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Byrd Says Frontline Ibrutinib Approval Moves CLL Closer to a Cure

Laura Panjwani
Published: Thursday, Mar 24, 2016

John Byrd, MD

John Byrd, MD

With ibrutinib (Imbruvica) recently receiving FDA approval as a frontline treatment for patients with chronic lymphocytic leukemia (CLL), oncologists now have a wider pool of patients to consider that could potentially benefit from the BTK-inhibitor.

For John Byrd, MD, the challenge will not encompass identifying which patients with CLL should receive ibrutinib, but identifying the few who should not.

“Outside of the rare patients who are on blood thinners or have the more favorable IGVH-mutated CLL that could be cured by FCR chemotherapy, there is really not another patient population that I wouldn’t consider giving ibrutinib to as their initial therapy for CLL,” says Byrd, director of the Division of Hematology, Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. “The results of this drug look really look good. It is something that is going to completely change how we treat CLL in the United States.”

The frontline ibrutinib approval was based on the RESONATE-2 trial,1 which included 269 treatment-naïve patients aged ≥65 years with CLL or SLL. Patients were randomized 1:1 to receive either 420 mg of ibrutinib daily until progression or 0.5 to 0.8 mg/kg of chlorambucil on days 1 and 15 of each 28-day cycle, for a total of 12 cycles.

The study’s primary endpoint was progression-free survival (PFS) as evaluated by an independent review committee, which found that compared with chlorambucil, ibrutinib led to an 84% reduction in the risk of progression or death (HR, 0.16; 95% CI, 0.09-0.28).

At a median follow-up of 18.4 months, the median PFS was not yet reached with ibrutinib versus 19 months with chlorambucil (P <.0001) .The median 18-month PFS rates were 94% and 45%, respectively, and the results were consistent across subgroups.

OncLive spoke with Byrd to learn more about the RESONATE-2 trial and the impact of ibrutinib in CLL. In his interview, Byrd explains why he believes the ibrutinib approval is practice changing, and how he thinks the agent should be utilized next.

OncLive: Can you discuss the value of the RESONATE-1 and RESONATE-2 studies?

Byrd: The RESONATE-1 study was the first study that led to the full approval of ibrutinib in relapsed/refractory CLL. We updated the data just this past year, showing that the remissions in the study are continuing to be persistent.

Patients are doing quite well in both the arm that was initially assigned to ibrutinib and the many patients that have crossed over. The value of the study, in addition to showcasing the significant benefit of ibrutinib, also identified relatively uncommon, but present adverse events. These include atrial fibrillation and bleeding.

In most patients, this is not clinically significant; however, it is in a subset of patients. It calls to our attention the need to manage them effectively for patients.

RESONATE-2 was just published in The New England Journal of Medicine and that is a groundbreaking paper. The study used a very weak control regimen—chlorambucil—but, really, you could use any therapy that we give in CLL and the results would have been the same.

Patients on ibrutinib have done phenomenal; there have been very, very few progressions. The survival curve is essentially flat, and it looks like a survival curve with patients who are age-matched without CLL.

Were there any concerning toxicities seen in the RESONATE-2 trial?

The study, again, showed that atrial fibrillation occurred in some patients. This was a little bit more common with ibrutinib than chlorambucil. However, it is manageable in most. This study is really a paradigm-changing study.

How will the recent approval of ibrutinib impact patients?

I suspect we are going to see a treatment paradigm with this as a single agent or with other active drugs given with it in combination. We will also cure the disease in a subset or convert the disease to one where patients are either on a medicine long-term or on and off a very targeted medicine.

Do you see CLL completely moving away from chemotherapy?

Yes. Except in a subset of CLL where we can cure their disease with FCR, I don’t think we will be using chemotherapy very much in the future. Patients who receive FCR can get infections, secondary leukemias from immune suppression, and it can negatively impact organ function.


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