Pirtobrutinib Yields Sustained Efficacy in R/R Mantle Cell Lymphoma

“The [DOR] and the long-term safety data are encouraging,” Michael Choi, MD, an associate professor of medicine, medical oncologist, and hematologist at the University of California, San Diego, said in a presentation on findings from the phase 1/2 BRUIN trial.

A cohort of heavily pretreated patients with relapsed/refractory mantle cell lymphoma (MCL) continues to derive clinical benefit from pirtobrutinib (Jaypirca) monotherapy including those with high-risk disease features, according to updated findings from the phase 1/2 BRUIN trial (NCT03740529).

Across the total cohort of 90 patients, pirtobrutinib produced an overall response rate (ORR) of 56.7% (95% CI, 45.8%-67.1%), consisting of complete responses in 18.9% and partial responses in 37.8%. The median duration of response (DOR) among responding patients was 17.6 months (95% CI, 7.3-27.2) after a median follow-up of 12.7 months. The estimated DOR rate was 58.0% at 12 months and 44.6% at 18 months. The median overall survival (OS) was 23.5 months (95% CI, 15.9-not estimable [NE]), and the median progression-free survival (PFS) was 7.4 months (95% CI, 5.3-13.3).

Clinical benefit was also observed among patients with high-risk disease features. The ORR was 50.0% (95% CI, 15.7%-84.3%) and the median DOR was not estimable (95% CI, 1.4-NE) among 8 patients with blastoid disease. The corresponding figures were 50.0% (95% CI, 21.1%-78.9%) and 27.2 months (95% CI, 3.7-NE) among 12 patients with pleomorphic disease.

Additionally, the ORR in patients with TP53-mutated disease was 47.1% (95% CI, 23.0%-72.2%) and the median DOR was 17.6 months (95% CI, 1.7-NE); the corresponding figures were 57.9% (95% CI, 33.5%-79.7%) and 14.8 months (95% CI, 1.9-NE) for those without TP53-mutated disease. Among patients with an elevated Ki-67 index, the ORR was 56.0% (95% CI, 34.9%-75.6%) and the median DOR was 21.6 months (95% CI, 1.7-NE), with corresponding figures of 66.7% (95% CI, 29.9%-92.5%) and 17.6 months (95% CI, 1.6-NE) among those without an elevated Ki-67 index.

These data were recently presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

“The [DOR] and the long-term safety data are encouraging,” Michael Choi, MD, said in a presentation on findings from the BRUIN trial. “For patients [who] achieve a response, we may not have to think of pirtobrutinib as simply a bridge to other therapies.”

Choi is an associate professor of medicine, medical oncologist, and hematologist at the University of California, San Diego.

These findings come from the prespecified primary efficacy cohort of the BRUIN trial, and include the first 90 enrolled patients who had undergone prior treatment for MCL with covalent Bruton tyrosine kinase (BTK) inhibitors. The median age of this cohort was 70 years old (range, 46-87), and patients had undergone a median of 3 prior lines of therapy (range, 1-8). Additionally, 82.2% of these patients had discontinued treatment with a prior BTK inhibitor due to disease progression.

Roughly 78% of patients had a simplified MCL International Prognostic Index (sMIPI) score classified as either intermediate- or high-risk. Of 36 patients with relevant samples available, 17 had TP53-mutant disease. Of 34 with relevant samples available, 25 had an elevated Ki-67 index, defined as an index of 30% or greater.

In the first, dose-expansion phase of this trial, patients received pirtobrutinib monotherapy starting at a dose of 25 mg and up to a maximum dose of 300 mg daily during each 28-day cycle. In the second phase, they received the agent at a dose of 200 mg daily.

The primary end point was ORR according to independent review committee assessment. Secondary end points included DOR, pharmacokinetics, and safety.

The MCL safety cohort included 166 patients. Fatigue (31.3%), diarrhea (22.3%), and dyspnea (16.3%) were the most common treatment-emergent adverse effects (TEAEs). The most common grade 3 or higher toxicity was neutropenia (15%). Instances of grade 3 or higher hemorrhage (2.4%) and atrial fibrillation/flutter (1.8%) were uncommon.

“This longer follow-up demonstrates that pirtobrutinib has promising efficacy and safety in this highly pretreated population despite prior covalent BTK exposure,” study author Nirav Niranjan Shah, MD, said in a poster presentation of these data. Shah is an associate professor at the Medical College of Wisconsin.

“We look forward to sharing longer-term follow-up in future abstracts,” he concluded.

Reference

Shah NN, Jurczak W, Zinzani PL, et al. Pirtobrutinib in covalent BTK-inhibitor (cBTKi) pre-treated mantle cell lymphoma (MCL): updated results and subgroup analysis from the phase 1/2 BRUIN study with >3 years follow-up from start of enrollment. J Clin Oncol. 2023;41(suppl 16):7514.