Pirtobrutinib Demonstrates Durable Efficacy in Pretreated Mantle Cell Lymphoma

Nirav Shah, MD

The novel, noncovalent, highly selective reversible BTK inhibitor, pirtobrutinib (Jaypirca), continued to elicit responses in patients previously treated with a covalent BTK inhibitor for relapsed/refractory mantle cell lymphoma (MCL), according to the updated results from the phase 1/2 BRUIN study (NCT03740529) presented at the 2023 ASCO Annual Meeting.¹

In the cohort of 90 patients, pirtobrutinib elicited in an overall response rate (ORR) of 56.7% (95% CI, 45.8%-67.1%), with complete responses observed in 18.9% of patients and partial responses in 37.8%. At a median follow-up of 12.7 months, the median duration of response was 17.6 months (95% CI, 7.3-27.2).

At a median follow-up of 13.8 months, the median progression-free survival (PFS) with pirtobrutinib was 7.4 months (95% CI, 5.3-13.3), and at a median follow-up of 23.5 months, the median overall survival (OS) was 23.5 months (95% CI, 15.9-not evaluable).

Now, the global, open-label phase 3 BRUIN MCL-321 study (NCT04662255) will compare the safety and efficacy of pirtobrutinib with investigator’s choice of ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa) in patients with MCL who have previously received at least 1 line of therapy as well as those who are naïve to BTK inhibition.²

“I look forward to hopefully sharing those results in a couple of years because, as you know, trials take time, but I think that will help answer a question of whether this mechanism of inhibiting BTK superior to the current methodologies that we have,” explained Nirav Shah, MD, who is an assistant professor of medicine in the Division of Hematology and Oncology, at the Medical College of Wisconsin, in Milwaukee, Wisconsin.

In an interview with OncLive^®, Shah, discussed the efficacy of pirtobrutinib in patients with MCL who were previously treated with a covalent BTK inhibitor and progressed, and next steps for exploration of the noncovalent BTK inhibitor in this population.

OncLive: What data have previously been reported from the BRUIN trial?

Shah: The BRUIN study was a very large phase 1/2 clinical trial evaluating a new type of BTK inhibitor [that is] noncovalent [and] reversible. This [agent] has a different mechanism than the covalent BTK inhibitors that are widely established in practice.

This drug, pirtobrutinib, was tested in patients with B-cell malignancies. However, what was unique about this trial is that it allowed those who had prior BTK exposure to enroll.

The data that were presented focused on the specific subgroup of patients with MCL, with the focus on those who had prior BTK exposure and came off either due to intolerance, or more commonly, progression.

What updated efficacy findings were presented at the 2023 ASCO Annual Meeting?

We now have a longer survival follow-up of about 2 to 3 years. With these data, the overall response rate, which was previously reported, was 58%. However, we now have survival data. The median OS was 22 months. When thinking about the patient population, that had progressed on] a prior BTK inhibitor, this really represents a stark improvement in survival.

In addition, what also matters is not just being alive, but how long the drug works. Among those patients who are responders, the median duration of response was nearly a year and a half, and that demonstrates that this drug does have some ability to maintain a response for a period of time.

We also now have more safety data that have matured over a longer period. It continues to be in line with [what was] previously reported, [in that is has] a very favorable safety profile, with low rates of grade 3/4 adverse effects [AEs], as well as low rates of the traditional BTK inhibitor–associated AEs, such as atrial fibrillation, cardiotoxicity, high blood pressure, and bleeding.

How did pirtobrutinib perform in patients with different MCL histologies?

The interesting thing about the drugis that regardless of the variable that you looked at, pirtobrutinibshowed equivalent efficacy among all the different subgroup analyses. Regardless of p53 mutation or elevated Ki67, we saw responses in all these subgroups, and didn’t find a particular pattern of patients that this drug did not work well in.

What are some of the next steps for this research with pirtobrutinib?

These data led to the FDA approval of pirtobrutinibfor MCL, after treatment with a covalent BTK inhibitor, whether that be [due to] progression or toxicity. The next step is to try to move this up to the next line of therapy. This is an ongoing trial that our institution is participating in, called the BRUIN MCL-321 study. This is a second-line study comparing pirtobrutinib, which we know works even after covalent BTK inhibitors, head-to-head against dealer’s choice of an alternative BTK inhibitor from the covalent class in MCL.

References

1. Shah NN, Jurczak W, Zinzani PL, et al. Pirtobrutinib in covalent BTK-inhibitor (cBTKi) pre-treated mantle cell lymphoma (MCL): updated results and subgroup analysis from the phase 1/2 BRUIN study with >3 years follow-up from start of enrollment. J Clin Oncol. 2023;41(suppl 16):7514. doi:10.1200/JCO.2023.41.16_suppl.7514.
2. Study of BTK Inhibitor LOXO-305 versus approved BTK Inhibitor drugs in patients with mantle cell lymphoma (MCL) (BRUIN-MCL-321). ClinicalTrials.gov. July 11, 2023. Accessed August 2, 2023. https://clinicaltrials.gov/study/NCT04662255