Pirtobrutinib Monotherapy Demonstrates Early Activity in R/R Follicular Lymphoma

Treatment with single-agent pirtobrutinib (Jaypirca) showed encouraging efficacy with a tolerable safety profile in a cohort of heavily pretreated patients with relapsed/refractory follicular lymphoma (FL), according to findings from the phase 1/2 BRUIN trial (NCT03740529) presented during the 2023 ASH Annual Meeting.¹

Among efficacy-evaluable patients (n = 48), the overall response rate (ORR) was 50% (95% CI, 35.2%-64.8%), including a complete response (CR) rate of 14.6%. Additionally, the median duration of response (DOR) was 5.5 months (95% CI, 3.7-not evaluable [NE]) at a median follow-up of 18.4 months. At a median follow-up of 16.8 months, the median progression-free survival (PFS) was 5.8 months (95% CI, 3.8-8.1); the median overall survival (OS) was NE (95% CI, NE-NE) at a median follow-up of 20.4 months.

“FL is a chronic, indolent, and incurable disease with frequent relapses. Unfortunately, survival outcomes decrease with each subsequent line of treatment,” Nirav N. Shah, MD, an associate professor at the Medical College of Wisconsin in Milwaukee, said during an oral presentation of the data. “There have been some data looking at the role of covalent BTK inhibitors in relapsed/refractory FL; however the single-agent efficacy is overall limited, with an ORR of approximately 20% to 38%. We [accordingly explored] pirtobrutinib, a non-covalent BTK inhibitor, for patients with relapsed/refractory FL.”

BRUIN was a dose escalation and expansion study that enrolled adult patients with mantle cell lymphoma (n = 166), chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 317), and other histologic subtypes (n = 295), including FL. Patients were required to be at least 18 years old, have an ECOG performance status of 2 or less, have received previous treatment, and have active disease in need of treatment to be eligible for enrollment.

During the phase 1 dose escalation and expansion phase, patients received pirtobrutinib monotherapy at a dose ranging from 25 mg to 300 mg once daily. In the phase 2 portion, patients received pirtobrutinib at 200 mg once daily.

The coprimary end points in the phase 1 potion were identification of the maximum tolerated dose, as well as the recommended phase 2 dose. In phase 1b the coprimary end points were determining the safety of pirtobrutinib in combination with venetoclax as well as with venetoclax and rituximab. The primary end point in phase 2 was ORR per independent review committee. Secondary end points included OS, DOR, PFS, pharmacokinetics, and safety.1,2

At baseline, patients were a median age of 64.5 years old (range, 37-85). Most patients had an ECOG performance status of 0 (54%), 4 or less involved nodal sites (46%), tumor bulk of less than 5 cm (69%), Ann Arbor stage III/IV disease (81%), and baseline lactate dehydrogenase levels not above the upper limit of normal (71%). Regarding FLIPI risk group, 19% of patients were FLIPI low, followed by intermediate (29%), high (46%), and missing (6%).1

The median number of prior lines of systemic therapy was 3 (range, 1-12). Patients received prior therapy with an anti-CD20 antibody (100%), chemotherapy plus an anti-CD20 antibody (90%), a PI3K inhibitor (35%), lenalidomide (29%), autologous stem cell transplant (13%), a bispecific antibody (10%), a covalent BTK inhibitor (8%), CAR T-cell therapy (8%), a BCL-2 inhibitor (6%), and other systemic therapies (38%).

Findings from a subgroup analysis revealed that pirtobrutinib displayed activity across specified subgroups. Patients who had not previously received chemotherapy plus an anti-CD20 monoclonal antibody (n = 5), had FLIPI low-risk disease (n = 9), and had prior cBTK inhibitor treatment (n = 4) experienced ORRs of 80% (95% CI, 28.4%-99.5%), 77.8% (95% CI, 40.0%-97.2%), and 75% (95% CI, 19.4%-99.4%), respectively.

Patients with FLIPI low-, intermediate-, and high-risk disease experienced a median PFS of 8.1 month (95% CI, 3.5-NE), 6.9 months (95% CI, 3.5-NE), and 5.3 months (95% CI, 1.9-7.3), respectively. The 18-month PFS rates were 44.4% (95% CI, 13.6%-71.9%), 44% (95% CI, 16.8%-68.4%), and 24.1% (95% CI, 8.8%-43.4%), respectively. The median OS in the respective subgroups was NE (95% CI, NE-NE), NE (95% CI, 10.4-NE), and 21.2 months (95% CI, 10.6-NE); the 18-month OS rates were 100% (95% CI, 100%-100%), 90% (95% CI, 47.3%-98.5%), and 60.3% (95% CI, 35.7%-78.0%), respectively.

In terms of safety, any-grade adverse effects (AEs) included diarrhea (29.2%), fatigue (25.0%), nausea (22.9%), arthralgia (18.8%), back pain (18.8%), and neutropenia (16.7%); these events occurred at a grade 3 or higher severity at rates of 2.1%, 4.2%, 2.1%, 0%, 0%, and 14.6%, respectively. AEs of special interest that were reported at any-grade severity included infections (47.9%), rash (14.6%), bruising (10.4%), hemorrhage (6.3%), hypertension (4.2%), and atrial fibrillation/flutter (2.1%); these events occurred at grade 3 or higher severity in 18.8%, 2.1%, 0%, 0%, 2.1%, and 0% of patients, respectively.

Treatment-related AEs (TRAEs) of any-grade included diarrhea (8.3%), fatigue (14.6%), nausea (12.5%), arthralgia (8.3%), and neutropenia (10.4%); 2.1% of patients experienced grade 3 or higher treatment-related nausea and 8.3% had grade 3 or higher treatment-related neutropenia. Any-grade TRAEs of special interest consisted of infections (8.3%), rash (8.3%), bruising (2.1%), hemorrhage (2.1%), and atrial fibrillation/flutter (2.1%); 2.1% of patients experience grade 3 or higher treatment-related rash.

The median time on pirtobrutinib treatment among patients with FL was 7.6 months. Discontinuation of pirtobrutinib due to TRAEs occurred in 2.1% of patients. Dose reductions due to TRAEs were reported in 8.3% of patients.

“These data suggest there is a role for pirtobrutinib as a clinically meaningful option for patients with relapsed/refractory FL. [However,] additional data will be needed,” Shah said in conclusion.

References

1. Shah NN, Zinzani PL, Wang ML, et al. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in relapsed/refractory follicular lymphoma: results from the phase 1/2 BRUIN study. Blood. 2023;142(suppl 1):3026. doi:10.1182/blood-2023-181309
2. A study of oral LOXO-305 in patients with previously treated CLL/​SLL or NHL. ClinicalTrials.gov. Updated March 8, 2023. Accessed December 10, 2023. https://clinicaltrials.gov/study/NCT03740529