Pirtobrutinib Shows Activity in Relapsed/Refractory MCL After Covalent BTK Inhibitor Therapy

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Pirtobrutinib demonstrated promising efficacy and a tolerable safety profile in heavily pretreated patients with relapsed/refractory mantle cell lymphoma who received prior therapy with a covalent BTK inhibitor.

Lymphomas: © David A Litman - stock.adobe.com

Lymphomas: © David A Litman - stock.adobe.com

The highly-selective, non-covalent Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca) delivered promising efficacy and a manageable safety profile in heavily pretreated patients with relapsed/refractory mantle cell lymphoma (MCL) who received prior therapy with a covalent BTK inhibitor, according to findings from the phase 1/2 BRUIN trial (NCT03740529) presented during the 2023 ASH Annual Meeting.1

In the study, patients with MCL who received prior treatment with a covalent BTK inhibitor (n = 152) achieved an overall response rate (ORR) of 49.3% (95% CI, 41.1%-57.6%) comprised of a 15.8% complete response (CR) rate. The median time to first response was 1.8 months (range, 0.8-13.8). At a median follow-up of 14.7 months, the median duration of response (DOR) was 21.6 months (95% CI, 9.2-27.2).

Additionally, at a median follow-up of 15.9 months, the median progression-free survival (PFS) was 5.6 months (95% CI, 5.3-9.2). At a median follow-up of 24.2 months, the median overall survival (OS) was 23.5 months (95% CI, 17.1-not evaluable [NE]).

“There's been a number of series [of data] over the last several years which have continued to demonstrate that patients with relapsed/refractory MCL who experience disease progression or otherwise have to discontinue a covalent BTK inhibitor have a very poor prognosis with a median OS of less than 1 year,” Jonathon B. Cohen, MD, MS, the codirector of the Lymphoma Program and the chair of the Data and Safety Monitoring Committee at Winship Cancer Institute of Emory University, as well as an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, all in Atlanta, Georgia, said during the presentation. “Fortunately, pirtobrutinib has been shown to be efficacious in this setting. As a result of these findings, pirtobrutinib is now approved to treat relapsed/refractory MCL in adults both in the United States as well as in Europe.”

In patients naive to a covalent BTK inhibitor (n = 14), the ORR was 85.7% (95% CI, 57.2%-98.2%), including a CR rate of 42.9%. The median DOR, PFS, and OS were NE (95% CI, 13.0-NE), NE (95% CI, 16.7-NE), and NE (95% CI, NE-NE), respectively.

“It’s very important to stress that this was a cohort of 14 patients, but certainly very encouraging data [in this group of patients],” Cohen noted.

BRUIN Trial Patient Characteristics

BRUIN was a dose escalation and expansion study that enrolled adult patients with MCL (n = 166), chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 317), and other histologic subtypes (n = 295). Within the MCL cohort, patients underwent prior treatment with a covalent BTK inhibitor (n = 152) or were covalent BTK inhibitor naive (n = 14). Eligible patients were at least 18 years old with an ECOG performance status of 2 or less, received previous treatment, and had active disease in need of treatment.

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. Phase 1 used a 3+3 design in 28-day cycles, intra-patient dose escalation was permitted, and cohort expansion was allowed at doses that were deemed to be safe. In the phase 2 portion, patients received pirtobrutinib 200 mg once daily.

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

The baseline patient characteristics among patients with MCL in the prior covalent BTK inhibitor and covalent BTK inhibitor-naive subgroups were generally well balanced; the median age was 70 years (range, 46-88) and 67 years (range, 60-86), respectively. Most patients in both arms were males (79% vs 71%), had classic/leukemic histology (79% vs 79%), and had bulky lymphadenopathy less than 5 cm (62% vs 57%).1

The median number of prior lines of systemic treatment received in the prior covalent BTK inhibitor and covalent BTK inhibitor-naive subgroups were 3 (range, 1-9) and 2 (range, 1-3), respectively. Prior lines of therapy included BTK inhibitor (100% vs 0%), anti-CD20 antibody (97% vs 100%), chemotherapy (90% vs 100%), immunomodulator (17% vs 7%), stem cell transplant (22% vs 50%), BCL2 inhibitor (16% vs 0%), CAR T-cell (9% vs 0%), and PI3K inhibitor (4% vs 7%). Patients who received prior BTK inhibitor treatment discontinued due to progressive disease (84%), toxicity/other reasons (14%), and unknown reasons (2%).

In terms of TP53 mutation status, patients in the prior covalent BTK inhibitor and covalent BTK inhibitor-naive subgroups had mutations (20% vs 21%), no mutations (20% vs 29%), and missing status (61% vs 50%). Patients had a Ki-67 index of less than 30% (12% vs 14%), 30% or more (30% vs 43%), and missing (59% vs 43%), respectively.

Additional Findings From Subgroup Analyses

Data from subgroup analyses revealed that patients who received prior covalent BTK inhibitor treatment with a Ki-67 index of less than 30% (n = 18) and 30% or more (n = 45) achieved a median PFS of 19.5 months (95% CI, 3.5-NE) vs 5.3 months (95% CI, 3.0-9.1), respectively. The median DOR was 17.7 months (95% CI, 1.9-NE) vs 21.6 months (95% CI, 5.6-27.2), respectively, and the median OS was NE (95% CI, 9.4-NE) vs 23.4 months (95% CI, 13.1-NE), respectively.

Among patients previously treated with a covalent BTK inhibitor who had unmutated TP53 (n = 30) and mutated TP53 (n = 30), the median PFS was 6.9 months (95% CI, 3.7-16.6) vs 3.7 months (95% CI, 1.8-5.5), respectively. The median DOR was 14.8 months (95% CI, 1.9-NE) vs 17.6 months (95% CI, 1.7-NE), respectively, and the median OS was NE (95% CI, 10.7-NE) vs 15.9 months (95% CI, 7.8-NE), respectively.

Patients with MCL who received prior covalent BTK inhibitor treatment experienced efficacy following pirtobrutinib therapy across subgroups. Notably, patients who discontinued prior BTK therapy due to toxicity or other reasons (n = 21), with a Ki-67 index of less than 30%, and a low-risk sMIPI score (n = 30), achieved ORRs of 90.5% (95% CI, 69.6%-98.8%), 66.7% (95% CI, 41.0%-86.7%), and 66.7% (95% CI, 47.2%-82.7%), respectively.

A Manageable Safety Profile

Regarding safety, any-grade adverse effects (AEs) among patients with MCL (n = 166) included fatigue (31.9%), diarrhea (22.3%), dyspnea (17.5%), anemia (16.9%), and decreased platelet count (15.1%). These events occurred at grade 3 or higher severity at rates of 3.0%, 0.0%, 1.2%, 7.8%, and 7.8%, respectively. Treatment-related AEs (TRAEs) of any grade included fatigue (21.1%), diarrhea (12.7%), dyspnea (9.0%), anemia (7.2%), and decreased platelet count (7.8%). Grade 3 or higher TRAEs consisted of fatigue (2.4%), anemia (2.4%), decreased platelet count (3.0%), and dyspnea (0.6%).

Any-grade AEs of special interest included infections (42.8%), bruising (16.3%), rash (14.5%), arthralgia (9.0%), hemorrhage (10.2%), hypertension (4.2%), and atrial fibrillation/flutter (3.6%). These events were reported at grade 3 or higher severity at rates of 19.9%, 0.0%, 0.6%, 1.2%, 2.4%, 0.6%, and 1.8%, respectively. Treatment-related infections (15.7%), bruising (11.4%), rash (9%), arthralgia (2.4%), hemorrhage (4.2%), hypertension (1.8%), and atrial fibrillation/flutter (0.6%) were all present; 3.6% of patients experienced grade 3 or higher infections and 0.6% experienced grade 3 or higher hemorrhage.

The median time on treatment in the overall MCL cohort was 5.5 months. Discontinuations and dose reductions due to TRAEs occurred at rates of 3% and 5%, respectively.

“There were low rates of discontinuation due to clearly drug-related toxicity,” Cohen said. “For many of us, [pirtobrutinib] a new standard of care for patients who have received a prior covalent BTK inhibitor. There’s now an ongoing, randomized, global phase 3 trial [BRUIN MCL-321; NCT04662255] which is comparing pirtobrutinib with investigator’s choice of covalent BTK inhibitor in patients with relapsed MCL who are otherwise BTK-[inhibitor] naive. This will be an important study to help us better understand where the different BTK inhibitors fit in treatment sequencing for patients with relapsed disease.”

REFERENCES:
1. Cohen JB, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed/refractory (R/R) mantle cell lymphoma (MCL) patients with prior cBTKi: safety and efficacy including high-risk subgroup analyses from the phase 1/2 BRUIN study. Blood. 2023;142(suppl 1):981. doi:10.1182/blood-2023-181627
2. A study of oral LOXO-305 in patients with previously treated CLL/​SLL or NHL. ClinicalTrials.gov. Updated March 8, 2023. Accessed December 12, 2023. https://clinicaltrials.gov/study/NCT03740529
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