Pirtobrutinib’s Approval Addresses Unmet Need in MCL Treatment Paradigm

The noncovalent BTK inhibitor pirtobrutinib (Jaypirca) offers patients with mantle cell lymphoma (MCL) an alternative treatment to overcome resistance to standard therapy, according to Michael L. Wang, MD. On January 27, 2023, the FDA granted accelerated approval to the agent for patients with MCL after at least 2 lines of prior therapy including a BTK inhibitor, based on data from the phase 1/2 BRUIN trial (NCT03740529).¹

Among 120 patients previously treated with a covalent BTK inhibitor the overall response rate (ORR) was 50% (95% CI, 41%-59%), with 13% of responders having a complete response. The median duration of response was 8.3 months (95% CI, 5.7-not estimable).²

“[Pirtobrutinib will] have unlimited usage in the current treatment paradigm,” Wang said. “We can use it to overcome [resistance to] BTK inhibitors, we can use it before chimeric antigen receptor [CAR] T cells, in combination with CAR T cells, and after CAR T cells. It’s going to be a big change in the paradigm of [MCL] therapy.”

In an interview with OncLive^®, Wang, a professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston, discussed the efficacy of the noncovalent BTK inhibitor, as well as safety data from the BRUIN trial.

OncLive^®: Please describe the significance of the approval for MCL.

Wang: BTK inhibitors have revolutionized therapy for B-cell malignancies. So far, the 3 FDA approved BTK inhibitors are covalent, nonreversible BTK inhibitors including the first-generation ibrutinib [Imbruvica], and the second generation [agents] acalabrutinib [Calquence] and zanubrutinib [Brukinsa]. Those drugs bind to the same epitope of the ADP binding site in the BTK protein, binding to the same pocket containing C481. If C481 is mutated, [that] 1 mutation [after] 1 therapy would render cross-resistance to the other 2 BTK inhibitors.

If the BTK inhibitor becomes ineffective we will change to another kind of therapy, and oftentimes that means CAR T-cell therapy, and bispecific antibody therapies, or other T-cell engager therapies. But those are invariably associated with cytokine release syndrome [CRS] and neurotoxicity.

Ideally, we would have a [drug] like acalabrutinib, ibrutinib, and zanubrutinib that would overcome this resistance. Therefore, the third-generation BTK inhibitor is born and this BTK inhibitor is the first-in-class pirtobrutinib. The characteristic of this drug is that it binds to the BTK protein, in a reversible noncovalent manner, so there’s constant binding [and] rebinding. When you use a covalent BTK inhibitor it binds to a target and it does not let it go, so when a new target is synthesized by the body it will bypass the covalently bound BTK inhibitors. With the reversable BTK inhibitor its constantly binding and rebinding in equilibrium, so there’s a constant binding even with the newly produced BTK proteins.

Reversible BTK inhibitors such as pirtobrutinib, not only bind to new proteins, but also bind to the ATP site independent of C481. So, even [when] C481 is mutated [and] it’s no longer responsive to the covalent BTK inhibitors, pirtobrutinib can still exert its effect. In other words, if the covalent BTK inhibitors stopped working, we can still use the pirtobrutinib to rescue it. This is a significant [approval] for our patients and their families. It is so far very effective.

In a clinical trial called the BRUIN study, in the MCL cohort, those [patients] who received prior covalent BTK inhibitors achieved a response rate of 51% and for those who never used a prior BTK inhibitor the response rate was 82%.

What were the top safety takeaways from the BRUIN trial?

In terms of toxicity, BRUIN is a first-in-human study with pirtobrutinib, [and] in 618 patients no dose-limiting toxicities were reported, therefore [the] maximum-tolerated dose was not reached. Ninety-six patients received pirtobrutinib at a dose of 200 mg orally daily, a dose that we chose to move [forward] with in other studies. Only 1% of patients permanently discontinued the drug due to treatment-related [adverse effects and] 1% is a remarkably small number for such a big number of patients.

Of particular note, the atrial fibrillation rate with the first-generation covalent BTK inhibitor is approximately 6% to 11% and in the second-generation covalent BTK inhibitors is approximately 3% to 5%. However, in the 618 patients in this study the atrial fibrillation rate was only 2%. This is a very low atrial fibrillation rate and please remember our study entry age was 70 [years]. In the general population in the United States without a history of cancer the baseline atrial fibrillation rate is approximately 3% to 4%. With a limited follow-up for 600 patients, the atrial fibrillation rate is promisingly low.

What unmet needs remain in MCL and how might they be addressed going forward?

All BTK inhibitors plus other targeted agents such as bortezomib [Velcade], lenalidomide [Revlimid], and venetoclax [Venclexta] share 1 good aspect: They can reduce big tumors to be very small. [There are] big reductions in the tumor mass; however, they’re universally not curable because they only attack 1 link in 1 pathway and the proteins can mutate and other pathways can easily bypass them to continue to activate the MCL growth.

[So,] then what are we going to do? We’re using CAR T cells, immunotherapies, such as [bispecific T-cell engagers] BiTEs, bispecific antibodies, [natural killer] NK T cells, etc. There are limitations and such, but we already have many therapies that could overcome this limitation.

Is there any ongoing or upcoming research in MCL at MD Anderson that you’re excited about?

At MD Anderson we are testing new bispecific antibodies such as mosunetuzumab-axgb [Lunsumi] and we’re also testing new CAR T-cell therapies such as CD19 × CD20 dual CAR T cells, CAR ROR1-CAR T cells, and other CAR T-cell therapies, and immunotherapies. MD Anderson has a great program for MCL, we call it the Mantle Cell Lymphoma Program of Excellence. I welcome all the patients and families who look us up on the internet to come to us [because] we’ll help you.

References

1. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. News release. FDA. January 27, 2023. Accessed January 30, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
2. Jaypirca. Prescribing information. Eli Lilly and Company; 2023. Accessed January 30, 2023. https://www.accessdata.fda.gov/