Sponsored by
With commentaries by
Jiajoyce Richardson, DNP, CRNP Andrews & Patel Penn State Medical Healthcare Group Camp Hill, PA
Katherine Tobon, PharmD, BCOP Clinical Pharmacy Specialist, Malignant Hematology Moffitt Cancer Center Tampa, FL
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western countries.1 Small lymphocytic lymphoma (SLL) is when the dominant clinical manifestation of the disease is lymphadenopathy. Targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and the B-cell lymphoma 2 (BCL2) inhibitor, venetoclax, have become the standard of care for patients with CLL and SLL, although chemoimmunotherapy may be beneficial for certain patients.1
Although outcomes for patients with CLL and SLL have improved with the introduction of BTK inhibitors, there are still limitations to their use.1 Covalent BTK (cBTK) inhibitors are often not used in sequence after disease progression due to resistance mechanisms; therefore, other therapy options with different mechanisms should be used.1 Despite the fact that patients can be maintained with dose reductions, many patients discontinue cBTK inhibitors because of progression or intolerance.2,3
There are limited therapeutic options when patients progress on a BTK inhibitor.1,2 The BCL2 inhibitor, venetoclax, is often the next treatment with a response in up to 85% of patients.1,2 However, venetoclax can induce tumor lysis syndrome and requires careful monitoring. Even in patients who receive venetoclax, the duration of disease control remains at approximately 2 years.1 There are many patients who have received both a cBTK inhibitor and a BCL2 inhibitor. The median time to treatment failure or death is <6 months in these heavily pretreated patients.1
Pirtobrutinib, which was granted accelerated approval by the FDA in December 2023 for adults with CLL/ SLL who have received at least 2 previous lines of therapy, including a BTK inhibitor and a BCL2 inhibitor, is a selective noncovalent (reversible) BTK inhibitor that was designed to overcome the limitations of currently approved BTK inhibitors.1,2,4 This article offers an overview of the mechanism of action of pirtobrutinib, clinical data of pirtobrutinib in patients with CLL and SLL from the BRUIN trial, and considerations for clinical use, including expert commentary from Katherine Tobon, PharmD, BCOP, and Jiajoyce Richardson, DNP, CRNP.
BTK is a mediator of normal B-cell development. It is activated downstream on the surface of the B-cell receptor (BCR) and is crucial for proliferation, differentiation, and survival of peripheral B cells.4-8 BTK is overexpressed in CLL B cells and is constitutively phosphorylated in some CLL samples.5,8 This phosphorylation promotes the catalytic activity of BTK and results in its autophosphorylation.5,8 BTK signaling may also play a role in migration of malignant cells to lymph nodes.5,8
Inhibiting the BTK domain can block BTK catalytic activity, suppress downstream BCR signaling, and impair malignant B-cell survival.5,6 The kinase domain contains a C481 residue in the ATP binding site that is crucial for covalent and irreversible binding.5,7-10 By binding with C481, BTK autophosphorylation and activation is blocked, suppressing downstream BTK activity in CLL cells. Mutations in C481 are a mechanism of acquired resistance to covalent inhibition of BTK.6 Noncovalent, reversible binding is independent of the C481 residue and interacts with the target through binding, unbinding, and rebinding.10-12 Noncovalent inhibition of BTK can overcome C481 resistance, and could provide an alternate treatment option for patients who have developed resistance to a covalent BTK inhibitor (Figure 1).6,9,11
Pirtobrutinib is a highly selective, noncovalent (reversible) BTK inhibitor that inhibits wild-type and C481-mutant BTK with equally low nM potency.13 Pirtobrutinib has a steady-state plasma exposure corresponding to 96% BTK target inhibition and a circulating half-life of approximately 20 hours. Compared with covalent BTK inhibitors, pirtobrutinib stabilizes and maintains BTK in a closed inactive conformation.13
Commentary by Katherine Tobon, PharmD, BCOP: Patients who fail a BTK inhibitor require a different mechanism to have true [B-cell receptor] inhibition. As we know, pirtobrutinib is reversible at the BTK protein and does not depend on the specific mutation that can make other BTK inhibitors inactive. This allows for pirtobrutinib to be utilized for common mutations, however there are still emerging mutations that render these patients resistant to pirtobrutinib also.
Commentary by Jiajoyce Richardson, DNP, CRNP: [An] educational point for patients when discussing the difference between pirtobrutinib and other BTK inhibitors is understanding the difference in how they work. My philosophy of practice is making it simple to the patients…. I always compare [BTK inhibitors when] educating my patients to the highways by which we live. And that when there is a traffic jam on one side, there’s always an alternative route that you can take to bypass that traffic jam to get to your place of destination.
[On December 1, 2023, the FDA granted accelerated approval to pirtobrutinib for adults with CLL/SLL who have received at least 2 previous lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.2]
BRUIN is a phase 1/2 trial, which included the phase 1 dose-escalation and dose-expansion phases and phase 2 (Figure 2).2 In the phase 1 portion, patients received pirtobrutinib at doses ranging from 25 to 300 mg once daily in 28-day cycles.1 In the phase 2 portion, patients received the recommended dose of 200 mg once daily until disease progression, unacceptable adverse events, or patient withdrawal. Patients with disease progression could continue treatment if ongoing clinical benefit was evident, according to the investigator’s discretion.1
Among patients with CLL and SLL, the primary endpoint was overall response. This was defined as partial response or better in accordance with the 2018 International Workshop on Chronic Lymphocytic Leukemia response criteria.1 Additional endpoints included overall response, partial response with lymphocytosis (PR-L), progression-free survival (PFS), overall survival (OS), safety, and an exploratory analysis of biomarkers.1
A total of 778 patients with B-cell cancers were enrolled; 317 had relapsed or refractory CLL or SLL after a data cutoff of May 2023 (approximately 30 months of follow-up).2 Two-hundred eighty-two patients with CLL or SLL previously received at least 1 BTK inhibitor. Of those 282 patients, 154 patients with CLL or SLL did not have previous BCL2 inhibitor exposure (BCL2i-N) and 128 patients did have previous BCL2 inhibitor exposure (BCL2i-E).2 Baseline characteristics of patients who received previous cBTK inhibitors are shown in Table 1.
Among all 282 patients with CLL/SLL who received a previous BTK inhibitor, the overall response rate (ORR) was 81.6% (95% confidence interval [CI], 76.5-85.9).2 Analysis of best response revealed that 1.8% of patients had a complete response (CR), 0.7% of patients had a nodular partial response (nPR), 69.5% of patients had a partial response, and 9.6% of patients had a PR-L. The median PFS in patients who previously received a BTK inhibitor was 19.4 months (95% CI, 16.6-22.1). The median OS in this patient population was not reached.2
Among the 154 patients in the BCL2i-N subgroup, the ORR was 83.1% (95% CI, 76.2-88.7).2 Analysis of best response revealed that 3.2% of patients had a CR, 1.3% of patients had an nPR, 70.1% of patients had a partial response, and 8.4% of patients had a PR-L. These patients exhibited a median PFS of 23.0 months (95% CI, 19.6-28.4). The median OS in this patient population was not reached.2
Among the 128 patients in the BCL2i-E subgroup, the ORR was 79.7% (95% CI, 71.7-86.3).2 Analysis of best response revealed that 0% of patients had a CR, 0% of patients had an nPR, 68.8% of patients had a partial response, and 10.9% of patients had a PR-L. The median PFS in patients who received a previous BCL2 inhibitor was 15.9 months (95% CI, 13.6-17.4). The median OS in this patient population was not reached.2
Favorable efficacy was observed in patients who received previous BTK inhibitors with or without previous BCL2 inhibitor exposure regardless of BTK C481 mutation status, age, TP53 and/or del(17p) mutation status, and in patients with additional lines of therapy.2 In patients with C481-mutated disease, the ORR was 87% in the BCL2i-N group and 87.2% in the BCL2i-E group. In patients with del(17p) and/or TP53 mutations, the ORR was 84.2% and 91.5% in the BCL2i-N and BCL2i-E groups, respectively.
Among all 282 patients with CLL/SLL who received previous BTK inhibitors, treatment-related adverse events (TRAEs) of interest of any grade included infection (12.8%), bruising (19.1%), rash (5.7%), arthralgia (4.3%), hemorrhage (4.6%), hypertension (3.5%), and atrial fibrillation/flutter (1.4%). Grade ≥3 TRAEs of interest included infection (4.3%), rash (0.4%), hemorrhage (1.1%), hypertension (0.4%), and atrial fibrillation/flutter (0.7%) (Table 2).2
Median time on treatment was 18.7 months (previous cBTK inhibitors), 24.3 months (BCL2i-N), and 15.3 months (BCL2i-E). Eleven (3.9%; 9 BCL2i-N, 2 BCL2i-E) patients had TRAEs leading to a pirtobrutinib dose reduction and 7 (2.5%; 4 BCL2i-N, 3 BCL2i-E) patients had TRAEs leading to pirtobrutinib discontinuation. The safety profiles of the BCL2i-N and BCL2i-E subgroups were similar.2
In a recent analysis of the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies (317 with CLL/SLL, 166 with mantle cell lymphoma, and 290 with other B-cell lymphomas) with extended exposure (≥12 months) from the BRUIN trial, no new toxicities were noted.13 Forty-two percent (326/773) of patients remained on treatment for ≥12 months. Most (77.6%) patients had received a previous BTK inhibitor. The most common all-cause treatment-emergent adverse events (TEAEs) were fatigue (32%) and diarrhea (31%); TEAEs leading to dose reduction occurred in 23 (7%) patients, with discontinuations in 11 (3%) extended-exposure patients.14
In another analysis of the BRUIN trial, 127 patients treated with pirtobrutinib with intolerance to at least one prior BTK inhibitor therapy in the absence of progressive disease were evaluated. The most frequent TEAEs were fatigue (39.4%), neutropenia (37.0%), and diarrhea (29.9%). No patients discontinued pirtobrutinib for the same adverse event that led to discontinuation of the prior BTK inhibitor.15
Pirtobrutinib demonstrated clinically meaningful and durable efficacy with an ORR of approximately 80% despite previous exposure to a BTK inhibitor with or without previous BCL2 inhibitors. Pirtobrutinib was well tolerated with low rates of drug discontinuation, even in patients with extended pirtobrutinib exposure.
Commentary by Katherine Tobon, PharmD, BCOP: The BRUIN study provides a lot of positive information for patients. The efficacy seen in the BRUIN study is promising, but the safety data is also extremely impactful for patients. Although pirtobrutinib has a slightly different mechanism, it hasn’t been shown to introduce new toxicities or worse toxicities than the other BTK [inhibitor].
Commentary by Jiajoyce Richardson, DNP, CRNP: I found the most impactful data are that pirtobrutinib demonstrated clinically meaningful durable efficacy with an overall response rate of 80%. Additionally, the rates for pirtobrutinib are low in terms of tolerance and adverse events.
Optimal sequencing of therapies has not yet been established; however, based on results from the BRUIN trial, BTK pathway inhibition may be an important sequencing approach to consider in patients with CLL/SLL.2 BCL2 inhibitor combination regimens have shown success in the first-line treatment of patients with CLL.16 In a phase 3, open-label trial of venetoclax-based regimens in patients with CLL who did not have TP53 mutations, venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) as a first-line treatment. Among patients with undetectable minimal residual disease, 86.5% received venetoclax-obinutuzumab, 92.2% received venetoclax-obinutuzumab-ibrutinib, and 52% underwent chemoimmunotherapy.16 In the first-line setting, cBTK inhibitors have also been shown to improve outcomes for patients with CLL, although the available cBTK inhibitors share common resistance mechanisms.1 BCL2 inhibitors are also commonly used after a patient progresses on a cBTK inhibitor. In a multicenter, open-label, single-arm, phase 3b trial (VENICE-1), venetoclax monotherapy demonstrated deep and durable responses in patients with relapsed or refractory CLL. Of 191 BCR inhibitor–naïve patients, 66 had complete remission and 18 of 67 patients in the BCR inhibitor–pretreated group had complete remission.17 However, treatment options remain limited in pretreated patients with CLL/SLL who have progressed on a BTK inhibitor, BCL2 inhibitor, or both a BTK inhibitor and BCL2 inhibitor.1,2 A real-world database study of patients with CLL investigated time-to-event outcomes for patients treated with a cBTK inhibitor, both a cBTK inhibitor and BCL2 inhibitor, or treated with all 4 drug classes, including a cBTK inhibitor, a BCL2 inhibitor, rituximab, and chemotherapy. Among patients who discontinued both a cBTK inhibitor and BCL2 inhibitor, the average time to next treatment, discontinuation, or death was 5.6 months.18 Data from the BRUIN trial suggest that pirtobrutinib may provide a benefit in these patients who have progressed on a regimen containing a cBTK inhibitor, as well as heavily pretreated patients who have failed both a cBTK inhibitor and BCL2 inhibitor. As previously mentioned, after treatment with a BTK inhibitor and a BCL2 inhibitor, the ORR was 79.7%.2 CAR T-cell therapy may be an option for select patients; however, after weighing toxicities and outcomes in the literature, patients should talk with their healthcare provider about goals of therapy.19
Commentary by Katherine Tobon, PharmD, BCOP: If patients have failed other BTK inhibitors due to tolerability, we know pirtobrutinib is an option. You must consider the patient’s comorbidities, treatment goal, history, financial toxicity, their mutation panel, etc. What is their treatment goal? What is their social support like? We don’t want to compromise quality of life and still ensure we are meeting the number one goal of the patient. We know that pirtobrutinib is well tolerated. And a lot of these patients are older with other comorbidities, so that is also something that is taken into consideration.
Commentary by Jiajoyce Richardson, DNP, CRNP: The nonclinical consideration I think [is] important when selecting a therapy for patients who have been heavily pretreated is quality of life. How am I impacting this patient’s quality of life with these medications? Because ultimately what you will find is that when patients feel their quality of life is being compromised, they’re not going to do it or they’re going to be very hesitant about one more thing impeding what they can do and how they can do it. Important clinical considerations are management of toxicities and side effects. Educating patients upfront about when to call the doctor’s office, when symptoms have exceeded a threshold where they no longer try to manage symptoms at home, so they don’t end up with missed doses.
Shared decision-making is “an approach where clinicians and patients share the best available evidence when making decisions, and where patients are supported to consider options, to achieve informed preferences.”20 The healthcare team and patient work together toward a treatment plan in line with the patient’s goals of therapy. When assisting patients with treatment decisions, important things to consider include a patient’s verbal and nonverbal reactions, a review of the information the patient has been given, a check of the patient’s knowledge, exploration and focus on patient preferences, summarizing options, and supporting patients to help them make informed decisions.20,21 Pirtobrutinib is a promising treatment option for healthcare professionals to discuss with their patients who have CLL/SLL and are heavily pretreated.
Commentary by Katherine Tobon, PharmD, BCOP: The key characteristics about pirtobrutinib that we convey to patients when assisting them with their treatment decision include side effects, how to take the oral medication, drug interactions, and how it’s going to affect their lives. We must also keep in mind that there are limited treatment options for true “double-refractory” patients.
I think shared decision-making with the team and patient, is key; this is what leads to positive treatment outcomes [for] CLL patients. We want them to feel empowered in the treatment decision-making process and understand all of their options. This includes the current treatment options, considering future options, physical, emotional, and financial toxicity.
Commentary by Jiajoyce Richardson, DNP, CRNP: When participating in shared decision-making, it is important to convey to patients that they do have a say. We have dedicated time in which we spend with our patients, so we let patients know that this is their time to ask the questions that they have about the medication. Ask the questions that they’re not sure [about] or even convey their feelings about uncertainty about their disease, about one more medication, about going to the next lineage of therapy. But helping them understand that this is not a one-sided conversation, that we are making a shared decision.
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