Transcript
My name is Kerry Rogers. I am an assistant professor in the Division of Hematology at the Ohio State University.
This is a really exciting study and was based on the idea of combining the three most effective drugs that we had in chronic lymphocytic leukemia at the time this study was designed.
We have ibrutinib, the BTK inhibitor. BTK inhibitors, as a class, are just an outstanding therapy for CLL, have changed the entire treatment landscape, especially for high-risk disease patients. Very effective, but since they do not eliminate all leukemia, you have to give them indefinitely.
Then, we have venetoclax, which is a BCL-2 inhibitor. Different mechanism that would combine well with BTK inhibitors or some preclinical data to support the combination that was available before this study was designed.
Then, we added in an antibody called obinutuzumab. That is an anti-CD20 monoclonal antibody. Anti-CD20 monoclonal antibodies combined with chemotherapy move the mark on survival and outcomes in CLL, so it is a standard idea to combine them with other therapies to improve the efficacy.
We have two targeted agents that are oral and an antibody. The idea was to combine all three of these things in a fixed-duration regimen to try to get deep remissions, and then observe patients off treatment.
The power of this regimen is going to be how long people remained in remission after they stop taking the drugs. The toxicities, except for hematologic toxicities, are non-overlapping.
This study did have a Phase 1b that was completed to make sure that we have found the correct dose of venetoclax for combination, and then moved into this Phase 2 study, where we had a cohort of 25 treatment-naive and 25 relapsed/refractory patients.
Overall, the study did well. Patients seemed to enjoy being in the study, at least the ones I treated. We did see cytopenias as a very common adverse event, although not too many issues with the patients for that. While there was a reasonable rate of neutropenia, people were not getting admitted for infections or febrile neutropenia.
Other adverse events are what you would expect for these classes of drugs. You would see hypertension occurring with the ibrutinib, diarrhea, things like that. Anyone that's used any of these classes of drugs sort of guess what side effects we might see.
I do think the hematologic toxicity might have been a bit additive, meaning higher because of the combination. Again, it did not seem to be limiting for the patients or impaired their life too much. The adverse events were what we expected for this combination of these drugs. In terms of the outcomes for the patients, we had a very high overall response rate.
This was an intention-to-treat analysis, meaning everyone that took a single dose of any of the drugs was included in the analysis for the primary endpoint, which was basically the rate of minimal residual disease-undetectable complete remission at the end of treatment, and then assessments two months after they finished the drugs.
Anyone that discontinued for adverse events or otherwise was included as a non-responder in this intention-to-treat analysis. Everyone that was assessed for response did have a response.
In both the treatment-naive and relapsed/refractory cohort, we had 7 out of 25 patients, which is 28 percent of patients, having a minimal residual disease-undetectable complete remission. That is undetectable CLL in both the blood and the bone marrow at that time, so we defined it as both compartments.
We also had a fairly high rate of MRD-negative responses in general, so it was over 50 percent in both these cohorts. Again, with 25 patients that are relapsed/refractory, 25 patients are treatment-naive, those are pretty small numbers.
We had over half of them having undetectable minimal residual disease in both compartments at the end of treatment, which is pretty high, so some of those partial remissions were MRD-undetectable.
It is possible, if you are familiar with the response criteria for CLL, that they just had small residual lymph nodes greater than 1.5 centimeters, which is the cut-off for complete remission. Still, maybe not with actual disease in it.
It will be exciting to see over the next couple years how the people who are MRD-negative versus MRD-positive in PR versus CR do in follow-up.
The publication we had, we only had one death and one case of progression. The disease progression was in the relapsed/refractory cohort, so I do think it will take more time and more follow-up to see the median progression-free survival, who is benefiting most, in terms of PFS.
We did do an analysis looking at some of the patient and disease features to see if we could predict response. Things like deletion 17p, which are a high-risk feature or just prior treatment versus not. We couldn't identify anything on a univariable analysis that predicted response.
That is not uncommon with these targeted agents, so we expected that. It'll be very interesting to see if some of those will predict progression-free survival in the future. Obviously, we need more than one person to progress before we can do that analysis.
We did update this at ASH this past year with about 36 months of follow-up. Similarly, it looks like most of the patients are doing well and not progressing. Hopefully, it will be a while before these patients progress, because again, the power of this regimen is how people do when they stop taking treatment. These were expected findings. They are highly effective drugs.
We did expect a very reasonable rate of minimal residual disease-negative complete remission. I was not at all surprised that we didn't identify any features that were correlated with response at this point, because again, those might be correlated with progression-free survival and not response or achieving MRD-negative CR. This is pretty much what we expected to see with this particular treatment.
I do not think this regimen's ready for prime time yet. There's some questions that have to be answered before.
This was a Phase 2 study, and the goal of it was to learn about this regimen and to see if it was worth putting into Phase 3 trials. This regimen is now in two Phase 2 studies through US oncology cooperative groups.
It is a slight variation of this, but it was based on the regimen in this study. The Alliance is a study in people 70 years and older and ECOG, which is the Eastern Oncology Cooperative Group, in younger patients.
There are a few small differences in design, but they are both comparing, in a randomized fashion, this regimen of obinutuzumab, ibrutinib, and venetoclax—again, slight variation in dosing with this—to ibrutinib/obinutuzumab, looking at which might have a better progression-free survival.
The ibrutinib/obinutuzumab, ibrutinib's given indefinitely, obinutuzumab's given for a fixed duration of several months. The three-drug combination is given for a fixed duration for everybody in the ECOG study with younger patients. Discontinuation is based on achievement of an MRD-negative status in the study in older patients.
The goal here was to see if this was worth testing in Phase 3 trials. This is now being tested in two large US oncology cooperative group Phase 3 trials, and that is how we set the standard for what we should be using in CLL.
There are other studies now coming along that are looking at ibrutinib/venetoclax combinations. Some of those might be larger and have more information available sooner, hopefully, rather than those cooperative trials are going to take a little bit of time before we get results from those, as expected with a randomized Phase 3. That will be exciting to see.
I do think it is also open question as to how important adding obinutuzumab is to this. Is this obinutuzumab/ibrutinib/venetoclax better than ibrutinib/venetoclax? That is also interesting.
This is not something I would start treating patients with, based on our study, but it certainly did provide enough evidence that this regimen is worth further study and this idea of giving a BTK inhibitor and venetoclax for a fixed-duration or time-limited treatment is something that's moving forward with this type of regimen and other combination studies with these drugs.
We do have a new cohort in this study of 25 treatment-naive patients. We amended it to add a new cohort to get more experience. Those patients are finishing treatment and being assessed for the primary endpoint.
Another goal of that was to do some correlative science. We have a couple time points where we took samples from those patients, and then to treat a bigger number of previously untreated patients that we will get results from about 50 then before we have results from our cooperative group trials.
We have not reported the results from that new cohort, and the response assessment, we are going to have to make some adjustments because of the pandemic. Not everyone got all their response assessment exactly as scheduled.
I look forward to seeing how they do in that study, but I already covered most of our plans for what we are doing next. My colleague, Jennifer Woyach, is leading the Alliance study, which is one of the large cooperative group studies that I was discussing.
One thing I would like to add is that for this study in particular, the patients seemed to enjoy participating in it and liked this idea of taking both the classes of drugs that are available that are oral targeted agents that they know are effective together.
Currently, for initial treatment of CLL, which is, again, half of the patients in this study, one of the cohorts was untreated. That is what the Phase 3 studies that are ongoing are in, are they are not previously treated patients. That's the area we're looking at.
Currently, the options there are indefinite BTK inhibitor therapy versus venetoclax and obinutuzumab are in relapsed/refractory. It is indefinite BTK inhibitor, ibrutinib or acalabrutinib, versus venetoclax and rituximab for a fixed duration.
When you discuss that with patients, that is either BTK inhibitor and venetoclax. I think a lot of the patients were excited to take both those drugs in combination. A lot of them were very excited to be doing this for around a year as opposed to taking things longer term.
It will be important to learn going forward, with this type of fixed-duration regimen, who might benefit from BTK inhibitor venetoclax combinations with or without obinutuzumab compared to venetoclax anti-CD20 monoclonal antibody combinations.
I think that is exciting, and the patients seem to like being in the study, and that's why we do this type of research, to make treatments safer and more effective for our patients.
