Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor-Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321)

Abstract

Purpose: Pirtobrutinib, a noncovalent, Bruton tyrosine kinase inhibitor (BTKi), has shown clinical efficacy and a favorable safety profile. BRUIN CLL-321 was an open-label, randomized phase III study conducted exclusively in patients with R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) previously treated with cBTKi, and compared pirtobrutinib with investigator's choice (IC) of idelalisib/rituximab (IdelaR) or bendamustine/rituximab (BR).

Methods: Patients were randomly assigned 1:1 to receive pirtobrutinib (200 mg once daily) or IC of IdelaR or BR, and were stratified by previous use of venetoclax and del(17p). The primary end point was independent review committee-assessed progression-free survival (PFS). Secondary end points included time to next treatment or death (TTNT), overall survival (OS), and safety. The primary PFS end point was met at the time of the primary analysis (August 29, 2023), and updated results are reported from the final OS analysis (August 29, 2024).

Results: A total of 238 patients were randomly assigned to receive pirtobrutinib (n = 119) or IC (n = 119; IdelaR [n = 82], BR [n = 37]). The PFS hazard ratio (HR) was 0.54 ([95% CI, 0.39 to 0.75]; P = .0002), with a median PFS of 14 months (95% CI, 11.2 to 16.6) in the pirtobrutinib group and 8.7 months (95% CI, 8.1 to 10.4) with IC. The unadjusted OS HR was 1.09 ([95% CI, 0.68 to 1.75]; P = .7202), and 18-month OS rate was 73.4% (95% CI, 63.9 to 80.7) in the pirtobrutinib group and 70.8% (95% CI, 60.9 to 78.7) with IC. Median TTNT was 24 months (95% CI, 17.8 to 29.7) with pirtobrutinib versus 10.9 months (95% CI, 8.7 to 12.5) with IC (HR, 0.37 [95% CI, 0.25 to 0.52]). At a median follow-up of 17.2 months, grade ≥3 treatment-emergent adverse events (AEs) were lower with pirtobrutinib (57.7%) than IC (73.4%). Treatment discontinuation due to AE occurred in 20 (17.2%) patients receiving pirtobrutinib and 38 (34.9%) patients receiving IC.

Conclusion: Pirtobrutinib improved PFS and TTNT, and demonstrated favorable tolerability, versus IdelaR/BR in exclusively cBTKi pretreated patients with CLL/SLL.

Trial registration: ClinicalTrials.gov NCT04666038.

FIG 1.

CONSORT diagram. Eligible patients receiving the investigator's choice could crossover to receive pirtobrutinib upon confirmation of PD by IRC per protocol. Visit cut: August 29, 2024. ^aThe remaining 17 patients discontinued treatment. ^bAmong patients whose event was investigator-assessed PD and thus had the opportunity to crossover. BR, bendamustine plus rituximab; IdelaR, idelalisib plus rituximab; IRC, independent review committee; PD, disease progression.

FIG 2.

Kaplan-Meier curve of PFS as assessed by (A) IRC and (B) investigator. *Nominal P value. BR, bendamustine plus rituximab; HR, hazard ratio; IdelaR, idelalisib plus rituximab; IRC, independent review committee; PFS, progression-free survival.

FIG 3.

Kaplan-Meier curve of (A) event-free survival and (B) overall survival. *Nominal P value. BR, bendamustine plus rituximab; HR, hazard ratio; IdelaR, idelalisib plus rituximab; NE, not estimable.

FIG 4.

Time to next treatment or death in the (A) ITT population, (B) venetoclax-naïve patients, and (C) venetoclax-treated patients. *Nominal P value. BR, bendamustine plus rituximab; HR, hazard ratio; IdelaR, idelalisib plus rituximab; ITT, intention-to-treat; NE, not estimable.

FIG A1.

Forest plot of IRC-assessed PFS across patient subgroups treated. ^aComplex karyotype (yes = ≥3 chromosomal abnormalities; no ≤3 chromosomal abnormalities). ^bHighly complex karyotype (yes = ≥5 chromosomal abnormalities; no = <5 chromosomal abnormalities). BR, bendamustine plus rituximab; cBTKi, covalent Bruton tyrosine kinase inhibitor; CLL, chronic lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group; IdelaR, idelalisib plus rituximab; IGHV, immunoglobulin heavy chain gene; IRC, independent review committee; IWRS, Interactive Web Response System; PD, progressive disease; PFS, progression-free survival; SLL, small lymphocytic lymphoma.

FIG A2.

Forest plot of TTNT across subgroups. ^a≥3 abnormalities in same clonal population. BCL2, B-cell lymphoma-2; BR, bendamustine plus rituximab; cBTKi, covalent Bruton tyrosine kinase inhibitor; CLL, chronic lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group; IdelaR, idelalisib plus rituximab; IGHV, immunoglobulin heavy chain gene; IWRS, Interactive Web Response System; NE, not estimable; PD, progressive disease; SLL, small lymphocytic lymphoma; TTNT, time to next treatment or death.