Byrd Says Frontline Ibrutinib Approval Moves CLL Closer to a Cure

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

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.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.

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

How will the recent approval of ibrutinib impact patients?

Do you see CLL completely moving away from chemotherapy?

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.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.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.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.

What combinations do you see the most potential for with ibrutinib in CLL?

There is also a growing knowledge of “chemo brain” where patient’s cognitive function is not the same after chemotherapy. These targeted agents have significantly fewer side effects than chemotherapy.There are many combination trials out there, but the ones our group is most excited about are with some very active agents, such as venetoclax and bevacizumab, given with ibrutinib.

I am also interested in using ibrutinib not only to improve CLL survival, but also to repair the immune system and then give immunotherapy with it. We just published a paper showing that, when you give ibrutinib you can generate better CAR T cells. This is leading to trial over a period of time that will give patients ibrutinib for a period of time, and then give them CAR T cells.

What are the biggest challenges that remain in CLL?

The exciting thing about ibrutinib is that it is going to have that same application in enhancing immune response not only in CLL, but also in other blood cancers and a lot of solid tumor work.We have a couple of challenges. One challenge is that we have these great therapies, but we have people on chronic medicines for a long period of time that cost a lot of money. The strategy of getting people to complete remissions and to be able to get off therapy is one that will be exciting.

Another challenge is that, unfortunately, we have a subset of patients who don’t benefit from these drugs; we need new therapies for them.

We have a relatively uncommon syndrome called Richter’s Syndrome, where CLL changes to an aggressive large cell lymphoma. When that happens, it is almost always bad; therapies for that patient population are not good. That is another area we need to focus on.

We also need to come up with ways that patients—whether they are rich or poor—whether they are on Medicare or not, can get these novel agents if they need them. There is nothing worse than having a great drug that you talk to a patient about who says they would love to take it, but their insurance won’t cover it or their copay is too high.

The cost of drugs, especially for life-saving drugs such as ibrutinib, is very important. We really need to look, as a country, at how we are going to make these available to people in all socioeconomic groups.

1. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-2437.