While several BTK inhibitors are available for the treatment of B-cell malignancies, all are based on the same molecular target. Therefore, their clinical roles are primarily determined by the respective disease, prior treatment, resistant disease and the scope of approval for each drug. Recently, two new BTK inhibitors, Zanubrutinib and Pirtobrutinib, have been introduced to the clinical arena. Zanubrutinib is an irreversible covalent BTK inhibitor, whereas Pirtobrutinib is a non-covalent, reversible BTK inhibitor. Importantly, Pirtobrutinib was developed to overcome resistance to covalent BTK inhibitors, including Zanubrutinib.
BTK Inhibition in Precision Oncology
The B-cell receptor (BCR) signaling pathway relies on the activities of several key enzymes, including Bruton’s tyrosine kinase (BTK). BTK not only mediates B-cell proliferation, survival, migration, and tumor immune microenvironment interactions, but also supports the activities of B-cell malignancies. BTK inhibitors thus represent a targeted class of drugs for a number of hematologic malignancies and related conditions.
In terms of mechanism of BTK inhibition, Zanubrutinib is a covalent BTK inhibitor which forms covalent bonds with BTK and thereby irreversibly inhibits the enzyme. Pirtobrutinib is a non-covalent, reversible BTK inhibitor. The development of Pirtobrutinib was based on the strategy to keep BTK inhibited in diseases that have progressed on prior covalent BTK inhibitors. Thus, the two agents are expected to be used in different clinical situations.
Of particular note, the development of Pirtobrutinib illustrates an important concept in the application of precision oncology to the treatment of cancer: the consideration of cancer type, prior therapy, mechanisms of resistance, patient-specific molecular features, comorbidities and pre-existing medications when selecting a treatment for a particular patient.
Zanubrutinib: Established Covalent BTK Inhibition
The FDA approved Zanubrutinib for treatment of CLL/SLL in January 2023. The SEQUOIA study reported PFS in treatment-naïve patients with CLL/SLL without 17p deletion compared with bendamustine plus rituximab (HR: 0.76; p = 0.0028). The ALPINE study compared the ORR of Zanubrutinib with ibrutinib in a randomized study of 652 patients with relapsed or refractory CLL/SLL. The combination of clinical trial results demonstrated that covalent BTK inhibitors may be considered as treatment options of B-cell malignancies.
Pirtobrutinib: A Non-Covalent BTK Inhibitor
Pirtobrutinib, marketed as Jaypirca, is a non-covalent (reversible) inhibitor of BTK. In January 2023, the FDA granted accelerated approval of Pirtobrutinib for adults with R/R MCL who have received ≥2 prior lines of therapy including a BTK inhibitor. Approval was based on data from the BRUIN study of 300 patients with R/R MCL previously treated with a BTK inhibitor with a median of 3 prior therapies, with the primary reason for discontinuation of prior BTK inhibitor therapy being refractory/progressive disease on therapy.
Pirtobrutinib was approved by the FDA for CLL/SLL in December 2023. This approval was for the treatment of adults with CLL/SLL who have received at least two prior regimens, including both a BTK inhibitor and a BCL-2 inhibitor. Pirtobrutinib was granted traditional approval for the treatment of adults with CLL/SLL who were previously treated with one or more BTK inhibitors in December 2025. This approval was based on data from the BRUIN-CLL-321 study.
Pirtobrutinib vs Zanubrutinib: Clinical Context
Since the two drugs differ in their mechanism of BTK inhibition and are approved for different indications, a comparison between Pirtobrutinib and Zanubrutinib must always take into account the specific disease for which treatment is indicated and the respective prior treatment. Therefore, the two drugs are not alternatives and should not be used interchangeably.
In the context of Pirtobrutinib vs Zanubrutinib, the two agents are used in different settings of disease and treatment. Thus, to consider the two agents in the treatment of an individual patient, it is necessary to consider the patient’s diagnosis and prior treatments. In addition, it is necessary to understand the potential effects of co-administered treatments (e.g. chemotherapy, immunotherapies), as well as those of prior treatments.
In determining a sequence of therapies, including other targeted agents, for a patient with a B-cell malignancy, a number of factors must be considered including the patient’s specific diagnosis, prior therapies, clinical response and/or disease progression on prior therapies including BTK inhibitors, disease-specific biology, current and prior concomitant therapies, organ function and clinical trial evidence supporting a particular treatment.
Evidence in CLL and SLL
Importantly, there is growing evidence that treatment history, specifically prior therapy and development of resistance, will become increasingly important in selecting targeted therapies for patients with CLL and SLL (white blood cell cancer). Zanubrutinib, a BTK inhibitor, has demonstrated activity in both treatment-nave and previously treated CLL/SLL patients. In the SEQUOIA study, 479 treatment-naïve patients without 17p deletion were randomized to receive Zanubrutinib versus bendamustine + rituximab (SEQUOIA). The ALPINE study also compared Zanubrutinib to ibrutinib in 652 patients with relapsed or refractory CLL/SLL.
The approval of Pirtobrutinib for CLL/SLL is specific to use in patients with relapsed or refractory disease who have been previously treated with a covalent BTK inhibitor. The Phase 3 BRUIN-CLL-321 trial randomized 238 patients with previously treated CLL/SLL to Pirtobrutinib versus investigator choice of therapy. All the BTK inhibitors have been studied in a variety of clinical trials for the treatment of CLL and MCL, and each has unique characteristics for use in specific clinical contexts.
Mantle Cell Lymphoma and Treatment Resistance
Pirtobrutinib, on the other hand, was approved for the treatment of adults with mantle cell lymphoma (MCL) after having received 2 or more prior lines of therapy, including a BTK inhibitor as part of the prior therapy. The randomized BRUIN study involved 120 patients with MCL who had received prior treatment with a BTK inhibitor as part of their therapy.
Pirtobrutinib received accelerated approval for relapsed or refractory MCL after at least two lines of systemic therapy including a BTK inhibitor as part of therapy for MCL. In the BRUIN study, there were 120 patients with MCL previously treated with a BTK inhibitor. The most common prior use of a BTK inhibitor was ibrutinib, acalabrutinib, or Zanubrutinib. Understanding the prior treatment context of BTK inhibitors is critical for assessing data from patients who have relapsed on prior BTK inhibitors and are considering a switch to Pirtobrutinib.
Safety and Practical Treatment Considerations
When evaluating the use of BTK inhibitors, consideration needs to be given to the potential risks of treatment with these agents, including bleeding events, infection, cytopenias, cardiac arrhythmias, hepatotoxicity, and drug-drug interactions.
Note that atrial fibrillation or flutter and ventricular arrhythmias have also been reported in the trials conducted to evaluate Zanubrutinib for use as treatment of several malignancies.
The FDA Warning and Precaution for Pirtobrutinib for CLL/SLL includes warnings for infection, for bleeding, for cytopenias, for atrial fibrillation and flutter and for second primary malignancy. Importantly, treatment choice will need to consider the patient’s comorbidities, their current medications, organ function, the disease itself and how the patient responded to previous treatment(s).
The Future of BTK-Directed Precision Oncology
The covalent and non-covalent BTK inhibitors that are currently under development to overcome resistance to current BTK inhibitors will be important in the evolving management of the B-cell malignancies. Future studies may evaluate sequencing and combination strategies involving BTK inhibitors.
As BTK inhibitors, including covalent and non-covalent drugs, continue to evolve as treatments for B-cell malignancies, there will be additional clinical evidence to establish optimal treatment sequencing as well as to explore the combination of various BTK inhibitors with other therapies for precision oncology in B-cell malignancies.
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.
