Pirtobrutinib Exhibits Favorable Efficacy in R/R Follicular Lymphoma

Single-agent pirtobrutinib (Jaypirca) conferred favorable efficacy among patients with relapsed or refractory follicular lymphoma, according to data from a cohort analysis of the phase 1/2 BRUIN study (NCT03740529) published in Blood Advances.¹

Efficacy data from the trial revealed that among 48 patients with relapsed/refractory follicular lymphoma, the objective response rate (ORR) was 52.1% (95% CI, 37.2%-66.7%), with 35.4% of patients attaining a partial response (PR) and 16.7% achieving a complete response (CR). Moreover, among 44 patients with tumor assessments done at baseline and after, 84.1% experienced a reduction in the sum of product of tumor diameters. A total of 75% of patients who had received prior covalent Bruton tyrosine kinase inhibitors (cBTKis; n = 4) attained PRs, and 100% had a reduction in the sum of product of tumor diameters.

Among patients in the trial who experienced a response, the median time to response was 1.9 months (range, 1.6-17.5). After a median follow-up of 40.5 months (IQR, 31.6-43.5), the median duration of response (DOR) was 10.2 months (95% CI, 3.7-25.7), with an estimated 24-month rate of 33.3% (95% CI, 15.9%-51.9%). Additionally, among 8 patients who had attained a CR, 4 (50%) experienced disease progression within 18 months of achieving a response; 4 patients are experiencing ongoing CRs at 36.8, 40.5, 43.5, and 59.2 months, respectively.

The median progression-free survival (PFS) among all patients with follicular lymphoma was 5.8 months (95% CI, 3.8-8.1), and the estimated 24-month rate was 25.6% (95% CI, 13.9-39.1). Among 17 patients without a response to previous therapy, the median PFS was 4.1 months (95% CI, 3.5-7.3) vs 6.8 months (95% CI, 2.3-27.6) among those who responded to prior therapy. After a median follow-up of 35.2 months (IQR, 31.1-41.8) for overall survival (OS), the median value was not reached in the follicular lymphoma population, with an estimated 24-month rate of 75.1% (95% CI, 59.5%-85.4%).

“[P]irtobrutinib, a noncovalent (reversible) BTKi, showed promising efficacy and safety as a single agent in a [relapsed/refractory follicular lymphoma] cohort. Pirtobrutinib was well-tolerated, with low rates of cBTKi-associated adverse effects [AEs] and discontinuations due to AEs,” Nirav N. Shah, MD, associate professor of Hematology and Oncology and clinical director of BMT and Cellular Therapy at the Medical College of Wisconsin, wrote in the publication with study coinvestigators.¹ “These findings highlight the potential for pirtobrutinib as a clinically meaningful addition to available therapies for patients with [relapsed/refractory follicular lymphoma].”

Efficacy stratified by Follicular Lymphoma International Prognostic Index (FLIPI) risk revealed an ORR of 77.8% (95% CI, 40.0%-97.2%), 50.0% (95% CI, 23.0%-77.0%), and 47.8% (95% CI, 26.8%-69.4%) in the low-, intermediate-, and high-risk subgroups, respectively. The median PFS in the respective groups was 8.1 months (95% CI, 3.5-27.6), 6.9 months (95% CI, 3.5 to not estimable), and 5.3 months (95% CI, 2.3-7.3). The respective 24-month PFS rates were 22.2% (95% CI, 3.4%-51.3%), 35.2% (95% CI, 11.2%-60.7%), and 22.9% (95% CI, 8.4%-41.7%), respectively.

Patients in the follicular lymphoma cohort of the phase 3 study received 200 mg of oral pirtobrutinib daily for each 28-day cycle. Treatment persisted in the absence of disease progression, unacceptable toxicity, or other discontinuation criteria met.

In this cohort, the median age was 64.5 years (range, 37.0-85.0), 60.4% of patients were male, and 54.2% had an ECOG performance status of 0. The median number of prior lines of therapy was 3 (range, 1-12), and the most common previous therapies included anti-CD20 antibodies with (89.6%) or without chemotherapy (100%), PI3K inhibitors (35.4%), and lenalidomide (Revlimid; 29.2%). A total of 45.8% of patients had a high FLIPI risk, 56.3% had 4 or fewer involved nodal sites, and 68.8% had a tumor bulk of less than 5 cm.

The primary end points of the trial included the maximum tolerated dose, ORR per independent review committee assessment, and treatment-emergent AEs (TEAEs).² Secondary end points included DOR, PFS, and OS.

Among those with follicular lymphoma treated with pirtobrutinib, 60.4% experienced treatment-related AEs (TRAEs). The most common TRAEs included fatigue (14.6%), nausea (12.5%), infections (12.5%), and neutropenia or neutrophil count decreases (10.4%). Grade 3 or higher TEAEs occurred in 16.7% of patients and included neutropenia or neutrophil count decreases (8.3%), nausea (2.1%), and rash (2.1%).

One grade 5 instance of COVID-19 pneumonia was observed but was deemed not related to study treatment by the investigators. Dose reductions and discontinuations occurred in 4 and 2 patients, respectively.

Recently, based on results from the phase 3 BRUIN-CLL-321 trial (NCT04666038), the FDA granted traditional approval to pirtobrutinib as a single-agent for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who were previously treated with a BTK inhibitor.³ Additionally, pirtobrutinib was granted accelerated approval in 2023 as a treatment for patients with relapsed/refractory mantle cell lymphoma previously given 2 prior lines of therapy, including a BTK inhibitor.⁴

References

1. Shah NN, Zinzani PL, Wang M, et al. Pirtobrutinib, a highly selective, noncovalent (reversible) BTKi in R/R follicular lymphoma: phase 1/2 BRUIN study. Blood Adv. 2025;9(23):5954-5964. doi:10.1182/bloodadvances.2024014975
2. A study of oral LOXO-305 in patients with previously treated CLL/​SLL or NHL. ClinicalTrials.gov. Updated September 25, 2025. Accessed December 5, 2025. https://tinyurl.com/2mw4wk8r
3. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. News release. FDA. December 3, 2025. Accessed December 5, 2025. https://tinyurl.com/3tyaw463
4. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. News release. FDA. January 27, 2023. Accessed December 5, 2025. https://tinyurl.com/46vum4ns