Venetoclax Plus Ibrutinib Combination Therapy for Treating Patients With CLL With Resistance Mutations

In a study by Kerry Rogers, MD, The Ohio State University, and colleagues investigated whether the combination of BTK inhibitors (BTKi) ibrutinib and venetoclax could help eliminate molecular resistance for patients with chronic lymphocytic leukemia (CLL) who have resistance mutations, leading to better progression-free survival. Dr Rogers discussed the results from the study in an interview with the Journal of Clinical Pathways.

Please share your name, title, and affiliation.

I'm Kerry Rogers. I'm an associate professor in the division of hematology at The Ohio State University.

Can you give some background about your study and what prompted you to undertake it?

This is a really exciting study that we started as a proof-of-concept study. The idea was to see if we could do something for patients who are developing resistance to a covalent BTK inhibitor to catch that resistance earlier and, therefore, positively impact their disease course.

As I think everyone knows, ibrutinib is the first-in-class covalent BTK inhibitor for the treatment of chronic lymphocytic leukemia. However, it's given indefinitely, and resistance to ibrutinib is a very pressing clinical problem. And now, as we've seen with the advent of additional covalent BTK inhibitors, this continues to be an issue.

The standard therapy that's approved in this setting is venetoclax, which was studied as a continuous monotherapy and had a progression-free survival of about 2 years. We also saw that patients who were taking venetoclax did sometimes get very deep remissions.

So our research question was, could you add venetoclax to ibrutinib for patients who are developing resistance to it and then get deeper missions and maybe stop treatment if they get a deep enough remission, or at least positively impact their overall disease course or how much they might benefit from additional treatment with venetoclax?

Can you briefly describe how the study was conducted?

The study conducted was a phase 2 study, which took place at The Ohio State University. The study included patients who were taking ibrutinib and developed a resistance mutation. These are known mutations in BTK or phospholipase C-gamma-2 (PLCG2) that are established to be associated with progressive disease or resistance to ibrutinib. The participants could’ve had progressive disease or not, but it had to have one of these identified resistance mutations, and then they would keep taking ibrutinib and add on venetoclax as a second therapy and take them together. So, we added a second agent rather than switching to venetoclax to get a better outcome. We also enrolled some patients who didn't have progressive disease yet to see if catching them earlier when these resistant clones are smaller would make a difference. We also had patients with progressive disease and without progressive disease in the study. 

Patients in the study were treated for 12 cycles, which is about a year of the combination. If they achieved a complete remission with no detectable CLL, they stopped treatment. If not, they did a second year, at which point they stopped the treatment if they developed that deep response with complete remission with no detectable CLL, meaning that it was assessed in the blood or marrow by flow cytometry. If they still didn't achieve that response by 24 cycles, ibrutinib was stopped, and they continued on venetoclax alone, mainly because it was unclear what the benefit of continued combination might be relative to other risks such as toxicity in this setting.

The primary endpoint was the rate of mutation-negative status, which means patients had no detectable resistance mutations after 12 cycles. For most patients without detectable resistance mutations, it was largely because there wasn’t detectable CLL. So, if there's no CLL, there's no CLL with resistance mutations. 

What were the main findings of your study? 

There were a few main findings from this study. The one that I was most excited about, which was not the primary endpoint, was that the median progression for survival in this study was 40.7 months. This compares favorably to the 3 years or around 24 months you would get with a single agent venetoclax in a similar setting. There are some reasons to expect this would be better: (1) It's a combination, and (2) some patients hadn’t yet developed progressive disease because these mutations in BTK and PLCG2 are identifiable before overt progressive disease develops. Therefore, it's expected that it would be a bit longer, but I think 40.7 months is an outstanding PFS benefit with this approach.

The other nice result was that a high number of patients, 43% overall, discontinued treatment, and some patients were followed for some time off treatment. We don't know that we've cured anyone with this approach. Still, the expectation for CLL patients that progress on a covalent BTK inhibitor, such as ibrutinib, is that they'll usually receive sequential therapies over their lifespan. So, it's cool that we did have a reasonable fraction of patients who could benefit from some time off treatment. Again, with a smaller study of 28 patients and limited follow-up of a median of only a little over 30 months, I think more work will be done to see exactly how long patients can remain off treatment or how long they can expect that. But I was excited to see that was the case.

A couple of other things that I think are important to the field are that while the progression-free survival was reached at 40.7 months, the overall survival was not. I think that is due to better therapies that are available now for patients who have been treated with both a BTK inhibitor and venetoclax.

Some of these patients stopped taking treatments in response and then progressed later. But still, it's nice to see that the survival is better than the progression-free survival in this population. And I want to mention that our primary endpoint—the rate of undetectable mutations, like known resistance mutations after 12 cycles, which was the primary endpoint—was 48%. That is sort of an intention to treat. The time when the initial patients in the study reached that time point was actually at the beginning of the COVID-19 pandemic. So, we had patients who were could not come for assessment at that time point as we weren't having people in person for bone marrow biopsies.

We did an analysis including patients whose cycle 12 assessment was delayed due to COVID-19 and found that actually it was 59% of patients with this mutation-negative status achieved it after 12 cycles if you include the delayed assessments. The assessments were up to about 16 or 18 cycles, so it could be that some of them achieved that later and would not have achieved that at cycle 12. But I think that's the best way to account for unanticipated changes in the research plan due to the pandemic.

Is there anything else you would like to add?

One thing that we found, which I think will shock nobody, is that the regimen was well tolerated. The adverse events are similar to what we’ve seen with this combination used in other CLL patient populations. That part is helpful confirmation that this combination strategy can be tolerated here and is useful. Much of this BTK inhibitor venetoclax combination work has been done in a previously untreated setting or in patients that haven't been exposed to these drugs. So it's nice to see that you can still get a good fraction of people achieving really deep remissions and durable responses of the combination in patients that even have resistance to one of the drugs.

Going forward, it would be interesting to apply this approach of an add-on therapy or BTK inhibitor of venetoclax combination therapy in patients who have progressed on other covalent BTK inhibitors that are in use now, such as zanubrutinib  and acalabrutinib. The other thing that is a question in my mind is, if you change from like a covalent BTK inhibitor to a drug like pirtobrutinib along with venetoclax, would you get better results? Because pirtobrutinib, at least when we're thinking about mutations, is selected for the BTK C481S mutation. And 46% of the patients in the study had only the BTK C481S mutation. And we had one that had PLCG2 mutation and some that had other BTK mutations in addition to BTK C481S.

So at least for that group and given the good responses to pirtobrutinib and the safety that's been demonstrated of pirtobrutinib and venetoclax together, that’s an approach where you could take someone who's progressing or has mutations that predict progression and molecular resistance on any covalent BTK inhibitor that's currently approved, not just ibrutinib but also acalabrutinib and venetoclax. And can you then treat them with a combination of pirtobrutinib  and venetoclax and get deeper remissions and make that kind of a fixed duration treatment, which I expect the PFS would better. Another question would be, would you get deeper responses and more time off therapy? Overall, I think that’s the next approach. We do have an investigator-initiated study planned here at The Ohio State University to test that.

I would like to just point out that this investigator-initiated study I'm discussing now was funded by AbbVie. And we have another study that will be funded by Loxo@Lilly, which will test pirtobrutinib with venetoclax under the same circumstances. So I'm very excited to see how that works out. I also would hope that a BTK inhibitor venetoclax combination could be tested ultimately in phase 3 trials for patients who have received prior targeted therapy.

We did have a small cohort study here looking at using BTK inhibitor venetoclax approaches in patients who had developed CLL and were resistant to both covalent BTK inhibitors and individually. We published it a few years ago and did see responses. The combination is apparently effective in some patients where their CLL is resistant to the drugs individually. So, I think this is a powerful tool to get deeper mission than some patients and potentially favorably alter their disease course.