Pirtobrutinib Exhibits Promising Efficacy in Heavily Pretreated MCL and Other Non-Hodgkin Lymphomas

Alvaro J. Alencar, MD

Pirtobrutinib (LOXO-305) elicited encouraging responses across all dose levels in patients with mantle cell lymphoma (MCL) and other non-Hodgkin lymphoma who previously received all classes of available therapy, with benefit observed independent of prior therapy received, according to data from the phase 1/2 BRUIN study (NCT03740529) presented during the 2021 Pan Pacific Lymphoma Conference.¹

The highly potent and selective non-covalent BTK inhibitor resulted in an overall response rate (ORR) of 52% (95% CI, 38%-65%) in patients with MCL (n = 56), with a 25% complete response (CR) rate, a 27% partial response (PR) rate, and a stable disease rate of 18%.

Among patients who were pretreated with BTK inhibitors (n = 52), the ORR achieved with pirtobrutinib was the same, at 52% (95% CI, 38%-66%); the CR, PR, and stable disease rates were 25%, 27%, and 17%, respectively. Notably, efficacy with the agent was also observed in those who previously underwent stem cell transplant (n = 9/14) or CAR T-cell therapy (n = 2/2), with rates of 64% and 100%, respectively.

The ORR with pirtobrutinib was higher in those with Waldenström macroglobulinemia (n = 19), at 68% (95% CI, 44%-87%), which included a PR rate of 47%, a molecular response (MR) rate of 21%, and a stable disease rate of 16%. BTK pretreated patients with Waldenström macroglobulinemia (n = 13) experienced an ORR of 69% (95% CI, 39%-91%), with a PR rate of 39%, a MR rate of 31%, and a stable disease rate of 8%.

The ORRs experienced in patients with Richter’s transformation (n = 8), follicular lymphoma (n = 8), marginal zone lymphoma (n = 9), and diffuse large B-cell lymphoma (n = 25) were 75% (95% CI, 35%-97%), 50% (95% CI, 16%-84%), 22% (95% CI, 3%-60%), and 24% (95% CI, 9%-45%), respectively.

“Pirtobrutinib is well tolerated and exhibits promising efficacy in heavily pretreated patients with MCL and other non-Hodgkin lymphomas,” lead study author Alvaro J. Alencar, MD, of Sylvester Comprehensive Cancer Center, and colleagues, wrote. “Durable responses in BTK pretreated MCL are particularly notable, given poor outcomes with existing therapeutic options.”

In the phase 1/2 BRUIN trial, investigators set out to evaluate the safety and efficacy of pirtobrutinib in previously treated patients with advanced B-cell malignancies. To be eligible for participation, patients needed to be 18 years of age or older, an ECOG performance status of 0 to 2, and active disease in need of treatment.

A total of 323 patients were enrolled to the trial; 203 of these patients were enrolled to the phase 1 escalation and expansion portion of the trial, where they received the agent at a once-daily dose ranging from 25 mg to 300 mg, and 120 patients to the phase 3 portion, where they received a once-daily dose of 200 mg.

Key end points of the trial include safety and tolerability, determining the maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D), pharmacokinetics, and efficacy with respect to ORR and duration of response based on disease criteria.

The median age of participants was 68.3 years, 69% were male, 50% had an ECOG performance status of 0, and the median number of prior lines of systemic therapy was 3. Previous treatments included BTK inhibitors, chemotherapy, anti-CD20 antibody, BCL-2 inhibitors, PI3K inhibitors, lenalidomide (Revlimid), CAR T-cell therapy, autologous stem cell transplant, and allogeneic stem cell transplant. The majority of patients who discontinued prior BTK inhibitors did so because of disease progression.

Among 323 patients included in the safety population, no dose-limiting toxicities were reported and the MTD had not been reached. The most frequent treatment-emergent adverse effects (TEAEs) experienced by 10% or more of patients included fatigue, diarrhea, and contusion. AEs of special interest included bruising, rash, arthralgia, hemorrhage, hypertension, atrial, and fibrillation/flutter.

Of these patients, 1.5% discontinued treatment because of treatment-related AEs. The RP2D for pirtobrutinib was established as once-daily 200 mg. No notable covalent BTK inhibitor–associated toxicities were rarely reported.

“Longer follow-up is needed to better understand the pirtobrutinib safety profile associated with chronic administration,” the study authors concluded.

Reference

1. Alencar AJ, Shah NN, Gerson JN, et al. Pirtobrutinib (LOXO-305), a next generation highly selective non-covalent Bruton’s tyrosine kinase inhibitor in previously treated mantle cell lymphoma and other non-Hodgkin lymphomas: results from the phase 1/2 BRUIN study. Presented at: 2021 Pan Pacific Lymphoma Conference; August 9-13, 2021; Big Island, HI. https://bit.ly/3n3XzPl