Panelists: Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; Leo I. Gordon, MD, Robert H. Lurie Comprehensive Cancer Center; John Byrd, MD, Ohio State University; Michael Keating, MB, BS, University of Texas MD Anderson Cancer Center; John Leonard, MD, New York-Presbyterian Hospital
Krishna V. Komanduri, MD: I want to talk about a vexing subset of CLL, which is deletion 17p. Your former colleague, Susan O’Brien, published—in Lancet Oncology this year—the RESONATE-17 results, which were really the results of ibrutinib in relapsed/refractory deletion 17p CLL. You want to talk about that and perhaps the role of venetoclax in this subgroup of patients?
Michael J. Keating, MB, BS: I think it’s an example of common sense in developing a clinical trial, because all of the investigators had their own expectations for the 17p group and they were all bad. So, instead of having an FCR arm as a comparator, or some other chemotherapy as a comparator, the FDA allowed the company to do a single-arm study, which recruited about 100 patients in a period of 14 minutes. When you call up to answer a thing to win a prize, the prize was you could get your patient on the study. The results ended up being this very, very nice response rate—75% to 80%. These are very good responses. But, in fact, there was this consistent relapse pattern that tended to occur anyway. One of the things is that we have to realize that in all of these studies, follow-ups are around about 24 months, 36 months, 48 months, etc.
Krishna V. Komanduri, MD: Rare disease with a very long natural history.
Michael J. Keating, MB, BS: So, we have to be a little humble about it. Getting back to venetoclax, the data say the remissions are not quite as long with ibrutinib, but you seldom get MRD (minimal residual disease) negativity with ibrutinib. But it’s fairly consistent that a subset of 30% to 40% will get to be MRD-negative with venetoclax, and whether or not, that’s just a median disease. You don’t change the median time to progression, but there may be a tail that emerges in those that get to be MRD-negative. It’s nice for us to at least think of the fact that ibrutinib seems to be better at getting rid of nodal disease than venetoclax, and venetoclax is better at getting rid of marrow disease than ibrutinib. So, there’s a clamor all around the world, what’s your combination study? It’s one of the very complicated issues that we have at the present time when you have a number of effective drugs that come at the same time. Everyone has their own little studies, and it will be interesting to see how many definitive big studies can be mounted.
Krishna V. Komanduri, MD: The last thing I want to talk about is, could you quickly comment on combinations that you think are particularly promising? I know it’s a difficult question because there are so many possibilities and, really, the natural history of this disease is so long.
John Byrd, MD: There are a lot of possibilities, but I think you could put 10 CLL experts in a room and at the top, there would be a few things that everybody is excited about. Obviously, ibrutinib and venetoclax are both active agents. Obinutuzumab is also very active. Giving all 3 of those together is quite exciting, and there are several studies that are doing that. There’s one that we presented at this ASH 2016 meeting, Jeff Jones is presenting. Another question that people are very interested in, relative to these combinations, is that if you knock the disease down to MRD, then the paradigm for venetoclax probably is not going to be to give continuous therapy forever; it’s going to be 1 year or 2 years, but with ibrutinib, it is. Can we use these combinations to get people off medicine? That becomes very attractive because—we’ve not really talked about it—of the cost of these agents for patients taking it for a long time.
I’m quite excited about some of the trials that are ongoing now with lenalidomide with these new targeted agents or CC-122, which is a new immune-modulating agent that may have improved properties. We’ll have to see what the trials are. And, really, I’d be interested in Michael’s perspective. The challenge that we have at our center—where we used to do our clinical trials in, where you’d get a sense of where things are going to be better or not—is our relapsed patients. That population is really shrinking and it’s making doing clinical research more difficult at a time when we have these drugs and we can really answer important questions. I don’t know if that’s been the experience at MD Anderson.
Michael J. Keating, MB, BS: When patients come in and they know their status, they have been following all these studies along the way. And if you start to talk to them about a new agent that is very promising, they say, “Oh, now we want this.” So, the patients are asking very realistically for approved agents that are coming. We have seen this in other situations before, that these are very successful drugs. You wouldn’t be giving people with CML anything except Gleevec, if there was a new agent that came along, because the Gleevec was so good. It just alters the temper of the research unless we can discover specific biologic areas that we can develop that are likely to be somewhat superior. It’s going to be harder work for us to do it.