Emerging Treatments in MCL

Transcript: Ian Flinn, MD: Let’s switch from the approved therapies and talk a bit about emerging therapy and combinations. There are a variety of ongoing trials. We have to wait for the data with zanubrutinib and rituximab in the frontline setting. What about the whole story with combining anti-CD20 antibodies with a BTK [Bruton tyrosine kinase] inhibitor? This is controversial in CLL [chronic lymphocytic leukemia], right? There are data suggesting that rituximab doesn’t help, but obinutuzumab does and that’s with 1 BTK inhibitor and maybe not another. What do you think about the story in mantle cell lymphoma?

Tycel Jovelle Phillips, MD: It’s a conundrum, as you accurately pointed out. Part of the issue is that it speaks to some of the differences among the BTK inhibitors. We all know ibrutinib does hit ITK, which in theory would downregulate T-cell expression, which in some ways may modulate some of the benefits you get from rituximab. Then, in the same situation, we’ve had combinations of them in mantle cell lymphoma, and it seems to actually be responsive. At this point, it’s going to take a lot more time to tease this out.

The other second-generation BTK inhibitors—given that none of them seems to impact T-cell function—seem to be very good partners to the CD20 antibody. In my opinion, obinutuzumab will probably be a better partner long term. Mantle cell lymphoma seems to behave a bit more like CLL than it does large-cell lymphoma, in which it doesn’t appear that a CD20 partner makes a difference. Obviously, even though obinutuzumab has increased benefit, it does come with extra baggage. There are more cytopenias that you’ll see with that drug, compared with rituximab. Cost will become a picture. As more rituximab biosimilars come on board, obinutuzumab will be the expensive alternative.

Ian Flinn, MD: Right, there’s always that.

Tycel Jovelle Phillips, MD: We have to keep that in mind what the financial consequences are to our patients while we’re putting some of these novel agents up front. These drugs aren’t cheap. Without having, as Javier said, finite treatment regimens, nobody is going to be on these medications for 6 or 10 years. How many thousands of dollars, hundreds of thousands, or millions of dollars are we burdening our patients with? There has to be a justifiable benefit to attach these things together and put them on some of these treatment courses.

Ian Flinn, MD: I hear you, although we do have some data here at ASH [American Society of Hematology Annual Meeting & Exposition] 2019 with the combination of ibrutinib and rituximab. I like the data. It’s not a huge data set. It doesn’t answer all the questions, but what do you think?

Javier Munoz, MD, FACP: Going back to our previous discussion, we try to shy away from chemotherapy, so this would be a novel, nonchemotherapy approach. It has a BTK inhibitor and a monoclonal antibody. That same platform has been explored in other settings; for example, zanubrutinib plus rituximab versus bendamustine and rituximab. We do not have data when it comes to that combination.

Also, with acalabrutinib plus bendamustine and rituximab versus bendamustine-rituximab, that particular platform does include chemotherapy. It does not answer—and people will probably comment about this once we have the final data, that you should have had perhaps a single-agent cohort for the BTK inhibitor to truly answer—whether you need the dancing partner to be a monoclonal antibody. It’s a similar story as in chronic lymphocytic leukemia. Some people wondered if we truly need the monoclonal antibody to be added to the BTK inhibitor.

Ian Flinn, MD: With regard to borrowing from CLL, the ibrutinib-venetoclax combination is dynamite in CLL. It also gets very controversial, for some of the reasons that Tycel was talking about—the cost of the treatment, could you get the same thing sequentially? It is a targeted therapy. It’s an all-oral approach to this. Is that the future?

Bijal Shah, MD: I think we’re going to be looking at the history of myeloma as we think about what we’re going to be doing in mantle cell lymphoma. It’s another notoriously chemotherapy-resistant disease that saw us evolve through dozens and dozens of different chemotherapy approaches to what we see now, which is a purely biological approach to help really extend the lives of these patients. As it relates to venetoclax specifically, we are doing it, but boy, is it still hard for us to get from an insurance-approval standpoint and a co-pay standpoint. That’s what has really challenged our ability to get more experience.

When we do give it, it certainly has activity, and I think we’re still trying to tease out what group is going to benefit the most. It was beautiful work by the Australian group trying to delve a bit deeper into some of those mutations that may drive some of the lack of benefit—in this case, looking specifically at the SWI/SNF mutations. These are also coming back to getting that excisional biopsy, banking those samples, and being able to go back and do the sequencing if it wasn’t done up front, so we have this information to guide us as we go forward. That is going to be important as we pivot into this biological revolution.

Ian Flinn, MD: While the early data are efficacious, you’re not changing your paradigm today on using ibrutinib and venetoclax on frontline treatment for patients?

Bijal Shah, MD: No.

Ian Flinn, MD: You’re waiting for larger studies to come out. A lot of us have used that regimen in bad situations in relapsed setting. It certainly helped. Again, you never know whether you’re better off with the single agent or in sequence. Venetoclax data, at least as a single agent from the initial phase I, were pretty exciting. That really lends itself to the argument for combining others, although it’s clearly not FDA approved at this point.

Bijal Shah, MD: Correct, but the Australian data were powerful. If I’m correct, they updated at this ASH 2019 meeting as well, showing that the remissions we’re getting are durable, and that’s powerful. There were even MRD-negative patients who came off the study who continue to remain in remission, getting to the ability to begin a biological doublet, or maybe even a triplet with rituximab. Being able to pull off therapy and continue to see a durable remission is something our patients want to see. It’s something all of us want to see.

Ian Flinn, MD: Javier, that’s a nice lead-in to what I was going to ask you. What do you think of this “if 2 drugs are great, are 3 drugs better” rituximab, venetoclax, and ibrutinib data that are presented at ASH 2019. What’s your feeling?

Javier Munoz, MD, FACP: They’re impressive data. As you said, it started with the publication from Constantine Tam in the New England Journal of Medicine just looking at a BTK inhibitor plus a BCL2 inhibitor—ibrutinib plus venetoclax. Of course, we want to build on that platform. I feel that we’re walking the same pathway that is under investigation in chronic lymphocytic leukemia in which you try BTK inhibitor, a BCL2 inhibitor, and a monoclonal antibody. Do we know if it’s needed? We would need a randomized trial to answer that question.

Transcript Edited for Clarity