Introduction
Brukinsa (zanubrutinib) and Jaypirca (pirtobrutinib) are two targeted cancer therapies used to treat Chronic Lymphocytic Leukemia (CLL). Over the last decade, CLL has transitioned from chemotherapy to targeted therapies that attack specific pathways which cancer cells use to survive and proliferate. These two new treatments are part of the next generation of BTK inhibitors and have specific profiles of efficacy for patients with this disease.
The efficacy profiles of Brukinsa and Jaypirca will help to educate patients, their families, and their health care providers on how these two drugs may be best used in the treatment of patients with CLL. While the decision of which drug to use is best made on a case-by-case basis by a patient’s health care provider, reviewing the available clinical data on these two drugs will hopefully provide patients, their families, and their health care providers with a greater understanding of the potential benefits and uses of these two important drugs for the treatment of patients with CLL.
Understanding BTK Inhibition in CLL
Brukinsa and Jaypirca are two BTK inhibitors used in the treatment of CLL. Both of these drugs target Bruton’s Tyrosine Kinase (BTK), a protein that is part of the B-cell receptor signaling complex. BTK is important in the survival of B-cells. In the case of CLL, BTK helps the cancer cells to survive and multiply. By targeting BTK with a drug, the cancer cells are unable to survive, and the disease is slowed. Eventually, the cancer cells die, leading to a reduction in the amount of CLL present in the body.
Both Brukinsa (zanubrutinib) and Jaypirca (pirtobrutinib) work as Bruton’s Tyrosine Kinase (BTK) inhibitors. BTK is part of B-cell receptor signaling. It helps CLL cells to survive and multiply. BTK inhibitors interfere with B-cell receptor signaling, which causes CLL cells to die. BTK inhibitors are considered targeted therapies because they are designed to target a specific process in cancer cells. There are differences between the two drugs. There is a permanent bond between zanubrutinib and the active site of BTK. The connection between pirtobrutinib and the active site of BTK is non-covalent. This is one of the main differences between Brukinsa and Jaypirca. This is one reason why Jaypirca may still be effective when there are certain BTK mutations.
Brukinsa is a covalent BTK inhibitor that targets BTK at a particular site where it makes a permanent bond with the enzyme. As a non-covalent BTK inhibitor, Jaypirca targets BTK at a different site, which allows the drug to remain active in the presence of resistance mutations that can affect the binding of covalent BTK inhibitors to BTK.
Brukinsa: Clinical Efficacy in CLL
Studies on Brukinsa in CLL/SLL patients have shown strong efficacy in treatment-naïve patients as well as in patients who have received prior treatments for their disease. This targeted agent is very selective for BTK and does not interfere with many other cellular processes.
Brukinsa also has high BTK selectivity, which should allow the drug to target CLL cells while having a minimal effect on other cells within the body.
Brukinsa has been studied in several clinical trials in patients with CLL and/or SLL. In trials that followed patients treated with Brukinsa for several years, patients experienced high complete or overall response rates. Patients experienced significant reductions in the amount of CLL found in their blood and in the size of affected lymph nodes. Patients also experienced increases in normal blood cells, including platelets. Patients experienced long periods of progression-free survival. Overall, results from clinical trials of Brukinsa have been very promising and support its use as a treatment for patients with CLL and/or SLL.
Also, many studies have been performed to compare Brukinsa with other BTK inhibitors. In all the studies performed so far, the results of patients treated with Brukinsa have been very good, and thus, the duration of response has been long. Therefore, for now, it can be said that, also in the context of other BTK inhibitors, it represents a good option of treatment for patients with CLL.
Jaypirca: Clinical Efficacy in CLL
Jaypirca, a second-generation BTK inhibitor, was designed with the specific goal of overcoming treatment resistance that is associated with BTK mutations. Most BTK inhibitors form covalent bonds with the BTK enzyme, forming a permanent alteration in the enzyme, but the unique design of Jaypirca allows it to bind BTK in a non-covalent manner, therefore maintaining its potency against even the most resistant BTK mutations.
Most BTK inhibitors have been associated with the development of BTK mutations in the tumor after a period of initial response. These mutations in BTK can decrease the sensitivity of the enzyme to the small molecule inhibitor, resulting in tumor progression on therapy. Jaypirca is designed to be effective in the presence of these mutations by binding to BTK at a different site than the covalent BTK inhibitors.
By design, Jaypirca has been shown to be active in CLL patients who have been previously treated with other BTK inhibitors. Since most patients receive multiple lines of treatment for their cancer prior to being treated with a BTK inhibitor, Jaypirca is expected to be active in treating patients with a wide range of disease states.
There are also promising results from clinical trials for Jaypirca in the treatment of patients with CLL who have received previous therapies for their disease, including prior BTK inhibitors, and who have developed BTK mutations that confer resistance to these therapies.
Further follow-up is planned to clarify Jaypirca’s long-term efficacy as well as to confirm its position in treatment strategies for CLL patients.
Comparing Response Characteristics
The comparison of Jaypirca vs. Brukinsa must also take into consideration the differences in the patient populations in which the drugs have been studied in clinical trials.
Patients newly diagnosed with CLL can be treated with Brukinsa as part of their first treatment for the disease, as well as patients with previously treated CLL. The clinical data from studies with Brukinsa support the use of the drug in a number of different treatment settings for patients with CLL. The clinical data have also shown that patients can have a long duration of disease control with Brukinsa.
Jaypirca is effective in patients with BTK inhibitor-resistant CLL who have been previously treated with BTK inhibitors. It has the unique ability to treat patients with BTK mutations. It can also be used in patients who have failed other therapies for CLL.
Instead, both Jaypirca and Brukinsa can be used for different indications.
Progression-Free Survival Considerations
Cancer researchers measure a cancer drug’s effectiveness by two main criteria: overall survival and progression-free survival. We’ve already described overall survival, which is how long a patient lives with a particular cancer after he or she has begun treatment with a new drug. Progression-free survival is the length of time a patient lives with a particular type of cancer after he or she has begun treatment with a new cancer drug, while the cancer does not get worse.
Data from large numbers of patients in late-stage clinical trials support long-term progression-free survival (PFS) in CLL patients.
Data on the duration of disease control with Jaypirca are still immature and need to be monitored as more clinical experience is gained, especially for patients who have received prior therapies, including BTK inhibitors.
Please see above for the discussion of PFS for Jaypirca and Brukinsa. When reviewing PFS for either agent, it is critical to understand the prior treatments that a patient has received.
Impact on Treatment Sequencing
Modern CLL management is also increasingly focused on a sequential use of targeted therapies as part of a broader strategy to control CLL. Some of these drugs will be used as part of an initial or early-line strategy of management, while other drugs will be reserved for use as later-line therapies following development of resistance to prior targeted therapies. Jaypirca is a drug that is used for the treatment of CLL following prior therapy with BTK inhibitors. It represents an alternative approach to controlling CLL following the development of resistance to prior BTK inhibitors. As such, Jaypirca will often be used in combination with other therapies as part of a broader strategy to manage CLL.
Brukinsa is a frequently considered first-line or early-line targeted therapy option. It is effective in treating patients with CLL in various stages of their disease and can provide long-lasting control of CLL.
Jaypirca can play a role in late-line therapy after resistance has occurred to prior BTK inhibitor therapies. It has a distinct mechanism of action and, therefore, can be considered for the treatment of patients who are on their last BTK inhibitor and are not on BCL2 inhibitor therapy.
This is why Jaypirca is often discussed in relation to brukinsa, as to where in the treatment of CLL this new medication will be used, as opposed to other targeted therapy treatments already established on the market.
Conclusion
For Brukinsa and Jaypirca, two latest drugs for the treatment of CLL, both targeting the BTK signaling pathway but in different fashions, are most appropriate for different parts of CLL treatment.
While Brukinsa has shown efficacy in all types of patients, including those newly diagnosed with CLL, Jaypirca has shown particularly promising results in patients who have failed previous treatment with BTK inhibitors. As such, Jaypirca is addressing an important unmet medical need in the treatment of CLL.
As more information becomes available about these two drugs, treatment of CLL will continue to evolve and become more individualized, hopefully leading to the best possible treatment of CLL for each individual patient.
