Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Pirtobrutinib provides longer progression-free survival and is safer than idelalisib–rituximab and bendamustine-rituximab for treating relapsed CLL.
Who Performed the Research and Where Was it Presented:
Dr. Jeff Sharman from Willamette Valley Cancer Institute and Research Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Bruton tyrosine kinase inhibitors (BTKi) revolutionized the treatment of chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). Covalent BTKi (ibrutinib, acalabrutinib, zanubrutinib) were the first to be developed, and they irreversibly bind to the BTK protein. However, CLL / SLL can develop resistance mutations to these drugs over time. Pirtobrutinib is a noncovalent BTKi that binds in a reversible manner and can overcome covalent BTKi resistance mutations. This study compared the efficacy of pirtobrutinib vs. investigators’ choice of either idelalisib plus rituximab or bendamustine plus rituximab in patients with CLL / SLL previously treated with a covalent BTKi.
Methods and Participants:
The BRUIN CLL-321 study is a phase 3 clinical trial comparing pirtobrutinib with investigators’ choice of either idelalisib-rituximab or bendamustine-rituximab in patients with CLL / SLL previously treated with a covalent BTKi.
Results:
- 238 patients enrolled in the study.
- This was a high-risk group of patients; almost all patients had unmutated IGHV, and approximately 70% had TP53 mutation or complex karyotype.
- All patients had previously been treated with a covalent BTKi, and half had been previously treated with venetoclax.
- About 70% of patients had discontinued prior covalent BTKi therapy due to progressive disease.
- Progression-free survival was significantly longer with pirtobrutinib (14 months) vs investigators’ choice therapy (7 months).
- For patients treated with pirtobrutinib, the time to the next treatment was approximately 24 months, which was significantly longer than the investigators’ choice group.
- Pirtobrutinib was very well tolerated with lower rates of side effects than idelalisib-rituximab or bendamustine-rituximab, with the exception of pneumonia and low neutrophil counts.
- The most common side effects in the pirtobrutinib group were anemia (21%), pneumonia (20%), low neutrophil counts (16%), and diarrhea (16%).
- The most common side effects in the investigators’ choice group were diarrhea (29%), fever (26%), nausea (20%), COVID-19 (18%), fatigue (18%), low neutrophil count (17%), and increased liver enzymes (17%).
Conclusions:
Pirtobrutinib provides longer progression-free survival and is safer than idelalisib-rituximab and bendamustine-rituximab. Currently, pirtobrutinib is approved for patients with CLL / SLL who have previously been treated with both a covalent BTKi and a BCL2 inhibitor. Hopefully, this study will help pirtobrutinib get approved for patients who have only been treated with a covalent BTKi. And that makes good sense as using pirtobrutinib after relapsing with a covalent BTKi keeps patients in the same broad class of drugs, saving drugs with different targets for later therapy.
If you are interested in getting access to pirtobrutinib, several ongoing clinical trials can be found on ClinicalTrials.gov. We will learn a lot more about pirtobrutinib in the future as there a many ongoing clinical trials, including studies examining how pirtobrutinib compares with ibrutinib for treatment-naïve CLL and how pirtobrutinib plus venetoclax-rituximab compares with venetoclax-rituximab for relapsed / refractory CLL.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: BRUIN CLL-321: Randomized Phase III Trial of Pirtobrutinib Versus Idelalisib Plus Rituximab (IdelaR) or Bendamustine Plus Rituximab (BR) in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
