Longer Follow-Up BRUIN Data Continues to Support Pirtobrutinib in MCL


In an interview with Targeted Oncology, Nirav Shah, MD, discussed long-term follow-up results from the phase 1/2 BRUIN study and how the approval of pirtobrutinib has changed the MCL treatment landscape.

Nirav Shah, MD

Nirav Shah, MD

Treatment with pirtobrutinib (Jemperli) maintains durable efficacy and a favorable safety profile in heavily pre-treated patients with relapsed/refractory mantle cell lymphoma (MCL) who received prior therapy with a covalent Bruton’s tyrosine kinase (BTK) inhibitor, according to longer follow-up from the phase 1/2 BRUIN trial (NCT03740529).1

In January 2023, the FDA has granted approval to pirtobrutinib for the treatment of adult patients with relapsed/refractory MCL who previously received at least 2 lines of systemic therapy, including a BTK inhibitor, based on data from the phase 1/2 BRUIN study.

According to results from a subgroup analysis with >3 years follow-up from the time of the start of enrollment, the overall response rate (ORR) among patients with MCL who had received prior therapy with a BTK inhibitor was 57% (95% CI, 46-67), including 19% complete responses (n = 17) and 38% partial responses (n = 34). The median duration of response (DOR) at a median follow-up of 13 months was 17.6 months (95% CI, 7.3-27.2) among the 51 patients who responded, and the 12- and 18-month estimated DOR rates were 58% (95% CI, 41-72) and 45% (95% CI, 27-61), respectively.

The median progression-free survival among patients was 7.4 months (95% CI, 5.3-13.3), and the median overall survival was 23.5 months (95% CI, 15.9-not evaluable).

A total of 166 were in the MCL safety cohort with the most frequent treatment-emergent adverse events (TEAE) observed being fatigue (31%), diarrhea (22%), and anemia (17%). Neutropenia was the most common grade ≥3 TEAE (15%) seen among these patients.

“This is the first BTK inhibitor to have robust data that shows its efficacy after prior BTK inhibitor use,” Nirav Shah, MD, told Targeted OncologyTM, in an interview.

In the interview, Shah, associate professor at the Medical College of Wisconsin, discussed long-term follow-up results from the phase 1/2 BRUIN study and how the approval of pirtobrutinib has changed the MCL treatment landscape.

Targeted Oncology: Can you discuss the mechanism of action of pirtobrutinib?

Shah: Pirtobrutinib is sort of a first of its kind BTK inhibitor. It's a noncovalent or reversible BTK inhibitor, and that makes it distinct from the BTK inhibitors that are currently FDA-approved in mantle cell lymphoma and CLL, which are sort of irreversible inhibitors. By having this different mechanism of action, the thought is that this drug could work, even when other BTK inhibitors have failed.

Can you discuss the FDA approval of pirtobrutinib in the relapsed/refractory MCL space?

Pirtobrutinib was FDA-approved for relapsed/refractory mantle cell lymphoma after covalent BTK inhibitors based on the BRUIN study. This study had a cohort, which is now published in the Journal of Clinical Oncology that has the final dataset of about 90 patients that had prior BTK exposure.

What we showed in [the BRUIN] clinical trial was not only that the drug was efficacious, but it was safe. That's difficult to say for a lot of drugs that are being developed. The safety profile of this drug seems to be best in class. We didn't see a lot of the traditional BTK inhibitor toxicities, meaning very low rates of hypertension, atrial fibrillation, although we probably need 2-,3-, or, 4-year data to make sure those things don't develop over a prolonged period. This was sort of a slam dunk approval. The drug has efficacy, it's relatively safe, and well-tolerated, and it was an unmet patient need. For those reasons, we thought that approval would come through.

How does pirtobrutinib differ from other BTK inhibitors?

This is the first BTK inhibitor to have robust data that shows its efficacy after prior BTK inhibitor use. The study that I [presented] at ASCO was part of the BRUIN study looking at long-term data of patients with mantle cell lymphoma. Looking at those patients who got pirtobrutinib, the majority of patients on this study had prior BTK exposure, and the agent either came off of a covalent BTK inhibitor due to either toxicity, meaning they couldn't tolerate the drug, but for the most of them, it was due to progression. Despite that, pritobrutinib had an overall response rate of 58% in this difficult-to-treat group of patients, which shows for the first time that if you use a different BTK inhibitor with a different mechanism of action, you can overcome resistance that may occur with the current class of BTK inhibitors available.

Can you discuss some of the data you presented at ASCO 2023 regarding this study?

I presented the longer-term MCL outcome data, which shows the median duration of response at 2-3 years of follow-up was a year and a half, which shows that if you are a responder to the drug that there is durability. That's important [because you] can't just take a pill and say it worked for 2 or 3 months. With longer follow-up, we're seeing that there are some patients that do get those durable responses, even in a refractory state.

Now, I think a study that's going to be very interesting that we're participating in is the BRUIN-MCL study [NCT04662255], which is a head-to-head study of pirtobrutinib against covalent BTK inhibitors. If this drug works well, even after other BTK, maybe it's better BTK. That study is going to help us delineate that and if it is a positive study and pirtobrutinib shows better outcomes, we should be using it earlier in lines of therapy rather than saving it as our last option.

How else has the treatment landscape for MCL changed over the past few years?

MCL is an interesting disease. There are patients who have very long remissions, but eventually they relapse. The unmet need in mantle cell is really for patients after they get a BTK inhibitor where options are limited. Now, pirtobrutinib is FDA-approved in that space. I think it gives us a viable option.

The other option in this group of patients is CAR [chimeric antigen receptor] T-cell therapy, which is also an incredibly effective therapy for relapsed/refractory mantle cell lymphoma, but mantle cell is a disease that disproportionately affects older people and not everybody is a candidate for CAR T, has access to CAR T, or wants to go through an intensive treatment like CAR T. I think it's great that we now have an oral, well-tolerated option that people can take at home that has shown efficacy, even in that difficult-to-treat patient population.

Are there any other studies that have piqued your interest?

I've been focusing on hematological malignancies. I think there's some exciting data coming out. I think the plenary session in Hodgkin is compelling. We're talking about a disease that for 20 years, the standard of care was a DVd [daratumumab, bortezomib, and dexamethasone] And then it became ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine]. Now, there's data that maybe nivolumab [Ipilimumab] can be added, so that's compelling and practice changing data.

The overall survival benefit of CAR T in the second-line is sort of a late breaking abstract, and again, to say that a cell therapy has a survival benefit over stem cell transplant is data that I'm looking forward to seeing and hearing, along with the data on cilta-cel [ciltacabtagene autoleucel; Carvykti] in the second-line setting. There's some powerful data coming out that's going to change the way that we practice and show remarkable improvement in patient care.

Wang ML, Jurczak W, Zinzani PL, et al. Pirtobrutinib in covalent bruton tyrosine kinase inhibitor pretreated mantle-cell lymphoma. J Clin Oncol. 2023;41(24):3988-3997. doi:10.1200/JCO.23.00562
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