Pirtobrutinib Yields Durable Efficacy in Pretreated Mantle Cell Lymphoma

Treatment with pirtobrutinib (Jaypirca) led to enduring, promising efficacy in a heavily pretreated cohort of patients with mantle cell lymphoma (MCL) who received prior therapy with covalent Bruton tyrosine kinase (BTK) inhibitors, according to updated findings from the phase 1/2 BRUIN trial (NCT03740529).

Among 90 patients who received prior treatment with a covalent BTK inhibitor, the overall response rate (ORR) was 56.7% (95% CI, 45.8%-67.1%), which included partial responses (PRs) in 37.8% of patients and complete responses (CRs) in 18.9%. Additionally, the ORR was 85.7% (95% CI, 57.2%-98.2%) among 14 patients who were naïve to covalent BTK inhibitors; the PR and CR rates in this group were 42.9% and 42.9%, respectively.

In the pretreated cohort, investigators reported a median overall survival (OS) of 23.5 months (95% CI, 15.9-not evaluable [NE]), with OS rates of 84.7% at 6 months, 69.1% at 12 months, and 59.0% at 18 months. The median progression-free survival (PFS) in this group was 7.4 months (95% CI, 5.3-13.3), and the PFS rates were 51.7%, 39.4%, and 34.6% at 6 months, 12 months, and 18 months, respectively. Pirtobrutinib elicited a median duration of response (DOR) of 17.6 months (95% CI, 7.3-27.2), with ongoing responses observed in 75.0% at 6 months, 58.0% at 12 months, and 44.6% at 18 months.

Investigators highlighted that the median OS, PFS, and DOR were not reached in the covalent BTK inhibitor-naïve cohort. At 18 months, the PFS rate was 92.3% (95% CI, 56.6%-98.9%), and the OS rate was 92.3% (95% CI, 56.6%-98.9%). Additionally, 100.0% (95% CI, 100.0%-100.0%) of the patients had ongoing responses at 18 months.

Among patients with a Ki-67 index of less than 30%, the median DOR was 17.6 months (95% CI, 1.6-NE), the median PFS was 19.5 months (95% CI, 0.9-NE), and the median OS was NE (95% CI, 6.9-NE). The corresponding values for those with a Ki-67 index of 30% or higher were 21.6 months (95% CI, 1.7-NE), 5.2 months (95% CI, 1.9-23.4), and NE (95% CI, 14.7-NE).

For those with TP53-negative disease, pirtobrutinib yielded a median DOR of 14.8 months (95% CI, 1.9-NE), a median PFS of 7.4 months (95% CI, 3.8-23.4), and a median OS that was NE (95% CI, 6.9-NE). Among patients with TP53-positive disease, the corresponding values were 17.6 months (95% CI, 1.7-NE), 5.2 months (95% CI, 1.7-19.5), and 15.9 months (95% CI, 8.3-NE).

In the phase 1 escalation and expansion portions of the BRUIN trial, patients received pirtobrutinib at 25 mg to 300 mg once a day. In the second phase , investigators administered pirtobrutinib at 200 mg once a day to a total of 773 patients.

Patients 18 years and older with an ECOG performance status of 0 to 2, active disease, and who received prior therapy were able to enroll on the trial. The MCL cohort included 166 patients, 152 of whom received prior treatment with a covalent BTK inhibitor and 14 who did not previously receive a covalent BTK inhibitor. Among those who were previously treated with a covalent BTK inhibitor, the first 90 patients who had measurable disease and no known central nervous system involvement were included in the trial’s primary analysis set.

The trial’s end points included safety and tolerability, the maximum tolerated dose and recommended phase 2 dose, pharmacokinetics, and ORR and DOR based on Lugano criteria as assessed by an independent review committee.

The median patient age was 70.0 years (range, 46.0-87.0) among those who received prior treatment with a covalent BTK inhibitor and 67.0 years (range, 60.0-86.0) among those who had no prior treatment with covalent BTK inhibitors. Most patients in each respective group had classic histology (77.8% vs 78.6%), TP53-negative disease (21.1% vs 28.5%), a Ki-67 index of 30% or more (27.8% vs 42.9%), and received prior treatment with an anti-CD20 agent (95.6% vs 100.0%). A higher proportion of patients in the pretreated group had bone marrow involvement (51.1% vs 28.6%).

Among 166 patients with MCL who were included in the safety population, the most common any-grade and grade 3 or higher treatment-emergent adverse effects (TEAEs), respectively, included fatigue (31.3% and 3.0%), diarrhea (22.3% and 0.0%), and dyspnea (16.3% and 1.2%). The most common any-grade and high-grade TEAEs of special interest, respectively, included bruising (16.3% vs 0.0%), hemorrhage or hematoma (10.2% vs 2.4%), and rash (8.4% vs 0.6%).

Patients with MCL received pirtobrutinib for a median of 5 months. Additionally, 3% (n = 5) discontinued study treatment following treatment-related AEs (TRAEs), and 6% (n = 10) required dose reductions due to TRAEs.

According to the investigators, the ongoing, international phase 3 BRUIN MCL-321 trial (NCT04662255) will evaluate pirtobrutinib compared with investigator’s choice of covalent BTK inhibitor among pretreated patients with MCL who are naïve to treatment with BTK inhibitors.

Data from the BRUIN trial were presented at the 2023 Society of Hematological Oncology (SOHO) Annual Meeting.

Reference

Wang ML, Shah NN, Jurczak W, et al. Pirtobrutinib in covalent BTK-inhibitor pre-treated mantle cell lymphoma: updated results and subgroup analysis from the phase 1/2 BRUIN study with 2 years of survival follow-up. Presented at: 2023 Society of Hematologic Oncology (SOHO). Annual Meeting; September 6-9, 2023; Houston, TX. Abstract MCL-155.