Matthew S. Davids, MD, MMSc, discusses data from BRUIN CLL-322 that may shake up the CLL treatment paradigm.
“The biggest takeaway from BRUIN CLL-322 is that pirtobrutinib plus venetoclax and rituximab adds a significant benefit in terms of progression-free survival [PFS] compared [with] the standard of care, venetoclax plus rituximab,” Davids said in an interview with OncLive®. “[The pirtobrutinib combination] does so without much additional toxicity, and it's a really exciting result. We're looking forward to hopefully getting this [regimen] approved and being able to use this outside of clinical trials.”
Findings from the study’s interim analysis showed patients treated with pirtobrutinib plus venetoclax and rituximab (n = 321) achieved a median PFS that was not estimable (NE; 95% CI, 43.3-NE) compared with 39.7 months (95% CI, 35.9-NE) for those given venetoclax plus rituximab alone (n = 318; HR, 0.547; 95% CI, 0.400-0.748; P = .0001). The 24-month PFS rates were 86.9% (95% CI, 82.3%-90.4%) and 71.8% (95% CI, 65.7%-77.0%), respectively.
In the interview, Davids broke down the efficacy and safety data from BRUIN CLL-322, as well as the subsequent impact they are poised to make on the relapsed or refractory CLL treatment paradigm. Davids also discussed how noncovalent Bruton tyrosine kinase (BTK) inhibitors like pirtobrutinib may play a role in the frontline CLL setting in the future. Pirtobrutinib is
Davids is the Harold and Virginia Lash Endowed Chair in Lymphoma Research and chief of the Division of Lymphoma at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.
Davids: Pirtobrutinib is approved in the relapsed/refractory setting for CLL as a continuous therapy, and the data do suggest that it's very active in that setting and also well tolerated. Pirtobrutinib remains a great option for patients [in later lines of therapy]. However, as a field, CLL has really been moving more toward time-limited therapies. I'd say particularly in the frontline setting, where we have great data now combining BTK inhibitors with BCL2 inhibitors.
However, one of the main data gaps in the field has been in the relapsed/refractory setting. We have not yet had phase 3 data looking at a combination of a [noncovalent] BTK inhibitor with a BCL2 inhibitor, [but] we know that there's synergy between that type of combination approach, [which] was really the foundation of developing the BRUIN CLL-322 trial.
[BRUIN CLL-322] combined pirtobrutinib with venetoclax and rituximab to compare this regimen to the control arm of venetoclax plus rituximab. [The trial aimed] to help understand what the benefit would be of this triplet regimen and [determining] the incremental benefit of adding pirtobrutinib to standard venetoclax plus rituximab.
On this trial, patients had to have relapsed/refractory CLL that met the International Workshop on CLL [criteria] for treatment. Patients were excluded if they had prior BCL2 inhibitor–based therapy. An important inclusion criterion was that the study allowed patients who had [received] a prior covalent BTK inhibitor to come on study. In fact, most of the patients on the study had been exposed to a prior covalent BTK inhibitor and had either progressed on it, which was true for the majority, or had come off of the treatment due to intolerance, which was a smaller number [of patients].
[BRUIN CLL-322] had broad eligibility otherwise in terms of various genetic markers. The study also allowed patients [with disease harboring] TP53 aberrations, which is high-risk CLL, as well as those with mutated or unmutated IGHV and those with a complex karyotype, to enroll. Overall, [the participants are] a very representative population of the modern relapsed/refractory CLL [population].
At the 2026 EHA Congress, we presented the interim analysis of [BRUIN CLL-322], and this is the first time that we've presented data on this study. The primary end point of the study was independent review committee–assessed PFS. With relatively short follow-up at a median [of 27.3] months, we showed that pirtobrutinib plus venetoclax and rituximab was superior to venetoclax plus rituximab with respect to PFS.
The magnitude of the benefit was quite significant. The hazard ratio favoring the pirtobrutinib-based regimen was 0.54. In terms of the 24-month landmark PFS, it was [86.9%] with pirtobrutinib plus venetoclax and rituximab vs [71.8%] with venetoclax plus rituximab.
We had several preplanned subgroup analyses for BRUIN CLL-322, particularly looking at subgroups based on genetic markers, as well as based on prior therapies with respect to genetic markers. The group with TP53 aberrations [and/or 17p deletions], which comprised about 40% of the patient population, seemed to derive particular benefit from the pirtobrutinib-based regimen [HR, 0.372; 95% CI, 0.237-0.586].
Secondly, we looked at whether patients had prior exposure to a covalent BTK inhibitor, and both subgroups benefited from pirtobrutinib plus venetoclax and rituximab. However, again, the magnitude of the benefit was greater in patients with prior covalent BTK inhibitor exposure [HR, 0.509; 95% CI, 0.351-0.738] vs those with no prior exposure [HR, 0.662; 95% CI, 0.368-1.190]. [This benefit was observed] particularly in those patients who had progressed on a prior covalent BTK inhibitor [HR, 0.444; 95% CI, 0.293-0.673], even in the second-line population.
This is a question that comes up very frequently now in CLL practice: If you have a patient on a frontline covalent BTK inhibitor and they progress, what should you use in the second line? BRUIN CLL-322 is very reassuring that those patients did particularly well with the pirtobrutinib combination compared with the standard-of-care treatment of venetoclax plus rituximab.
One of the nice aspects of the monotherapy experience is that [pirtobrutinib] is an extremely well-tolerated drug, and although it has some of the same class effects as other BTK inhibitors, such as bleeding risks. Other risks, like atrial fibrillation, appear to be significantly less and possibly not even increased at all with pirtobrutinib. This is how the trial looked in terms of the safety profile of pirtobrutinib when combined with venetoclax and rituximab. For example, with atrial fibrillation, the rate was similar between the 2 arms; therefore, pirtobrutinib did not add any risk there. [Pirtobrutinib] did have a slightly higher risk of hypertension, but not a meaningful difference.
[Additionally, the pirtobrutinib regimen] did lead to slightly higher rates of infections, including grade 3 or higher infections—not so much COVID-19, but pneumonias and other infections. [Higher risk of infections] is something that we expect when we have 3 drugs together. However, the magnitude of that risk was very small [in BRUIN CLL-322]. Overall, [pirtobrutinib] did not add much in the way of toxicity, which is one of the really appealing aspects of rolling out this regimen. As you imagine in a population of patients with CLL with comorbidities and other medical issues, having a drug that adds very little toxicity but has a significant magnitude of efficacy benefit is a strength of the regimen.
The pirtobrutinib-based regimen in this trial is the experimental arm; it met the primary end point, and this trial was designed as a registrational study. We're hopeful that the BRUIN CLL-322 trial will lead to regulatory approval of pirtobrutinib plus venetoclax and rituximab for relapsed/refractory CLL. [This regimen] adds to the potential standard-of-care options for patients in that relapsed/refractory setting. For patients who are looking to really maximize their PFS without a lot of additional toxicity, [pirtobrutinib plus venetoclax and rituximab] is going to be a great option for them to consider. We have other options like BTK inhibitor monotherapy, like with pirtobrutinib in the post–covalent BTK inhibitor setting, and for some patients, that would also be a good option. [BRUIN CLL-322 would give us] flexibility to have different options, whether they are time-limited or continuous, for that relapsed/refractory population.
As we look to the future, pirtobrutinib is being explored in the frontline setting. We've already seen some early data from the phase 3 BRUIN CLL-314 [NCT05254743] and BRUIN CLL-313 [NCT05023980] trials that look good for pirtobrutinib. However, a challenge in the frontline setting is that we need longer-term follow-up, and we need efficacy data for covalent BTK inhibitors after noncovalent BTK inhibitors to really switch that paradigm. For now, pirtobrutinib will have its greatest role in the relapsed/refractory setting [for CLL]. As those frontline studies evolve, it's certainly possible that pirtobrutinib may move into the frontline even before covalent BTK inhibitors.
