BTK Inhibitors Transform Treatment Landscape for Mantle Cell Lymphoma

In an interview with Targeted Oncology, Andre Goy, MD, discussed the evolving role of Bruton’s tyrosine kinase inhibitors for the treatment of patients with mantle cell lymphoma, as well as where this field is headed based on ongoing clinical trials in this space.

Andre Goy, MD

Bruton’s tyrosine kinase (BTK) inhibitors are available for the treatment of mantle cell lymphoma (MCL), including 3 agents that are approved by the FDA. BTK inhibitors are also demonstrating promise in combinations as well as in the frontline setting, according to Andre Goy, MD.

Most recently, the FDA granted approval in November 2019 tozanubrutinib (Brukinsa) for the treatment of patients with MCLwho have received at least 1 prior line of therapy. A phase II clinical trial demonstrated an objective response rate (ORR) of 83.5% with a complete response (CR) rate of 58.8%.

Acalabrutinib (Calquence) received its FDA approval in October 2017, in which the agent led to an ORR of 81% and a CR rate of 40% in the phase II ACE-LY-004 trial. Ibrutinib (Imbruvica) received its approval from the FDA in November 2013, but this agent continues to show efficacy alone and in combination with other therapies. In particular, ibrutinib plus venetoclax (Venclexta) has appeared promising in clinical trials and remains under investigation as treatment of patients with MCL.

In an interview with Targeted Oncology, Goy, chief in the division of lymphoma, chairman and director at John Theurer Cancer Center, discussed the evolving role of BTK inhibitors for the treatment of patients with MCL, as well as where this field is headed based on ongoing clinical trials in this space.

TARGETED ONCOLOGY: What is the role of BTK inhibitors in MCL?

Goy:In MCL, we have made a lot of progress over the last decade or so. We now have 6 agents approved, 5 in the US, including 3 BTK inhibitors. The first, ibrutinib, was approved with an ORR of 60% and 20% CR. CR is increasing overtime with a median DOR around 17 months. Acalabrutinib came next, and the ORR was higher at around 80%. Half of the patients achieve CR, and the median DOR, which was recently updated, is around 27 months. This is very impressive. Finally, zanubrutinib was approved on a very high ORR of 84% and close to a 60% CR. The DOR is around 19 months.

TARGETED ONCOLOGY: What is striking about the BTK inhibitors in the MCL treatment landscape?

Goy:What is interesting here is it provides a new platform in the relapsed/refractory MCL setting, and we are seeing some durability of response. We see the impact of novel therapies because when you look at long-term follow-up of BTK inhibitors, such as ibrutinib in which we have the longest follow-up, over 7 years now when you pull the study as a single-agent, it is interesting to see that if a patient had 1 prior line of therapy at the time of entering the study, they had a very durable response with a median PFS over 33 months versus 8 months for 2 or more [prior lines of therapy]. We also see that when the patient has a CR, the durability is over 5 years, which is very impressive.

This being said, BTK inhibition has a bit of an inconvenience in terms of toxicity, particularly from off-target effects. Atrial fibrillation and risk of bleeding are higher than the other 2 BTK inhibitors because they are more selective, particularly acalabrutinib. We don’t have a lot of data on the selectivity of zanubrutinib, but we have also observed the same toxicity. Otherwise, this is similar but with less atrial fibrillation and bleeding. This potentially allows for different treatment.

TARGETED ONCOLOGY: Could you speak to the data we have seen for BTK inhibitors in other settings or in combination with other agents?

Goy:We don’t have head-to-head comparison, but this is being done in chronic lymphocytic leukemia (CLL). It offers now a platform where we can start patients on BTK inhibitors, but it is also offering us a platform to build up on this. The data that was most impressive was the ASH data of ibrutinib plus venetoclax. We see patients with very high ORR of 80%, and the MRD-negativity is close to 40%. What is even more impressive is in this proof of concept [trial] is 4 of these patients stopped treatment without progression for up to 18 months. For the first time, we are offering a novel therapy in the relapsed setting where you can stop therapy. I find this quite remarkable.

This is being tested now in the frontline in a number of doublet and triplet combinations to see how we can combine this novel therapy [with other agents] in relapsed/refractory MCL. We found the same results in the PHILEMON trial from Sweden looking at this population where the CR rates is very high, even in patients who are P53-positive, which is frequently the case in that setting. This is offering a new backbone for the relapsed setting. In the frontline setting, I think there is a significant change happening in MCL; we tend to think of MCL as a very indolent disease with different presentations. These patients are very stable genetically and are often IDH-mutated and can be monitored for a long time. However, for all the others, the question is what is treatment, and how do we treat them. For now, it has been [based on] if the patient is fit for dose-intensive therapy and can they tolerate a high dose therapy.

I think these things have changed. We test patients routinely forP53by NGS looking at high-risk factors to try to see if those patients with high-risk molecular features do very poorly, regardless of treatment even with high-dose therapy and transplant. They generally have a median survival of less than 1 year. We treat this patient with a combination of ibrutinib and rituximab. There are ongoing trials looking at this to confirm, but we do this as per the clinical trial at MD Anderson Cancer Center and give them a shorter course of chemotherapy afterward.

If the patients are younger or 1 thing that is interesting is the rituximab (Rituxan) plus bendamustine and cytarabine (R-BAC) as consolidation. We don’t know if you need the chemotherapy at this point, this is still ongoing. We know that we can achieve MRD-negativity with ibrutinib and rituximab upfront which is impressive, but are you potentially killing the difficult clone and then you need chemotherapy? This still needs to be answered in the clinical trials as they mature.

BTK inhibitors are also being combined with a BR regimen, plus or minus ibrutinib or acalabrutinib. There are 2 trials looking at this, and 1 has been completed while the other is pending results. We are waiting to see if this is another platform in that setting.

TARGETED ONCOLOGY: What challenges must we still overcome with the BTK inhibitors?

Goy:We saw [data] at ASH where there is more data in CLL with longer experience, more combinations that have been tested where we see still more patients have become resistant. The mutations are very complex, but this brings forward a platform or need on how we can address that. There are trials of BTK inhibitors, third-generation agents, that are reversible BTK inhibitors that are binding at site and have shown some proof of concept activity in patients who were prior failing ibrutinib. I think that is remarkable. As we move them forward, particularly in a patient with high-risk molecular features and in combinations like with venetoclax, I think this is going to offer us a platform for a finite duration of therapy, and that is going to be very important.