MCL Research Must Refocus on Sequencing, Goy Says

Andre Goy, MD

Andre Goy, MD

Following in the footsteps of the BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence) in mantle cell lymphoma, investigators are exploring other novel agents in the relapsed/refractory population.

For example, ZUMA-2, a phase II, multicenter, open-label study is currently evaluating the efficacy of the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) in subjects with relapsed or refractory MCL (NCT02601313). In the single-arm study, researchers will use a primary endpoint of overall response rate. Patients enrolled on the study will be given a conditioning chemotherapy regimen of fludarabine and cyclophosphamide followed by a single infusion of axicabtagene ciloleucel.

In an interview withTargeted Oncology, Andre Goy, MD, chairman and director, chief of Lymphoma, and director of Clinical and Translational Cancer Research at John Theurer Cancer Center, Hackensack Medical Center, discussed the excitement surrounding novel therapies on the horizon in MCL.

TARGETED ONCOLOGY:The ZUMA-2 trial is ongoing. What is the potential impact of this study?

Goy:ZUMA-2 uses CD19-targeted CAR T cells dedicated for MCL in patients who have failed prior therapy, including ibrutinib. We know that patients who have failed ibrutinib typically have very poor outcomes, and those patients have seen multiple therapies. In this setting, there is no real curative option, expect if a patient can go on allogeneic transplant. The more we give therapies to patients with MCL, the more they become a blastoid-variant [subtype] with a higher prolific disease. They then don’t do well with additional therapies and are very hard to control. Therefore, the ability to [give patients] a CAR T-cell therapy is obviously very appealing.

We are a part of the ongoing ZUMA-2 trial that is being amended and is on hold for now, but we will start soon. Thus far, we have seen some impressive complete responses (CRs), and it seems from the early data that the CR rate is even higher than in large cell lymphoma. It is early, but we will have exciting data by the end of the year.

TARGETED ONCOLOGY:What other agents are showing promise in MCL?

Goy:In the field of MCL, like many lymphomas, there are a lot of novel therapies. The first BTK inhibitor that was approved initially in chronic lymphocytic leukemia (CLL) and then in MCL was ibrutinib. It has been a game changer, as the response rate is over 60% and the CR rate was initially up to 40% with not a lot of toxicity—though a fraction of patients had bleeding issues. We know that patients eventually progress, so there has been an effort to develop second-generation BTK inhibitors with other off-target effects and potentially a better toxicity profile.

Upcoming is the SHINE trial and a frontline randomized acalabrutinib trial. This is, as we build up on the backbone of the chemotherapy that is used by default in MCL, very exciting. We are also going to develop combinations of novel therapies in the frontline setting without chemotherapy that will allow us to hopefully reach a high level of CR and minimal residual disease (MRD)-negative status that will have an impact on outcomes. This could [perhaps] replace chemotherapy in a patient who cannot undergo intensive therapy, which is the only way to provide a deep molecular CR in that setting.

Similarly, we are going to see several additional trials that are going to take advantage of the better toxicity profile and [combinations] with immunotherapy, including cell therapy and CAR T cells to try and sensitize or mobilize the cells. That will give better access or clearance to the bone marrow.

TARGETED ONCOLOGY:How will the treatment paradigm shift in the next 5 to 10 years?

Goy:As much enthusiasm as there is for these novel therapies, we must refocus on sequencing. We must look at our database of MCL to determine what the best sequence of therapies is to treat this disease. It is a disease where it is important to achieve a CR early. There is a small subset of patients who can be monitored for quite a while. I am talking about the indolent-variant MCL patients who have a high white [blood cell] count, somatically mutated, genetically stable disease. These patients behave almost like a CLL and can be monitored for quite a long time.

There are some patients with low tumor burden who do not have those characteristics. The challenge is that, among these patients, there are still some who present withp53mutations at baseline or 17p deletion. [However], it is more common when you look at this in a large scale. We have published that if you look at ap53mutation at baseline, you find many more patients than those with 17p deletion. Those patients will present a challenge regarding chemotherapy, so we must look at novel therapies to bring them into remission—maybe cell therapy or CAR T-cell therapy as a consolidation in the future.

For patients who are younger and can undergo a more intensive transplant or dose-intensive strategies, there is a still a way to give them a progression-free survival that is well in excess of 5 to 7 years. If you look at the long-term follow-up, over 50% of these patients can do well over 10 years. There is clearly a fraction who have much better outcomes than just standard R-CHOP or bendamustine and rituximab (Rituxan)-type chemotherapy.

Given the median age of diagnosis in the late 60s, the usual patient cannot undergo intensive therapy. Therefore, for those patients, allogeneic transplant and CAR T-cell therapy might be very important. Finally, for the rest of patients, novel therapies will provide the option to either combine with chemotherapy or replace it.

Overall, the theme moving forward will be to gain a better understanding of the subset of MCL at baseline, bring them into complete remission early on, look at MRD status—because that is what affects the outcome—and potentially develop consolidation and maintenance based on MRD. That is basically the next 5 years in MCL.

TARGETED ONCOLOGY:You mentioned a database and patient characteristics. Do you see a place for Cota in this scenario?

Goy:The field of medicine is changing dramatically, but there are issues of sustainability on how we fit in the bigger picture of the pharmacological environment given the cost of the drugs, duration of treatment, etc. It is important that we have evidence that we are bringing clinical benefit to patients. If you look at the options for patients with lung cancer, there are 79 new options for non—small cell lung cancer. How do you pick the best option and how do you develop precision medicine? I would argue that precision medicine forces us to understand what we do best for what we know already.