Pirtobrutinib Transforms SOC in Later-Line CLL/SLL

The continued emergence of data for pirtobrutinib (Jaypirca) has demonstrated the viability of the noncovalent BTK inhibitor for the later-line treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, according to Jean L. Koff, MD, MS.

In December 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with CLL or SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.¹ Updated findings from the phase 1/2 BRUIN trial (NCT03740529)—which supported this regulatory decision—presented at the 2023 ASH Annual Meeting showed that patients with CLL/SLL (n = 282) experienced an overall response rate (ORR) of 81.6% (95% CI, 76.5%-85.9%). Notably, patients who were naive to a BCL2 inhibitor (n = 154) achieved an ORR of 83.1% (95% CI, 76.2%-88.7%).²

“As we've seen across the board for pirtobrutinib, it tends to be very well tolerated with encouragingly low discontinuation rates due to drug-related toxicities,” Koff explained.

In an interview with OncLive®, Koff discussed the implications of the BRUIN trial that supported the FDA approval of pirtobrutinib for patients with CLL/SLL and highlighted the ongoing phase 3 BRUIN-CLL-314 trial (NCT05254743), which will further evaluate pirtobrutinib vs covalent BTK inhibitors in the earlier-line treatment of patients with CLL/SLL.

Koff is an associate professor in the Department of Hematology and Medical Oncology and a clinical investigator in the Bone Marrow and Stem Cell Transplant Center at Emory University School of Medicine, as well as a member of the Discovery and Developmental Therapeutics Research Program at Winship Cancer Institute of Emory University in Atlanta, Georgia.

OncLive: What efficacy data have been derived from the BRUIN trial investigating pirtobrutinib in patients with pretreated CLL/SLL?

Koff: We've known for quite some time that pirtobrutinib is very effective in patients with CLL who have been exposed to a prior [covalent] BTK inhibitor. The overall response rate [(ORR) in updated data from the BRUIN trial] was 81.6%. It was a little bit higher [in patients who had] never seen venetoclax [Venclexta] before. The [updated] data from the 2023 ASH Annual Meeting showed us that in patients who have never seen a BCL-2 inhibitor, the [median progression-free survival (PFS)] was even longer at 23.0 months, whereas patients who had seen a BCL-2 inhibitor in the past [experienced a median PFS] of 15.9 months.

The double-exposed patient population historically has had very poor outcomes because we don't have a lot of effective therapies in patients who have previously received covalent BTK inhibition and a BCL-2 inhibitor. [Therefore], a 2-year overall survival [OS] rate of about 60.6% [in the BCL-2 inhibitor–exposed population in the BRUIN study] is an encouraging number.

What was the safety profile of pirtobrutinib demonstrated in the BRUIN trial?

In terms of [all-cause] adverse effects [AEs], [pirtobrutinib] is a well-tolerated drug, even in this heavily pretreated population. The majority of AEs we saw were more constitutional symptoms, including things like fatigue. There was some diarrhea in 28.4% of patients, but that's usually low grade. Some patients experienced cough [27.3%], and just like covalent BTK inhibitors, there was some risk of bruising and bleeding [pirtobrutinib] that were usually very mild.

Other AEs of interest that we're always on the lookout for with BTK inhibitors include hypertension, and [treatment-related hypertension] was low in incidence in the CLL cohort at 3.5%, and there very few [grade 3 or higher] events [0.4%]. There were also low rates of [treatment-related] atrial fibrillation and flutter at 1.4%. In terms of cytopenias, the main issue that we found with pirtobrutinib, which is a very common AE of almost any lymphoma-directed therapy, was neutropenia. [All-cause] grade 3 or higher neutropenia in these patients [occurred in 28.4%] of patients with CLL/SLL.

What are the implications of the FDA’s accelerated approval for pirtobrutinib in previously treated CLL/SLL?

This is an important approval in the CLL space because—especially for those patients with CLL who have already seen a covalent BTK or BCL-2 inhibitor like venetoclax—there are not a lot of options that we have available that are very effective for [patients in later lines of treatment].

It is a major benefit for the CLL community that we now have an FDA-approved drug that has been shown to be very effective in these heavily pretreated, double-exposed [patient] groups, and [pirtobrutinib] is also well tolerated.

What could be the implications of the phase 3 BRUIN-CLL-314 trial if pirtobrutinib displays superior efficacy vs approved covalent BTK inhibitors?

For the [BRUIN-CLL-314] study in the frontline management of CLL/SLL, investigators are trying to find out whether pirtobrutinib improves efficacy compared with what we currently use in terms of covalent BTK inhibitors. If there is improved efficacy either in terms of ORR or duration of response [DOR] in CLL, it could posit a role for pirtobrutinib earlier than its current indication. [Pirtobrutinib] may be jostling for a spot in frontline therapy, but that is a very high bar in CLL.

Based on the current standard of care, how do you sequence covalent BTK inhibitors and venetoclax-based regimens?

There are no head-to-head data that help us compare covalent BTK inhibitors with a venetoclax-based regimen in the frontline setting, and no studies are ongoing. We do have readouts from the various trials that have looked at these agents that were not head-to-head comparisons. In most cases, [determining how to sequence these therapies] tends to be a patient-driven discussion, in terms of which treatment—either a covalent BTK inhibitor or a venetoclax-based regimen—they would prefer based on AE profile and administration schedule.

There are exceptions to that [patient-driven approach. For patients with certain genetic abnormalities, such as 17p deletions, there is a preference for BTK inhibition in the frontline, given the better strength of the data for those agents in those populations. Both BTK inhibitors and venetoclax-based regimens have excellent ORRs and long-term DOR. Of course, they differ in terms of their AE profiles, as well as the schedule of administration.

What is sometimes very attractive to patients who are considering these 2 regimens is that the venetoclax-based regimen is a time-limited therapy; however, it does come with the added hassle of infusions during the first 6 months. Some patients are drawn to [time-limited therapy]. BTK inhibitors are given indefinitely. Some patients are happy to take a pill once or twice a day to keep their CLL under excellent control, and other patients are more likely to pick the time-limited option.

As we get more data from comparative studies and long-term follow-up of first-line studies investigating BTK inhibitors and venetoclax-based regimens, we may start to see more of a difference, especially in terms of very long-term efficacy between these 2 approaches, that might help inform [sequencing].For most patients, we [currently] have 2 good options that can be considered in the first-line space.

References

1. Jaypirca (pirtobrutinib) now approved by US FDA for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. News release. Eli Lilly and Company. December 1, 2023. Accessed May 13, 2024. https://investor.lilly.com/news-releases/news-release-details/jaypircar-pirtobrutinib-now-approved-us-fda-treatment-adult
2. Woyach JA, Brown JR, Ghia P, et al. Pirtobrutinib in post-cBTKi CLL/SLL: ~30 months follow-up and subgroup analysis with/without prior BCL2i from the phase 1/2 BRUIN study. Blood. 2023;142(suppl 1):325. doi:10.1182/blood-2023-185852