Novel Combination Therapies for CLL

Transcript: William G. Wierda, MD, PhD: So we’re seeing benefits certainly from the small-molecule inhibitor-based frontline therapy. I wonder, Susan, you were involved with the development of the iFCG [ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA-101)] before you moved to UCI [the University of California, Irvine] and Litton gave an update of the iFCG results for that trial. I wonder if you could just touch on—that trial was only for patients with a mutated V gene. Maybe you can just summarize a little bit what the results for the update were.

Susan M. O’Brien, MD: Yeah. So I think the idea behind that trial was, again, [it] harkens back to this plateau on the progression-free survival curve for the mutated population. So there was a reluctance I think, and as you said, I was there at the time, among all of us, to give up chemotherapy in that population. But at the same time, that progression-free survival plateau is about 60%, so there was room for improvement. In particular, the patients who did the best were the ones who were MRD [minimal residual disease]—negative at the end of therapy. So the idea here was to use FC [fludarabine and cyclophosphamide], the chemo backbone, but to limit it to 3 cycles with the idea being you’d have less toxicity because you’d be giving less chemo, and hopefully less risk for late MDS or AML [acute myeloid leukemia] by limiting the amount of chemo. The G was changing from rituximab to Gazyva [obinutuzumab] because of the data from the CLL11 trial clearly showing that obinutuzumab chlorambucil was better than rituximab, chlorambucil. And then the “I” is adding in ibrutinib.

So patients get ibrutinib with the chemotherapy, which would be FCG, for 3 cycles. Then the chemo stops and then they continue to get ibrutinib and obinutuzumab for a variable number of cycles, and then the MRD is assessed at various points, including 12 months. And if patients are MRD-negative, they come off treatment completely. So a potential for a time-limited therapy also. So I think that data looked very encouraging. I believe all the patients who had gotten to 12 months—and there wasn’t a huge number but all the ones [who] had made it 12 months—were MRD negative. So that looks very promising. I think Matt has a similar, although slightly different, trial using FDR with ibrutinib.

Matthew S. Davids, MD, MMSc: Yeah. I’ll just comment briefly on it. We didn’t update it for this meeting, but [it’s] kind of similar principle. We’re not quite as sophisticated as you, so we just had a very simple idea: What happens when we add ibrutinib to standard FCR? All-comers. We actually included some patients with deletion 17p initially. We ended up excluding them from the expansion of that study because they seemed to have lower response rates and depth of response. But we’ve seen very nice results, including in the unmutated IGHV patients, [for whom] I think we have even more room for improvement, and we know ibrutinib works particularly well in that population. But ours actually includes 6 cycles of FCR, so we’re not answering that question of whether reduced chemotherapy might improve the toxicity profile.

William G. Wierda, MD, PhD: So let’s take the next step or think about the next step. We talked about ibrutinib, [and] we talked about ibrutinib plus the CD20 antibody. Maybe, Alexey, you can comment on what are some of the other areas in development where you’re seeing promise and where is the standard of care likely to move to.

Alexey V. Danilov, MD, PhD: Well that’s an interesting question. I think the future of our care in CLL is novel combination therapies. So one of the problems with BTK [Bruton tyrosine kinase] inhibitors as single agents or in combination with immunotherapy is that the treatment is indefinite so far, and this is how we prescribe this drug.

However, the expectation is combination with novel agents or with chemoimmunotherapy will result in good outcomes and we will be able to stop therapy. And that would certainly be convenient for the patients, [and] hopefully reduce the number of [adverse] effects and discontinuations [caused by adverse] effects, as well as reduce financial burden on the individual and the society.

So there were several studies, which have been presented here, and this one is looking at combination of BCL2-targeting agent venetoclax, and BTK inhibitor ibrutinib. And both are frontline and relapsed setting. And I believe this is where this field will continue to go.

William G. Wierda, MD, PhD: Any concerns with using combinations, Anthony, and what’s in development of those combinations?

Anthony R. Mato, MD: I think I agree with Alexey that the field is definitely moving toward combination therapy. I think we’re sort of at a point [in which] we have a lot of interesting active combinations compared [with] controls that are not necessarily the control we want, and we’d be left in a situation [in which] we have multiple exciting combinations without any data to…know how to pick one over other, minus maybe a toxicity issue that could drive a decision point. That’s one issue, one concern I have.

Another is that the, you know, time limited means different things to different people. And length of time from a financial and patient perspective of 2-plus years, for example, to me borders on not being able call something time-limited, to be honest with you.

I think the other area [in which] I have a concern is that we have barely begun to define mechanisms of resistance to the individual novel agents. We have no idea what resistance looks like to a combination, and how to deal with that or how to sequence in the setting of transformation or disease progression.

I think we have not a lot of information about toxicity profiles. My limited experience with combinations, novel-novel combinations, is that there are certainly areas [in which] many patients can tolerate [only] lower doses of either drug than I would have accepted as a monotherapy. And then I guess my biggest concern is that there are probably a fair number of patients who will get combinations, who are overtreated, who would have done completely fine with individual targeted agents [and] sequential monotherapies, and how do we tease out the patient who would benefit from the double or triple or quad? We might get to 5 at some point, I guess. Or who could just do fine with ibrutinib followed by venetoclax, followed by an antibody or however you want to define it. And I think to get over that bar, from a clinical trial’s perspective, is going to be really hard to do.

Transcript Edited for Clarity