BTK Inhibitors: Real-World Insights on Patient Management and Therapy Selection

Published: Saturday, Sep 29, 2018
Nathan Fowler, MD
Nathan Fowler, MD
BTK inhibitors have evolved into a more prominent role in the treatment paradigm of mantle cell lymphoma (MCL) and other B-cell malignancies. However, work remains to completely refine this class of agents for patients, particularly in terms of toxicity.

"In MCL, BTK inhibitors have not only changed the natural history of the disease, but have also changed the treatment options for patients," said Nathan H. Fowler, MD. 

Both BTK inhibitors, ibrutinib (Imbruvica) and acalabrutinib (Calquence), are approved by the FDA as a treatment for patients with MCL who have received at least 1 prior line of therapy.

Future steps include these agents as combination therapy. The phase II ENRICH trial, for example, is investigating the combination of the first-generation BTK inhibitor ibrutinib with rituximab (Rituxan) maintenance therapy in elderly patients with newly diagnosed MCL, as well as in those with relapsed disease.

Similarly, the second-generation BTK inhibitor acalabrutinib is also being tested in untreated patients with MCL. One phase I study is testing the safety and efficacy of the agent plus alternating cycles of bendamustine/rituximab and cytarabine/rituximab, to determine whether the addition of BTK inhibition will increase the rates of complete response.

In an interview with OncLive, Fowler, a medical oncologist in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, discussed the use of BTK inhibitors in B-cell malignancies.

OncLive®: How would you characterize the role of the BTK inhibitor class among the evolving treatment landscape for B-cell malignancies?

Fowler: What we are seeing now and what we will likely continue to see is a shift away from traditional combination chemotherapy regimens, not only in the relapse setting but also in the front-line. There are several ongoing clinical trials evaluating BTK inhibitors, alone or in combination, as initial treatment for MCL. In the coming years, we are going to see more trials, not only in elderly or infirm populations, but also in younger patients, in [whom] we are using BTK inhibitors in combination with other agents, such as venetoclax, targeted small molecular inhibitors, or monoclonal antibodies.

Today, we are lacking comparative data for BTK inhibitors. Hence, if a clinician had several agents available, treatment selection would most likely be determined by adverse effect profiles. For example, with ibrutinib, concerns for atrial fibrillation and rash are higher when compared with acalabrutinib, whereas we seem to be seeing more headache in patients receiving acalabrutinib. Convenience in dosing may also affect selection, as acalabrutinib has twice a day dosing.

In chronic lymphocytic leukemia (CLL), we are seeing similar concepts, in that we are moving away from chemotherapy in the relapse setting and in treatment naïve patients. However, the therapeutic field is arguably further along in development than MCL. For example, in addition to the availability of ibrutinib, other targeted kinases, such as idelasilib are also available.

These agents are still fairly new, and the enduring benefit and toxicity is still unknown with several drugs. CLL is a chronic disease, and several emerging drugs are potentially prescribed life-long, so clearly it is essential to understand the long-term adverse effects and financial toxicities of prolonged treatment.

Can you discuss key differences between the available BTK inhibitors, both in terms of efficacy and safety/tolerability?

The availability of multiple agents not only allows physicians to tailor therapy based on a patient’s prior medical history, but also to their willingness to accept a given risk profile. The availability of multiple agents also allows us to potentially switch these drugs if a patient develops a adverse effect that’s unique to that drug. If a patient receiving ibrutinib and has atrial fibrillation, switching to another drug in the same class could have potential benefit.

Although phase III trials are ongoing to evaluate BTK inhibitors head-to-head, it remains a challenge to compare results across trials, due to differences in patient selection and various other factors. What we have learned about ibrutinib and acalabrutinib based on current data is that they appear to offer fairly similar efficacy with respect to outcomes.

If the adverse effect profiles for second-generation BTK inhibitors, such as acalabrutinib, continues to be favorable, use of these agents may increase. Currently, long-term efficacy data for ibrutinib is available and therefore many physicians are comfortable using it for longer durations. The adverse effect profile for ibrutinib is also well known, and most physicians are comfortable adjusting dosing if a patient develops adverse effects.

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