Type of information: Granting of a Market Authorisation in the EU
Product name: Zykadia® (LDK378)
Therapeutic area: Cancer - Oncology
Action mechanism: kinase inhibitor/tyrosine kinase inhibitor. LDK378 (ceritinib) is a highly selective inhibitor of anaplastic lymphoma kinase (ALK) that blocks proteins that promote the development of cancerous cells.
Company: Novartis (Switzerland)
Disease: treatment of patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who had progressed during treatment with, or were intolerant to, crizotinib - first-line treatment of patients with advanced NSCLC whose tumors are ALK+
- • On June 29, 2017, Novartis announced the European Commission approved 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.
- The first-line approval of Zykadia® is based on results from an open-label, randomized, multicenter, global, Phase III trial, ASCEND-4. The study met its primary endpoint, demonstrating a 45% reduction in the risk of disease progression in the Zykadia arm, compared to the chemotherapy arm (hazard ratio [HR] = 0.55 [95% confidence interval (CI): 0.42, 0.73; one-sided p value <0.0001]). Patients treated with first-line Zykadia® had a median progression-free survival (PFS) of 16.6 months (95% 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.
- Overall intracranial response rate (OIRR) in patients with measurable brain metastases at baseline and at least one post-baseline assessment was 72.7% (95% CI: 49.8, 89.3; n = 22) for patients treated with Zykadia®, versus 27.3% (95% CI: 10.7, 50.2; n = 22) for patients treated with chemotherapy. The whole body overall response rate (ORR) was 72.5% (95% CI: 65.5, 78.7; n = 189) in patients treated with Zykadia®.
- Further, patients without brain metastases at screening receiving Zykadia® 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]). Among patients with brain metastases at screening, 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]).
- • On May 8, 2015, Novartis announced that the European Commission has approved Zykadia® (ceritinib) to treat adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib. 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 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.
- 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.
- • On 26 February 2015 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a conditional marketing authorisation for Zykadia®, 150 mg, hard capsule, intended for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib. The benefits with Zykadia® are its important activity on ALK-positive NSCLC in patients previously treated with crizotinib, with an objective response rate of 56.4 %and 37.1% in a phase I and II study, respectively. The median duration of response was 8.3 and 9.2 months, respectively. The most common side effects are diarrhoea, nausea, vomiting, fatigue, liver laboratory test abnormalities, abdominal pain, decreased appetite, constipation, rash, blood creatinine increased, oesophageal disorder and anaemia. The most serious adverse reactions are hepatotoxicity, gastrointestinal effects, QT interval prolongation, bradycardia, interstitial lung disease/pneumonitis and hyperglycaemia. A pharmacovigilance plan for Zykadia® will be implemented as part of the marketing authorisation. It is proposed that Zykadia® be prescribed by physicians experienced in the treatment of anti-cancer medicinal products. The marketing authorisation is conditional.
• On April 29, 2014, the FDA has granted accelerated approval to Zykadia® (ceritinib) for patients with metastatic ALK-positive NSCLC who were previously treated with crizotinib, the only other approved ALK tyrosine kinase inhibitor. Zykadia® is the fourth drug with breakthrough therapy designation to receive FDA approval. It is being approved four months ahead of the product’s prescription drug user fee goal date of Aug. 24, 2014, the date the agency was scheduled to complete review of the drug application. The FDA granted Zykadia® breakthrough therapy designation, priority review and orphan product designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies; the drug had the potential, at the time of the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and the drug is intended to treat a rare disease, respectively. Zykadia®’s safety and effectiveness were established in a clinical trial of 163 participants with metastatic ALK-positive NSCLC. All participants were treated with Zykadia®. Results showed that about half of the participants had their tumors shrink, and this effect lasted an average of about seven months. Common side effects of Zykadia® include gastrointestinal symptoms such as diarrhea, nausea, vomiting and abdominal pain. Laboratory abnormalities such as increased liver enzymes, pancreatic enzymes and increased glucose levels were also observed. Among previously-treated patients, Zykadia® achieved an overall response rate (ORR) of 54.6% [95% CI, 47-62%] and a median duration of response (DOR) of 7.4 months [95% CI, 5.4-10.1 months].
- • On March 15, 2013, Novartis has announced that its investigational compound LDK378 has received Breakthrough Therapy designation by the FD) for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who had progressed during treatment with, or were intolerant to, crizotinib. According to the FDA, 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 over an available therapy on at least one clinically significant endpoint. The designation includes all of the fast track program features, as well as more intensive FDA guidance. The Breakthrough Therapy designation is a distinct status from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met. Initial results from a Phase I study investigating the maximum tolerated dose, safety, pharmacokinetics and antitumor activity of LDK378 in 88 patients with ALK+ advanced malignancies, as detected by an FDA-approved test and who had progressed during treatment with, or were intolerant to, crizotinib, were presented at the European Society of Medical Oncology 2012 annual congress. The data showed marked responses in a majority of patients with ALK+ NSCLC. A response rate (including complete response [CR], partial response [PR] and unconfirmed PR) of 80% was observed in the patients who had experienced disease progression after crizotinib treatment. Novartis has initiated two Phase II clinical trials to further evaluate the compound in this patient population with plans to initiate several Phase III clinical trials later this year. First regulatory filing is anticipated by early 2014.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2014-04-29/2017-05-29
UE authorization: 2015-05-06/2017-06-29
Favourable opinion UE: 2015-02-26
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: