Moving Pirtobrutinib to a First-Time Treatment for CLL/SLL?

Expanding pirtobrutinib’s role beyond bypassing BTK resistance

Although much of the discussion around pirtobrutinib (Jaypirca, Eli Lilly) has centered on its ability to extend BTK inhibition for patients with resistance to covalent BTK inhibitors, emerging data suggest that it may be highly effective for those who have never been treated with covalent BTK inhibitors. 

This raises the possibility of pirtobrutinib becoming a front-line therapy, potentially changing the standard of care for people with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). 

Pirtobrutinib’s effectiveness for high-risk patients not treated with covalent BTK inhibitors 

Recent research indicated that pirtobrutinib provides exceptional responses in patients who have not previously received covalent BTK inhibitors, even among those with high-risk features. 

The study reviewed 35 patients who received an average of two prior treatments, including either chemotherapy, venetoclax, anti-CD20 antibodies, or other systemic therapies. 

The results were highly promising, with the following patient groups experiencing a partial or full reduction of CLL cells (overall response rate [ORR]): 

• 17p deletion CLL: 100% ORR
• TP53-mutated CLL: 85.7% ORR
• Unmutated IGHV CLL: 90.0% ORR
• Complex karyotype CLL: 100% ORR 

At the 24-month follow-up since starting pirtobrutinib, 81.8% of patients maintained cancer control, and 88% were alive. Additionally, only 5.7% of patients required treatment discontinuation due to side effects or cancer progression—an impressive improvement compared to the 50% discontinuation rate observed with ibrutinib in other studies. 

Moving pirtobrutinib to front-line CLL treatment

Given these findings, researchers are now exploring whether pirtobrutinib could serve as a first-time treatment for CLL/SLL patients, shifting its role beyond a third-line option. This has led to the launch of phase 3 clinical trials investigating it as a standalone treatment for newly diagnosed patients. 

• The BRUIN CLL-313 trial is evaluating pirtobrutinib by itself as the first treatment for CLL/SLL patients.
• The BRUIN CLL-314 trial is reviewing pirtobrutinib as a standalone treatment for individuals with CLL/SLL as their first therapy or for those who have not previously received BTK inhibitors.

These studies could redefine pirtobrutinib’s place in the treatment landscape, potentially establishing it as a first-line option for patients who have not previously been treated with covalent BTK inhibitors. As more data emerges, this new approach could significantly impact future CLL/SLL therapy strategies. 

Although the above phase 3 studies are active but not recruiting, ask your CLL specialist about innovative treatments available in clinical trials or discover them here. 

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Sources: 

• Pirtobrutinib in Relapsed/Refractory CLL/SLL: Results From BTKi Naïve Cohort in the Phase 1/2 Bruin Study
• Understanding Ibrutinib Treatment Discontinuation Patterns for Chronic Lymphocytic Leukemia
• A Study of Pirtobrutinib (LOXO-305) Versus Bendamustine Plus Rituximab (BR) in Untreated Patients With Chronic Lymphocytic Leukemia (CLL)/​Small Lymphocytic Lymphoma (SLL) (BRUIN CLL-313)
• A Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Participants With Chronic Lymphocytic Leukemia (CLL)/​Small Lymphocytic Lymphoma (SLL) (BRUIN-CLL-314)