"Molecular testing for genetic drivers in lung cancer plays a critical role as patients and physicians determine how to proceed with therapies, especially after they have experienced disease progression following initial treatment," said Stefania Vallone, international relations, Women Against Lung Cancer in Europe and board member, Lung Cancer Europe (LuCE). "Patients with resistant ALK+ NSCLC have had very few treatment options available that specifically target the genetic makeup of their disease. The approval of Zykadia brings new hope to the lung cancer community as we continue to advocate for innovative therapies."
Each year, there are 1.6 million people diagnosed worldwide with lung cancer, the leading cause of cancer death. The most common type of lung cancer is NSCLC, accounting for 85-90% of all cases. Of those, 2-7% are driven by a rearrangement of the ALK gene, which increases the growth of cancer cells and can be identified by a molecular test of the cancer tumor. Despite significant treatment advances for patients with ALK+ NSCLC, disease progression is often inevitable and more treatment options are needed.
The EU approval of Zykadia is based on data from two global, multicenter, open-label, single-arm studies [Study A (also known as ASCEND-1) and Study B (also known as ASCEND-2)]. Data from Study A demonstrated patients with ALK+ NSCLC who received Zykadia 750 mg daily after previous treatment with chemotherapy followed by an ALK inhibitor experienced an overall response rate (ORR) of 56.4%. Detailed results from Study B will be presented at an upcoming medical congress.
"The approval of Zykadia in the European Union is significant for ALK+ NSCLC patients who have exhausted the other treatment options for their disease," said Bruno Strigini, President, Novartis Oncology. "This approval is yet another example of our commitment to precision oncology and our continued focus on developing treatment approaches that target specific genetic and molecular characteristics of cancer."
The EU approval follows a positive opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) in February 2015 and applies to all 28 EU member states, plus Iceland, Norway and Liechtenstein. Outside the EU, Zykadia is approved in the United States and other countries within North America, South America, Central America and Asia. Additional regulatory reviews for Zykadia are underway worldwide.
About the Zykadia Clinical Trials
The primary efficacy endpoint for these studies was overall response rate (ORR), including complete response and partial response, for patients who were treated with a 750 mg dose of Zykadia, confirmed by repeat assessments performed not less than four weeks after the criteria for response was first met. Additional evaluations included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Tumor evaluations were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 in Study A and RECIST 1.1 in Study B. Tumor-related endpoints (ORR, DOR and PFS) were assessed by investigator and by blinded independent review committee (BIRC). Comparative efficacy data from randomized clinical studies are not available.
Study A was a Phase I study, which included a dose-escalation phase and an expansion phase at the recommended dose of 750 mg. The study evaluated a total of 246 ALK+ NSCLC patients who were treated with 750 mg of Zykadia: 163 had received prior treatment with an ALK inhibitor and 83 were ALK inhibitor-naïve. In patients who had previously received treatment with an ALK inhibitor, the ORR was 56.4% [95% CI, 48.5-64.2%], the median DOR was 8.3 months [95% CI, 6.8-9.7 months] and the median PFS was 6.9 months [95% CI, 5.6-8.7 months] based on investigator assessment.
Study B was a Phase II study designed to evaluate the efficacy and safety of 750 mg Zykadia in patients with locally advanced or metastatic ALK+ NSCLC. Study B evaluated 140 patients who had been previously treated with one to three lines of chemotherapy followed by treatment with crizotinib, and who had then progressed on crizotinib. Detailed results from Study B will be presented at an upcoming medical congress.
In Studies A and B, brain metastases at baseline were seen in 60.1% and 71.4% of patients who had received prior treatment with an ALK inhibitor, respectively. The ORR, DOR and PFS by BIRC assessment for patients with brain metastases at baseline were similar with those reported for the overall population of these studies.
The most common adverse reactions with an incidence of >=10% were diarrhea, nausea, vomiting, tiredness (fatigue), liver laboratory test abnormalities (requires blood test monitoring), abdominal pain, decreased appetite, constipation, rash, kidney laboratory test abnormalities (requires blood test monitoring), heartburn and anemia. Grade 3-4 adverse reactions with an incidence of >=5% were liver laboratory test abnormalities, tiredness (fatigue), diarrhea, nausea and hyperglycemia (requires blood test monitoring).
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 approved by the European Commission for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib. Outside the European Union, Zykadia is approved for patients with ALK+ NSCLC in the United States and other countries within North America, South America, Central America and Asia. Additional regulatory reviews for Zykadia are underway worldwide.
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, eye care and cost-saving generic pharmaceuticals. Novartis is the only global company with leading positions in these areas. In 2014, the Group achieved net sales of USD 58.0 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 120,000 full-time-equivalent associates. Novartis products are available in more than 180 countries around the world.
1. Zykadia® (ceritinib) Summary of Product Characteristics. Basel, Switzerland: Novartis Pharma AG; 06-May-2015.
2. Jemal A, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90.
3. American Cancer Society. Detailed Guide: Lung Cancer (Non-Small Cell). Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf. Accessed March 2015.
4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer. NCCN 2014 3:1-148.
5. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4(120):1-12.