Pirtobrutinib Yields Promising Efficacy, Safety in R/R Follicular Lymphoma

Findings from the phase 1/2 BRUIN study (NCT03740529) show that pirtobrutinib (Jaypirca), a Bruton tyrosine kinase inhibitor (BTKi), monotherapy offers promising clinical efficacy and a favorable safety profile in patients with relapsed/refractory (R/R) follicular lymphoma (FL).¹

With a data cut off of January 27, 2025, pirtobrutinib demonstrated substantial and durable antitumor activity.

The investigator-assessed overall response rate (ORR) was 52.1% (95% CI, 37.2%–66.7%). Of the total patients, 8 achieved complete response (CR; 16.7%), 17 achieved partial response (PR; 35.4%), and 11 achieved stable disease (SD; 22.9%). Among 44 evaluable patients, 84.1% achieved a reduction in tumor size from baseline. The median time to first response was rapid at 1.9 months.

The responses to pirtobrutinib were durable, and survival outcomes were promising, with a median follow-up of 35.2 months for overall survival (OS). Notably, 4 of the 8 patients who achieved a CR remained in remission at 36.8, 40.5, 43.5, and 59.2 months.

The median duration of response (DOR) was 10.2 months (95% CI, 3.7–25.7), and the 24-month DOR was 33.3% (95% CI, 15.9%–51.9%). The median progression-free survival (PFS) was 5.8 months (95% CI, 3.8–8.1), and the 24-month PFS was 25.6% (95% CI, 13.9%–39.1%).

Pirtobrutinib showed consistent activity across various patient subgroups, including those with high-risk disease features.

Among the 4 patients previously treated with a covalent (c)BTKi, 3 achieved a PR and 1 had SD. All 4 experienced a reduction in tumor size. Efficacy was observed across all FLIPI risk categories, with ORRs of 77.8% in the low-risk group, 50.0% in the intermediate-risk group, and 47.8% in the high-risk group. Patients who had responded to their most recent prior therapy had a median PFS of 6.8 months compared with 4.1 months for those who had not responded.

Safety and Tolerability Profile of Pirtobrutinib

Pirtobrutinib was well tolerated, with a median treatment duration of 7.6 months. At the time of data cut off, 16.7% of patients remained on treatment.

Two patients (4.2%) discontinued treatment due to a treatment-emergent adverse event (TEAE), with just 1 discontinuation deemed treatment-related (rash). Four patients (8.3%) required a dose reduction due to a TEAE, all of which were considered treatment related.

The most frequent TEAEs of any grade were generally low-grade and manageable. Grade ≥ 3 TEAEs occurred in 50% of patients, with neutropenia being the most common.

Other common TEAEs of any grade included diarrhea (29.2%), fatigue (25.0%), nausea (22.9%), infections (56.3%), and rash (14.6%).

Patient Characteristics

The study enrolled 48 patients with R/R FL who were treated with at least 1 dose of pirtobrutinib between October 2019 and June 2022. The patient population was heavily pretreated, with a median of 3 prior lines of therapy. All patients had received a prior anti-CD20 antibody, and a significant portion had been exposed to other advanced treatments.

The median age of patients was 64.5 years (range, 37–85 years.) Of the total patients (n = 48), 29 were male (60.4%). Patients had an ECOG performance score of 0 (54.2%) or 1 (45.8%).

Study Overview and Rationale

The multicenter, phase 1/2 BRUIN study evaluated the safety and efficacy of pirtobrutinib in patients with various B-cell malignancies. This analysis focuses specifically on the cohort of 48 patients with R/R FL.

While cBTKis are used in other B-cell malignancies, their efficacy as single agents in R/R FL has been limited, with ORRs ranging from 20.9% to 37.5%. Newer treatments like chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies, while effective, present challenges related to patient eligibility, access, and toxicity.

Pirtobrutinib is a highly selective, noncovalent BTKi. Its mechanism allows for continuous BTK inhibition independent of the BTK protein turnover rate. This high selectivity is designed to reduce off-target inhibition, thereby minimizing AEs while maximizing on-target efficacy.

“This trial presents some limitations, including the limited number of patients with R/R FL, which affects the in-depth investigation in FL subgroups,” stated Shah N et al, authors of the study. “Additionally, the lack of comprehensive molecular analysis in FL subgroups limits the possible identification of FL genetic signatures and their potential impact in treatment outcomes. Other limitations include that the BRUIN clinical trial is an open-label, single-arm study, and formal comparison with other available therapies was not possible.

These promising results support further investigation of pirtobrutinib in R/R FL. Future research will explore its role in combination therapies. Specifically, in the phase 1 (NCT05990465)² trial of pirtobrutinib in combination with CAR T-cell therapy, and the phase 2 (NCT06948786)³ trial of pirtobrutinib combined with the bispecific antibody mosunetuzumab (Lunsumio).

REFERENCES:

1.Shah N, Zinzani P, Wang M et al. Pirtobrutinib, a highly selective, noncovalent (reversible) BTKi in R/R follicular lymphoma: phase 1/2 BRUIN study. BloodAdv  (2025) 9 (23): 5954–5964. November 26, 2025. Accessed December 19, 2025. doi:10.1182/bloodadvances.2024014975.

2.LV20.19 CAR T-Cells in Combination With Pirtobrutinib for Relapsed, Refractory B-cell Malignancies. ClinicalTrials.gov. Updated February 19, 2025. Accessed December 22, 2025. https://clinicaltrials.gov/study/NCT05990465

3.Pirtobrutinib and Mosunetuzumab for the Treatment of Relapsed/ Refractory Grades 1-3A Follicular Lymphoma, PROMOTE-FL Trial. ClinicalTrials.gov. Updated November 26, 2025. Accessed December 22, 2025. https://clinicaltrials.gov/study/NCT06948786