Timothy Fenske, MD, MS
Beyond effective BTK inhibitors, novel combinations with venetoclax (Venclexta), PI3K inhibitors, and proteasome inhibitors all have the potential to further improve survival in patients with relapsed/refractory mantle cell lymphoma (MCL), said Timothy Fenske, MD, MS.
Next-generation BTK inhibitors are also moving through the pipeline with the hope of joining the treatment armamentarium—which currently consists of ibrutinib (Imbruvica) and acalabrutinib (Calquence)—that could potentially overcome acquired resistance.
“I could envision a day, hopefully not too far down the road, when we could perform a BTK mutation analysis for a patient who shows resistance to ibrutinib or acalabrutinib and that would tell us which BTK inhibitor we should switch them to,” said Fenske, an associate professor at the Medical College of Wisconsin. “This is like what we are already doing in chronic myeloid leukemia with BCR
-ABL mutation analysis.”
In an interview during the 2019 OncLive®
State of the Science Summit™ on Hematologic Malignancies, Fenske discussed promising ongoing research in MCL that will look to further advanced the evolving paradigm.
OncLive: What advice would you give to oncologists who have patients who are progressing on ibrutinib?
: I would take a step back and ask if they are truly progressing on ibrutinib or if it is an intolerance. Sometimes, the drug gets stopped due to adverse events. For example, if someone is having atrial fibrillation, renal insufficiency, diarrhea, rash, or some of the more musculoskeletal complaints to ibrutinib but they are actually responding to it, then a switch to the other FDA-approved BTK inhibitor acalabrutinib might be a very sensible choice in that setting.
However, if the patient has actually progressed—the lymphoma is progressing, and the patient has been compliant—we don't have evidence that acalabrutinib would be effective in that setting. I presented some data that looked at newer-generation BTK inhibitors that may [have the potential to] overcome resistance. For now, off-protocol, we would switch to a different drug, such as lenalidomide (Revlimid), or a proteasome inhibitor. In a non–FDA-approved case, we would switch to venetoclax or turn to a clinical trial.
What are some of the next-generation BTK inhibitors that you’re excited about?
There are quite a few in development—probably 10 or more out there. The takeaway from that is that there are 2 classes of BTK inhibitors: covalent inhibitors [and noncovalent inhibitors]. Acalabrutinib and ibrutinib covalently bind to the BTK enzyme, and when you get a mutation where the drug resides, the drug can't bind anymore; this [results in the development of] resistance. There is a new category of BTK inhibitors that are noncovalent binders that, in vitro, still seem to block the enzyme even when that mutation is present.
What data do we have with venetoclax?
With venetoclax, there has been a phase I/II trial performed in multiple lymphoma subsets, and one of those types was MCL. There were 20 or 30 patients with MCL included in that study, and the overall response rate [with the agent] was 75%. It does appear to be quite active in MCL. Hopefully, we will have some larger data coming. There are many trials looking at novel combinations of venetoclax and BTK inhibitors.
Could you expand on some of the combination strategies that are being explored with venetoclax?
There was one paper published in the New England Journal of Medicine
within the last year or 2, where investigators combined ibrutinib with venetoclax. They saw very high rates of minimal residual disease (MRD) negativity. Even patients who had p53
mutations, which historically is a group that does very poorly, they saw what looked like favorable outcomes. It was a small, single-arm study of under 30 patients. We definitely need more data with that particular combination, but it looked interesting. The bigger question will be whether combination therapy or sequential therapy is better in the long run.
Are there any specific targets that are being evaluated in ongoing studies?
The proteasome has been a target; that was one of the original approved targets in MCL. There are some new proteasome inhibitors being tested. There is an oral agent called ixazomib (Ninlaro), with which we have a trial open for at the Medical College of Wisconsin. The trial is exploring the combination of ibrutinib and ixazomib in patients with relapsed/refractory MCL. There are several other interesting targets. The PI3K inhibitors have been of interest in MCL and there has been some activity there, but not dramatic single-agent activity. None of these agents have an FDA approval in MCL, but we may see some combinations involving PI3K inhibitors, potentially.
Could daratumumab (Darzalex) have a future in this space?
Daratumumab has been disappointing as a lymphoma drug, but maybe there have been some exceptions like natural killer/T-cell lymphomas. In that space, there has been some anecdotal activity [with daratumumab.] In general, in the B-cell lymphomas, there hasn't been a lot of activity [with this agent], despite the fact that some of these lymphomas express CD38. It's not entirely clear why the drug has been so successful in plasma cell disorders but less so in B-cell malignancies. As I mentioned, PI3K inhibitors are quite active in chronic lymphocytic leukemia and follicular lymphoma, but in other lymphomas like MCL, there has been modest activity.
In MCL, you see a high proportion of genomic instability, chromosome complex karyotypes, p53
mutations, and other factors that promote drug resistance. However, if you look over the last several years, there has definitely been an improvement in survival in MCL, so we are definitely making strides little by little. There has probably been more progress made with frontline therapy.
With some of our more aggressive induction strategies, we’re seeing 8- to 10-year first remissions. Once the patient relapses, though, it becomes a more difficult problem. For most of the drugs, remissions are in the 1- to 2-year range. The long-term follow-up with acalabrutinib actually does look to be an excess of 2 years. We are starting to crack that [puzzle], but it's been little by little.
What recent data have we seen with CAR T-cell therapy?
CAR T-cell [products] are approved commercially for use in diffuse large B-cell lymphoma, but there is no reason or theory to suggest that the approach couldn't work in other B-cell lymphomas. We have an open trial at our center that uses a dual-targeted CAR T-cell construct that goes after both CD19 and CD20. In terms of MCL, the excitement there is in the initial wave of patients recently presented. Of the first 12 patients treated [with this approach], 5 had MCL, and 4 of those patients achieved complete remission (CR). To date, I'm pretty sure that none of those patients have relapsed yet. I personally have a patient who was highly refractory to multiple therapies, and that was really quite remarkable. Another unique feature of that particular study was that we produced the cells on site. We didn't have to ship them off to a third party. This has the potential to not only be innovative but market disruptive in terms of how the production happens.
What is your take-home message to your colleagues?
It is important to inquire about clinical trials because many academic centers will have trials open for relapsed MCL. In the frontline setting, we have a study that's led by ECOG and is using a next-generation sequencing (NGS) MRD assay that measures minute amounts of circulating tumor DNA. The premise of the study is that probably not all patients benefit from autologous stem cell transplantation (ASCT) in first response. Patients can get any induction by their community oncologist, and then when they are finishing induction, we assess them with PET scan, bone marrow, and this NGS test. Only those patients who are in CR and who are MRD-negative are then randomized to undergo either immediate ASCT followed by maintenance rituximab (Rituxan) or deferral of ASCT and just rituximab. The hypothesis is that if a patient is MRD-negative, maybe they don't benefit as much from the transplant. The study is accruing very well.