Comparing Jaypirca vs Brukinsa: What Patients Need to Know

BTK (Bruton’s tyrosine kinase) inhibitors are important treatment options for a number of B-cell malignancies including CLL (chronic lymphocytic leukemia), SLL (symmetric small lymphocytic lymphoma), and MCL (mantle cell lymphoma). While both Jaypirca (pirtobrutinib) and Brukinsa (zanubrutinib) are BTK inhibitors, there are some key differences between the two drugs. First, Jaypirca and Brukinsa inhibit BTK by different mechanisms. In addition, the evidence for Jaypirca supports use in specific patient populations, whereas evidence for Brukinsa supports use in a number of different disease states and patient populations. As such, Jaypirca and Brukinsa should be considered in different contexts when determining an appropriate treatment sequence for a patient.

Understanding the Two BTK Inhibitors

BTK is a component of the B-cell receptor (BCR) signaling pathway that regulates important B-cell functions including proliferation, survival, migration, and interaction with the tumor microenvironment. The inhibition of BTK with small molecule inhibitors has emerged as an effective therapeutic strategy for a variety of B-cell malignancies.

Bruton tyrosine kinase (BTK) inhibitors are increasingly used for the treatment of several B-cell malignancies. Pirtobrutinib (Jaypirca) is a non-covalent, reversible BTK inhibitor. It was developed for use in patients whose disease has progressed on therapy with prior covalent BTK inhibitors. Zanubrutinib (Brukinsa) is a covalent BTK inhibitor.

Note that the comparison of Jaypirca (pirtobrutinib) and Brukinsa (zanubrutinib) should be assessed in the context of the specific malignancy as well as the patient’s previous treatment history, including prior exposure to other BTK inhibitors and corresponding clinical effects.

Brukinsa: Established Covalent BTK Inhibition

Zanubrutinib, a BTK inhibitor, is approved for the treatment of adults with MCL who have received at least one prior therapy, Waldenström’s macroglobulinemia, marginal zone lymphoma (R/M LZL) that is relapsed or refractory and had received at least one prior treatment with anti-CD20 therapy, CLL/SLL, and follicular lymphoma (R/R FL) in combination with obinutuzumab for patients who have received two or more prior lines of systemic therapy for follicular lymphoma.

In January 2023, FDA approved zanubrutinib for treatment of adults with CLL/SLL. Approval was based on SEQUOIA trial, a treatment-naive population without 17p deletion. SEQUOIA trial included 479 patients randomized to either zanubrutinib or bendamustine plus rituximab (BR). Severity of adverse event led to discontinuation in 5% of patients on zanubrutinib compared to 13% of patients on BR. Median treatment duration was not reached for zanubrutinib and was 33.7 months for BR.

Zanubrutinib has been shown to be active in previously treated CLL/SLL patients in the ALPINE study, a randomized study of 652 patients with relapsed or refractory CLL/SLL comparing zanubrutinib to ibrutinib. The ORR was 80% for zanubrutinib and 73% for ibrutinib.

Jaypirca: Non-Covalent BTK Inhibition

Pirtobrutinib was developed as a non-covalent BTK inhibitor and has been evaluated in patients previously treated with a covalent BTK inhibitor. In December 2023, the U.S. FDA granted accelerated approval for Jaypirca (pirtobrutinib) for adults with CLL/SLL that is relapsed or refractory and has received at least two prior regimens, including a BTK inhibitor and a BCL-2 inhibitor.

Brukinsa (zanubrutinib) received FDA approval in January 2023 for adults with relapsed or refractory Mantel Cell Lymphoma (MCL) following at least two lines of prior systemic therapy including a BTK inhibitor. The approval of Brukinsa was based on the results of the BRUIN study, a single arm trial conducted in 120 patients with MCL previously treated with a BTK inhibitor. The patients had received a median of three prior therapies with 83% of patients discontinuing their prior BTK inhibitor therapy due to refractory or progressive disease.

For CLL/SLL, pirtobrutinib was granted accelerated approval on December 4, 2023, for the treatment of adults with CLL/SLL who have received at least two prior therapies for their disease including a BTK inhibitor and a BCL-2 inhibitor. Approval was granted based on data from BRUIN-CLL-321 (a randomized, open-label trial) in which pirtobrutinib showed to achieve a median progression-free survival (mPFS) of 11.2 months versus 8.7 months with investigators choice treatment of idelalisib/rituximab or bendamustine/rituximab.

Jaypirca vs Brukinsa: Clinical Context

While Jaypirca vs Brukinsa, they should not be viewed as equivalent therapies. The two are distinct with Brukinsa being a covalent BTK inhibitor and Jaypirca a non-covalent BTK inhibitor. The evidence regarding their respective FDA-approved indications is distinct as well.

Zanubrutinib is indicated for treatment of adult patients with CLL/SLL, including previously treated and treatment-naïve patients, whereas pirtobrutinib is approved for adult patients with CLL/SLL previously treated with one or more BTK inhibitors. Thus, a prior treatment with covalent BTK inhibitors is a specific element to consider in treatment sequencing. Previous treatment with BTK inhibitors would be an important factor to consider in determining whether Jaypirca or Brukinsa would be the most appropriate treatment for a particular patient.

Evidence in CLL and SLL

For the treatment of CLL/SLL, it is also important to know the prior treatment history of patients. Zanubrutinib has been evaluated in both treatment-nave and previously treated patients with CLL/SLL in the SEQUOIA study and ALPINE study, respectively.

The approval for CLL/SLL was based on traditional approval of Pirtobrutinib for patients previously treated with a covalent BTK inhibitor (BRUIN-CLL-321). In this randomized (open-label) trial, 238 patients were assigned to pirtobrutinib versus investigator’s choice of idelalisib + rituximab or bendamustine + rituximab. The median PFS was 11.2m for pirtobrutinib versus 8.7m for investigator’s choice. The BRUIN-CLL-321 study showed different PFS between treatment groups.

Mantle Cell Lymphoma and Treatment Sequencing

In MCL, Brukinsa has been approved to treat adults with this cancer after one prior therapy. Jaypirca was approved to treat adults with MCL that is relapsed or refractory after two or more prior therapies including at least one prior treatment with a BTK inhibitor.

Jaypirca is approved for treatment of adult patients with Relapsed or Refractory MCL following at least two prior lines of systemic therapy for MCL, including a BTK inhibitor. In the BRUIN study, 60% of study participants were previously treated with ibrutinib, 24% with acalabrutinib, and 12% with zanubrutinib.

Treatment history can provide very important clinical information in the assessment of a patient and how they may respond to pirtobrutinib after progression on a covalent BTK inhibitor.

Safety and Practical Considerations

It is also important to note that both zanubrutinib and pirtobrutinib have adverse reactions and have precaution and warning sections in their prescribing information. These sections detail the potential side effects that patients can experience and also specify any steps that clinicians should take when monitoring patients taking these medications.

For zanubrutinib, the most common adverse reactions (≥ 20%) were reported to be neutropenia, upper respiratory tract infections, thrombocytopenia, hemorrhage and musculoskeletal pain. Additional adverse reactions of serious grade reported in the zanubrutinib treatment groups were atrial fibrillation/atrial flutter and ventricular arrhythmias.

Pirtobrutinib warning and precaution areas include infections, hemorrhage, cytopenias, cardiac arrhythmias, secondary primary malignancies, hepatotoxicity, and embryo-fetal toxicity.

Be sure to consider patient specific factors (e.g. comorbidities, concomitant medications) as well as organ function, previous treatment and response, as well as the specific disease being treated and indication for the drug as detailed in the prescribing information.

Positioning Jaypirca and Brukinsa in Clinical Practice

As treatment options for B-cell malignancies are being developed, the role of treatment sequencing in precision oncology is increasingly unfolding. Non-covalent BTK-inhibitor Jaypirca has been studied in patients previously treated with covalent BTK-inhibitors like Brukinsa which is approved for multiple B-cell malignancies and used in various treatment settings.

Importantly, the treatment of B-cell malignancies is evolving. When selecting a BTK inhibitor for a particular patient and setting, it is essential to take into consideration the various factors that are relevant for the specific malignancy, the respective treatment line, previous BTK inhibitor therapy, resistance and/or disease progression on prior BTK inhibitors and other relevant factors such as concomitant medications, and emerging clinical evidence from various ongoing and future studies.