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

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.

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

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.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.

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

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.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.

When prescribing BTK inhibitors, what are some of the variables that influence treatment selection?

In CLL, perhaps even more so than MCL, there is significant attention on some of the milder effects of BTK inhibitors, which may include myalgias, mild fatigue, and loose stools. Although in the short term these adverse effects are very tolerable, over the course of years they can affect quality of life (QOL) and compliance.If acalabrutinib is approved for CLL, it is likely that a small population of patients will be started on it immediately; these are probably patients with a history of known risk factors, such as atrial fibrillation and bleeding, both of which can give patients pause when starting ibrutinib. Based on early data, it appears that acalabrutinib has fewer of those adverse effects. It is also likely that practices will take longer to change in other scenarios, especially as patients and doctors become more comfortable using acalabrutinib in various indications.

Can you discuss next steps for therapy when a BTK inhibitor is discontinued because of lack of efficacy or intolerability?

It is also worth noting that there are certain drugs that are contraindicated when using BTK inhibitors, which may also impact treatment selection.In MCL, healthy patients who fail ibrutinib would be considered for alternate drugs like venetoclax, lenalidomide, or combination chemotherapy. If the disease has an aggressive presentation on relapse, I would be thinking about combination chemotherapy followed by transplant. In patients with long remissions, there are several approved non-chemotherapy options that should be considered. In CLL, in the absence of Richter’s transformation, drugs such as venetoclax, idelalisib, and obinutuzumab have shown efficacy. Prior to these agents, outcomes were generally poor in patients with CLL who relapsed on ibrutinib. What factors should guide prescribers in their conversations with patients about adverse effects and long-term use of BTK inhibitors? It is very clear from real world data that certain “mild” adverse effects often lead to discontinuation of drug. In fact, discontinuation rates of BTK inhibitors can be 30% or greater within two years of use, and many patients discontinue due to grade 1 or grade 2 toxicity. This is unfortunately because many adverse effects can be managed with dose interruption or reduction. If not prepared for these adverse effects, however, many patients will stop the drug completely.

It is essential that physicians discuss the importance of continuing the drug and the potential for adverse effects. In these conversations, physicians should be forthright and explain that most adverse effects associated with BTK inhibitors, although not life-threatening, can affect QOL. Patients should be encouraged to talk to their physician if unexpected adverse effects occur, so that they can be managed. This approach will not only improve a patient's QOL, but it will also reduce the likelihood of discontinuation of the drug.

What is your perspective on future directions in research and management regarding the use of BTK inhibitors in MCL and CLL?

If an adverse effect is perceived as serious or a significant impairment of QOL, physicians should investigate and address the symptom regardless of severity. This is especially true when a patient is on chronic therapy, as affects which are unrelated to drug are often still attributed to therapy, especially in the absence of an appropriate workup.BTK inhibitors, as a class, have changed the natural history of several B-cell cancers, specifically MCL, CLL, and other emerging subtypes. Next-generation studies are even more exciting, because we are now seeing data combining [BTK inhibitors] with agents such as venetoclax and next-generation anti—CD-20 agents, and responses are phenomenal.

Specifically, we are seeing patients that are receiving new combinations of BTK inhibitors with high complete remission rates, never seen before with any of these drugs in single agent trials. Although prior studies demonstrated high overall response rates, high complete remissions have been elusive. With next-generation combination trials, we are seeing high complete and overall remission rates, which is very promising.

Despite the promise of this new class of agents, one factor that continues to pose significant challenges is cost, particularly due to the length of therapy required. As we move into combination trials, total cost will be prohibitive unless we discuss and explore new solutions. It is simply not feasible or sustainable to put all future patients on therapeutic regimens costing several hundred-thousand dollars per year for decades. Therefore, it imperative as we move into the future thinking about how we’re going to use these drugs in a sustainable way, we will need to find creative ways to control costs.