MCL Expert Highlights Recent Advancements in Field

Peter Martin, MD

With the October 2017 FDA approval of the BTK inhibitor acalabrutinib (Calquence) for the treatment of patients with mantle cell lymphoma (MCL), the treatment armamentarium for this disease continues to expand.

Acalabrutinib joined ibrutinib (Imbruvica), which is another BTK inhibitor that has been approved for the treatment of patients with MCL since 2013. Long-term follow-up data out of the 2017 ASH Annual Meeting with single-agent ibrutinib demonstrated continued efficacy in patients with relapsed/refractory MCL.¹ More than one-quarter of the patients in this pooled analysis remained progression free, and nearly half were alive at 3 years after treatment with ibrutinib. The median overall survival was 26.7 months and the complete response rate was 26.5%, with patients who were treated with ibrutinib following 1 line of prior therapy experiencing the best outcomes.

Additionally, there are treatment regimens in the pipeline that appear promising, such as the combination of lenalidomide (Revlimid) and rituximab (Rituxan). Patients treated with this combination experienced a high rate of complete response and were able to achieve minimal residual disease negativity with durable remission beyond 4 years. These results suggest that lenalidomide plus rituximab is a feasible regimen that is also safe and active as initial and maintenance therapy.²

OncLive: We now have 2 BTK inhibitors approved in the MCL paradigm—ibrutinib and acalabrutinib. Can you discuss the similarities and differences between these agents?

In an interview with OncLive, Peter Martin, MD, an associate professor of medicine and the chief of the Lymphoma Program at Weill Cornell Medicine, reflected on the MCL data presented at the 2017 ASH Annual Meeting, and shared his insight on the future of clinical trials in the disease.Martin: These are both BTK inhibitors, so there are more similarities than differences. I can't speak from a payer perspective on what the differences might be with price, accessibility, or copay. There is obviously a difference in scheduling; one is once a day and the other is twice a day. They are both taken until progression, intolerance, or patient preference. With ibrutinib, there has been experience in MCL dating back to about 2009 or 2010 and probably thousands of patients have been treated. With acalabrutinib, we have seen data with just over 100 patients with MCL. It is clear that both drugs are effective in patients with preciously treated MCL.

They are both pretty similar in terms of efficacy, although there are theoretical advantages in terms of pharmacokinetics, drug-drug interactions, bioavailability, and effects on other aspects of the immune system for either drug. Without a head-to-head phase III trial, I am not sure that it is easy to say which drug is necessarily more effective. I am not sure that it is the most important question that we face in MCL either. Both drugs are effective, but there is still a lot of room for improvement. In terms of tolerability, each of them are pretty well tolerated, particularly compared with how patients with MCL were treated in the past. There are probably some differences in terms of gastrointestinal side effects, rash, headache, bleeding, and potential atrial fibrillation. Again, the magnitude of these differences is hard to compare without a phase III head-to-head trial.

We saw long-term follow-up data with ibrutinib at the 2017 ASH Annual Meeting. Do you foresee combinations with this agent in MCL now that we know its single-agent efficacy?

I suspect that, by and large, physicians will be comfortable using both, but some may be more comfortable using one or the other. For the most part, it is equally reasonable to start with either of the 2 medications. One thing to emphasize is that it’s great to have more medications available for people with MCL.Sure, we have already seen a lot of combinations with ibrutinib in multiple histologies—follicular lymphoma, diffuse large B-cell lymphoma, and MCL. Some of the most exciting trials that are either recently completed or ongoing are those trials that include other drugs that have some rationale in MCL, such as lenalidomide, venetoclax (Venclexta), or palbociclib (Ibrance). Some pretty important trials are getting underway with those drugs. PI3-kinase inhibitors are another class of medications that make sense. It makes sense to study these drugs in combination and see if we can improve on efficacy.

What are the options for patients who relapse on either ibrutinib or acalabrutinib?

One of the key questions in looking at these data is, “What is the increase in toxicity?” No doubt, when you add another medication to ibrutinib, there will be increased side effects. These are questions we will face as physicians. It is great to have phase I and II trials underway, for sure. If someone has a lymphoma that becomes resistant to BTK inhibition, we have other approved medications for MCL, such as bortezomib (Velcade), lenalidomide, monoclonal antibodies, and chemotherapy. It makes sense to do the same thing that MCL doctors have been doing for years now—look at what the prior therapies are, what the responses were, and make a decision based on that information. If someone has lymphoma that has been resistant to every known therapy under the sun and is progressing on ibrutinib, then that is going to be a challenging situation.

Aside from BTK inhibition, are there any other advancements moving through the pipeline?

We should look for a class of drugs that the patient hasn’t received before. There are some patients with MCL for whom ibrutinib has stopped working, and I assume that would be true for acalabrutinib, as well; some people have good outcomes with standardly available therapies. Some of it is based on observations and some of it is based on biology, which is somewhat limited. You can look at things like Ki-67 and TP53—some of it may be intuitive, and some of it may be a little bit of luck.Dr. Jia Ruan from Weill Cornell Medicine, previously published early data in the New England Journal of Medicine on a phase II trial of lenalidomide and rituximab. It was clear early on that this combination was pretty active. It’s fair to say that it was a relatively small number of patients treated, and it was at a handful of centers around the United States, so there was probably some selection bias that occurred. I don't think it was intentional, but that is just the nature of medicine and medical research.

Is there any research that you are participating in that you would like to highlight?

It was nice to see with longer-term follow-up, now out 5 years, that there are several people in complete remission or free from progression. Therefore, not only is the regimen effective, but there are some patients who continue to tolerate it 5 years out. It is clearly a regimen that is worth further evaluation. Our feeling is that it is also a regimen worth building on. There is some evidence of strong activity, and we are wondering if we can improve on that activity. Although people can be on it for 5 years, it would be nice to be able to improve the tolerability. I know that Dr Ruan is working on ways to improve on that lenalidomide/rituximab regimen. I would like to highlight Dr Ruan's study for sure in the frontline setting—that is something that our institution is putting a lot of effort into. Additionally, there is the palbociclib plus ibrutinib clinical trial. That study comes from data that were generated by Selina Chen-Kiang, PhD, in the Department of Pathology at Weill Cornell Medicine, and she is somebody that has made a career out of studying the cell cycle of CDK4 inhibition; she probably understands it better than anyone else around. Based on our initial experience with the phase I trial through the National Cancer Institute, we now have a phase II trial through the Alliance Foundation that is looking at a combination of ibrutinib plus palbociclib.

What do you believe to be the most pressing unmet need in the treatment of MCL?

If our phase I data are correct, we will find that there is a subset of patients who seem to have rapid, deep, and durable responses to that combination. We are getting to a point to where we can predict who those patients are, and so we hope that, through this phase II trial, we can get to a point that this is absolutely the right regimen for this patient, or it’s not the right regimen and we should look for different options. This upcoming trial will be interesting and important, not just from a patient perspective, but because it has a lot of heavy-duty science behind it and will undoubtedly move the whole field forward in ways that are otherwise uncommon.Patients drive everything, and there is no way you can say we are close to where we need to be with the treatment of MCL. Everybody has an unmet need, and randomly designing trials isn't going to get us far. We need scientifically derived mechanistic clinical trials and deliverables that help us move the whole field forward. This would be an easy question if MCL presented itself in one way or relapsed in one way. The truth is that this is a disease that is heterogeneous, and although it is a small number of patients, every one of those people is an individual. They could be 32 years old, 90 years old, someone with a lymphoma that is progressing very quickly involving the central nervous system, or it could be a disease that is quiet and hasn't moved in a decade. You are dealing with such a variety of presentations and people.

One thing you can do is understand the disease biology. If we can do that, we will be able to do a better job of picking and designing better therapies in the future. Therefore, better science is probably the biggest unmet need.

References

1. Rule S, Dreyling M, Goy A, et al. Median 3.5-year follow-up of ibrutinib treatment in patients with relapsed/refractory mantle cell lymphoma: a pooled analysis. In: Proceedings from the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 151.
2. Ruan J, Martin P, Christos P, et al. Initial treatment with lenalidomide plus rituximab for mantle cell lymphoma: 5-year follow-up and correlative analysis from a multi-center phase II study. Presented at: ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 154.