Background
Phase 1/2, open-label, single-arm study (BRUIN). N=725 patients with B-cell malignancies who had progressed on or were intolerant of prior BTK inhibitor therapy; CLL/SLL cohort N=317 (BTKi-pretreated). Pirtobrutinib is a highly selective, non-covalent (reversible) BTK inhibitor retaining activity against C481S and other BTKi-resistance mutations. This is the foundational efficacy/safety trial. Primary results published NEJM 2023.
Interventions and follow up
Regimen: Pirtobrutinib 200 mg PO once daily continuously (non-covalent BTK inhibitor) in relapsed/refractory CLL/SLL
Primary endpoint: ORR (investigator-assessed per iwCLL 2018 criteria)
Median follow-up: 19.4 months (CLL/SLL cohort)
Primary endpoint: ORR (investigator-assessed per iwCLL 2018 criteria)
Median follow-up: 19.4 months (CLL/SLL cohort)
Results
ORR (CLL/SLL, BTKi-pretreated): 73.3%
CR/CRi: 2.5%
mDOR: 22.1 months
mPFS: 19.6 months
ORR (BTKi-intolerant CLL): 88%
ORR (venetoclax-pretreated CLL): 70%
ORR (MCL, BTKi-pretreated): 52%
CR/CRi: 2.5%
mDOR: 22.1 months
mPFS: 19.6 months
ORR (BTKi-intolerant CLL): 88%
ORR (venetoclax-pretreated CLL): 70%
ORR (MCL, BTKi-pretreated): 52%
Adverse events
Hematologic: Grade ≥3 neutropenia 30%; overall grade ≥3 AEs 54%
Cardiovascular: AFib any grade 2.5% (markedly lower than covalent BTKi), major hemorrhage 3.3%, hypertension any grade 13% (grade ≥3 4%)
Other: Fatigue any grade 22% (grade ≥3 2%); diarrhea any grade 17% (grade ≥3 1%)
Discontinuation due to AEs: 7%; no dose-limiting toxicity at 200 mg in phase 1
Cardiovascular: AFib any grade 2.5% (markedly lower than covalent BTKi), major hemorrhage 3.3%, hypertension any grade 13% (grade ≥3 4%)
Other: Fatigue any grade 22% (grade ≥3 2%); diarrhea any grade 17% (grade ≥3 1%)
Discontinuation due to AEs: 7%; no dose-limiting toxicity at 200 mg in phase 1
Conclusions
Pirtobrutinib achieved a 73% ORR in heavily pretreated BTKi-pretreated CLL/SLL, including patients with C481S BTK mutations, with a favorable safety profile — notably low AFib (2.5%) and low discontinuation (7%). These results established pirtobrutinib as the first non-covalent BTKi with proven efficacy in covalent BTKi-resistant CLL.
Key Limitations
Single-arm phase 1/2 design with no randomized comparator; ORR is the primary endpoint with limited PFS maturity (mPFS 19.6 months). Low CR/CRi rate (2.5%) and the heavily pretreated population mean responses are largely partial. Durability beyond 2 years and outcomes after pirtobrutinib progression are not defined. Definitive PFS benefit was subsequently established by the randomized BRUIN CLL-321. The heterogeneous histology cohort limits CLL-specific precision.
Clinical Context
BRUIN supported accelerated FDA approval of pirtobrutinib for relapsed/refractory mantle cell lymphoma (2023) and subsequently for CLL/SLL after prior covalent BTKi and a BCL2 inhibitor (2023), confirmed by the randomized BRUIN CLL-321. Pirtobrutinib is now standard for BTKi-pretreated R/R CLL. For triple-refractory disease, lisocabtagene maraleucel (TRANSCEND CLL 004) and clinical trials remain options. ESMO-MCBS: not assigned.