Pirtobrutinib Produces Responses in BTK Inhibitor–Naive R/R CLL/SLL

Treatment with pirtobrutinib (Jaypirca) led to responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who were not previously treated with a BTK inhibitor, according to data from the phase 1/2 BRUIN trial (NCT03740529).¹

Findings presented at the 2024 EHA Congress showed that evaluable patients (n = 35) achieved an overall response rate (ORR) of 91.4% (95% CI, 76.9%-98.2%) per independent central review (ICR) assessment. The complete response (CR) and partial response (PR) rates were 2.9% and 85.7%, respectively; the PR with lymphocytosis (PR-L) rate was 2.9%. Stable disease (SD) was reported in 5.7% of patients, and 2.9% were not evaluable for response.

Per investigator assessment, the ORR was 94.3% (95% CI, 80.8%-99.3%). The CR rate was 2.9%, the PR rate was 77.1%, the nodular PR rate was 5.7%, and the PR-L rate was 8.6%. SD occurred in 2.9% of patients, and 2.9% of patients were not evaluable for response.

“Pirtobrutinib also demonstrated promising efficacy in [patients with] relapsed/refractory, BTK inhibitor–naive CLL/SLL with high-risk molecular features, although the number of patients was small,” lead study author Toby A. Eyre, MBChB, DipMedEd, MRCP, FRCPath, MD, of Oxford University Hospitals NHS Foundation Trust in the United Kingdom, and colleagues wrote in a poster presentation of the data.

In December 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with CLL or SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.² That regulatory decision was supported by prior data from BRUIN.

The phase 1/2 trial enrolled patients at least 18 years of age with previously treated hematologic malignancies, including CLL, SLL, mantle cell lymphoma, and others. Patients needed to have active disease in need of treatment and an ECOG performance status of 0 to 2.¹

The CLL/SLL group (n = 317) included 2 cohorts featuring patients with previous exposure to a covalent BTK inhibitor (n = 282) and those naive to a BTK inhibitor (n = 35).

During dose escalation and expansion, enrolled patients received oral pirtobrutinib once per day at doses ranging from 25 mg to 300 mg. In phase 2, all patients received the noncovalent BTK inhibitor at 200 mg once per day.

The trial’s key end points were safety and tolerability; determining the maximum tolerated dose and recommended phase 2 dose; pharmacokinetics; and efficacy, including ORR per International Workshop on CLL criteria, duration of response, progression-free survival (PFS), and overall survival (OS).

In the BTK inhibitor–naive cohort, patients with CLL/SLL had a median age of 67 years (range, 38-81), and 51% of patients were male. Patients had a Rai stage of 0 to 2 (63%), III to IV (34%), or missing (3%); ECOG performance statuses included 0 (49%), 1 (46%), and 2 (3%). Patients received a median of 2 prior lines of therapy (range, 1-8). Prior therapies were comprised of chemotherapy (100%), an anti-CD20 antibody (97%), a PI3K inhibitor (23%), a BCL-2 inhibitor (9%), and other systemic therapies (6%).

The median time from diagnosis to first dose of pirtobrutinib was 112.5 months (range, 67-152). Forty-three percent of patients had bulky lymphadenopathy of at least 5 cm. Regarding high-risk molecular features, 43% of evaluable patients had a complex karyotype (n = 3/7), 80% had unmutated IGHV (n = 20/25), 23% harbored TP53 mutations (n = 7/30), 27% had 17p deletions (n = 7/26), and 37% harbored a TP53 mutation and/or a 17p deletion (n = 10/27).

Additional data showed patients with TP53-mutated disease experienced an ORR of 85.7% (95% CI, 42.1%-99.6%); those harboring 17p deletions had an ORR of 100% (95% CI, 59.0%-100%); patients with unmutated IGHV achieved an ORR of 90.0% (95% CI, 68.3%-98.8%); and those with a complex karyotype had an ORR of 100% (95% CI, 29.2%-100%).

The overall population experienced a median PFS that was not evaluable (NE; 95% CI, 27.6-NE) per IRC assessment at a median follow-up of 28.1 months. The 6-, 12-, 18-, and 24-month PFS rates were 90.7%, 84.5%, 81.2%, and 74.7%, respectively. The investigator-assessed median PFS was NE (95% CI, 30.9-NE) at a median follow-up of 29.9 months. The respective 6-, 12-, 18-, and 24-month PFS rates were 93.9%, 87.9%, 84.8%, and 81.8%.

The median OS was NE (95% CI, NE-NE) at a median follow-up of 33.4 months. The 6-, 12-, 18-, and 24-month OS rates were 97.1%, 91.1%, 88.0%, and 88.0%, respectively.

The median time on treatment was 28.8 months, and the safety profile of pirtobrutinib was consistent with other cohorts from BRUIN. Treatment-related adverse effects (TRAEs) led to dose reductions and treatment discontinuation in 11.4% and 5.7% of patients, respectively.

All-cause AEs reported in at least 20% of patients included COVID-19 (any-grade, 45.7%; grade ≥3, 8.6%), neutropenia (42.9%; 34.3%), diarrhea (31.4%; 5.7%), anemia (20.0%; 8.6%), fatigue (20.0%; 2.9%), cough (20.0%; 0%), contusion (20.0%; 0%), and pyrexia (25.7%; 0%). All-cause AEs of interest included infections (any-grade, 80.0%; grade ≥3, 45.7%), rash (31.4%; 0%), hypertension (28.6%; 8.6%), hemorrhage (14.3%; 2.9%), bruising (20.0%; 0%), arthralgia (14.3%; 0%), and atrial fibrillation/flutter (5.7%; 2.9%).

TRAEs included COVID-19 (any-grade, 8.6%; grade ≥3, 0%), neutropenia (40.0%; 28.6%), diarrhea (20.0%; 2.9%), anemia (11.4%; 8.6%), fatigue (8.6%; 2.9%), cough (5.7%; 0%), contusion (14.3%; 0%), pyrexia (5.7%; 0%), infections (25.7%; 2.9%), rash (17.1%; 0%), hypertension (5.7%; 0%), hemorrhage (2.9%; 0%), bruising (14.3%; 0%), arthralgia (5.7%; 0%), and atrial fibrillation/flutter (2.9%; 0%).

The ongoing phase 3 BRUIN CLL-313 trial (NCT05023980) trial is further investigating pirtobrutinib monotherapy in patients with treatment-naive CLL/SLL, and the phase 3 BRUIN CLL-314 (NCT05254743) is evaluating the agent as monotherapy in those with CLL/SLL who are treatment naive or received a prior non–BTK inhibitor therapy.

References

1. Eyre TA, Lech-Maranda E, Roeker LE, et al. Pirtobrutinib in relapsed/refractory CLL/SLL: results from BTKi naive cohort of the phase 1/2 BRUIN study. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P656.
2. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 1, 2023. Accessed August 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic