Pirtobrutinib May Be a Novel Treatment Option for Heavily Pretreated MCL

Updated results from a phase I/IIb study demonstrated promising efficacy for the novel agent pirtobrutinib in heavily pretreated patients with mantle cell lymphoma (MCL).

Jonathon B. Cohen, MD, MS, of the Winship Cancer Institute at Emory University in Atlanta, Georgia, presented the study’s results during the Society of Hematologic Oncology (SOHO) Annual Meeting.

Once a patient with MDS fails treatment with a BTK inhibitor, outcomes are poor. Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor that inhibits both wild-type and C481-mutated BTK with equal low nM potency.

The BRUIN study is a multicenter, phase I/II trial assessing oral pirtobrutinib in patients with advanced B-cell malignancies. The phase I dose-escalation study assessed pirtobrutinib in a standard 3+3 design to determine a recommended phase II dose. In phase II, patients received continuous pirtobrutinib for 28-day cycles, with the primary objective being overall response rate (ORR).

As of July 16, 2021, 618 patients were treated at pirtobrutinib dose levels ranging from 25 mg to 300 mg. The study population included 296 patients with chronic lymphocytic leukemia/small lymphocytic leukemia, and 134 with MCL. Median patient age was 70 years (range, 46-88 years), and most (n=82; 61%) had an Eastern Cooperative Oncology Group performance status score of zero. Patients had received a median of three prior lines of therapies (range, 1-9 therapies).

No dose-limiting toxicities occurred during phase I, and the maximum tolerated dose was not reached, so pirtobrutinib 200 mg daily was the recommended phase II dose. Most patients (96%) received one or more doses of pirtobrutinib at or above the phase II recommended dose level. Six patients (1%) permanently discontinued treatment due to treatment-related adverse events.

The most common any-grade treatment-related adverse events associated with pirtobrutinib were fatigue (23%), diarrhea (19%), neutropenia (18%), and contusion (17%).

Among 100 patients with MCL who previously received BTK inhibitor therapy, the ORR was 51% (95% CI, 41-61), including 25 complete responses (CRs; 25%), 26 partial responses (PRs; 26%), and 16 patients (16%) with stable disease. Among BTK-naïve patients, the ORR was 82% (95% CI, 48-98), including two CRs (18%), seven PRs (64%), and one patient (9%) with stable disease.

Among 28 patients who received prior transplant, the ORR was 64% (95% CI, 44-81), and among the six patients who received prior chimeric antigen receptor T-cell therapy, the ORR was 50% (95% CI, 12-88).

The median follow-up among responders was 8.2 months (range, 1.0-27.9 months), with 60% of responses (n=36/60) ongoing.

“Pirtobrutinib demonstrates promising efficacy in MCL patients previously treated with BTK inhibitors, a population with extremely poor outcomes,” the researchers concluded.

Reference

Cohen JB, Shaha NN, Alencar AJ, et al. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in previously treated mantle cell lymphoma: updated results from the phase 1/2 BRUIN study. Abstract #MCL-133. Presented at the 2022 Society of Hematologic Oncology (SOHO) Annual Meeting, September 28-October 1, 2022.