Paper Details

ABSTRACT

Background: Pirtobrutinib is a highly selective, non-covalent Bruton tyrosine kinase inhibitor (BTKi) approved for the treatment of patients (pts) with CLL after prior systemic therapy that includes a covalent (c)BTKi. In the BRUIN CLL-322 trial, pirtobrutinib combined with venetoclax-rituximab (PVR) significantly improved PFS compared with venetoclax-rituximab (VR) in pts with previously treated CLL/SLL, with comparable safety to VR alone (Davids et al, Lancet 2026). With the durability provided by modern targeted agents, many pts with CLL may require only 1-2 lines of therapy in their lifetime; thus, optimizing outcomes in the second-line setting is critical. Here, we describe outcomes in pts from BRUIN CLL-322 who had received only 1 prior line of therapy, a population representative of contemporary pts who have received prior targeted therapy and may be candidates for a time-limited regimen.  

Methods: The phase 3 BRUIN CLL-322 trial (NCT04965493) randomized pts 1:1 to PVR or VR. Pts were stratified by del(17p) status and prior cBTKi treatment. Pts with prior exposure to noncovalent BTKi or BCL2 inhibitor were excluded. The VR arm consisted of V (25 cycles [C]) and R (6C); the PVR arm also contained fixed-duration pirtobrutinib (28C), with a 3C pirtobrutinib-rituximab lead-in before venetoclax initiation. The primary endpoint was IRC-assessed PFS (iwCLL 2018). Secondary endpoints included investigator-assessed PFS, OS, TTNT, ORR and safety. MRD analyses (ClonoSEQ®) were exploratory. In this exploratory subgroup analysis, P-values <0.05 were considered statistically significant and not adjusted for multiplicity. 

Results: A total of 639 pts were randomized (PVR, n=321; VR, n=318). Of those, 278 pts (median age of 68 y [range 34 – 87]) had received only 1 prior line of therapy (PVR, n=135; VR, n=143), with 177 (63.7%) pts receiving prior cBTKi in the first line (64.4% ibrutinib; 23.7% acalabrutinib; 11.3% zanubrutinib), 45.0% with prior anti-CD20 antibodies, and 39.6% with prior chemotherapy, all were well balanced between arms. cBTKi was discontinued in 110 (62.1%) pts (PVR, n=56; VR, n=54) due to progressive disease. PVR demonstrated superiority in IRC-PFS vs VR in pts with one prior line of therapy (stratified HR, 0.466; 95% CI, 0.288-0.753; p=0.0014); median follow-up 35.8 months (95% CI, 27.79, 37.06). 24-m PFS was 86.8% with PVR vs 70.0% with VR. Investigator-assessed PFS was consistent with IRC-assessed results (stratified HR, 0.377; 95% CI, 0.225-0.632; p=0.0001). In IRC-PFS, PVR was superior to VR in pts whose one prior line of therapy was cBTKis (n=177, stratified HR = 0.356; 95% CI, 0.177-0.716; p=0.0023), and was consistent across agents. In the overall group with only 1 prior line of therapy, TTNT favored PVR (stratified HR, 0.390; 95% CI, 0.220-0.692; p=0.0008). OS HR numerically trended in favor of the PVR arm (stratified HR, 0.706; 95% CI, 0.336-1.482; p=0.3523), although data are immature. ORR (stratified p=0.52) was 90.4% with PVR (CR 30.4%; CRi 4.4%) vs 88.1% with VR (CR 21.7%; CRi 2.8%). Peripheral blood undetectable MRD4 rates at end of treatment in pts with evaluable samples were higher with PVR (47/52 [90.4%] vs 38/62 [61.3%]; p=0.0004). Rates of any grade adverse events (AEs) (PVR vs VR: 99.3% vs 100%) and grade ≥3 AEs (82.1% vs 73.8%) were similar between arms, including low rates of any grade atrial fibrillation/flutter (3.7% vs 2.8%) and hypertension (11.2% vs 6.4%). Grade ≥3 AEs of interest included neutropenia (55.2% vs 45.4% [febrile neutropenia 3.7% vs 4.3%]) and tumor lysis syndrome (0.7% vs 5.0%). Rates of any-grade infections were 76.1% vs 72.3%. Treatment regimen discontinuation rates due to AEs were 11.9% for PVR vs 14.2% for VR. 

Conclusion: Fixed-duration PVR demonstrated superior PFS over VR in the second-line setting in pts with CLL/SLL, including in those with prior cBTKi therapy, with deeper undetectable MRD and a 61% reduction in risk of next treatment or death, and a safety profile similar to that previously reported with pirtobrutinib monotherapy and VR. The results further support consideration of fixed-duration PVR as a new standard of care option for pts with CLL in the second-line setting.