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BTK Inhibitors Continue to Improve the MCL Treatment Landscape

Nichole Tucker
Published Online:6:00 PM, Tue October 29, 2019
Jia Ruan, MD, PhD
Jia Ruan, MD, PhD
The emergence of Bruton’s tyrosine kinase (BTK) inhibitors into the treatment landscape for mantle cell lymphoma (MCL) has improved patient outcomes over the past 6 years. Specifically, the use of BTK inhibitors results in higher overall response rates (ORRs), more complete remissions (CRs), and a lower number of adverse events (AEs) in patients with MCL. 

One first-generation BTK inhibitor, ibrutinib (Imbruvica), results in a 65% ORR, 20% of which are CRs. Lenalidomide (Revlimid) typically leads to a 30% ORR with about 8% CRs, according to Jia Ruan, MD, PhD. These data show that the introduction of novel BTK inhibitors has improved patient outcomes in relapsed and refractory diseases. Ruan believes that such advances will continue with the adoption of precision medicine and stratification of treatment intensity based on the measurement of minimal residual disease (MRD), including the use of circulating tumor DNA (ctDNA) liquid biopsies, once research related to this technology matures. 

“We're moving toward precision medicine and personalized treatment [in MCL]. The objective is to overcome resistance and come up with treatment plans that address the underlying disease biology and take personal factors about the patients into consideration,” Ruan stated.

In an interview with Targeted Oncology, Ruan, hematologist/oncologist, Weil Cornell Medicine, examined the evolving treatment landscape for MCL. She also discussed modern strategies like precision medicine and ctDNA liquid biopsy that are aiding the evolution.

TARGETED ONCOLOGY: What are some of the novel agents that show activity in this patient population?

Ruan: Since the introduction of lenalidomide, which was approved in 2013, a number of newer agents have been approved and they all belong to the family of Bruton's tyrosine kinase inhibitors. The representative is ibrutinib and it’s a first-generation, irreversible BTK inhibitor, and it was also approved in 2013. So far, this class of agents has the best single-agent activity in MCL to date. For example, ibrutinib would give about a 65% to 67% ORR, and about 20% of that would be CRs. In contrast, lenalidomide would give you about a 30% ORR and up to about 8% CR.

A newer agent in that class is acalabrutinib (Calquence). It is also a BTK inhibitor but has a narrower target spectrum. Therefore, we presume that it causes less off-target [adverse events]. The overall feeling is that it's as effective as ibrutinib, and in the phase II study that led to the approval of acalabrutinib, the ORR was 81%, and over 40% of patients had a CR. That's quite remarkable for a single agent for patients who have relapsed/refractory MCL. 

Many other agents are being tested in MCL, and they belong to a number of target categories. There's a BCL-2 inhibitor, venetoclax (Venclexta), which is an oral agent and it has been approved in chronic lymphocytic leukemia and other indolent B-cell non-Hodgkin lymphomas. In MCL, we have data to suggest that it has promising activity as a single agent. Currently, it's being studied in combination with a variety of other agents, including BTK inhibitors. They seem to work very well and are helping to move treatment away from chemotherapy. 

Another target category is the PI3K inhibitor. A number of them have been studied including; idelalisib (Zydelig), copanlisib (Aliqopa), and duvelisib (Copiktra). They have activity in MCL, although, the duration of response seems to be limited, which is a limiting factor in terms of PI3K inhibitors playing an active role as treatments for MCL.

TARGETED ONCOLOGYWhat are the ongoing challenges with treating MCL? 

Ruan: The treatment resistance continues to be a central issue with providing effective treatment for patients with MCL. All of the agents are being introduced, tested, and approved in the setting of relapsed disease. Resistance occurs as either primary resistance or secondary resistance. The primary resistance refers to the patients who wouldn't respond at all to the biological agents. In the BTK inhibitor category, we have the most data with ibrutinib and acalabrutinib. If 60% of patients respond, you would assume that up to 40% would not respond. That's the primary resistance to acalabrutinib data, 20% to 30% do not respond at all. 

Then, we have more and more data to suggest that the majority of patients will eventually come off the responding group. That's about 2 more years for patients on the ibrutinib study and about 30% may stay on treatment and continue to respond by the end of the 2 years. About 70% of those patients would've developed a variable degree of resistance at some point during that time. That would make them not benefit from treatment and have to come off of therapy. That is a big challenge for a sizable portion of patients who do not respond—maybe they have a genetic mutation that is not responsive to targeted therapy or they develop a secondary mutation in the process of being treated and then they become resistant. This is a very important issue [to consider] when treating MCL. We have to provide novel agents that sensitive to the disease at every stage of the evolution and come up with additional therapies that can overcome the resistance.

TARGETED ONCOLOGY: Looking toward the future of treatment for MCL, where is the field heading?

Ruan: We're moving toward precision medicine and personalized treatment. The objective is to overcome resistance and come up with treatment plans that address the underlying disease biology and take personal factors about the patients into consideration. This is important for us to understand MCL individually. We are moving toward doing more sequencing analyses or targeted mutation analysis at dedicated centers that are doing those assays. They would provide information on critical gene mutations such as TP53, which could be associated with an aggressive type of disease course that may not respond well to chemotherapy or specific biological agents. 

If we could know [about mutations] ahead of time, we could have the treatment designed and tailored to maximize treatment effectiveness and minimize adverse events. It doesn't make sense to subject patients to all of the cytotoxicity associated with conventional intensive chemotherapy while other options, such as participation in clinical trials with novel agents, could be very effective.

TARGETED ONCOLOGY: Can you discuss the role of ctDNA liquid biopsy in the management of MCL? 

Ruan: ctDNA liquid biopsy is a very forward-looking technology platform. It is in the experimental stage to [eventually] be applicable in guiding our clinical practice. ctDNA has been looked at in other types of B-cell lymphomas because there is always tumor DNA in circulation, which could serve as a sensitive indicator of MRD. Our current standard to detect MRD is cell-based and in the condition of MCL that could still come from peripheral blood because patients with MCL generally have circulating tumor cells.

Cell-free technology [will be] an attractive and promising platform if it proves to be correlating with a disease burden to guide some kind of treatment decision such as continuing treatment, continuing maintenance, or change treatment. My personal view is that we don't have the data to concretely support the application of this yet. Nevertheless, there's a huge interest and an effort being implemented to precisely answer those questions. It requires a lot of prospective correlative sample analyses on outcomes and intervening treatment strategies. It may take a while, but it is exciting for both the patients and the clinicians.

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