ASH 2023 | Venetoclax added to ibrutinib in patients with CLL with molecular resistance to BTKi treatment

So we’re very excited to present the kind of first results of this Phase II study at this meeting. So this is a very novel Phase II study, and it’s really looking at the concept of what’s the best way to treat patients who are taking ibrutinib, who have developed molecular resistance to the point where you know they’re going to develop progressive disease, or they have a known resistance mutation and have progressive disease. 

Currently, the standard would be to switch them to venetoclax, which is continuous monotherapy, and looks to have a progression-free survival of about two years median. So the concept is, can you add venetoclax to people with these mutations who either haven’t developed progressive disease yet to avoid relapse or who have to see if you can get a really deep remission and eliminate the residual leukemia and allow them to discontinue therapy in remission and enjoy some time off treatment, as opposed to continuous monotherapy treatment with different targeted agents. 

The kind of rationale for this is that venetoclax has efficacy after ibrutinib, as demonstrated in a Phase II study specifically in this population, so it’s the most effective approved drug in this setting -although I’m going to have to think about that now because the non-covalent BTK inhibitor pirtobrutinib just got approved in the United States- and also decreases the allelic frequency of known BTK mutations, the one everyone thinks of, the most prevalent one, is the BTK C481S mutation. So we thought maybe this would kind of target the resistant clone because you see the allelic frequency of these mutations decrease and is very effective after ibrutinib. And, of course, we know the combination of ibrutinib and venetoclax is both highly effective and very tolerable in other settings. So the idea was, you have people taking ibrutinib who develop molecular resistance with or without progressive disease, add in venetoclax with a standard ramp up and then at the label dose of 400 mg, and then after 12 cycles, which is a little less than a year, do an assessment and if they have undetectable CLL and have a complete remission, stop treatment and observe them. If they don’t achieve the response, do another 12 cycles, and then after 24 cycles, if they achieve that response, discontinue. If they do not, stop ibrutinib and just continue with venetoclax because probably the benefit of the combination isn’t really realized by that point. 

So that’s kind of the scheme of the study and we included 28 patients. Some of the patients are still on treatment, so I do think longer follow-up will be helpful. But we’re very excited about the results, not only with the responses achieved but also the progression-free survival. So the median progression-free survival with this approach is 40.7 months, which is longer than the, you know, around two years you would expect with venetoclax monotherapy. Of course, we are catching people before they have progressive disease in many cases. But then on the other hand, we have people who are off therapy enjoying remission, so that’s really exciting. The overall survival was not reached, which is really important. 

When you think about what’s happening with the mutations, we did have about two-thirds of the patients have an undetectable BTK C481S mutation. We had one patient that didn’t ever have a BTK C481S mutation, but of those that did, about two-thirds became negative for those mutations. So they actually had them eliminated and the median time to do that was seven cycles, cycles of 28 days. So it really is showing that this concept that you can eliminate resistant clones or at least suppress them below the detection limit. And then, you know, the rate of minimal residual disease was substantial. So it’s kind of showing you can actually get deep remissions with the strategy of an add-on of venetoclax rather than switching to a different monotherapy. 

Just towards my point that the therapy works, we did have 43% of patients that discontinued due to the achieved response, either a complete remission with an undetectable disease, or some that elected to discontinue with a partial remission with no detectable disease, and one person with a complete remission with some detectable CLL. So that’s a high number of people who achieved kind of a goal response and could be off treatment. I do think that we’ve, you know, got a reasonable analysis of the BTK C481S mutations, where we have a really good assay that you can get even low levels of it detectable. We need to make sure we understand what happens to the other mutations patients had. So, about 40% of patients at the time of enrollment had only BTK C481S mutations, but we did have some that had both BTK and PLCgamma2 or multiple types of BTK mutations. So, trying to understand what happened with those will be critical. And then continuing to see the experience of patients, how long people can be off treatment, and then at some point, when we have enough follow-up, doing an exploratory analysis of those that entered the study with low disease versus a higher disease burden, just to describe if there are any differences between those patients. 

So this is not a strategy that I’m proposing could be implemented in a general practice setting, but it’s certainly very exciting to see these really nice responses, durable benefit, and time off treatment in a population of people who have molecular resistance in their CLL to ibrutinib and would expect to get continuous treatment. So I think the concept of us doing this, we’ve shown that that is the case, and we just need to do some more work to understand this better.