Novel Agents, Combinations on Horizon for MCL

Bijal D. Shah, MD

The completion of pivotal clinical trials and the FDA approval of new therapies have dramatically changed the treatment paradigm for patients with mantle cell lymphoma (MCL). This evolution was initiated by the accelerated approval of ibrutinib (Imbruvica) as a treatment for patients with MCL following at least one prior therapy in November 2013.

Shortly after the approval of ibrutinib, the FDA approved the immunomodulatory agent lenalidomide (Revlimid) for patients with MCL following progression on two prior therapies including at least one prior treatment with bortezomib. In October 2014, the FDA approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) as a frontline treatment for patients with MCL. The combination of rituximab and lenalidomide has also demonstrated promise in the frontline setting, though not yet approved.

Other combination strategies under exploration hope to transform the role of chemotherapy and transplantation in subsets of patients with MCL. Novel therapies such as the BCL-2 inhibitor venetoclax (ABT-199) and HDAC inhibitors are also being explored as potential strategies in MCL.

Researchers are also diving deeper into the concept of maintenance therapy and targeted therapeutic inductions in the frontline setting for patients with MCL, according to Bijal D. Shah, MD. In an interview with OncLive, Shah, medical oncology, Moffitt Cancer Center, discussed some of these targeted agents and exactly how the treatment paradigm is poised to change for patients with MCL.

OncLive: How has the treatment landscape for patients with MCL evolved since the approval of ibrutinib?

Shah: I think it has changed in several ways. Ibrutinib clearly showed us that we could begin to approach MCL with targeted therapy and expect good responses. We have now seen emerging data with lenalidomide and rituximab, and we are starting to see similar data with BCL-2 inhibitors from AbbVie, showing that we can act within this disease and expect good outcomes.

What impact does the frontline approval of bortezomib have on the treatment of patients with MCL?

I’m still struggling with the frontline approval for bortezomib. It’s not a drug that we use often, largely due to the neuropathy that we commonly see with it. Certainly administering the drug subcutaneously has helped, and that decreases the instance of grade III neuropathy. However, we still see grade II neuropathy, and that can take awhile to improve.

I think the other, bigger piece of the puzzle, with the VR-CAP data (J Clin Oncol. 2014; 32:5s, suppl; abstr 8500) is that it was done without maintenance. It was bortezomib (VR-CAP) for six cycles compared with rituximab, cyclophosphamide, doxorubicin, and prednisone plus vincristine (R-CHOP) for six cycles. How easily are we going to be able to integrate VR-CAP into frontline therapy with maintenance built in, and what is going to be the optimal maintenance? Is it going to be single-agent rituximab, or are we going to go beyond that?

There is a study that cooperative groups are doing with bendamustine, bortezomib and rituximab. Essentially, the trial randomizes between bendamustine and rituximab, and bendamustine, bortezomib and rituximab. Then, there is a second randomization comparing rituximab alone to rituximab and lenalidomide. I think this also will help answer some more questions.

What novel agents are being explored in MCL?

I think ABT-199, the new BCL-2 inhibitor from AbbVie and Genentech, is showing a lot of promise. We had eight patients that were treated on the initial studies, and all eight of them had a remission. If I recall, six patients had partial responses and two had complete responses. This is very promising and is similar to the data ibrutinib had generated when it was first being explored in MCL. I think that is absolutely an exciting candidate moving forward.

We have yet to see what the CDK4 and CDK6 inhibitors will do, and what are these going to do in conjunction with some of our other therapies.

Finally, we have the HDAC inhibitors. We are getting smarter with those. Personally, here at Moffitt, we have elected to invest in the HDAC6 inhibitor from Acetylon Pharmaceuticals [rocilinostat], specifically with interest to explore this in MCL. We have generated a lot of preclinical data, and I’m excited to see what is going to happen when we bring it into the clinic.

What does the future hold for rocilinostat in MCL?

The preclinical data have been fantastic, and I think, for the clinical data, we have to wait and see. It’s very early. We are exploring this particular HDAC6 inhibitor across not just MCL, but all B cell and T cell lymphomas. It will be very interesting to see what falls out.

What potential role do HDAC inhibitors, like vorinostat, have in MCL?

Vorinostat is a very interesting agent. Vorinostat had generated stable disease in patients that lasted as long as 20 to 24 months, so almost two years.

Although we don’t like to think of stable disease as the optimal response, MCL is an otherwise highly aggressive disease in the relapse-refractory setting. Therefore, to generate that kind of a response, it shows that we really do have something that we can build off of in this context.

We are now finding that HDAC inhibitors may actually modulate the tumor to make it more recognizable by the immune system. It has the potential to bring in not just vorinostat, but also panobinostat and other HDAC inhibitors forward as a component of immunotherapy. This is very exciting. We have been seeing that happen in melanoma, and it is only a matter of time before we start seeing the same thing in lymphomas.

What other work is being done to modulate the immune system in MCL?

The phase II study on the combination of lenalidomide plus rituximab deserves special mention. This is one of the few times in MCL where we tried to bring the targeted agents to frontline therapy and with incredible success. In many ways, this is going to establish a new paradigm for MCL—perhaps reflecting what we’ve been doing in myeloma for many years—where chemotherapy is brought in only to the most proliferative variance.

For the less proliferative subtypes, the favored approach is immunotherapy, such as lenalidomide and ibrutinib. Bortezomib may also find its way in that frontline setting or, more likely, second-generation proteasome inhibitors will, where we can avoid some of the neuropathy we have seen. I think this is the future.

I think we are also going to start questioning the role of transplant, particularly in the context of maintenance rituximab. The data I love to quote is the ECOG-E1405 study. It was a VcR-CVAD treatment, and it was supposed to be followed by maintenance rituximab. About half of the patients ended up going onto transplant. It wasn’t planned, but it sort of ended up happening that way. The groups turned out to be well balanced. When they went and did the analysis comparing how these two groups fared—be it maintenance rituximab or autologous transplant—the responses in progression-free survival and overall survival were identical. It wasn’t planned, so you can always ask, “How valid is this comparison?”

However, now we have the data from the European Mantle Cell Consortium looking at maintenance rituximab after R-CHOP (New Eng J Med. 2012; 367: 520-531). That data was almost superimposable upon the maxi-CHOP transplant data that were first generated by Geisler.

We are seeing a new paradigm: the concept of maintenance, the concept of targeted therapeutic inductions in the frontline setting, and reserving chemotherapy for those subtypes that are more proliferative, or are more risky situations.

What questions still need to be answered in MCL?

We have not cured MCL, so we have a lot of work to do in that regards. I hope, one day, we can look at this disease and talk very seriously about these subtypes where we can actually consider cure much the same way we do in diffuse large B-cell lymphomas. I realize that is 10 to 20 years off, but I think it’s reasonable to start thinking about that. We are moving in that direction when we talk about CAR T cell therapies, bispecific antibody therapies, and immunotherapy as a whole.

In the meantime, the challenges that I think lay before us are in understanding resistance to some of our current agents. Ibrutinib is one that I think deserves special attention, because we are seeing so much resistance. It may even be that we are accelerating disease in a subset of these patients. We need to better understand how to identify and predict resistance, and hopefully prevent what may even be an acceleration of disease in some patients.