Activity Transcript

Kami Maddocks, MD: Hello, I'm Kami Maddocks from the Ohio State University James Comprehensive Cancer Center. Welcome to this program titled Mantle Cell Lymphoma: Exploring the Feasibility of Moving Bruton Tyrosine Kinase (BTK) inhibitors to the Frontline.

Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma with heterogeneous disease behavior. Outcomes in MCL are driven by disease biology. While we have prognostic factors that help us identify how patients may respond to treatment, currently, those prognostic factors are not really used to drive our treatment decisions. Survival for MCL has improved in the era of current therapies. We treat patients when they present with MCL based on their age and comorbidities. With those patients who are younger and fit, they are treated with more intensive chemo-immunotherapy, followed by autologous stem cell transplant (ASCT), followed by rituximab maintenance. For those patients who are older or less fit, they are treated with less intensive chemo-immunotherapy, plus or minus rituximab maintenance. However, the benefits of some of these approaches in the era of the current therapies have remained unclear. For patients with relapsed/refractory disease, we now have a number of novel biologic or targeted therapies and cellular immunotherapy available at relapse. While these agents are very effective for relapsed/refractory MCL, the majority of patients will become resistant to these agents, and access to some of them such as chimeric antigen receptor (CAR) T-cell therapy still remains a challenge.

Taking a look at the National Comprehensive Cancer Network (NCCN) guidelines for the frontline treatment of MCL, it is of note that there is no standard approach to treating MCL, and instead there are a number of different effective regimens used. These are different combination chemo-immunotherapy regimens as listed, with more intensive regimens in younger fit patients and less aggressive therapies in older patients or those with comorbidities. Rituximab maintenance has been shown to benefit patients treated with ASCT, as well as those patients treated with less intensive chemo-immunotherapy regimens.

For patients who relapse with MCL, the standard preferred treatment has become the oral BTK inhibitors with three currently approved BTK inhibitors at relapse: ibrutinib, acalabrutinib, and zanubrutinib. While these agents are very effective, the majority of patients will relapse. Because these agents are very effective in the relapsed/refractory setting and generally well tolerated, there has been a lot of effort to move these therapies into the frontline setting. Today we will discuss some of the clinical trial safety and efficacy data involving BTK combinations in the frontline setting.

I would like to first talk about different regimens that have been utilized in older patients or patients who are not going to be considered for consolidation with ASCT. These look at the combination of BTK inhibitors with immunotherapy or chemo-immunotherapy.

The first trial I will highlight is the SHINE trial, as this trial was recently reported out. This trial was a randomized phase 3 study that randomized 523 patients in a 1-to-1 fashion to treatment with standard chemotherapy, which included 6 cycles of bendamustine-rituximab (BR) followed by rituximab maintenance every 8 weeks for 12 cycles, vs that standard treatment in combination with the BTK inhibitor ibrutinib, which was given orally daily with the BR and continued with rituximab maintenance until progression or unacceptable toxicity. The primary endpoint of this trial was progression-free survival (PFS). With a little over 7 years of follow-up, this trial did meet its primary endpoint with a median PFS in the standard arm of 52.9 months vs a median PFS in the ibrutinib plus standard treatment of 80.6 months, which translated into an improvement in PFS of a little over 2 years.

There was no difference in the overall survival (OS) with the current follow up in this trial. While there were a higher number of deaths due to disease progression on the standard arm, there were a higher number of deaths related to toxicity on the ibrutinib-containing arm. Looking at overall toxicities in this trial, the most common were cytopenias and rash. When looking at events of clinical interest that occur with the BTK inhibitors, there was a higher rate of atrial fibrillation, any bleeding and grade 3 or higher bleeding; however, there was no difference in major hemorrhage or hypertension between the 2 arms.

This trial did conclude that the addition of the BTK inhibitor ibrutinib to the standard BR plus rituximab maintenance, showed an improvement in PFS that was statistically significant, but this did come at a cost of some increased toxicity. This is not yet Food and Drug Administration (FDA) approved. If it is FDA approved in the future, I think that we will have to consider the balance between which patients could potentially benefit from the additional therapy vs the additional toxicity that is seen in these patients.

There are 2 other trials that I would like to highlight that are looking at BTK inhibitors in the frontline setting. These trials both use the second-generation BTK inhibitors.

The first trial is the ECHO trial, and this trial is very similar to the SHINE trial, but it uses the second-generation BTK inhibitor acalabrutinib in combination with the BR maintenance rituximab regimen. This trial is accrued, but the results have not been reported. I think the question with this surrounds the fact that the second-generation BTK inhibitors acalabrutinib and zanubrutinib have shown different toxicity profiles, particularly fewer cardiac toxicities, than the first-generation BTK ibrutinib. The question is what is considered to be potentially better tolerated, as these BTK inhibitors may also show improvement in outcomes, but not with the same risk of toxicity as was observed in the SHINE trial.

The last trial I will highlight in this population of patients is a trial looking at the role of zanubrutinib. This trial randomizes patients also to BR, although there is no maintenance rituximab in this trial. The other arm is actually non-chemotherapy, so it is the second-generation BTK inhibitor zanubrutinib in combination with rituximab, continued until progression. This trial is ongoing.

Now to pivot and look at the use of BTK inhibitors in combination with chemo-immunotherapy in those patients who are considered younger and fit for more intensive regimens with ASCT consolidation. I would like to highlight two trials here: the TRIANGLE study and the WINDOW-1 study, both which have been reported out.

Most recently, the TRIANGLE study was just presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition. The TRIANGLE study was a randomized 3-arm study that looked at the role of ibrutinib in combination with chemo-immunotherapy and as a maintenance with or without ASCT.

This trial randomized patients who were younger then 66 years of age and considered candidates for ASCT to 1 of 3 arms. The standard arm was R-CHOP/R-DHAP chemo-immunotherapy, followed by ASCT consolidation. Then two experimental arms. The first, which added ibrutinib to the standard chemo-immunotherapy, R-CHOP/R-DHAP, treated patients with consolidation ASCT, and then gave them maintenance ibrutinib. The third arm added the ibrutinib to the chemo-immunotherapy, eliminated the ASCT, and then gave ibrutinib as maintenance. When this trial had initially started to enroll, rituximab maintenance post-ASCT was not currently the standard, although that did change in the guidelines and the trial was amended to include rituximab maintenance in all 3 arms with a similar number of patients in each arm receiving the rituximab maintenance.

Looking at the outcomes of this trial, they showed that there was superiority to the addition of ibrutinib to ASCT with an improvement in the 3-year failure-free survival (FFS) of ASCT plus ibrutinib over ASCT alone. They showed that there was no superiority of ASCT as compared to ibrutinib, so eliminating the ASCT and giving ibrutinib in induction and maintenance did not lead to a worse outcome than doing the ASCT. And finally, when they looked at the use of ibrutinib, both ibrutinib-containing arms, so with or without the ASCT, at the current follow up there was not a difference, but it is too early to say how this data will mature. Looking at outcomes based on toxicity, they showed that there was not an increased rate of toxicity in the patients receiving ibrutinib. This trial showed that ibrutinib given during induction and maintenance with or with ASCT was very efficacious with manageable toxicity. Based on the primary endpoint of FFS, the ASCT plus ibrutinib was superior to doing ASCT only, and ASCT was not superior to ibrutinib with or without ASCT. Currently there is not enough follow-up to determine whether ASCT adds to ibrutinib, but the toxicity favors ibrutinib only.

The second trial was the WINDOW-1 trial, which also looked at the role of ibrutinib in combination with more intensive chemo-immunotherapy. This trial looked at treating patients with rituximab-ibrutinib induction followed by rituximab/hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) consolidation, but with limited numbers of rituximab/hyperCVAD cycles. This trial treated patients who were 65 years and younger with induction rituximab-ibrutinib for up to 12 cycles, but it assessed response after every 2 cycles, and for those patients who achieved a complete response, they were then treated with 4 cycles of rituximab/hyperCVAD, so they were given limited duration chemotherapy. The median number of rituximab-ibrutinib cycles in this trial was 7, and the primary endpoint was overall response. The current follow-up shows a 5-year PFS of 67% and a 5-year OS of 95%. The most common toxicities in the induction part were cytopenias, rash, infection, and fatigue with no patients discontinuing therapy due to toxicity. What this trial showed was that the by giving induction with this chemo-free approach with the BTK combination, that patients were able to receive a shortened course of chemo-immunotherapy. This minimized the numbers of intensive chemotherapy cycles that patients were receiving, and overall, there was less adverse events reported with the induction followed by intensive chemo-immunotherapy than more aggressive cycles of chemo-immunotherapy.

Lastly, I want to conclude with some BTK combination trials that are all targeted therapy or immunotherapy, so completely eliminating chemo-immunotherapy in these patients. I will highlight a few combinations.

There was a small trial conducted at MD Anderson that looked at the combination of rituximab and ibrutinib in older patients with MCL. This was a 50-patient trial and it showed very high response rates with this combination of therapy and an overall response rate of 96%, with 71% of patients achieving a complete response. And at the current follow up, median PFS and OS were not reached. In this trial, about 40% of patients had to go off therapy due to toxicity. A large number of these toxicities included atrial fibrillation. Despite this, there were very good outcomes, but I think this just shows that we have to be selective in the patients that we are identifying for these and identify these cardiac risk factors at baseline so we can optimize their therapy.

The OASIS trial was a phase 1/2 trial that evaluated patients with both relapsed/refractory and previously untreated MCL. It was a small number of patients treated with this combination in the frontline setting, but this triplet combination showed very high overall response, complete response rate, and 1-year PFS. Again, this was a small number of patients and we do not have long follow up, but there are ongoing larger trials to look at this triplet combination, including the OASIS-2 trial, which is looking at this in a time-limited fashion with both double and triplet therapy.

There is another small trial looking at the second-generation BTK inhibitor acalabrutinib plus the BCL-2 inhibitor venetoclax and rituximab in patients with MCL. This trial, although small numbers, again showed a very promising overall response rate, complete response rate, and early promising PFS with more follow up and a larger number of patients needed to really determine the role of this.

There was a phase 2 trial looking at rituximab, acalabrutinib and lenalidomide in this patient population. Again, this triplet combination showing very high overall response rate, complete response rate, and early promising PFS.

To conclude, we have now seen trials utilizing the oral BTK inhibitors in combination with chemo-immunotherapy, both with less intensive regimens and with more intensive regimens, showing benefit in patients in the frontline setting. While this has not yet led to approvals, I would anticipate that in the future we will see approval for BTK inhibitors in the frontline setting with these combinations.

Moving forward, there is a lot of interest in looking at the role of these BTK inhibitors in combination with other targeted immunotherapies, trying to eliminate the use of chemo-immunotherapy in the frontline setting, at least in subgroups of these patients with MCL. CAR T-cell therapy is approved in the relapsed/refractory setting and we have seen very promising results with other immunotherapies such as the bispecific antibodies. I think as we move forward, there will be a lot of interest in moving these treatments into earlier lines and potentially combining those with BTK therapies as well.

With that, I would like to thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.