Pirtobrutinib Approval Adds Effective Third-Line Option to Previously Treated CLL/SLL Armamentarium

January 3, 2024

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Lori A. Leslie, MD, discusses the significance of the FDA approval of pirtobrutinib for this population alongside the unmet needs it may address, highlights the efficacy and notable toxicities seen with the agent in the BRUIN study, and expands on the continued investigation of pirtobrutinib vs other standard-of-care regimens in various CLL subtypes.

Lori A. Leslie, MD

The FDA approval of the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) for patients with pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) provides a new approach to targeting BTK and addresses the need for more treatment options after patients progress on prior covalent BTK inhibitors or BCL2 inhibitors, according to Lori A. Leslie, MD, who added that many of these patients will develop resistance to BTK or BCL2 inhibitors and accordingly experience poorer outcomes.

The efficacy and safety of pirtobrutinib were evaluated in the phase 1/2 BRUIN trial (NCT03740529), in which the agent elicited an overall response rate (ORR) of 72% (95% CI, 63%-80%) within the cohort of patients with CLL/SLL who had received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor (n = 108). Additionally, patients achieved a median time to response of 3.7 months (range, 1.7-27.9), and the median duration of response was 12.2 months (95% CI, 9.3-14.7).

Based on these data, the FDA granted accelerated approval to pirtobrutinib on December 1, 2023, for adult patients with CLL or SLL who previously received 2 or more prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.

The continued approval of pirtobrutinib for this indication is contingent upon results from the confirmatory phase 3 BRUIN CLL-321 trial (NCT04666038).

“Though pirtobrutinib is a BTK inhibitor, it’s noncovalent and works differently. It has the [ability to potentially] overcome resistance to covalent BTK inhibitors,” said Leslie, who is the director of Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs at John Theurer Cancer Center, and an assistant professor at Hackensack Meridian School of Medicine in New Jersey. “In general practice, pirtobrutinib should be considered a different line of therapy that can be used [after progression on a] covalent BTK inhibitor.”

In an interview with OncLive^®, Leslie discussed the significance of the FDA approval of pirtobrutinib for this population alongside the unmet needs it may address, highlighted the efficacy and notable toxicities seen with the agent in the BRUIN study, and expanded on the continued investigation of pirtobrutinib vs other standard-of-care (SOC) regimens in various CLL subtypes.

OncLive: What is the significance of the FDA approval of pirtobrutinib for patients with previously treated CLL and SLL?

Leslie: It’s been an exciting decade in CLL. We know that BTK is central to B-cell receptor signaling, and CLL cells are basically "addicted" to BTK. We currently have 3 approved covalent BTK inhibitors in CLL that bind irreversibly: ibrutinib [Imbruvica], which is a first-generation agent, and acalabrutinib [Calquence] and zanubrutinib [Brukinsa], which are considered second-generation agents. These agents have changed our treatment armamentarium. Patients can switch among these options [when they experience] intolerance.

However, [these 3 agents] have [essentially] the same mechanism of resistance, so it is not considered appropriate to switch a patient to a different covalent BTK inhibitor if they’re progressing on prior acalabrutinib, zanubrutinib, and ibrutinib. Pirtobrutinib is a noncovalent BTK inhibitor, so it inhibits BTK differently and can overcome resistance or be used in patients who have previously progressed on or been exposed to a covalent BTK inhibitor. This is great news for our patients with CLL/SLL, as pirtobrutinib serves as a different line of therapy compared with what we have already available.

Could you discuss the unmet needs that currently exist in CLL? How might the approval of pirtobrutinib address them?

CLL remains an area with unmet need, particularly in the relapsed/refractory setting. With each approval of a new group of drugs, such as the covalent BTK inhibitors, pirtobrutinib as a noncovalent BTK inhibitor, and BCL2 inhibitors, such as venetoclax [Venclexta], we’ve been able to prolong patients’ remissions and how many treatment options we have. Moving forward, [we will] investigate combinations, how to sequence these drugs, and how to hopefully provide [all patients with] an opportunity for response and minimal residual disease [MRD]–adapted, time-limited therapy. Pirtobrutinib provides us with another medication to investigate in CLL as we continue to improve the treatment paradigm.

Please expand on some of the key efficacy findings from the BRUIN trial that supported this regulatory decision.

The BRUIN study evaluated pirtobrutinib in a variety of hematologic malignancies. Focusing on the CLL/SLL cohort, 247 patients had been previously treated with a covalent BTK inhibitor. The evaluation of pirtobrutinib in [the population of patients who had received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor], was encouraging, with an ORR of 72%. When data [from this study] were presented at a median follow up of [27.5 months], the median progression-free survival with pirtobrutinib was [19.4 months]. Pirtobrutinib was effective regardless of whether patients had one of the most common covalent BTK resistance mechanisms, which is a mutation in BTK C481. Pirtobrutinib also demonstrated efficacy [regardless of] whether patients had been previously treated with a BCL2 inhibitor or had stopped treatment with a prior covalent BTK inhibitor due to intolerance or progression.

What should be known about the safety profile of this agent?

The general safety profile of pirtobrutinib has been in line with what we would expect from BTK inhibition in general. Most of the safety concerns we have with this class are cardiac in nature. What we’ve seen so far [with pirtobrutinib] in CLL has been consistent with what was also reported in mantle cell lymphoma, where pirtobrutinib is also approved. The rate of cardiac events was relatively low. We’ll need to continue with longer follow up.

Any-grade adverse effects [AEs] reported from the BRUIN study included hypertension in 12% of patients, and any-grade atrial fibrillation or atrial flutter in 3.2% of patients. [The incidence of] major hemorrhage was quite low, [occurring] in 3% of patients, and only 9% of the 317 patients treated in the CLL cohort [stopped receiving pirtobrutinib] due to treatment-related AEs. There was a low rate of discontinuation, which speaks to the tolerability of this drug.

What might the role of pirtobrutinib be for this population in your own practice?

The FDA’s accelerated approval of pirtobrutinib was for patients who have had at least 2 prior lines of therapy, including a covalent BTK inhibitor and a BCL2 inhibitor. Based on that approval, pirtobrutinib would be used in the third line for my patients. Typically, we’re using targeted therapy for all patients. It’s incredibly rare that we consider chemotherapy anymore, outside of patients with Richter transformation.

I will highlight that [before the FDA approval of pirtobrutinib for patients with CLL/SLL], the National Comprehensive Cancer Network had endorsed the use of pirtobrutinib in patients [with CLL/SLL] who have previously been exposed to a covalent BTK inhibitor. That recommendation is a bit broader than the formal FDA approval. If I have a patient who has been exposed to, and has not necessarily progressed on, a covalent BTK inhibitor and has also become intolerant to available covalent BTK inhibitors, I am likely to use pirtobrutinib after a BCL2 inhibitor. This would be in line with the FDA approval.

Could you expand on design of the confirmatory BRUIN CLL-321 study of pirtobrutinib in CLL?

The accelerated approval of pirtobrutinib [for patients with CLL/SLL] is contingent upon confirmatory studies. [One] confirmatory study is the BRUIN CLL-321 study. This is a randomized study investigating pirtobrutinib vs investigator’s choice of SOC bendamustine and rituximab [Rituxan] or idelalisib [Zydelig] plus rituximab in patients who [have received] covalent BTK inhibitors.

This is a global study. Outside the United States, the availability of some of these medications is different. If a patient has been already exposed to a covalent BTK inhibitor, agents such as idelalisib and bendamustine could still be considered. In the United States, most patients would receive venetoclax before those treatment options. The patients [in BRUIN CLL-321] will be stratified by 17p deletion status and whether they have had prior venetoclax exposure. Crossover to the pirtobrutinib arm at the time of progression in the SOC arm is also [allowed as] part of the study.

What other studies of pirtobrutinib are ongoing for patients with CLL?

There are many other ongoing studies of pirtobrutinib combinations vs SOC. The [phase 3] BRUIN CLL-322 trial [NCT04965493] is investigating the [phase 3] MURANO trial [NCT02005471] regimen of venetoclax and rituximab with or without fixed-duration pirtobrutinib in relapsed/refractory CLL. This is a nice study comparing doublet vs triplet therapy in that relapsed/refractory [population]. We are participating in that trial at Hackensack Meridian Health. Another study is the [phase 3] BRUIN CLL-314 study [NCT05254743]. That is a randomized study evaluating pirtobrutinib vs ibrutinib in patients with CLL [who are naive to BTK inhibitors]. Other studies are investigating combinations of pirtobrutinib and venetoclax in [patients with] treatment-naive CLL who are MRD-positive after venetoclax-based frontline therapies. A lot of exciting research is going on in CLL, and we will hopefully see the treatment paradigm evolve quickly over the next few years.