Insights on New Data With BTK Inhibitors for CLL and MCL From the SOHO 2022 Annual Meeting

Key Takeaways

• Early trials of pirtobrutinib in mantle cell lymphoma have demonstrated efficacy in pretreated patients, including those who have received prior BTK inhibitors
• Phase III data demonstrated a progression-free survival benefit with ibrutinib/venetoclax vs chlorambucil/obinutuzumab in older and unfit patients with previously untreated chronic lymphocytic leukemia

New data on treatments for mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are continually emerging. In this commentary, Christopher R. Flowers, MD, MS, and Kami Maddocks, MD, discuss select studies with BTK inhibitors from the SOHO 2022 Annual Meeting and their potential impact on the current standard of care in these hematologic malignancies.  

MCL: BRUIN

Kami Maddocks, MD:
The BRUIN study evaluated pirtobrutinib, a noncovalent or reversible BTK inhibitor that differs from the 3 currently approved BTK inhibitors for MCL that are all covalent or irreversible inhibitors and are approved in the relapsed/refractory (R/R) disease setting after ≥1 previous therapies.

This was a phase I/II study including 134 patients with R/R MCL, with 111 patients evaluable for outcomes. Most (100 patients) had been exposed to previous BTK inhibitor therapy, which was a combination of patients who had progressed or discontinued for other reasons, of whom, 51% responded to pirtobrutinib. Typically, if there is progression on one of the currently approved BTK inhibitors, we do not see response if we change to a different covalent agent. But we can switch to an alternative BTK inhibitor due to toxicity and see a response, and we may or may not see the same toxicity recur. It’s exciting to see this new type of BTK inhibitor that binds differently and can still get a response in patients who have progressed after previous BTK inhibitor therapy.

There was a small population of patients who had not received previous BTK inhibitors (11 patients), and the overall response rate in those patients was much higher at 82%, but without a head‑to‑head comparison, that is probably similar to what we see with the 3 approved BTK inhibitors. The median number of previous therapies was 3, and there were some heavily pretreated patients—a small number who had received transplant and previous cellular therapy. As for the duration of response, although the medium follow-up is relatively short, for those patients who did respond, a little less than two thirds had maintained their response at the median follow-up of 8 months.

There were no dose-limiting toxicities in the phase I portion. The most common toxicities of any grade were fatigue, diarrhea, neutropenia, and contusion, with only fatigue occurring in 20% or more of the patients. Some of the toxicities we are concerned about with BTK inhibitors, such as bruising, bleeding, including major hemorrhage, and atrial fibrillation, occurred in a small percentage of patients who were treated with pirtobrutinib: any‑grade hemorrhage in 8% and atrial fibrillation/flutter in 2%. Only 6 patients, or 1%, discontinued treatment due to treatment-related adverse events. So at this time, pirtobrutinib does appear to have a favorable toxicity profile.

To summarize, we have a BTK inhibitor that binds differently, has activity in patients who progress on previous BTK inhibitors, and appears safe. The ongoing phase III BRUIN-MCL-321 (NCT04662255) trial randomizes patients with previously treated, BTK inhibitor–naive MCL to pirtobrutinib vs investigator’s choice of one of the 3 approved BTK inhibitors. At present, it appears pirtobrutinib may be an option we would use in the setting of progression on a covalent BTK inhibitor if it were to get an approval, but with the ongoing phase III trial, we’ll see if that is truly the future setting for this agent or if pirtobrutinib will be the BTK inhibitor of choice and considered before the other currently approved BTK inhibitors.

Christopher R. Flowers, MD, MS:
I was also impressed by the high percentage of patients who had received a previous BTK inhibitor in this study. I know it’s not fair to do head‑to‑head comparisons across trials, but in terms of the toxicity profile, how do you think pirtobrutinib compares with the other BTK inhibitors, particularly the second- and later-generation BTK inhibitors?

Kami Maddocks, MD:
Overall, pirtobrutinib looks like it may have an improved safety profile, including those adverse events of special interest. In particular, the cardiac events look like they may be even more favorable than the second-generation covalent BTK inhibitors. But again, with such short follow-up, this is my very preliminary assessment. I do think the randomized trial will show us if this toxicity profile is really accurate, and with longer follow-up, we’ll see if more cumulative toxicities are observed.

Christopher R. Flowers, MD, MS:
What do think about the results with pirtobrutinib in other MCL populations that are commonly difficult to treat in the relapsed setting, such as those who relapse after stem cell transplant or after CAR T-cell therapy?

Kami Maddocks, MD:
Pirtobrutinib had similar activity in patients who had relapsed after transplant or CAR T-cell therapy, but there was such a small number of patients progressing after CAR T-cell therapy (6 patients) who were treated on this study that I think it’s too soon to say. Hopefully, as these data become more mature, we’ll have more information on outcomes for these different groups of patients.

CLL: GLOW

Christopher R. Flowers, MD, MS:
The GLOW study evaluated the combination regimen of ibrutinib/venetoclax vs chlorambucil/obinutuzumab in previously untreated patients with CLL. This trial looked at the BTK inhibitor and venetoclax combination in a time‑limited fashion. In total, 12 cycles of therapy were given in the combination oral therapy regimen after an ibrutinib lead-in and that was compared with the regimen of chlorambucil/obinutuzumab, which is an approved regimen in the frontline setting for patients with CLL. This trial included older and unfit patients but excluded patients who had known TP53 mutation or del(17p). Here chlorambucil and obinutuzumab was given for 6 cycles, so again time‑limited therapy.

This trial did show superior progression‑free survival (PFS) with the combination of ibrutinib/venetoclax vs chlorambucil/obinutuzumab, and with 34 months of follow-up, there was an ongoing benefit. Looking at the 30‑month PFS, it was almost 81% for the group that received ibrutinib/venetoclax vs approximately 36% for the chlorambucil/obinutuzumab group. There are not yet data to suggest that there is an overall survival benefit, but the follow-up for this study is still relatively short with PFS curves that are quite distinct in the 2 populations.

Also presented were data looking at undetectable minimal residual disease (MRD) using assays defining undetectable MRD at the level of 10^‑4 and 10^‑5. MRD was evaluated in both the bone marrow and peripheral blood, with the combination of ibrutinib/venetoclax more commonly producing undetectable MRD. One example of that is in looking at the 10^‑5 level, the most sensitive way of looking MRD, in the bone marrow compartment, approximately 41% of patients who received ibrutinib/venetoclax had undetectable MRD vs only approximately 8% of patients in the chlorambucil/obinutuzumab arm. Furthermore, MRD benefit held across the various prespecified subgroups, including by age, Eastern Cooperative Oncology Group status, cumulative illness rating scale for patients with CLL score, Rai stage, bulky disease, elevated lactate dehydrogenase at baseline, IGHV status and del(11q) status.

They also evaluated the dynamics of MRD in the posttreatment phase and evaluated sustained undetectable MRD, defined as repeated measures of undetectable MRD at 3 months and 12 months after the end of treatment. That rate for the ibrutinib/venetoclax arm was 80.4% vs 26.3% using the 10^‑5 level, which suggests that not only are patients reaching deep remissions, but those deep remissions are sustained even after discontinuation of the therapy, supporting this time‑limited therapy approach. These are quite provocative data for the use of the combination of ibrutinib/venetoclax in the setting of CLL.

This is a combination that’s been looked at in other settings, including in MCL. Dr. Maddocks, what are your thoughts on these data in CLL, what that might hold both for patients with CLL, and also for patients with MCL where we might think about using this kind of approach as well?

Kami Maddocks, MD:
I think this is interesting. For CLL, we know that BTK inhibition in the frontline setting is a good treatment option. We know also that venetoclax/obinutuzumab is a good time‑limited frontline therapy option. I think one of the questions becomes: Is the combination of a BTK inhibitor plus venetoclax better than the individual currently approved regimens? I do think time‑limited therapy here is a nice option because when you do give a BTK inhibitor in the frontline setting, it is given until disease progression and some patients get a very long response, but there can be some cumulative toxicity and certainly cumulative costs for patients. How do you think these data may affect practice in CLL?

Christopher R. Flowers, MD, MS:
I think these data may give us new treatment options in this setting, but I will wait to see how these data mature before considering this approach in my practice. But it is nice to be able to see time‑limited options with BTK inhibitor therapy, particularly in frontline CLL where you sometimes have patients with relatively indolent disease. It can be a difficult tradeoff at times to have a relatively indolent disease that needs to be controlled by a therapy that needs to be given for the rest of the patient’s life or until progression. For me, it’s exciting to see time-limited therapy as a potential option in this setting.

Kami Maddocks, MD:
I agree, and there is some potentially exciting combination data for MCL as well. We know that BTK inhibitors are effective as single-agent therapy in the second-line setting, but we also know that almost all patients become resistant to or progress on BTK inhibitor therapy. So, there’s been a lot of effort to improve both response rates and duration of response seen with single‑agent BTK inhibitors. The ongoing phase III SYMPATICO trial (NCT03112174) includes randomization to single‑agent ibrutinib vs the ibrutinib plus venetoclax combination in R/R MCL. If this study shows an improvement in the primary endpoints, which include both safety and efficacy with the combination regimen in the setting of R/R MCL, it could be practice changing. Hopefully, we’ll see results from this trial in the next year or so.

There are also studies looking at this strategy in the frontline setting. The phase I/II OAsIs trial looked at the combination of ibrutinib and venetoclax with obinutuzumab in both the R/R and frontline settings for MCL and demonstrated promising response rates and tolerability. The OASIS II trial (NCT04802590) is looking at the combination of ibrutinib/venetoclax and anti-CD20 monoclonal antibody in a frontline population for MCL. So, we’re not quite to where CLL is with this combination, but I do think we’re getting there and hopefully, we’ll start to see some of these combination regimens in MCL that lead to time‑limited BTK inhibitor‑based therapy in that setting as well.

CLL: SHINE

Christopher R. Flowers, MD, MS:
The other data that were presented at the SOHO meeting were from the SHINE study that was published in the New England Journal of Medicine earlier this year, looking at the combination of ibrutinib plus bendamustine/rituximab in the frontline setting for older individuals and showing that adding ibrutinib provided benefits. What are your thoughts about the SHINE study? How does that affect frontline treatment in the future?

Kami Maddocks, MD:
As far as the role of treatment with ibrutinib plus bendamustine/rituximab, we’ll have to wait and see if and when we get an FDA approval. The study showed an improvement in PFS, but there was no difference in overall survival. Some of the higher‑risk patient populations, such as the blastoid and TP53 mutated, did not have a statistically significant improvement in PFS, and that was disappointing, because for those high‑risk patients it would have been nice to be able to see a signal there.

In my opinion, this regimen is not appropriate for everyone, but the reason is not due to the lack of overall survival benefit, but because of toxicity. Although there were more deaths due to progression in the bendamustine/rituximab plus placebo arm, there was more deaths due to toxicity with bendamustine/rituximab plus ibrutinib, and there was a higher number of patients discontinuing treatment due to adverse events. Although I wouldn’t say it is for everyone, I do think that it can be an individual patient discussion and there are patients who could benefit from the combination. What I find potentially most promising is that we will see data on combinations with second-generation BTK inhibitors. Whereas this combination improved PFS, it did come at the cost of toxicity, and if we use what is thought to be a better-tolerated or safer BTK inhibitor, will that provide a benefit without the toxicity cost? If so, then that may be a regimen that I would recommend more in the frontline setting.

With these data, it is difficult to say what is the best initial therapy approach. Is it that much better to give the combination regimen upfront than to give patients the standard bendamustine/rituximab regimen, followed by rituximab maintenance and then when they progress give them the BTK inhibitor? The trial wasn’t designed to answer that question, but that is the question that comes up since it appears that outcomes may be similar in patients treated with sequential therapy as with combination therapy upfront.

Christopher R. Flowers, MD, MS:
I completely agree with you. This does create another option for some patients where you feel there might be a benefit in that particular situation for giving the BTK inhibitor in the frontline setting. But I think the common approach of giving bendamustine/rituximab or another regimen in the frontline and then using BTK inhibitors in the second line is still a very reasonable option for the majority of patients to pursue.

Looking Ahead

Christopher R. Flowers, MD, MS:
One intriguing trial that we will hopefully see data on soon is the randomized phase III TRIANGLE study (NCT02858258) in MCL, addressing the question of whether BTK inhibitors in combination with therapy in the transplant setting may provide benefits for those patients who are higher risk and younger and fit enough to be able to undergo transplantation. What are your thoughts about that study and those data that we might see?

Kami Maddocks, MD:
I am not sure what we’re going to see, but this study is aiming to answer 2 questions: (1) What is the benefit of adding a BTK inhibitor? And (2) what is the benefit of the BTK inhibitor with or without the transplant? Are we able to eliminate the transplant and use the BTK inhibitor in induction with combination chemotherapy and as maintenance or give it with maintenance after the transplant or—of course—not at all? What I would like to see from that study is our ability to eliminate autologous stem cell transplant in some of these patients and be able to treat them with combined chemoimmunotherapy and a BTK inhibitor. It will also be interesting to see the toxicity with the BTK inhibitor. Because that was some of the difficulty with the SHINE study and a number of patients had to discontinue therapy because of toxicity. Maybe in a younger population of patients the maintenance portion will be easier to tolerate.

Your Thoughts?
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