Pirtobrutinib Showcases Encouraging Activity in CLL, MCL, and Other B-Cell Malignancies

April 8, 2021
Kristi Rosa
Kristi Rosa

Managing Editor, OncLive®
Kristi Rosa joined MJH Life Sciences in 2016 and has since held several positions within the company. She helped launch the rapidly growing infectious disease news resource Contagion, strengthened the Rare Disease Report, of HCPLive, and now serves as the main digital news writer for OncLive. Prior to working at the company, she served as lead copywriter and marketing coordinator at The Strand Theater. Email: krosa@onclive.com

Pirtobrutinib showcased encouraging efficacy with an acceptable safety profile in patients with chronic lymphocytic leukemia or small lymphocytic leukemia, mantle cell lymphoma, and Waldenström macroglobulinemia who previously received a BTK inhibitor.

Pirtobrutinib (LOXO-305) showcased encouraging efficacy with an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia who previously received a BTK inhibitor, according to data from the first-in-human phase 1/2 BRUIN trial (NCT03740529).

Among a total of 121 evaluable patients with CLL or SLL who had previously received a covalent BTK inhibitor, pirtobrutinib elicited an overall response rate (ORR) of 62% (95% CI, 53%-71%). The ORR was found to be comparable in patients with CLL who were resistant to prior covalent BTK inhibitor treatment, who were intolerant to prior covalent BTK inhibition, who had BTK C481-mutant disease, and who had BTK wild-type disease, at 67%, 52%, 71%, and 66%, respectively.

Additionally, the ORR was 52% (95% CI, 38%-66%) in the 52 evaluable patients with MCL who previously received covalent BTK inhibitors, 69% (95% CI, 39%-91%) in the 3 patients with Waldenström macroglobulinemia who previously received a BTK inhibitor, and 50% (95% CI, 16%-84%) among 3 patients with follicular lymphoma.

“In this first-in-human trial of pirtobrutinib, we showed promising efficacy and safety in patients with B-cell malignancies, including CLL or SLL, MCL, Waldenström macroglobulinemia, and follicular lymphoma,” lead author Anthony Mato, MD, MSCE, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, and colleagues, wrote in the paper published in the Lancet. “Activity was observed in heavily pretreated patients with resistance and intolerance to previous covalent BTK inhibitor treatment.”

Pirtobrutinib is an orally available, highly selective, reversible BTK inhibitor that has low nM potency against wild-type and C481-mutated BTK. The agent has been shown to have 300-fold greater selectivity for BTK compared with 98% of 370 other kinases; this decreases the potential for off-target toxicities.

The open-label phase 1/2 trial was conducted at a total of 27 sites spanning 6 countries and utilized a 3+3 dose-escalation design. Enrollment of up to 150 patients was allowed across all dose levels examined. In the second phase of the trial, participants were enrolled to 1 of 6 cohorts based on the type of B-cell malignancy, prior therapy exposure, and BTK mutational status.

A total of 382 patients were evaluated for eligibility. Patients needed to have B-cell malignancies and had previously received at least 2 lines of treatment. Following the fifth protocol amendment, patients with CLL or SLL who had only received 1 prior BTK inhibitor were also allowed to participate. Notably, concomitant anticoagulant and antiplatelet agents were permitted, with the exception of warfarin.

Of the 382 patients, 323 were enrolled to the trial; 170 of these patients had CLL or SLL, 61 had MCL, 26 had Waldenström macroglobulinemia, and 66 had other B-cell malignancies.

Of the 323 patients, 203 were given pirtobrutinib at a once-daily dose ranging from 25 mg to 300 mg in the phase 1 portion of the research. Specifically, 7 dose levels of pirtobrutinib were evaluated: 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg. The primary end point for the phase 1 portion of the study was to identify the maximum-tolerated dose (MTD) and the recommended phase 2 dose of the agent. Secondary end points included ORR, pharmacokinetics, and safety.

In the phase 2 portion of the research, 120 patients were given pirtobrutinib at a once-daily dose of 200 mg. Treatment was administered until progressive disease, intolerable toxicity, or withdrawal. The primary end point for this portion of the study was ORR, which was evaluated via an independent review committee. Key secondary end points included ORR per investigator assessment, best overall response, duration of response, progression-free survival, overall survival, safety and tolerability, and pharmacokinetics.

The median age across the study was 68 years. Twenty-five percent (n =20/81) of evaluable patients with CLL had 17p deletion, 30% (n = 27) had TP53 mutation, 19% (n = 15) had 11q deletion, and 88% (n = 71) had unmutated IGHV.

Among 170 patients with CLL or CLL, the median number of prior lines of treatment received was 3. Eighty-six percent of these patients had received a prior BTK inhibitor, 90% had an anti-CD20 antibody, 82% had chemotherapy, 34% had venetoclax (Venclexta), 21% had a PARP inhibitor, 6% had CAR T-cell therapy, and 2% underwent allogeneic transplant.

Among the 61 patients with MCL, the median number or prior lines of treatment was also 3. Notably, 98% had previously received a BTK inhibitor, 92% had an anti-CD20 antibody, 92% had chemotherapy, 20% had lenalidomide (Revlimid), 25% underwent autologous transplant, 5% underwent allogeneic transplant, and 5% received CAR T-cell therapy.

A total of 269 patients were included in the efficacy-evaluable population; 139 of these patients had CLL or SLL, 30 had MCL, 11 had Waldenström macroglobulinemia, and 23 had another B-cell malignancy.

Additional data indicated that of those with CLL or SLL who responded to pirtobrutinib, 69 had a partial response (PR), 19 had a partial response with lymphocytosis, 45 had stable disease, 1 had disease progression, and 5 discontinued treatment.

Of those with MCL who responded to treatment, 14 achieved complete responses, 15 had PRs, 10 had disease stability, and 12 experienced disease progression. Notably, responses were observed in patients who previously received cellular therapy. Two of 4 patients with blastoid variant MCL also responded to treatment with pirtobrutinib. The median time to first response in these patients was 1.8 months.

Among those with Waldenström macroglobulinemia, 9 patients had a PR, 3 had stable disease, and 3 experienced progressive disease. Seventy-seven percent of those who responded to pirtobrutinib are still in response at a median follow-up of 5 months.

In the remaining 39 efficacy-evaluable patients, a total of 8 responses were reported; 6 of these patients had diffuse large B-cell lymphoma (DLBCL) and 2 of these patients had marginal zone lymphoma. Three of the 6 patients with DLBCL were still in response at a median follow-up duration of 4 months.

A total of 323 patients were included in the safety population of the trial. Notably, no dose-limiting toxicities were reported; as such, no MTD was determined. Eighty-seven percent of adverse effects (AEs) reported were grade 1 or 2 in severity, and toxicities that were grade 3 or higher were infrequent. However, the most common grade 3 or higher effect was neutropenia, which occurred in 10% of this population. Upper respiratory tract infection was the most frequently reported infection, and it occurred in 7% of patients.

AEs that were experienced by at least 10% of the safety population included fatigue (20%), diarrhea (17%), and contusion (13%). Eight percent of patients experienced dose interruptions, 2% required dose reductions, and 1% of patients discontinued treatment due to pirtobrutinib-related toxicities.

Atrial arrhythmias and hemorrhage are 2 important AEs that were linked with discontinuation. Two patients experienced grade 2 atrial fibrillation that was not determined to be associated with pirtobrutinib. One patient experienced grade 3 hemorrhage, a subarachnoid bleed sustained during a bicycle accident. Sixteen percent of patients experienced bruising but it was not associated with dose or exposure.

Eighteen patients had previously discontinued a BTK inhibitor due to cardiovascular toxicity (n = 15) or hemorrhage (n = 3) and none of these patients experienced these effects on pirtobrutinib.

“Consistent with its highly selective profile, pirtobrutinib appeared to be well tolerated, with a wide therapeutic index, as shown by the observed efficacy at all dose levels tests and the lack of a MTD,” the study authors wrote. “To date, low rates of important BTK-mediated toxicities, including atrial arrhythmias and major bleeding, have been observed, despite permitting patients with history of these events and patients on concurrent anticoagulation.”

Reference

Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5