First phase III results show PFS benefit with pirtobrutinib vs BR in treatment-naïve CLL/SLL

Single-agent pirtobrutinib significantly improved progression-free survival (PFS) vs bendamustine plus rituximab (BR) for patients with treatment-naïve chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), according to the first results from the phase III BRUIN CLL-313 trial.

Pirtobrutinib is a third-generation, highly selective, noncovalent Bruton’s tyrosine kinase inhibitor (BTKi) that has demonstrated safety and efficacy in relapsed/refractory CLL/SLL. “Selectivity is important, as off-target inhibition of other kinases … may be responsible for more pronounced adverse events [AEs],” said presenter Dr Wojciech Jurczak of Maria Skłodowska-Curie National Research Institute of Oncology in Krakow, Poland. [ASH 2025, abstract LBA25-141]

In addition, unlike the currently approved covalent BTKis, such as ibrutinib, acalabrutinib and zanubrutinib that irreversibly bind to the C481 residue of BTK, pirtobrutinib’s noncovalent binding enables it to maintain efficacy even in the presence of C481S mutations, which are the most common form of acquired resistance. [Future Oncol 2025;21:3435-3445]

In BRUIN-313, 282 patients with previously untreated CLL/SLL were randomized 1:1 to receive oral pirtobrutinib monotherapy (200 mg QD) or six cycles of BR. Patients with del(17p), known CLL/SLL central nervous system involvement, Richter transformation, or significant cardiovascular disease were excluded. Crossover after BR failure was allowed, and 52.9 percent of BR-treated patients subsequently received pirtobrutinib.

At a median follow-up of 28.1 months, the primary endpoint of independent review committee (IRC)–assessed median PFS was significantly improved with pirtobrutinib vs BR (hazard ratio [HR], 0.199; 95 percent confidence interval [CI], 0.107–0.367; p<0.0001). The 24-month PFS rate was 93.4 percent for pirtobrutinib and 70.7 percent for BR.

Pirtobrutinib’s PFS benefit was consistently observed among prespecified, clinically relevant patient subgroups, including those with mutated IGHV (n=61 in pirtobrutinib arm; HR, 0.293; 95 percent CI, 0.094–0.910) and unmutated IGHV (n=80 in pirtobrutinib arm; HR, 0.172; 95 percent CI, 0.083–0.357) and those aged <75 years (n=121 in pirtobrutinib  arm; HR, 0.183; 95 percent CI, 0.094–0.356) and ≥75 years at enrolment (n=20 in pirtobrutinib  arm; HR, 0.338; 95 percent CI, 0.068–1.690)

Jurczak also highlighted the consistent PFS benefit in patients with or without TP53 mutations and those with or without a complex karyotype. “We analyzed all of these subgroups and couldn’t find a weak point,” he said.

Despite the short observation time, a trend towards an overall survival (OS) superiority was observed for pirtobrutinib vs BR (HR, 0.257; 95 percent CI, 0.070–0.934; p=0.0261). “At 24 months, 97.8 vs 93.0 percent of patients were alive in the pirtobrutinib vs BR arm,” reported Jurczak.

The incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was 40.0 percent with pirtobrutinib and 67.4 percent with BR. Discontinuation of pirtobrutinib and BR due to TEAEs occurred in 4.3 vs 15.2 percent of patients, while AE-related dose reductions occurred in 3.6 vs 31.1 percent of patients.

Jurczak remarked that the safety data should be interpreted in the context of the median treatment duration, which was 32.3 months for patients receiving pirtobrutinib and 5.6 months for patients on BR, as pirtobrutinib was given until progression, while BR was a fixed-duration regimen. “Whether looking at crude or time-adjusted data, whichever way you analyze – pirtobrutinib is better,” he summarized.

Taken together, BRUIN CLL-313 data suggest that pirtobrutinib may be considered a potential new standard of care for patients with untreated CLL/SLL, especially older patients who may receive only one line of therapy.