Goy Underscores Impact of BTK Inhibitors in Relapsed/Refractory MCL

Andre Goy, MD, MS

BTK inhibitors have expanded the armamentarium of relapsed/refractory mantle cell lymphoma (MCL), said Andre Goy, MD, MS, adding that this class of agents has elicited unprecedented and durable responses in this patient population.

"What is interesting here is that [BTK inhibitors] provide a new platform in relapsed/refractory MCL," said Goy. "We see some durability of response, as well as the impact of novel therapy."

In November 2013, ibrutinib (Imbruvica) became the first BTK inhibitor to receive FDA approval as a treatment for patients with MCL who received ≥1 prior line of therapy. Later, in October 2017, acalabrutinib (Calquence) was granted a similar indication for patients with MCL.

Most recently, in November 2019, the FDA approved the next-generation BTK inhibitor zanubrutinib (Brukinsa) with the same indication.

In an interview with OncLive, Goy, chief of the Division of Lymphoma, and chairman and director of the John Theurer Cancer Center, discussed the utility of BTK inhibitors in patients with relapsed/refractory MCL.

OncLive: Could you discuss 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 [globally]. In the United States, there are 5 approved agents, 3 of which include BTK inhibitors.

Ibrutinib was the first BTK inhibitor approved; [data supporting its approval] demonstrated an objective response rate (ORR) of 60% with a 20% complete response (CR) rate that is increasing over time. The median duration of response (DOR) with ibrutinib is around 17 months.

Then came acalabrutinib, which elicited an ORR of greater than 80% with half of the patients achieving a CR, and the median DOR was updated to 27 months. These are very impressive data.

Finally, there is zanubrutinib, which was approved based on a very high ORR of 84%. The CR rate [with zanubrutinib] was closer to 60%, with a median DOR of around 19 months.

How have BTK inhibitors impacted the treatment paradigm of relapsed/refractory MCL?

We have the longest follow-up with ibrutinib. The study [looking at ibrutinib] as a single agent has more than 7 years of follow-up. It is interesting to see that in patients who had 1 prior line of therapy at the time of entering this study, they had very durable responses, with a median progression-free survival (PFS) of over 33 months; in patients who received ≥2 prior therapies, the median PFS was 8 months. Also, we see that when patients achieve a CR [with ibrutinib], the durability is longer than 5 years. That is very impressive.

How do the toxicity profiles of the BTK inhibitors compare?

BTK inhibitors are a bit of an inconvenience in terms of toxicity, particularly from off-target effects. Atrial fibrillation and risk of bleeding are higher [with ibrutinib] compared with the other 2 BTK inhibitors; this is because zanubrutinib and acalabrutinib are more selective BTK inhibitors.

Zanubrutinib and acalabrutinib don't have as much atrial fibrillation and bleeding, which allows for potentially more adherence to treatment.

We don't yet have head-to-head comparison data, but this [comparison] is being done in chronic lymphocytic leukemia (CLL). It now offers us a platform where we can start patients on BTK inhibitors while we build up a data platform.

The most impressive data were presented at the 2019 ASH Annual Meeting on ibrutinib and venetoclax (Venclexta); patients achieved a very high ORR of 80% and a minimal residual disease (MRD)—negative rate of close 40%.

For the first time, we are offering a concept of a novel therapy in the relapsed setting [with ibrutinib/venetoclax in which] you can stop therapy. I find that quite remarkable.

For example, we tested rituximab (Rituxan) plus lenalidomide (Revlimid; R²) with ibrutinib in relapsed/refractory MCL. We [replicated] the same results found in the Swedish PHILEMON trial of this patient population; the CR rate was high—even in p53-positive patients.

This is offering a new backbone for the relapsed/refractory setting and in the frontline setting. There is a real significant change happening in MCL in that we tend to think of MCL as a subset of very indolent disease. MCL has a different presentation, high white blood cell counts, splenomegaly, no lymphadenopathy, and a different gene expression profile. These patients are genetically stable. They are often IGHV-mutated, but these patients can be monitored for a long time.

How does treatment selection evolve for these patients?

The dichotomy has been [to determine whether the patient] can tolerate a high-dose regimen. It is arbitrary to [consider] age [as a deciding factor]; often patients are 60 or 65 years old.

Now, we routinely test patients for p53 mutations by next-generation sequencing looking at NOTCH and other [molecular] factors. Then, we try to see which patients have these molecular features because they typically do very poorly—particularly those patients with p53 mutations. Typically, the median survival is less than 1 year.

We treat these patients with a combination of ibrutinib and rituximab. There are ongoing trials looking at this to confirm [the efficacy], but we do this as per the a Window trial from The University of Texas MD Anderson Cancer Center. Then, we give patients—if they’re younger—a shorter course of chemotherapy afterward with either hyperfractionated cyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD). Or, they receive rituximab, bendamustine, and cytarabine (R-BAC) as consolidation therapy. We don't know if patients need the chemotherapy at this point; this is still ongoing. We know that we can achieve an MRD-negative status with ibrutinib plus rituximab, but are we potentially killing the difficult clone—and then patients need chemotherapy? This needs to be answered as the data mature.

Bendamustine and rituximab are also being combined with or without ibrutinib or acalabrutinib. The SHINE trial has completed, and the other trial is pending results. This is going to offer yet another platform in itself.

What challenges do we still have to overcome with BTK inhibitors?

At the 2019 ASH Annual Meeting, we saw data in CLL showing longer experience and more combinations that have been tested where we see patients still becoming resistant particularly patients with POLG-gamma mutation downstream or PI3K pathway activation. The mutations are obviously very complex, but this is offering a platform to address that.

There are emerging third-generation BTK inhibitors that are reversible and bind to a different site. They have shown some proof-of-concept and activity in patients who had prior failure on ibrutinib; that is remarkable.

As we move [these agents] forward, and in combination with venetoclax, in patients with high-risk molecular features, this is going to offer us a platform for a finite duration of therapy and it will be very important.

Finally, BTK inhibitors are also being looked at in the maintenance setting. We are starting to see very early data in the maintenance setting. The European MCL Intergroup study is looking at maintenance treatment for patients who had autologous stem cell transplant after rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), R-BAC, and transplant induction. This is going to be very interesting, as well.