Clinical Advances in Hematology & OncologyPirtobrutinib in Relapsed or Refractory CLL and SLL

Pirtobrutinib Emerges as a Viable Option for Refractory CLL and SLL Patients: Insights into Mechanisms, Efficacy, and Clinical Application

Pirtobrutinib, a novel noncovalent Bruton tyrosine kinase (BTK) inhibitor, has shown promising results in the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). This discussion with Jennifer A. Woyach, MD, a D. Warren Brown Professor of Leukemia Research at Ohio State University, provides an in-depth analysis of pirtobrutinib’s mechanisms of action, its comparative efficacy with existing BTK inhibitors, key findings from clinical trials, adverse event profiles, and future research directions.

Key Points:

• Mechanisms of Action:
  • Pirtobrutinib is a noncovalent BTK inhibitor, binding to distinct sites on BTK compared to covalent inhibitors like ibrutinib, acalabrutinib, and zanubrutinib.
  • Unlike covalent BTK inhibitors that bind at the cysteine 481 position, pirtobrutinib’s binding site allows it to remain effective even in cases where resistance to covalent inhibitors has developed.
• Comparative Efficacy:
  • Pirtobrutinib is used for patients who have relapsed or are intolerant to covalent BTK inhibitors.
  • It offers a treatment option when switching between covalent BTK inhibitors is not feasible due to shared mechanisms.
  • The FDA has approved pirtobrutinib for use after both a covalent BTK inhibitor and venetoclax, addressing a previously unmet need for double-refractory patients.
• Clinical Trial Findings:
  • Data from the phase 1/2 BRUIN study involving approximately 300 patients with relapsed or refractory CLL show an overall response rate (ORR) approaching 75%.
  • The median progression-free survival (PFS) observed was 19.6 months.
  • Patients with fewer prior lines of therapy, especially those without prior venetoclax treatment, demonstrated better responses and longer remission durations.
• Adverse Events:
  • Pirtobrutinib is generally well-tolerated with most adverse events (AEs) being grade 1 or 2.
  • Lower rates of toxicities commonly associated with covalent BTK inhibitors, such as hypertension, atrial fibrillation, and arthralgias, were observed.
  • Most patients tolerate the full dose without the need for dose interruptions or reductions, barring significant events like severe arrhythmia, bleeding, or fungal infections.
• Current and Future Research:
  • Several phase 3 trials and investigator-initiated studies are ongoing to evaluate pirtobrutinib both as monotherapy and in combination with other drugs.
  • Emerging data suggest potential efficacy in Richter’s transformation (RT), offering a possible option for bridging to further treatments.

“I am particularly excited to see the data as they mature, especially in combination with drugs like venetoclax or CD20 monoclonal antibodies, to see if we can further improve the remission duration currently observed with pirtobrutinib.”
– Jennifer A. Woyach, MD

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