Medically reviewed by Dr. Brian Koffman
The Bottom Line:
The combination of pirtobrutinib, venetoclax, and rituximab was very effective and produced deep remissions in patients with relapsed / refractory CLL. It was well-tolerated and continues to be studied in an ongoing phase 3 clinical trial that is recruiting patients.
Who Performed the Research and Where Was it Presented:
Dr. Lindsey Roeker from Memorial Sloan Kettering Cancer Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2023.
Background:
Two types of Bruton tyrosine kinase (BTK) inhibitors are used to treat chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Covalent BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) work by forming irreversible bonds with BTK that inhibit its activity. However, some patients develop resistance mutations at the binding site, which prevents covalent BTK inhibitors from binding to BTK and renders the drug ineffective, resulting in relapse. Non-covalent BTK inhibitors such as pirtobrutinib bind to BTK differently, reversibly. They can inhibit BTK even when it has mutations at the site where covalent BTK inhibitors bind. The BRUIN trial was a phase 1/2 clinical trial that established the safety and efficacy of pirtobrutinib. A sub-study of this trial also evaluated the safety and efficacy of pirtobrutinib in combination with venetoclax and rituximab.
Methods and Participants:
This study was a phase 1b study looking at the safety of pirtobrutinib in combination with venetoclax (PV) or venetoclax plus rituximab (PVR) in patients with relapsed / refractory CLL. Patients were excluded if they had received prior treatment with venetoclax. These were fixed-duration therapies where patients received treatment for two years and then stopped.
Results
- Fifteen patients received PV, and ten patients received PVR.
- Approximately 3 out of 4 patients had stopped prior covalent BTKi treatment because of progressive disease.
- The overall response rate for all patients was 96% (93% for PV and 100% for PVR).
- Seventy-one percent of all patients achieved undetectable measurable residual disease (uMRD).
- At 18 months, 93% of PV patients and 80% of PVR patients remained progression-free.
- One of the things researchers look at when testing new drug combinations is “dose-limiting toxicities,” which are side effects that are so clinically significant that patients are unable to stay on the drugs together. No dose-limiting toxicities were observed for either PV or PVR.
- The most common side effects were nausea (PV=60.0%; PVR=40.0%), fatigue (53.3%; 50.0%), and diarrhea (46.7%; 60.0%).
- The most common severe side effect was low white blood cell count (PV=46.7%; PVR=60.0%).
- Two patients experienced tumor lysis syndrome during venetoclax ramp-up, which is a well-known side effect of venetoclax.
- Two patients in the PVR group discontinued treatment, one due to low white blood cell counts and one due to infections.
Conclusion:
A combination of pirtobrutinib, venetoclax, and rituximab was very effective and produced deep remissions in patients with relapsed / refractory CLL. It was generally well-tolerated.
There is an ongoing phase 3 clinical trial comparing pirtobrutinib-venetoclax-rituximab with venetoclax-rituximab in patients with relapsed / refractory CLL. If you are interested in participating, more information can be found here: A Trial of Pirtobrutinib (LOXO-305) Plus Venetoclax and Rituximab (PVR) Versus Venetoclax and Rituximab (VR) in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (BRUIN CLL-322).
Links and Resources:
Watch the interview on the abstract here:
You can read the ASH abstract here: Fixed-Duration Pirtobrutinib Combined with Venetoclax ± Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results, Including MRD Data, from the BRUIN Phase 1b Study.
Take care of yourself first.
Ann Liu, PhD
