Intriguing Immunotherapy Regimens Investigated in MCL

Grzegorz S. Nowakowski, MD

The treatment paradigm of mantle cell lymphoma (MCL) is in the midst of extensive research with novel immunotherapy combination regimens, explains Grzegorz S. Nowakowski, MD.

For example, a phase I/Ib trial is looking at the safety and maximum-tolerated dose of the PD-1 inhibitor pembrolizumab (Keytruda) plus the BTK inhibitor ibrutinib (Imbruvica) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), which includes patients with MCL (NCT02950220).

A second clinical trial is investigating the combination of nivolumab (Opdivo) plus lenalidomide (Revlimid) in patients with relapsed/refractory NHL, including those with MCL (NCT03015896). The phase I/II study will also explore the incidence of adverse events and maximum-tolerated dose of the nivolumab/lenalidomide regimen.

OncLive: You spoke about MCL in your lecture. How has this paradigm evolved?

In an interview during the 2017 OncLive^® State of the Science Summit on Hematologic Malignancies, Nowakowski, an assistant professor of Medicine at Mayo Clinic, spoke to the ever-changing landscape of MCL, the intriguing combinations being studied, and the promise that immunotherapy could hold.Nowakowski: MCL is an area where a lot of new agents are being rapidly developed and entering the treatment landscape. What is interesting is that there is this paradigm shift from chemotherapy-based combinations, particularly in the relapsed setting, to more targeted-like approaches. Those include combinations of ibrutinib with rituximab (Rituxan) and lenalidomide with rituximab. Venetoclax (Venclexta) is another active agent in this setting.

Where are some of these regimens currently in the pipeline?

The focus of my presentation was to highlight this new data showing activity of those agents in MCL, how they are moving in clinical trials, and how, over time, it can replace the cytotoxic chemotherapy we usually use in this setting. That’s a very good question. Because they started at different times in development, they are at different stages in clinical development and introduction to therapy. The one that is closest to frontline therapy is the combination of lenalidomide and rituximab, or R-squared. This combination has been compared in a randomized study against chemoimmunotherapy. It has been completed and the results are now maturing. It will be a very interesting study to watch.

Another interesting study which has been done is with maintenance rituximab, which showed the benefit of maintenance rituximab in this setting of post-induction treatment in elderly patients, but also after high-dose chemotherapy and autologous transplantation in the younger and fit patients.

In terms of the other targeted agents, they appear a bit later in development. They are now being tested in the relapsed/refractory setting and slowly moving to the upfront setting. Ibrutinib has very significant single-agent activity in MCL.

We can also combine it with rituximab which further increases its activity, and now the addition of ibrutinib is being studied with a backbone of bendamustine and rituximab (BR) against BR alone in an ongoing phase III study. This is another example of an agent that moves from the relapsed/refractory setting to upfront; the study is very interesting and we will be watching it very closely, as well.

Is there a place for checkpoint inhibitors or chimeric antigen receptor (CAR) T-cell therapy in MCL?

Venetoclax just recently was found to have very significant single-agent activity in MCL. There are some combination studies being developed; I'm not aware of any frontline studies yet but I'm sure they will appear. What is interesting, though, is to see combinations of targeted agents such as venetoclax or ibrutinib together and basically getting rid of the chemotherapy backbone. This is particularly for older patients whom we did not treat with an intensive combination chemotherapy and autologous transplantation. In those patients, this approach should be very interesting. Those are both areas that are exploding. The activity of single-agent PD-1 inhibitors in MCL has not been as significant as we see in Hodgkin lymphoma. The single agents are somewhat limited; what would be very interesting to watch would be combinations of these agents with other agents. For example, lenalidomide is an immunomodulatory agent that stimulates the immune system, so a combination of PD-1 blockade plus lenalidomide could be a very interesting approach in MCL. The studies are currently being developed and are in progress.

You can almost imagine any combination of those PD-1 inhibitors with different therapies, including cytotoxic therapy, because chemotherapy traditionally tends to introduce additional mutations within tumor cells. Additional mutations can create new epitopes or antigens, which can then be recognized by the immune system. These combinations will be very interesting. So, immunotherapy may not be promising as a single agent but in combination with those other agents.

CAR T-cell therapy has shown very high efficacy in various lymphomas and is an area of rapid development. Unfortunately, there is still quite a bit of toxicity with this therapy. Patients require hospital admission, and many of them have significant neurotoxicity which requires intensive care unit admission.

You have to remember that MCL is a disease of the elderly; a lot of patients will be elderly and may not necessarily be candidates for CAR T-cell therapy. However, it is definitely for younger patients who exhausted standard therapy options—including progression on some of the targeted agents, such as ibrutinib. We know the outcomes of patients who progress after ibrutinib are quite poor, so those patients would be excellent candidates for CAR T-cell therapy.