Pirtobrutinib Expands Treatment Options for Relapsed Marginal Zone Lymphoma

Clinical Summary: 

• Design/Population: The phase 1/2 BRUIN study evaluated the noncovalent BTK inhibitor pirtobrutinib in patients with relapsed or refractory marginal zone lymphoma, including those previously treated with covalent BTK inhibitors. Eligible patients had received at least 1 prior line of therapy.
• Key Outcomes: Pirtobrutinib demonstrated encouraging overall response rates with durable responses and a favorable safety profile. Clinical activity was observed in patients whose disease had progressed following prior covalent BTK inhibitor therapy, supporting continued targeting of the BTK pathway after resistance develops.
• Clinical Relevance: These findings suggest that pirtobrutinib may provide an important treatment option for patients with relapsed or refractory marginal zone lymphoma, particularly after progression on covalent BTK inhibitors.

Krish Patel, MD, Sarah Cannon Research Institute, Nashville, Tennessee, discusses results from the phase 1/2 BRUIN study evaluating pirtobrutinib in patients with relapsed or refractory marginal zone lymphoma. The study examined whether noncovalent BTK inhibition could overcome resistance to prior covalent BTK inhibitors while maintaining durable disease control.

The study demonstrated meaningful and durable clinical responses with a favorable safety profile, including activity in patients previously treated with covalent BTK inhibitors. These findings support pirtobrutinib as a promising therapeutic option and reinforce the role of sequential BTK inhibition in the management of relapsed or refractory marginal zone lymphoma.

Transcript:

Hello, I'm Krish Patel, I’m the director of lymphoma research at Sarah Cannon Research Institute. It’s my pleasure to summarize for you results of the phase 1/2 BRUIN study, specifically in patients with relapsed or refractory marginal zone lymphoma.

This was a large, multicohort phase 1/2 study evaluating pirtobrutinib, which is a noncovalent, reversible BTK inhibitor. We’ve known for some years now that patients with marginal zone lymphoma can respond to BTK inhibition and we have a number of covalent BTK inhibitors that are used for that purpose.

A focus of this study was to understand whether patients who have had disease progression on a covalent BTK inhibitor can respond to a noncovalent BTK inhibitor, which may have a different mechanism of binding and may overcome mechanisms of resistance to covalent inhibitors, so that is the focus of this study that was published recently.

In the study, we enrolled patients who had at least 1 prior line of therapy and patients who had previously been treated with a covalent BTK inhibitor. What we saw in these patients is that the overall response rate with pirtobrutinib in relapsed/refractory marginal zone lymphoma was around 55%. 

Importantly, these were durable responses; the median duration of response was around 17.8 months and pirtobrutinib, consistent with its use in other lymphomas, was very well tolerated, with overall discontinuation of the drug due to adverse events being quite low, and the safety profile was very favorable.

I think the study is important for a number of reasons. It shows that pirtobrutinib can deliver durable responses with good tolerability for patients with marginal zone lymphoma, which is an area of unmet need. We know that patients with marginal zone lymphoma often have very few therapies that are developed specifically for them. Importantly, it also shows that patients who have had disease progression on covalent BTK inhibitors can remain within the same therapeutic pathway. We can inhibit BTK again with a noncovalent, reversible inhibitor like pirtobrutinib and still achieve very good outcomes.

These findings are especially relevant for patients who have experienced relapse after another BTK inhibitor.

Source: 

Patel K, Vose JM, Nasta SD, et al. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi in R/R marginal zone lymphoma: Phase 1/2 BRUIN study. Blood Adv. Published online: January 16, 2026. doi: 10.1182/bloodadvances.2025017489