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FDA Approves Imbruvica for Subset of CLL Patients with 17p Deletions

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Originally published July 29.

NEW YORK (GenomeWeb) – The US Food and Drug Administration has approved an expanded indication for the leukemia drug Imbruvica (ibrutinib) as a treatment for chronic lymphocytic leukemia patients who harbor a deletion in chromosome 17.

According to Samina Bari, a spokesperson for drug sponsor Pharmacyclics, Imbruvica is the first FDA-approved drug for CLL patients with 17p deletions, a subset in which there is high unmet need in terms of viable treatments.

CLL patients with 17p deletions respond poorly to standard chemoimmunotherapies for the disease. Approximately 7 percent of treatment naïve CLL patients and between 20 percent and 40 percent of relapsed or refractory patients harbor the 17p deletion. "A patient is defined as being del 17p when a minimum number [i.e., 5 percent to 7 percent] of malignant cells have a missing short arm on chromosome 17, as demonstrated by an antibody probe fluorescence in situ hybridization," Bari told PGx Reporter over email.

Imbruvica is a small molecule inhibitor of Bruton tyrosine kinase, an enzyme involved in B cell signaling and in driving cancer. The drug was co-developed by Pharmacyclics and Janssen Biotech. Under the terms of its deal with Janssen, Pharmacyclics is slated to receive $60 million in milestone payments based on this latest approval for Imbruvica.

The latest indication for Imbruvica comes more than two months ahead of its user fee goal of Oct. 7. The FDA granted breakthrough therapy designation to Imbruvica as a treatment for the subset of patients with 17p deletions.

Last year, Abbott announced that its Vysis fluorescence in situ hybridization probe kit for CLL will be used in clinical trials to identify patients who have this specific deletion and may respond well to Imbruvica. However, in approving the expanded indication for Imbruvica, the FDA did not approve any companion diagnostic kit that doctors can use to pick out best responders. This is likely because lab developed tests are readily used in clinical practice to test CLL patients for this marker.

"There are no specific requirements for the determination of the presence of del 17p in CLL patients," Bari said. "However, patients are assessed for the presence of del 17p as part of standard disease assessment using a FISH assay or via routine cytogenetic evaluation, although the FISH test is far more sensitive."

Abbott's Vysis FISH test is one option available to healthcare providers who wish to assess whether a CLL patient has the 17p deletion. The FDA in 2011 green-lighted Abbott's Vysis CLL FISH Probe Kit. The test gauges multiple genes, including TP53, which is located within the del 17p region, and is used to assess disease prognosis in CLL.

"FISH [testing] already is recommended as part of the pre-treatment evaluation for CLL patients in general clinical practice," Bari noted. "In the US, there is good access to this kind of assay."

Simultaneous with announcing the expanded indication for Imbruvica, "the FDA is also approving new labeling to reflect that Imbruvica's clinical benefit in treating CLL has been verified," the agency said in a statement.

In February this year, the agency granted accelerated approval for Imbruvica for all CLL patients based on study participants' overall response rate to the therapy. However, data from the Phase III RESONATE study show that the drug significantly impacted progression-free survival and overall survival for CLL patients generally, as well as for those with 17p deletions. Based on this, the FDA has converted Imbruvica's accelerated approval for previously treated CLL into a full approval.

The 391-patient, randomized study compared Imbruvica against another recently approved CLL agent, Arzerra (ofatumumab). In this cohort of previously treated CLL patients, 127 carried the 17p deletion. The study participants received their randomly assigned drugs until their disease progressed or they could no longer tolerate the side effects.

After a preplanned interim analysis, the trial was stopped early, showing that patients receiving Imbruvica experienced a 78 percent reduction in risk of disease progression or progression-free survival, as well as a 57 percent reduction in risk of overall survival. Meanwhile, in the subset of patients with the 17p deletion, Imbruvica-treated patients saw a 75 percent reduction of risk in progression-free survival and overall survival.

Patients on Imbruvica commonly reported side effects such as low levels of platelets, white and red blood cells, diarrhea, fatigue, muscle and bone pain, upper respiratory tract infection, rash, nausea, and fever. Additionally, Pharmacyclics and Janssen submitted to the FDA data from other studies involving Imbruvica, including treatment-naïve del 17p patients, Bari said.

CLL is a rare form of non-Hodgkin lymphoma that affects white blood cells, called B lymphocytes. According to the NCI, close to 16,000 people in the US will be diagnosed with the illness and more than 4,500 people will die from CLL this year. Imbruvica is the fourth CLL drug that the FDA has approved in eight months. Last November, the agency approved Genentech's Gazyva (obinutuzumab), then GlaxoSmithKline's Arzerra in April, and Gilead's Zydelig (idelalisib) in July.

In addition to Imbruvica's indications in CLL, the FDA previously granted accelerated approval for mantle cell lymphoma patients who have received at least one prior therapy. However, Pharmacyclics is still conducting studies to verify Imbruvica's clinical benefit in this setting.

The 17p deletion-characterized CLL indication marks the third breakthrough therapy designation for Imbruvica. The drug previously received this designation in the context of relapsed or refractory mantle cell lymphoma and Waldenstrom's macroglobulinemia, two B cell malignancies.

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