Pirtobrutinib Continues to Show Safety, Activity in Covalent BTK Inhibitor–Pretreated R/R MCL

Jonathon B. Cohen, MD, MS

Longer follow-up of the phase 1/2 BRUIN study (NCT03740529) continues to demonstrate the tolerability and durability of responses achieved with pirtobrutinib (Jaypirca) in patients with mantle cell lymphoma (MCL) who progressed on prior covalent BTK inhibitors, confirming the agent’s viability and supporting its approval for a patient subgroup with historically poor outcomes, according to Jonathon B. Cohen, MD, MS.

Primary findings from BRUIN supported the January 2023 FDA approval of pirtobrutinib for the treatment of adult patients with relapsed or refractory MCL following at least 2 lines of systemic therapy, including a BTK inhibitor.¹

In a presentation during the 2023 ASH Annual Meeting, pirtobrutinib elicited an overall response rate (ORR) of 49.3% (95% CI, 41.1%-57.6%) in covalent BTK–exposed patients with MCL (n = 152), with a median time to first response of 1.8 months (range, 0.8-13.8).² At a median follow-up of 14.7 months, the median duration of response (DOR) was 21.6 months (95% CI, 9.2-27.2). The median progression-free survival (PFS) was 5.6 months (95% CI, 5.3-9.2) at a median follow-up of 15.9 months, and the median overall survival (OS) was 23.5 months (95% CI, 17.1-not evaluable) at a median follow-up of 24.2 months.

The clinical benefit of pirtobrutinib is under further evaluation in comparison with investigator’s choice of covalent BTK inhibitor in patients with BTK-naive relapsed MCL as part of the ongoing, confirmatory phase 3 BRUIN MCL-321 (NCT04662255) trial.

“The prognosis [for BTK inhibitor–pretreated patients in MCL] has unfortunately been quite poor in the past,” said Cohen, who is codirector of the Lymphoma Program and chair of the Data and Safety Monitoring Committee at Winship Cancer Institute of Emory University, as well as an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, in Atlanta, Georgia. “With pirtobrutinib being approved, we have an option [for this subgroup] that’s less intensive than CAR T-cell therapy.”

In an interview with OncLive^®, Cohen expanded on updated efficacy findings from the BRUIN trial, discussed how pirtobrutinib addresses the need for less toxic but highly efficacious therapies to improve outcomes in relapsed BTK-exposed MCL, and spotlighted ongoing efforts dedicated to shedding light on where the agent fits in terms of sequencing.

OncLive: Could you provide some context on the current unmet needs in treating patients with relapsed/refractory MCL?

Cohen: MCL is a fairly uncommon form of non-Hodgkin lymphoma but has been associated in the past with a very aggressive disease course. Although we’ve made a lot of progress in the field, OS has unfortunately been quite poor for those patients who do progress after a covalent BTK inhibitor. In the current era, there’s a lot of work being done to try to improve outcomes for patients with relapsed MCL, including new oral therapies as well as CAR T-cell therapies and other immunotherapies.

Please provide a brief overview of the BRUIN study, including its design and primary objective.

The phase 1/2 BRUIN study [evaluated] the noncovalent BTK inhibitor pirtobrutinib in a variety of B-cell malignancies. The 2 most common malignancies that were enrolled were chronic lymphocytic leukemia and MCL. The initial goal of this study was to identify the most appropriate dose to move forward to the phase 2 setting. The larger, phase 2 portion of the study was designed to assess the efficacy of this therapy, especially in patients who had previously received a covalent BTK inhibitor.

What were the inclusion criteria for patients enrolled in the MCL cohort?

Patients could be selected for inclusion if they had relapsed or refractory MCL. The overwhelming majority of patients had received a prior BTK inhibitor, [although] a small number were BTK naive. Patients had to have a reasonable performance status and otherwise had to have relatively stable blood counts. The purpose of the study was to be available to as many patients as possible. As opposed to some of the other therapies that are more intensive, the inclusion criteria weren’t quite as stringent with this [effort].

What key efficacy findings from this study were presented at the 2023 ASH Annual Meeting?

We reviewed the updated data for patients with relapsed MCL. This included additional follow-up, as well as additional patients who had been accrued to the study since [data were] presented at the 2022 [ASH Annual Meeting]. We saw that even with some high-risk subgroups present in our cohort, the ORR is still 49.3% and the DOR is between 21 to 22 months. That is exciting—especially when we think about this patient population as being one that historically had a median OS of less than a year. For those patients who do respond to this therapy, responses appear to be quite durable.

Were any new safety signals observed?

We did have an opportunity to look at the safety profile with the additional patients and follow-up. We didn’t see any signals that were unexpected or that have changed significantly since the prior reporting. We do see some patients who experience fatigue or cytopenias. As with all BTK inhibitors, we also must think about bleeding risk and cardiac complications. Fortunately, the risk of atrial fibrillation was very low in this cohort of patients, and the risk of grade 3 or greater atrial fibrillation or flutter was particularly low; this is encouraging.

What is the role of pirtobrutinib in the MCL armamentarium? Where does it fit in among other available treatments for patients who progressed on prior BTK therapy?

For patients who have previously received a covalent BTK inhibitor, outcomes have historically been quite poor. In the current era, we often [consider administering] pirtobrutinib, which is now approved for patients who have progressed after a covalent BTK inhibitor or who have come off treatment due to intolerance. We also consider CD19-directed CAR T-cell therapy. Brexucabtagene autoleucel [brexu-cel; Tecartus] was associated with a high ORR and a very durable response for those patients who achieve a complete response; [however,] that therapy is somewhat intense and can’t be offered to everyone. When we think about a patient with relapsed MCL, especially one who is no longer able to receive a covalent BTK inhibitor, it comes down to how that patient is doing and what some of their comorbidities might be.

How are you hoping to build off this research through continued investigation?

There’s a lot of interest in trying to identify whether pirtobrutinib may have a role in the earlier management of MCL. We know that it’s well tolerated and active in patients who are pretreated with covalent BTK inhibitors. At this year’s meeting, we updated the data for the BTK-naive patients, and those data are also encouraging. There’s a large phase 3 trial being done to [determine] whether a noncovalent BTK inhibitor like pirtobrutinib may be preferred over a covalent BTK inhibitor for those BTK-naive patients. That will likely be one of the next big steps in the evaluation of this therapy and determination of where it may belong in the overall treatment landscape for MCL.

What other studies at the meeting were you particularly excited to see presented?

There are several exciting therapies in development for MCL, including bispecific antibodies. At last year’s ASH Annual Meeting, we heard about the activity with the bispecific antibody glofitamab-gxbm [Columvi]. At this year’s meeting, we also saw updates from a study of mosunetuzumab-axgb [Lunsumio] with polatuzumab vedotin-piiq [Polivy], which also incorporates a bispecific antibody. [The regimen] demonstrated excellent responses and what appear to be nice response durations. The role of bispecific antibodies has yet to be fully defined in MCL, but it’s one area I’m particularly excited about.

References

1. Cohen JB, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed/refractory (R/R) mantle cell lymphoma (MCL) patients with prior cBTKi: safety and efficacy including high-risk subgroup analyses from the phase 1/2 BRUIN study. Blood. 2023;142(suppl 1):981. doi:10.1182/blood-2023-181627
2. US FDA approves Jaypirca (pirtobrutinib), the first and only non-covalent (reversible) BTK inhibitor, for adult patients with relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a BTK inhibitor. News release. Loxo@Lilly. January 27, 2023. Accessed January 23, 2024. https://investor.lilly.com/news-releases/news-release-details/us-fda-approves-jaypircatm-pirtobrutinib-first-and-only-non