BCL2 Inhibition in Leukemia - Episode 3

Optimizing Frontline Therapy Selection and Follow-Up in CLL

June 25, 2019

Harry Erba, MD, PhD:This is getting complicated, isn’t it? In previously untreated patients, the Alliance and ECOG [Eastern Cooperative Oncology Group] have looked at comparison of BTK inhibition with rituximab versus immunochemotherapy, different regimens. And in both of those studies recently presented at ASH [the American Society of Hematology Annual Meeting & Exposition] and now published, there was a benefit in terms of progression-free survival [PFS] of the BTK inhibitor, ibrutinib.

Matthew Davids, MD, MMSc:That’s right.

Harry Erba, MD, PhD:Now we have venetoclax and obinutuzumab. Give us some idea—let’s start with how responses with venetoclax and obinutuzumab will compare with BTK inhibition.

Matthew Davids, MD, MMSc:In terms of the overall response rate, it’s very comparable. You’re looking in the 85%, 90% range. Nearly all patients will have some initial benefit. I think that where these 2 regimens are different is in the rates of complete remission and also getting into minimal residual disease, MRD, undetectability. For both of those latter 2, complete response rate and undetectable MRD, there’s a significant advantage for the venetoclax-based regimen. That’s really necessary because this is developed as a time-limited regimen, and so you need to get to that deep-MRD, undetectable response in order to be able to stop therapy and allow for treatment holiday.

In contrast, the model with the BTK inhibitors is to continue drug ongoing, and so in that scenario it’s actually maybe not necessary to get into such a deep response as long as the patients are able to continue taking the drug. I think both are great strategies, and I think it’s going to really be up to docs to understand the pros and cons of both and be able to discuss them with their patients.

Harry Erba, MD, PhD:Can you give us some idea of maybe some follow-up, then on the patients who get this time-limited venetoclax and obinutuzumab? What’s the median progression-free survival there?

Matthew Davids, MD, MMSc:Median progression-free survival has not been reached yet. Actually, even though this is the first time they’re reporting this study, they have a decent amount of follow-up. The median follow-up is about 26 months, and all the patients that they’re reporting at this meeting actually have completed the full year of therapy. And most of the patients have now gone a year afterward and are still in remission. When they look at 24 months, which is 12 months after finishing the therapy, they still have an 88% progression-free survival. So it certainly looks promising that this will be an effective time-limited regimen. But I think it’s still an open question as to just how durable the benefit will be. Will it be 2 years, 3 years? We really have no sense for that at this point. And the numbers of high-risk patients in the study were relatively small, only in the range of, I think, 8% to 10% deletion 17p. So it’s a little unclear how much these results will apply to that higher-risk population.

Harry Erba, MD, PhD:Now, in the cooperative groups, coming back to that, the Alliance and ECOG have recently activated studies looking at combinations of BTK inhibition and BCL2 inhibition with venetoclax and obinutuzumab, also looking at whether therapy could be stopped. Do you think we might someday move to a triple combination in time-limited therapy?

Matthew Davids, MD, MMSc:It’s certainly possible. These are very promising studies combining now 3 drugs with a BTK inhibitor, venetoclax, and obinutuzumab all in the same regimen. I think it certainly needs to be studied, and I think it’s got a good chance of success. In the back of my mind, I do worry a bit if we use our 3 best drugs first. What are we going to treat the patients with when they progress? We do have PI3-kinase inhibitors that could be an option. We have CAR [chimeric antigen receptor] T-cell therapy coming along for CLL. That could also be an option. I think it’s a great area to explore. It’s not clear to me whether the 3-drug regimen is going to be any better than the 2-drug regimen. Last week we also saw a really promising regimen of ibrutinib plus venetoclax published in theNew England Journal of Medicine, which also looks great. So maybe you don’t need the antibody at all. We just don’t know yet.

Harry Erba, MD, PhD:That’s what the Alliance study suggested in the up-front setting, that the PFS with both ibrutinib alone and ibrutinib with rituximab were equivalent.

Matthew Davids, MD, MMSc:That was certainly the case. Rituximab does not add any PFS benefit to ibrutinib. I would be careful to extrapolate that to other drugs, even to other CD20 antibodies. For example, ibrutinib with obinutuzumab may have a benefit over ibrutinib. Unfortunately, the recently published iLLUMINATE study didn’t have an ibrutinib-only arm, so that study won’t answer that particular question. But I think the ibrutinib-venetoclax combination is going to have very durable responses and certainly will add to ibrutinib monotherapy.

Harry Erba, MD, PhD:Can you give the listeners any insight into how you are going to choose between these 2 regimens?

Matthew Davids, MD, MMSc:When I sit down with my next patient who needs frontline CLL treatment, these are the factors that I’ll discuss with them. For ibrutinib, we have longer-term follow-up. We’ve seen 7-year data presented on ibrutinib now with excellent PFS. Granted, that 7-year data is only the original 31 patients who were treated in the frontline setting. If we look at phase III data, though, we have 4-, almost 5-year follow-up now on the RESONATE-2 frontline patients. Again, we see very nice durability. Two-thirds of patients are still on drug and in remission after 4 years, so that certainly looks good. Those are much longer follow-up numbers that we have so far for venetoclax plus obinutuzumab.

Secondly, another advantage of the ibrutinib data is that we have, as you alluded to, the comparison in the Alliance study and the ECOG study with standard chemoimmunotherapy regimens that we use in younger patients. So FCR [fludarabine-cyclophosphamide-rituximab] for the young, fit patients, and BR [bendamustine-rituximab] very commonly used for somewhat older patients and patients with some comorbidities, maybe not quite as frail as the chlorambucil-obinutuzumab. We don’t know yet how venetoclax plus obinutuzumab compares to FCR [fludarabine-cyclophosphamide-rituximab] or BR [bendamustine-rituximab], and I think those are important outstanding questions. Some patients like the idea of being able to just start on a drug and not necessarily need intensive monitoring. It’s very easy to start on ibrutinib. You don’t have to come back 6 to 8 hours later, 24 hours later for 5 weeks. It takes some time to safely ramp up venetoclax in CLL patients. I think that’s potentially an advantage in terms of the convenience of the drug.

On the other hand, with venetoclax plus obinutuzumab, you have the potential for time-limited therapy. Particularly if you’re talking to a younger patient, and you’re talking about 1 year of therapy with a potential for years of benefit versus lifelong therapy with a BTK inhibitor drug, I think there are some real advantages to that approach. Secondly, for patients who have cardiac comorbidities or bleeding issues, ibrutinib can be a problem. And so we worry about problems with atrial fibrillation, but we’ve even seen some reports of ventricular dysrhythmia in patients on ibrutinib. For patients with significant cardiac comorbidities, I think a venetoclax-plus-obinutuzumab regimen is quite appealing.

I think that patients in general like this idea of the punctuated therapy. Most of the patients I’ve talked to really prefer that approach. But there are always going to be patients who have different preferences, so I think you really need to kind of present both sides. And I think as the data mature with the venetoclax-plus-obinutuzumab regimen, that difference in the follow-up will even out, and we’ll have long-term follow-up on both regimens.

Harry Erba, MD, PhD:Well, it’s definitely something we hear from our patients on the myeloid side in CLL with the ABL/TKIs and with MDS [myelodysplastic syndrome] and AML [acute myeloid leukemia] with the HMAs [hypomethylating agents]. At some point along the way in patients responding, they’re going to ask if they could come off therapy. It definitely has to be included now in our discussions also in CLL. Now, in that study that led to the approval of venetoclax with obinutuzumab, there were very few patients with 17p deletion. And it’s about 5%, 10% of patients who at the time of initial therapy will have it, right?

Matthew Davids, MD, MMSc:That’s right, yes.

Harry Erba, MD, PhD:But do you use that to help decide 1 regimen or another? Do they differentiate?

Matthew Davids, MD, MMSc:So far, I’d say I don’t see any difference. But there are very small numbers in the venetoclax-plus-obinutuzumab study. We have much more data with ibrutinib in 17p CLL. So there’s maybe a little more confidence in the 17p data specifically with ibrutinib. We do see the PFS does not look quite as good forTP53-mutated patients in the venetoclax-plus-obinutuzumab study, but that’s the case with ibrutinib as well. We just have more data around ibrutinib right now.

Transcript edited for clarity.