Pirtobrutinib

Indeed, the, uh, the update of the guidelines are typically driven by practical issues, and the issue this time was the recent approval of two different combination of regimens.

One is the combination of acalabrutinib plus venetoclax plus, minus obinutuzumab, and the other one is the, uh, in frontline treatment, and the other one is the approval of pirtobrutinib, a non-covalent BTK inhibitor, in the relapse refractory setting, in particular in post BTKi-treated patients.

Other reason is that really we wanted to change the entire setting of the, of the guidance, and in fact, we involved for the first time patients, patients' advocates, that are in- indeed listed among the authors and participated in the drafting and writing of the guidance, so really to give a patient-centric perspec- perspective of the new guideline.

So CLL is biologically very heterogeneous.

Yeah.

So, um, in the relapse setting, we have these different scenarios depending on the prior treatment, pre-exposures of the patients.

And patients being pre-exposed to covalent BTK inhibitors, there we differentiate if patients are progressing while being on the covalent BTK inhibitor, so becoming really refractory to these, um, agents, like the three different covalent BTK inhibitors which are approved, which means if you want to stay, uh, want to give an additional treatment, either you switch to venetoclax plus rituximab, or you switch to pirtobrutinib, first non-covalent BTK inhibitor approved in that indication.

In case patients stop the continuous c- covalent BTK inhibitor due to toxicities and may have some in-treatment free interval, for example, in this scenario, patients, uh, have a relapse again.

Uh, this is the preferred NCCN regimen for using Ven in that relapse setting, largely based on extrapolation from a frontline trial, the CLL thirteen trial that showed VenO is superior to VenRetux, albeit in the front- frontline setting.

So what do we know about other options? Well, there's actually a great wealth of data looking at Pirtobrutinib in that post-covalent BTKI setting, and so there's good rationale for this.

We know Pirtobrutinib is a non-covalent BTK inhibitor, and it doesn't directly interact with the C481 residue, so it can inhibit this important target, BTK, both in the setting of wild-type protein but also the most commonly acquired resistance mechanism, which is a C481S mutation.

And so it was first studied in the phase one-two Bruin trial that showed, uh, I would say excellent PFS in a very heavily pretreated population, about four prior lines of therapy.

And, uh, the drug tends to work a little longer if someone's naive to venetoclax, where the PFS is twenty-three months.

And infections can be reported, and it's always hard to know, is it the drug or is it the underlying patient population who are very immunosuppressed? This trial specifically with CLL patients with three median prior lines of therapy and exclusively, uh, treated with covalent BTK inhibitor at a minimum, but most patients had, you know, other things as well.

Uh, so yeah, I'm very excited, uh, to share these results [laughs] that, uh, Dr. David's very, uh, uh, beautifully presented at, uh, in Stockholm at EHA last, uh, June or in June, uh, Bruin CLL three two two trial.

So what this did is it compared standard of care VenR to the triplet regimen that includes Pirtobrutinib with VenR.

Now, what if we, uh, uh, we've l- seen some data from the AVO triplet thus far.

What if we, uh, instead, uh, study the non-covalent BTK inhibitor b- uh, uh, pirtobrutinib in combination with venetoclax obinutuzumab in the frontline setting? This is a study that's been led, uh, here at the MD Anderson, and 80 patients were enrolled in this study.

This is an appealing strategy given the potential to incorporate pirtobrutinib into an earlier line of therapy as a time-limited option to potentially overcome some concerns about sequencing this prior to a covalent inhibitor.

In this study, uh, at the end of, uh, cycle, uh, 13 or one year of treatment, the UMRD4 and UMRD6 rates in the blood were 100% and 86% respectively.

And in the bone marrow were 96% and 74% respectively.

They did see relatively high rates of grades III, IV, uh, cytopenias, including neutropenia in 67% of patients.

Uh, although this translated only to relatively few incidents of neutropenic fever, just 5% of patients.

And they did observe, uh, a, a fair bit of dose reductions of the venetoclax and pirtobrutinib, but overall, patients were able to, to remain on therapy and tolerated treatment quite well.