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Novartis Gets US Approval for Zykadia for ALK-Positive NSCLC Patients Unresponsive to Xalkori

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NEW YORK (GenomeWeb) – For patients who have ALK-positive, advanced non-small cell lung cancer tumors and have stopped responding to Pfizer’s Xalkori (crizotinib), the US Food and Drug Administration this week approved a new option from Novartis called Zykadia (ceritinib).

The FDA granted breakthrough designation in March 2013 to Novartis’ ALK inhibitor Zykadia and approved it on a four-month priority review time frame, well ahead of the user fee deadline of August 24. The expedited approval enables Novartis to launch the drug on the market three and half years after enrolling the first patient in a clinical trial involving Zykadia.

The approval was based on data from a single-arm study involving 163 metastatic NSCLC patients, all of whom had ALK-positive tumors, had progressed on prior therapy, and received Zykadia. Approximately 55 percent of patients responded to the drug and the median duration of response was more than 7 months. Common adverse events that patients experienced in the study included diarrhea, nausea, elevated enzymes potentially indicative of liver damage, and vomiting.

“Despite treatment advances for patients with ALK-positive NSCLC, disease progression is often inevitable, typically less than a year after beginning initial therapy with an ALK inhibitor,” a Novartis spokesperson told PGx Reporter. Although Zykadia addresses an unmet need for those who are intolerant to or progress on Xalkori, NSCLC patients with ALK rearrangements in their tumors ultimately relapse on the follow-on treatment as well.

Of the patients enrolled in the study, 60 percent had brain metastases, 42 percent had their tumors spread to the bone, and the same proportion had metastases to the liver. Researchers retrospectively established that 99 percent of study participants’ tumors were ALK positive using local lab assays.

Zykadia is a personalized medicine agent indicated for a pharmcogenomically-defined subset of NSCLC but it was not approved alongside a companion diagnostic. “Zykadia is approved for second-line use, after a patient no longer responds or tolerates [Xalkori],” an FDA spokesperson told PGx Reporter, adding that it’s up to the sponsor to decide whether to develop a drug with a companion test. “In order to receive [Xalkori], a patient would have presumably already been screened for the ALK mutation.”

The Novartis spokesperson confirmed that the company didn’t develop a companion diagnostic for Zykadia, noting “there are several diagnostics available” to gauge the ALK status of tumors. Pfizer worked with Abbott Molecular to advance the Vysis FISH test as a companion test for Xalkori in the US and in Japan. Additionally, Ventana’s IHC ALK test is marketed in China and “is gaining use globally,” according to the Novartis representative.

Zykadia is considered an orphan drug since between 2 percent and 7 percent of NSCLC patients have ALK-positive tumors. According to estimates from the National Cancer Institute, more than 220,000 patients in the US will be diagnosed with lung cancer this year, of which 85 percent will have NSCLC.

The wholesale acquisition cost for a one-month supply of Zykadia (750 mg/day) is around $13,500. Novartis has a number of programs to help patients who are uninsured or underinsured to help pay for the drug. Under its co-pay assistance program for those who are privately insured, the company ensures that patients who meet certain criteria for the program will not pay more than $25 per prescription; Novartis can contribute up to $36,000 per year for each patient under this scheme.

Since Zykadia has been approved based on interim, early-stage data, the FDA requires Novartis to submit data from larger, late-stage trials proving the safety and efficacy of the drug in the NSCLC population. In this regard, Novartis is conducting two Phase II, single-arm trials in previously treated and previously untreated ALK-positive NSCLC patients. These studies have completed enrollment and are currently being conducted.

Additionally, Novartis is also recruiting patients into two Phase III trials comparing Zykadia against chemotherapy in treatment-naïve and previously treated patients. These late-stage studies in treatment-naïve patients, if successful, will enable Novartis to market Zykadia as a competitor to Pfizer’s Xalkori, indicated for front-line treatment of ALK-positive, metastatic NSCLC.

However, Novartis, at least at this time, isn’t prepared to disclose any future plans to differentiate Zykadia from Xalkori. “There are no head-to-head clinical studies comparing Zykadia to Xalkori, and cross-study comparisons are not appropriate because of substantial differences in study design, line of therapy, patient population demographics, and other factors,” the company spokesperson said. “At this time, we are focused on our post-marketing requirements and commitments and have not disclosed any plans for a head-to-head study of Zykadia with any other targeted agents.”

Although currently, Novartis’ priority is studying Zykadia in NSCLC, the company is exploring the drug in ALK-positive solid tumors beyond lung cancer, the spokesperson said.

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