Pirtobrutinib to be Compared with Ibrutinib in CLL/SLL Ongoing BRUIN CLL-314 Trial

The phase 3 BRUIN CLL-314 trial evaluating the selective noncovalent BTK inhibitor pirtobrutinib vs the potent covalent BTK inhibitor ibrutinib is currently enrolling patients with chronic lymphocytic leukemia and small lymphocytic lymphoma who previously received treatment with non-BTK inhibitor therapy.

The phase 3 BRUIN CLL-314 trial (NCT05254743) evaluating the selective noncovalent BTK inhibitor pirtobrutinib (Jaypirca) vs the potent covalent BTK inhibitor ibrutinib (Imbruvica) is currently enrolling patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) who previously received treatment with non-BTK inhibitor therapy, according to a presentation during the 2023 International Workshop on CLL (iwCLL). Enrollment is complete for treatment-naïve patients.1

Approximately 650 patients will be enrolled in the trial and randomly assigned to arm A to receive pirtobrutinib 200 mg orally once daily or arm B to receive ibrutinib 420 mg orally once daily. The agents will be given in 28-day continuous cycles until progressive disease or unacceptable toxicity. To be eligible for enrollment, patients must be aged at least 18 years and have an ECOG performance status of up to 2.Up to 30% of patients in the trial will be treatment naïve, with the remaining patient population comprised of those pretreated with non-BTK inhibitors. Stratification will occur based on presence of 17p deletions and prior lines of therapy received (0 vs 1 vs ≥ 2).

The open-label phase 3 study is building upon prior data from the phase 1/2 BRUIN trial (NCT03740529) in which pirtobrutinib yielded an overall response rate (ORR) of 73.3% (95% CI, 67.3%-78.7%) in patients with CLL or SLL who previously received a BTK inhibitor (n = 247). At a median follow-up of 19.4 months, the median progression-free survival (PFS) was 19.6 months (95% CI, 16.9-22.1). Pirtobrutinib was well tolerated regardless of prior therapies and number of lines received, BTK C481 mutation status, or reason for prior BTK inhibitor discontinuation.2

In January 2023, pirtobrutinib received accelerated approval from the FDA for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) who had received at least 2 lines of systemic therapy, including a BTK inhibitor. The approval was supported by data from BRUIN which demonstrated that patients with MCL who previously received a BTK inhibitor (n = 120) achieved an ORR of 50% (95% CI, 41%-59%) with a complete response rate of 13%.3 This is currently the agent’s only indication.4

Investigators have selected pirtobrutinib to be evaluated vs ibrutinib as covalent BTK inhibitors like ibrutinib have low oral bioavailability and a short half-life which may not result in optimal BTK target coverage. Pirtobrutinib is a highly selective noncovalent inhibitor that inhibits wildtype and C481-mutant BTK with equal low nM potency. Additionally, the oral pharmacology of pirtobrutinib allows for continued inhibition throughout the dosing interval.1

The clinical trial will enroll patients at sites in the United States, Canada, the United Kingdom, Austria, Belgium, the Czech Republic, France, Germany, Hungry, Italy, Poland, Portugal, Spain, Argentina, Brazil, Chile, Australia, New Zealand, Japan, the Republic of Korea, and Taiwan.

The primary end point of BRUIN CLL-314 is ORR per iwCLL 2018 criteria. Secondary end points include event-free survival, PFS, duration of response, overall survival, time to next treatment, and time to worsening of CLL/SLL related symptoms.5

Patients with prior exposure to BTK inhibitors, an active infection, or a recent myocardial infarction/grade 3 or higher heart failure event, will not be enrolled. Exclusion criteria also notes the use of warfarin or other vitamin K antagonists is prohibited.1

The most common any grade adverse effects (AEs) observed in the BRUIN trial in patients treated with pirtobrutinib monotherapy (n = 317) included fatigue (31.5%), diarrhea (26.5%), contusion (24.3%), cough (24.3%), COVID-19 (24.0%), nausea (18.9%), and abdominal pain (18.0%). Grade 3 or higher AEs consisted of infections (28.1%), neutropenia (26.8%), anemia (8.8%), COVID-19 (5.0%), fatigue (1.9%), abdominal pain (1.6%), back pain (0.9%), dyspnea (0.9%), headache (0.6%), diarrhea (0.6%), and upper respiratory tract infection (0.3%).2

AEs of special interest from the BRUIN trial were as follows: infections (any grade, 71.0%; grade ≥3, 28.1%), bleeding (any grade, 42.6%; grade ≥3, 2.2%), neutropenia (any grade, 32.5%; grade ≥3, 26.8%), bruising (any grade, 30.3%), hemorrhage (any grade, 21.1%; grade ≥3, 2.2%), hypertension (any grade, 14.2%; grade ≥3, 3.5%), and atrial fibrillation or flutter (any grade, 3.8%; grade ≥3, 1.3%).

References

  1. Escalón MP, Woyach JA, Coombs CC, et al. BRUIN CLL-314: a phase 3, open-label, randomized study of pirtobrutinib versus ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (trial in progress). Presented at: 2023 International Workshop on CLL; October 6-9, 2023; Boston, Massachusetts. Abstract 1548596.
  2. Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696
  3. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. FDA. January 27, 2023. Accessed October 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-relapsed-or-refractory-mantle-cell-lymphoma
  4. Jaypirca. Prescribing information. Eli Lilly and Company; 2023. Accessed October 11, 2023. https://uspl.lilly.com/jaypirca/jaypirca.html#pi
  5. A study of pirtobrutinib (LOXO-305) versus ibrutinib in participants with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (BRUIN-CLL-314). ClinicalTrials.gov. Updated July 11, 2023. Accessed October 11, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05254743