Post-Ibrutinib Treatments Show Promise in CLL

Sameem Abedin, MD

While long-term data have solidified the frontline role of ibrutinib (Imbruvica) in the chronic lymphocytic leukemia (CLL) paradigm for several patients, venetoclax (Venclexta), duvelisib (Copiktra), and acalabrutinib (Calquence) could be beneficial for those who fail on or are unable to tolerate the FDA-approved BTK inhibitor, explained Sameem Abedin, MD.

For example, venetoclax is indicated for patients with CLL or small lymphocytic lymphoma (SLL) with or without 17p deletion and following ≥1 prior therapy, and also for use in combination with rituximab (Rituxan) in the same patient population.

More recently, a supplemental new drug application (sNDA) was filed in March 2019 for venetoclax plus obinutuzumab (Gazyva) for use in patients with treatment-naïve CLL who also have coexisting medical conditions. The application is based on data from the phase III CLL14 study, which showed that a fixed-duration of venetoclax and obinutuzumab led to a statistically significant reduction in the risk of disease progression or death versus obinutuzumab plus chlorambucil in this patient population. Full findings will be presented at an upcoming medical meeting.

“What we are all kind of waiting for is what the results from CLL14 are,” said Abedin, an assistant professor at Medical College of Wisconsin. “We’re all aware that the combination has been registered for frontline approval, but we haven’t seen the formal presentation of those results. Therefore, we’re all eagerly waiting to see how well this combination performs in the frontline setting for CLL.”

Other agents have moved through the pipeline, such as the PI3K inhibitor duvelisib, which is approved as a treatment for patients with relapsed/refractory CLL/SLL or relapsed/refractory follicular lymphoma. Additionally, the BTK inhibitor acalabrutinib is being explored in a head-to-head comparison against ibrutinib in a phase III trial of patients with previously treated, high-risk CLL (NCT02477696).

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Abedin discussed the recent encouraging data in CLL with these therapeutic agents.

OncLive: What are the latest updates in CLL?

Abedin: Really, what I wanted to focus on [in my presentation] were new approvals in CLL. There have been a lot of new drugs that have been approved, and I wanted to put some context to it—in other words, what I feel is appropriate for patients on initial diagnosis and then subsequently thereafter. In CLL in general, there is a lot of excitement and a lot of new drugs with pretty good activity. The point of this talk was to really get a sense of what [drugs are] out there, how to use them, when to use them, and hopefully that’s what the audience got at the end of the talk.

Regarding these recent approvals, how are they fitting into the paradigm with regard to sequencing?

First of all, the biggest approval that came over the past year is the establishment of ibrutinib as the frontline treatment in CLL. So many physicians have been using ibrutinib as the frontline treatment for [patients with] CLL. There have been 2 randomized trials led by ALLIANCE and ECOG, which have now established ibrutinib as first-line treatment for all patients with CLL, so that is sort of the starting point and the most important finding.

Besides that, there is the efficacy of venetoclax alone and in combination in relapsed/refractory CLL, as well as the recent approval of duvelisib for relapsed/refractory CLL. Both are important because both agents, after initial treatment, provide decent responses as well as good PFS. What I wanted to focus on is which drug I would prefer to use first upon patients who relapse. At least in terms of trial design, the duvelisib trial did not include patients who failed BTK inhibitors, whereas there were a few patients [who failed BTK inhibition] with venetoclax. There are a bit more data outside the MURANO trial to suggest that there is efficacy for BLC-2 inhibition after BTK failure. There is a richness of data for using venetoclax after ibrutinib failure, if [ibrutinib] is going to be the first-line treatment for patients.

Also, there are differences between duvelisib and idelalisib (Zydelig), which is another PI3K inhibitor that is already approved in CLL. There is a slightly different mechanism; they are both PI3K inhibitors, although duvelisib has further immune properties. There is also the fact that duvelisib is given alone, whereas idelalisib was tried in combination with rituximab. An important point to make is that, at the end of the day, is it easier in that it’s a pill you can take alone versus the combination?

An sNDA was submitted for venetoclax plus obinutuzumab in frontline CLL. Where does that combination fit in if it gets FDA approval?

The interesting thing is that the combination of a CD20-directed antibody and venetoclax seems to have synergy. When you look at the studies that looked at combining rituximab with ibrutinib, or obinutuzumab with ibrutinib, what we haven’t seen is a significant improvement in terms of response rates or PFS. The interesting thing about venetoclax is—in the CLL14 trial for the combination for obinutuzumab and venetoclax—you’re seeing an improvement in ORR and PFS.

The important thing, first of all, is that there is synergy in combining CD20-directed antibody and venetoclax, which is interesting. If this approval does happen, then this would be great for patients with CLL because there are toxicities with ibrutinib use; atrial fibrillation and risk of bleeding are important considerations, and nausea as well. What it at least offers is an alternative for patients with these issues.

The thing I will say about ibrutinib is that there is certainly a lot of “meat” to using it in the first-line setting. We have 2 randomized trials that compared it with prior standard of care, and we have a lot more data in terms of long-term follow-up with ibrutinib. In terms of immediately switching over to venetoclax, those data just aren’t there. But, certainly the data that are there so far are very promising, particularly the responses and depth of response we’re seeing with venetoclax combinations.

Acalabrutinib and ibrutinib are being compared head-to-head in a phase III CLL trial. Could you discuss that study?

First of all, what are the differences? With acalabrutinib, one of the main issues that we’re not seeing are the cardiac toxicities that we see with ibrutinib. There are virtually no cardiac toxicities, and no atrial fibrillation. A major issue, particularly for older patients who develop CLL, are the issues of cardiac toxicity and atrial fibrillation. From at least that standpoint, acalabrutinib has a lot of promise to it.

In terms of responses, what we are seeing with this second-generation BTK inhibitor are more robust responses. I believe the responses are upwards of 90% with acalabrutinib, whereas for ibrutinib, it is closer to 88%. We are also seeing deeper responses with acalabrutinib, so more complete responses. Overall, the data are very exciting. Acalabrutinib offers a way to give BTK inhibition to patients whom otherwise would have been a risky proposition.

What other research areas in CLL are you currently interested in?

A last thing for patients with CLL that is exciting is the development of CAR T-cell therapy, so there is a lot of excitement for aggressive lymphomas. There are increasing data for its use in indolent lymphomas and CLL is no different. At the 2018 ASH Annual Meeting, [researchers from the University of Pennsylvania] demonstrated pretty remarkable results using CAR T-cell therapy in ibrutinib-primed patients with CLL [and potentially curing them].

The other thing that has sort of fallen off but remains important is allogeneic stem cell transplant. I am a leukemia doctor and a “transplanter.” We have agents that we are seeing responses with, then we have patients who are candidates and that is an important consideration. That is something that needs to continue to be considered for this population.

Genentech Submits Supplemental New Drug Application to FDA for Venclexta Plus Gazyva for Previously Untreated Chronic Lymphocytic Leukemia with Co-Existing Medical Conditions. Genentech (Roche). Published March 7, 2019. https://bit.ly/2C9as21. Accessed March 7, 2019.