Given that there is a better understanding of B-cell receptor signaling and its resistance profiles, as well as the issues of safety and of patient-specific factors, value-based oncology therefore goes beyond the assessment of efficacy of the btk inhibitor drugs for the treatment of B-cell malignancies. Clinicians and the healthcare systems must consider aspects of safety, quality of life, duration of treatment, the health care utilization, and economic aspects.
Understanding the Role of BTK in B-Cell Malignancies
The BTK protein is part of the B-cell receptor signaling pathway. The B-cell receptor signaling pathway controls the processes required for the development, activation, proliferation, migration, and survival of normal B-cells. Many B-cell malignancies also utilize the B-cell receptor signaling pathway to sustain the malignant cells.
BTK inhibitors target the BTK enzyme to block downstream signaling events. Because this class of agent targets specific signaling components rather than rapidly-dividing cells in general, agents that inhibit BTK have a different clinical profile than most chemotherapy agents. The targeted nature of BTK inhibitors is particularly notable given the increasing importance placed on value in cancer treatment.
The clinical importance of BTK inhibition for the treatment of different B-cell malignancies varies for individual cancers and can be influenced by the disease itself as well as by previous treatment.
BTK Inhibition Across Different B-Cell Cancers
Some BTK inhibitors are approved for the treatment of CLL and SLL and can be used for previously untreated patients as well as for patients with relapsed or refractory disease and depending on the indication of approval of the specific drug.
While survival and remission rates will always remain a major concern for patients with MCL, ultimately it is the potential benefit-to-toxicity ratio that supports value. In MCL, BTK inhibitors may be considered for patients with refractory or recurrent disease after previous therapy.
This class of therapy has also become established in WM given that the disease is driven in part by signaling pathways active in the B-cell receptor pathway. Thus, BTK inhibition has been evaluated in a spectrum of diseases driven by B-cell receptor pathway active malignancies.
Studies are also ongoing to evaluate new BTK inhibitors as well as their use in combination with other targeted therapies to treat patients with various B-cell malignancies and address issues related to drug resistance.
First-Generation and Next-Generation BTK Inhibitors
Most BTK inhibitors are second generation and have improved selectivity for BTK over other key enzymes. Next-generation inhibitors are increasingly selective for BTK while maintaining their ability to inhibit the B-cell receptor pathway. Many of these have reduced cross-reactivity with other protein kinases which may be responsible for certain side effects of previous generations of BTK inhibitors.
Even though first-generation and next-generation BTK inhibitors have similar degrees of efficacy at controlling disease in patients with B-cell malignancies, the value of a treatment depends on other factors as well. Differences between treatments in frequency and severity of adverse events, rates of discontinuation, and the degree of impact on daily functioning (and other functions) of patients taking a medication can affect clinical and economic decisions made by physicians.
Efficacy Is Only One Component of Value
Value-based care also considers value beyond efficacy of disease control for patients with B-cell malignancies. Several factors that affect patients greatly may be weighed in determining value of specific treatments.
For patients receiving BTK-targeted therapy, value may involve several interconnected factors:
- Duration and quality of disease control
- Overall survival and progression-free survival
- Frequency and severity of adverse events
- Treatment discontinuation or dose modification
- Need for supportive care
- Hospitalizations and emergency visits
- Monitoring requirements
- Treatment administration and adherence
- Patient-reported quality of life
- Total cost of care
Incorporating the intensity of management of treatment-related complications into assessment of value to patients and to health systems for similar degree of therapeutic benefit is important.
Safety and Patient Selection
There are a number of different adverse events seen with BTK inhibition with some agents having greater risk of certain types of adverse events than others. These include cardiovascular events, bleeding events, infections, gastrointestinal toxicity and cytopenias.
There are many factors that may affect the choice of a particular BTK inhibitor for a particular patient. A patient with cardiac disease, bleeding disorder, on concomitant medications or with multiple comorbidities will likely need to be treated differently than a younger healthy patient.
A complete list of medication that the patient is currently taking should be obtained to identify potential drug interactions and management where appropriate.
Treatment Resistance and the Need for Long-Term Planning
While many patients remain on BTK inhibitors for long periods of time and even indefinitely, for others BTK inhibitors can induce resistance after a few months. As with many other cancer drugs, acquired changes within the BTK molecule and its downstream targets are the major reasons of resistance to covalent BTK inhibitors.
When incorporating a BTK inhibitor into the treatment plan for a patient with a B-cell malignancy, consideration must be given to the future potential for disease relapse and for what other treatments may be needed to provide long-term disease control.
Non-covalent BTK inhibitors such as the reversible BTK inhibitors are alternative strategies under investigation and are used as alternative therapeutic options in diseases resistant to other BTK-inhibitors.
Economic Considerations in Value-Based Oncology
These new oral treatments can have many more costs than the list price of the treatment. These costs can include lab draws, treatment of side effects, possible hospitalizations, support medicines, and more visits to specialists such as hematology/oncology. There is also the duration of time that the patient is expected to take the cancer treatment for.
Financial burden of medication can also have an impact on how patients adhere to their cancer therapy and subsequently their overall cancer related quality of life. Assessments of health economics use a variety of different tools including cost-effectiveness, quality-adjusted life years, utilization of health care resources and patient-reported outcomes that measure overall value of the treatment compared to its costs.
The Future of BTK-Directed Therapy
The future of BTK inhibition is personal. The area of highest growth in the pipeline includes therapies designed to be used in combination with other therapeutic classes, such as BCL-2 inhibitors, anti-CD20 therapies, and others. Further, a growing number of therapies will be personalized based on molecular characteristics and overcoming resistance will be a key strategy in the development of future BTK inhibitors.
An important area of ongoing research is whether patients who achieve a deep response with combination therapy can discontinue treatment without the disease returning. Clinical trials are also evaluating the potential of fixed-duration treatment approaches across several B-cell malignancies.
Conclusion
BTK inhibition has now become an essential component in the treatment of various B-cell malignancies. Therefore, the value of these agents extends beyond their ability to cause tumor regression and needs to consider other important clinical parameters including efficacy, safety, resistance, patient quality of life and clinical treatment burden in addition to the overall cost of care.
As new BTK inhibitors and combinations are introduced, the wise selection of treatment for individual patients will depend on a comparison of the characteristics of individual therapies with the clinical situation of the patient and his/her circumstances. Value-based oncology considers patient outcomes alongside treatment burden and healthcare-resource utilization.
Medical Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, clinical guidelines, or a recommendation for any specific treatment.
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