BTK/BCL2 Inhibitors & Other Novel Agents in CLL Therapy

Transcript: Matthew S. Davids, MD, MMSc: There are multiple lines of preclinical evidence suggesting that combining a BTK [Bruton tyrosine kinase] inhibitor with a BCL2 inhibitor will be a very effective strategy in CLL [chronic lymphocytic leukemia]. Our group showed that you can actually sensitize the mitochondria of CLL cells to venetoclax by treating them first with ibrutinib. And this has now begun to translate in the clinical trial setting with multiple different trials around the world showing us a significant improvement in what we might expect from either drug on its own by combining ibrutinib with venetoclax. And I think, based on these studies, either this doublet of ibrutinib with venetoclax or a triplet of ibrutinib-venetoclax—NSCD20 antibody, may become standard therapies as we move into the future.

In the relapsed and refractory setting for CLL, there are now several new agents being developed. I think the first category that we can think of is what we’d call so-called second-generation agents. So for BTK inhibitors this could include drugs like acalabrutinib or zanubrutinib, both of which are more selective BTK inhibitors compared with the approved drug for CLL, ibrutinib. And I think both of these have potential to have at least comparably efficacious results but potentially with a better toxicity profile.

The other category of drugs in which we’re seeing a new agent being developed is with PI3 [phosphatidylinositol 3] kinase inhibitors. We currently have 2 of these drugs approved. These include idelalisib and duvelisib. But there’s another promising new PI3 kinase delta inhibitor called umbralisib, which is now in registrational trials. And that could potentially be a major advance both in terms of efficacy and safety, although I would say that in terms of efficacy, it seems comparable to the other drugs, so really safety may be where we see the biggest advantage with umbralisib.

I think the treatment landscape of CLL is going to continue to evolve rapidly over the next few years. I think an interesting question in the field right now is whether patients are better served by using sequential novel agent monotherapy, or by using combination strategies that include novel agents. I think for the older and frailer CLL patients, there may still be a good role for sequential novel agent monotherapy, because we know that patients can do very well on frontline ibrutinib for several years, and that they will then respond to a drug like venetoclax in the second-line setting, and often older patients with other comorbidities may die of something else before they need additional therapy for their CLL.

I think a more challenging situation is in the younger patients, particularly those with high-risk disease. This may be patients in their 5th, early 50s or early 60s, who may have 30 or 40 more years of life expectancy. For these patients, particularly if they have high-risk features, I think the field is going to be evolving toward novel agent combination approaches, which may not necessarily be curative, but may actually allow for time-limited treatment intervals where the patients can get a combination of 2 or 3 agents for a period of a year or 2, and then go into remission hopefully for several years.

If we use these drugs in combination, I think it’s less likely that patients will develop resistance, and therefore, the hope would be that we could then retreat these patients with a similar regimen, get them back into remission, and have another drug holiday, and that patients can enjoy potentially decades of life by using this approach.

Across hematologic malignancies and cancer more broadly, we have more and more agents coming into the clinic. And I think it can be hard to know who the optimal patient is for each of these drugs. We’ll certainly continue to have a growing list of options in patients with CLL. And I think we need to consider factors, such as the number of patients treated with these agents, in terms of the quality of the data we have, how long the follow-up is, and in some cases whether we have head-to-head comparisons. And so with these newer second-generation drugs, I think we need all that information before we can make a decision with a particular patient. We need to know how long the follow-up has been with the drug, what kind of toxicity profile it has, and what the efficacy profile looks like, and then we can have discussions with our patients about the pros and cons of each agent.

I think to summarize what we have in the field right now in CLL is that we have a lot of very effective treatment options. These include chemoimmunotherapy, novel agents like ibrutinib and venetoclax, and emerging agents such as second-generation molecules. And I think it’s increasingly important that we individualize therapy for our patients with CLL. I think most importantly, we should not be giving chemoimmunotherapy to CLL patients who have TP53 dysfunction. That could be deletion 17p, or TP53 mutation. Outside of that setting, I think we can still have conversations with our patients about the benefits of shorter-term therapies, like chemoimmunotherapy, or more continuous therapies like ibrutinib. And I think different patients may make different choices about that, but I think overall as a theme we’re very fortunate to have many effective therapy options for patients with CLL.

Transcript Edited for Clarity