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EU's CHMP Grants Conditional Marketing Authorization to Novartis' Personalized NSCLC Rx Zykadia


NEW YORK (GenomeWeb) – In granting conditional marketing authorization to Novartis' ALK-targeting non-small cell lung cancer drug Zykadia (ceritinib) last week, Europe's Committee for Medicinal Products for Human Use (CHMP) accepted data from two early-phase trials, but said it expects the drugmaker to submit data from later-stage trials in the next three years.

CHMP recommended that Zykadia receive conditional marketing authorization as a treatment for non-small cell lung cancer patients with ALK-positive tumors who have previously received treatment with Pfizer's Xalkori (crizotinib) and progressed.

Since Zykadia is intended for advanced patients, their tumors would have already been characterized for ALK rearrangements by a lab test or a companion diagnostic when they were considering treatment with Xalkori.

According to the EMA European Public Assessment Report for Xalkori, an "accurate and validated ALK assay" is required to select which patients should receive the drug. Similarly, if Novartis were to eventually launch Zykadia as a first-line NSCLC drug, the treatment would likely need to be launched with a companion diagnostic for gauging ALK rearrangements in patients.

In order to receive conditional marketing authorization, Novartis submitted data from a Phase I and a Phase II study. The Phase I study involved approximately 246 ALK-positive NSCLC patients – 163 had received prior treatment with Xalkori and 83 patients were treatment naïve. After receiving Zykadia (750 mg), 56.4 percent experienced an objective response; the median duration of response was 8.3 months and median progression-free survival was 6.9 months based on investigators' assessments.

The Phase II study considered 750 mg Zykadia in 140 advanced ALK-positive NSCLC patients who had previously received chemotherapy followed by Xalkori and had progressed. The objective response rate was 37.1 percent in this trial and the median duration of response was 9.2 months.

At the start of both the Phase I and Phase II studies, 60 percent and 71 percent of patients, respectively, had brain metastases. The objective response rate, the duration of response, and the progression-free survival were similar for patients with brain metastases and the overall study population, Novartis said in a statement.

Noting that there is unmet medical need for advanced lung cancer patients, CHMP said that the benefits of Zykadia, based on data submitted so far, outweighed the risks associated with treatment. However, CHMP has requested Novartis submit data from ongoing studies and a comparative Phase III trial within the next three years.

Novartis will have to submit final data from the Phase II, single-arm trial of Zykadia in previously treated ALK-positive NSCLC patients, that CHMP used to recommend conditional marketing authorization. Final data from this study is slated for the second quarter of 2016, and at a medical meeting later this year, Novartis will present progression-free survival data from this trial. The company will also have to report to European regulators data from a Phase III randomized trial comparing Zykadia against standard chemotherapy in patients previously treated with chemotherapy and Xalkori. Data from this study is slated for the third quarter of 2018.

The US Food and Drug Administration last year granted accelerated approval for Zykadia for the same indication. Accelerated approval is also a kind of conditional marketing authorization in the US, which allows patients earlier access to drugs based on preliminary data showing the treatments are "reasonably likely" to benefit them, and until confirmatory data are available.

For the US approval, Novartis submitted data from a study involving 163 patients with metastatic ALK-positive NSCLC, who all received Zykadia. In that trial, approximately half the patients experience tumor shrinkage, which lasted for around seven months.

According to the FDA approval letter to Novartis for Zykadia, the drugmaker will have to submit additional evidence from a multicenter, randomized trial showing that its drug is superior to standard therapy in ALK-positive, metastatic NSCLC patients who received Xalkori previously or those who are treatment naïve. The trial is slated for completion in 2019. Additionally, the FDA wants Novartis to do a number of studies to provide more data on the safety and dosing of Zykadia, and whether repeat doses of the drug interferes with other agents such as midazolam and warfarin. 

In Europe, CHMP noted that its recommendation for conditional marketing authorization for Zykadia is an "intermediary step" toward granting NSCLC patients access to the drug. The European Commission will now review CHMP's recommendation and decide whether to grant marketing authorization within the EU.

"Once a marketing authorization has been granted, a decision about price and reimbursement will then take place at the level of each member state considering the potential role/use of this medicine in the context of the national health system of that country," the European Medicines Agency said in a statement last week. Novartis will also have to put in place a pharmacovigilance plan for Zykadia once marketing authorization is granted, the EMA said.

The EC generally follows CHMP's recommendations, and is slated to issue a determination in three months. In addition to the US, Zykadia is currently approved in Mexico, Chile, South Korea, Guatemala, and Ecuador. Novartis is pursuing approval of the drug in additional markets in North, South, and Central America, as well as in Asia.

Although Zykadia is currently available in the advanced, previously treated NSCLC setting, Novartis is eyeing the first line indication. According to its clinical pipeline, in 2017 Novartis is planning to file for regulatory approval for Zykadia in the US as a first-line treatment for ALK-positive, advanced NSCLC patients.

In the first-line setting, Novartis will likely need to advance Zykadia with a companion diagnostic to identify patients with ALK-positive tumors who are most likely to benefit from treatment. The drugmaker is using a test from Ventana Medical Systems to identify patients in clinical studies investigating Zykadia.


This article has been updated with additional information from Novartis about the clinical trials it is conducting for Zykadia.