia (link is external) for additional information.

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. Lovly, C., L. Horn, W. Pao. 2016. Molecular Profiling of Lung Cancer. My Cancer Genome https://www.mycancergenome.org/content/disease/lung-cancer/ (Updated March 28). Accessed March 22, 2017.
3. 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 March 22, 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& (link is external) population=900&sex=0&cancer=11&type=1&statistic=0&prevalence=0& color_palette=default (link is external). Accessed March 22, 2017.
5. 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.
6. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175-180.
7. Paik PK, Arcila ME, Fara M, et al. Clinical Characteristics of Patients With Lung Adenocarcinomas Harboring BRAF Mutations. J Clin Oncol. 2011;29:2046-2051.
8. Takeuchi, K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nature. 2012;378-381.
9. Lindeman, N.I., et al. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors. Arch Pathol Lab Med. 2013; 137: 828-1174.

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