Facing treatment-resistant Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) can feel like hitting a wall. But what if there was a way to break through? A recent study on pirtobrutinib offers a beacon of hope for patients previously treated with BTK inhibitors. The final analysis of the phase 1/2 BRUIN trial reveals an impressive 81.6% objective response rate (ORR) in CLL/SLL patients who had already undergone treatment with covalent BTK inhibitors. This demonstrates both the efficacy and safety of pirtobrutinib.
Pirtobrutinib, also known as Jaypirca, is a noncovalent Bruton tyrosine kinase (BTK) inhibitor. Unlike its covalent counterparts, this medication works differently, offering a new approach to tackling the disease. The study, presented at the 2025 ASH Annual Meeting, showed that pirtobrutinib achieved various levels of positive responses, including complete responses (CR), partial responses (PR), and PR with lymphocytosis.
When we dive deeper into specific patient groups, the data gets even more interesting. Patients with deletion 11q, complex karyotype, and 17p deletion and/or TP53 mutation showed the highest ORRs, with results reaching up to 91.5%. However, patients with mutated PLCg2, unmutated BTK C481, and mutated IGHV appeared to derive less benefit.
According to Dr. William G. Wierda, the lead study author, pirtobrutinib continues to show favorable efficacy and promising overall survival (OS).
But here's where it gets controversial... Intolerance or treatment resistance to covalent BTK inhibitors remains a significant challenge. Pirtobrutinib was designed to overcome these resistance mechanisms. This trial's findings led to accelerated FDA approval in December 2023, which was later converted to full approval on December 3, 2025.
The BRUIN trial involved a 3+3 design, allowing for dose escalation and expansion. In Phase 2, patients received 200 mg of pirtobrutinib daily. A total of 778 patients were enrolled, including those with CLL/SLL, mantle cell lymphoma, and other malignancies.
The study's key endpoints included safety, tolerability, pharmacokinetics, ORR, progression-free survival (PFS), time to next treatment (TTNT), and OS. The study found that the median duration of response (DOR) was 18.4 months, with a 28.0% 36-month DOR rate. The median TTNT was 23.2 months, and the median PFS was 18.7 months.
The safety profile of pirtobrutinib is also worth noting. The median time on treatment was 20.0 months. The most common adverse effects included fatigue, neutropenia, diarrhea, and cough. The rates of dose reduction or discontinuation due to treatment-related adverse effects (TRAEs) were low.
And this is the part most people miss... Pirtobrutinib seems to be a well-tolerated option with low rates of serious side effects like hypertension, hemorrhage, and atrial fibrillation/flutter.
What do you think? Does this data change how you view treatment options for CLL/SLL? Are you surprised by the varying response rates across different patient subgroups? Share your thoughts in the comments below!
