A study published in Blood suggests that combining the noncovalent BTK inhibitor (BTKi) pirtobrutinib in a time-limited fashion with venetoclax, or with both venetoclax and rituximab, produces high rates of response in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL).
The findings — which come from a substudy that was part of the pivotal BRUIN trial of pirtobrutinib — provide a small but fresh look at pirtobrutinib as part of a doublet or triplet in patients treated with drugs more representative of today’s regimens, said lead author Lindsey Roeker, MD, of Memorial Sloan Kettering Cancer Center in New York.
“This is a unique study in that it specifically included patients who had prior exposure to novel agents and shows the efficacy of a time-limited regimen using a noncovalent BTKi,” Dr. Roeker said. “So, there’s rationale for using this combination for any patient who has been exposed to a prior novel agent, but there should also be efficacy in people who have progressed on a covalent BTKi because of the activity of noncovalent BTKis in that setting.”
Researchers evaluated 25 patients with R/R CLL. In the study, 15 patients were treated with pirtobrutinib and venetoclax (PV) and 10 with pirtobrutinib, venetoclax, and rituximab (PVR). Sixty-eight percent of patients had been previously treated with a covalent BTKi. Even in the setting of resistance to covalent BTKis, pirtobrutinib has demonstrated efficacy. While covalent BTKis act on a specific binding site in BTK, noncovalent BTKis can inhibit BTK even in the setting of certain BTK resistance mutations.
Patients were treated for 25 cycles of pirtobrutinib, with some patients still on treatment at the time of data cutoff and a median time on treatment of 23 months.
The overall response rate was 93.3% (95% CI 68.1-99.8) for the PV group and 100% (95% CI 69.2-100.0) for the PVR group, with complete response (CR) rates of 46.7% (95% CI 21.3-73.4) and 30.0% (95% CI 6.7-61.3) for PV and PVR groups, respectively. Among the patients who had received a prior BTKi, eight achieved CR, and nine achieved partial response. The progression-free survival (PFS) estimate at 24 months was 79.6% (95% CI 37.1-94.9) for the PV group. This was not yet evaluable in the PVR group, but researchers reported an 18-month PFS estimate of 80.0% (95% CI 40.9-94.6).
The rate of undetectable measurable residual disease was 85.7% (95% CI 57.2-98.2) within the PV group and 90.0% (95% CI 55.5-99.7) within the PVR group.
Treatment-related neutropenia led to dose interruptions in five patients receiving PV and two receiving PVR. There were two treatment-related discontinuations in the PVR group and none in the PV group. Other than neutropenia, treatment-related adverse events of grade 3 or higher were uncommon.
Dr. Roeker said the study was not designed to assess the difference between the doublet and triplet regimens, but the findings showed that both seem to work well.
“The take-home message is that both regimens are incredibly effective,” she said.
The patients have had nearly two years of follow-up, but the duration of responses will continue to be assessed, she said.
Limiting the duration of treatment is expected to reduce the risk of developing resistance to the drugs so that patients who have tried these combinations and stopped can begin using them again if their disease recurs, Dr. Roeker said.
“When we induce these deep responses, we think that patients can safely have treatment-free intervals and that continued therapy may not be adding benefit,” she said. “We know that continued exposure may allow for development of resistance, so by limiting the duration of exposure, re-treatment down the line might be feasible.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Roeker LE, Woyach JA, Cheah CY, et al. Fixed-duration pirtobrutinib plus venetoclax with or without rituximab in relapsed/refractory CLL: phase 1b BRUIN Trial. Blood. 2024;144(13):1374-1386.
