Abstract
Objective:
The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton’s tyrosine kinase (BTK) inhibitors.
Data sources:
A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca, and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed.
Study selection and data extraction:
Relevant English-language clinical trials were evaluated.
Data synthesis:
Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib.
Relevance to patient care and clinical practice in comparison with existing drugs:
Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib’s use in multiple B-cell malignancies and comparing it with other BTK inhibitors.
Conclusion:
The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use.
Keywords
Introduction
Hematologic B-cell malignancies primarily affect the older adult population and some subtypes, such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), may be difficult to treat due to limited responses with traditional chemotherapy, patient comorbidities, and overall tolerability of available therapies in this population. Targeted small molecule agents have been developed to improve tolerability and overall disease management compared with traditional monoclonal antibodies and cytotoxic chemotherapy. Specifically, Bruton’s tyrosine kinase (BTK) inhibitors have led to improvements in the treatment of B-cell malignancies including CLL/small lymphocytic lymphoma (SLL), MCL, Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). 1 The BTK enzyme is a key component in the B-cell receptor (BCR) signaling pathway, regulating B-cell proliferation, differentiation, and survival. 2 In many settings, BTK inhibitors have replaced chemoimmunotherapy as the preferred therapy due to their selectivity, clinical efficacy, and ease of oral administration. However, resistance and intolerance to these medications often result in treatment discontinuation. 2 Agents with increased selectivity for BTK are under investigation to reduce off-target toxicities and overcome common resistance mechanisms.
Pirtobrutinib (Jaypirca) was approved by the US Food and Drug Administration (FDA) on January 27, 2023, under the accelerated approval pathway for the treatment of relapsed or refractory (R/R) MCL after receiving at least 2 other lines of systemic therapy, including an earlier-generation BTK inhibitor. 3 Pirtobrutinib more recently received accelerated approval for the treatment of CLL/SLL after at least 2 prior lines of therapy, including a BTK inhibitor and B-cell lymphoma-2 (Bcl-2) inhibitor. 3 The accelerated approvals were based largely on positive results from the BRUIN trial, a phase 1/2 global study, which suggested a 58% overall response rate (ORR) in MCL and 73% ORR in CLL.4-6 However, continued approval of pirtobrutinib may be contingent on the results of ongoing phase 3 confirmatory trials. 3
Pirtobrutinib differs from currently available BTK inhibitors, in that it retains activity in those resistant to earlier-generation BTK inhibitors. 4 Kinase domain mutations, specifically C481 mutations, are the main mechanism for covalent BTK inhibitor resistance in CLL and have less frequently been observed in other B-cell malignancies.4,7 In an analysis of 46 patients with CLL progressing on ibrutinib, 80% had BTK C481 mutations at the time of progression. 7 Pirtobrutinib’s unique noncovalent, reversible mechanism of action and high selectivity for BTK allow for the potential to overcome previous BTK inhibitor resistance and may create a superior safety profile.3,4 The purpose of this review was to distinguish pirtobrutinib among other novel BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) and evaluate the available safety and efficacy data of this medication in the treatment of B-cell malignancies.
Data Sources
A PubMed search for articles published between January 2021 and November 2023 and a search of clinicaltrials.gov for ongoing studies were completed using the terms pirtobrutinib, Jaypirca, and LOXO 305. In addition, licensing trials of the previously FDA-approved BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) were reviewed to compare the safety of the agents in this class.
Pharmacology
Mechanism of Action
Pirtobrutinib is a reversible inhibitor of BTK, a key component of the BCR signaling pathway. 3 Inhibition of BTK results in a decrease in B-cell proliferation, differentiation, and survival. 2 Unlike the other BTK inhibitors currently approved by the FDA which bind covalently to BTK, pirtobrutinib is highly selective for BTK with noncovalent, reversible binding properties. 4 Pirtobrutinib’s distinct binding site on the BTK enzyme allows it to bind more selectively and with greater potency than other available BTK inhibitors (see “Pharmacodynamics” section).3,4 It binds to non-Cys481 amino acids in the receptor binding pocket in both wild-type BTK and C481 mutated BTK (Figure 1). 2 This alteration in the BTK binding site (C481 mutation) is a consequence of the covalent, irreversible binding of Cys481 with the first- and second-generation BTK inhibitors, especially ibrutinib. The mutation results in a BTK enzyme that is either unable to be bound by covalent BTK inhibitors or causes them to bind at a much lower potency. 2 The use of earlier-generation BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) and the persistent presence of drug at the receptor, due to covalent/irreversible binding, may initiate the development of drug resistance and the need for a BTK inhibitor with an alternate binding site. 2 An in vitro study demonstrated pirtobrutinib-mediated inhibition of B-cell proliferation and maturation in CLL cell line model systems irrespective of BTK status, wild-type or C481 mutated. 2
BTK inhibitor mechanism of action.
Pharmacodynamics
Pirtobrutinib is a small-molecule kinase inhibitor that competes with ATP for the BTK receptor, thereby inhibiting its BTK activity/signaling. 3 It binds with an equal potency to both wild-type BTK and C481 mutated BTK, inhibiting BTK-mediated CD69 expression and malignant B-cell proliferation. 4 When administered once daily at the recommended dose (200 mg), pirtobrutinib occupies BTK receptors throughout the entire dosing interval. 3 In contrast, covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) are hypothesized to obtain incomplete target inhibition at the end of their dosing periods, potentially driving resistance. 4 In addition, pirtobrutinib is highly selective for BTK, demonstrating a >300-fold selectivity for BTK in vitro against 363 (98%) of 370 other kinases evaluated in the BRUIN phase 1/2 trial, therefore minimizing off-target effects. 4 In an investigation of pirtobrutinib’s effect on QTc interval among 30 individuals receiving a single 900-mg dose, it was not associated with QTc prolongation. 3
Pharmacokinetics
Pirtobrutinib is administered orally and demonstrates linear kinetics as observed in the phase 1 portion of the BRUIN study, with proportional increases in exposure as doses increased from 25 to 300 mg daily. 4 The observed half-life was 20 hours in this study and efficacy was demonstrated at all dose levels. Moreover, at all 7 dose levels evaluated (25-300 mg daily), no dose-limiting toxicities were observed and a maximum tolerated dose was not established. A dose of 200 mg orally daily was selected for further investigation in the phase 2 portion of the study in B-cell malignancies based on the correlation with this dose and unbound pirtobrutinib trough steady-state concentrations attaining 96% target inhibition. 4 Overall, bioavailability is excellent at 85% (range = 76%-91%) and the time to peak levels is approximately 2 hours (range = 0.83-4.15 hours) after ingestion. 3 Steady-state concentrations are generally reached after 5 days of daily administration. Food intake, including high-fat, high-calorie meals, does not significantly affect pirtobrutinib area under the curve (AUC); however, there was a 23% decrease in Cmax and 1-hour delay in time to Cmax when administered with a high-fat meal. 3 Consequently, pirtobrutinib may be taken without regard to timing of meals. Volume of distribution of pirtobrutinib is 32.8 L and it is 96% protein bound. 3 Hepatic metabolism via CYP 3A4 and direct glucuronidation by UGT1A8 and UGT1A9 account for pirtobrutinib’s metabolism. 3 Because pirtobrutinib undergoes both fecal and renal elimination (37% recovered in feces [18% unchanged] and 57% recovered in urine [10% unchanged]), hepatic dysfunction, even severe (bilirubin >3× upper limit of normal and any alanine aminotransferase), did not result in significant alterations in pharmacokinetics. 3 Severe renal dysfunction (estimated glomerular filtration rate [eGFR] = 15-29 mL/min) did increase the pirtobrutinib AUC by 62%; however, mild/moderate renal dysfunction (eGFR = ≥ 30 mL/min) did not result in any significant alterations in pharmacokinetics. It is unknown if the coexistence of mild or moderate renal dysfunction and hepatic dysfunction significantly affect pharmacokinetics and caution should be advised in such patients.
Compared with other drugs in the class of BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib), pirtobrutinib has a much higher bioavailability and longer half-life (Table 1).3,8-10 All BTK inhibitors are highly protein bound and undergo hepatic metabolism to varying extents. Pirtobrutinib differs from other drugs in the class, in that it has more elimination via the urine and requires dose reduction in patients with severe renal impairment. Metabolism is similar among the available BTK inhibitors; however, there are slight differences between agents, such as pirtobrutinib’s susceptibility to glucuronidation and their individual ability to inhibit or induce various hepatic enzymes or transporters (Table 1) (see “Drug Interactions” section).
Abbreviations: AUC, area under the curve; BCRP, breast cancer resistance protein; CrCl, creatinine clearance; CYP, cytochrome P450; eGFR, estimated glomerular filtration rate; MATE1, multidrug and toxin extrusion protein 1; UGT, uridine 5′-diphospho-glucuronosyltransferase.
Half-life of parent compound; acalabrutinib has an active metabolite with approximately 50% of the activity of the parent compound.
Acalabrutinib’s active metabolite inhibits CYP 2C19 and MATE1.
Clinical Efficacy
The BRUIN trial was a first-in-human phase 1/2 open-label study evaluating the safety and clinical outcomes of pirtobrutinib. 4 Study enrolled adult patients with B-cell malignancies that had received at least 2 prior lines of treatment (the protocol was later amended to allow only 1 previous line of therapy in patients with CLL or SLL). All were eligible regardless of BTK C481 mutational status. The phase 1 portion of the study was designed to determine the maximum tolerated dose using a 3 + 3 dose escalation design, and it established the recommended dose of 200 mg daily for exploration in the phase 2 portion of the trial (see “Pharmacokinetics” section above). The safety population included all 323 patients enrolled, and the efficacy evaluable population included 269 patients (139 with CLL or SLL, 56 with MCL, 19 with WM, and 55 with other B-cell lymphomas). Of the 323 included patients, median age was 68 years, 66% were male, 93% had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1, and they received an average of 3 previous lines of systemic therapy (76% received a prior BTK inhibitor). The reasons for discontinuing the previous BTK inhibitor were progressive disease (71%) or toxicity/other (29%). After a median follow-up of 4 to 6 months, the ORR for CLL, MCL, and WM were 63%, 52%, and 68%, respectively, in the efficacy evaluable population. Complete responses (CRs) were noted in 0% with CLL, 25% with MCL, and 0% with WM at the time of reporting. Bruton’s tyrosine kinase mutation testing was performed in the population with CLL (N = 91), and the ORR was 71% in those with a BTK C481 mutation compared with 66% in those with wild-type BTK. Overall, responses were demonstrated in multiple B-cell malignancies and among patients who previously discontinued covalent BTK inhibitors due to tumor progression regardless of BTK C481 mutational status or intolerance. 4 Clinical trials are ongoing to further demonstrate pirtobrutinib’s place in therapy in the treatment of B-cell malignancies (Table 2).4,11-15
Abbreviations: BTK, Bruton’s tyrosine kinase; BTKi, Bruton’s tyrosine kinase inhibitor; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; NCT, National Clinical Trial; NHL, non-Hodgkin lymphoma; SLL, small lymphocytic lymphoma.
In May 2023, an update from the BRUIN trial was published for those patients included with a diagnosis of MCL. 6 Among the 164 patients included, 90 who received a prior BTK inhibitor and 14 who were BTK inhibitor naïve were evaluable for efficacy. After a median follow-up of 12 months, those receiving a prior BTK inhibitor had an ORR of 58% (CR = 20%), median progression-free survival (PFS) of 7.4 months (95% confidence interval [CI]: 5.3-12.5), and overall survival (OS) at 12 and 18 months of 68% and 59%, respectively. Those discontinuing a prior BTK inhibitor due to disease progression had an ORR of 50%, median PFS of 5.5 months (95% CI: 3.7-8.3), and median OS of 23.4 months (95% CI: 10.9-not estimable), while those discontinuing due to toxicity had an ORR of 92%, 12-month duration of response of 78% (95% CI: 38-94), 12-month PFS of 83% (95% CI: 46-95), and 12-month OS of 92% (95% CI: 54-99). Among the 14 patients naïve to BTK inhibitors, efficacy more closely resembled those discontinuing a prior BTK inhibitor due to intolerance where after a median follow-up of 7.1 months, ORR was 86% and 6-month PFS and OS were both 92%.
In July 2023, an update from the BRUIN trial was published regarding pirtobrutinib use in CLL/SLL patients after prior treatment with a covalent BTK inhibitor with a median follow-up of 19.4 months. 5 A total of 317 patients with R/R CLL/SLL were included in the BRUIN trial, and of those, 247 (78%) previously received at least 1 BTK inhibitor and were included in this analysis. The ORR was 73% (95% CI: 67-79) among the 247 patients included with the majority (71%) experiencing a partial response and 1.6% with a CR. Of those tested for BTK C481 mutation (n = 222), 84 patients (38%) had a BTK C481 mutation. In the efficacy evaluable population, the median PFS was 19.6 months (95% CI: 16.9-22.1) and was similar among those with and without BTK C481 mutations, 18.2 months (95% CI: 13.9-22.2) and 17.5 months (95% CI: 10.7-20.0), respectively. In this population of patients who received a prior BTK inhibitor for the management of CLL, at a median follow-up time of 22.6 months, the 12-month OS was 86% (95% CI: 81-90) and the 18-month OS was 81% (95% CI: 75-85). In the population of patients covered by the FDA approval of pirtobrutinib for CLL (those who received both a BTK inhibitor and a BCL-2 inhibitor), the ORR was 70% and median PFS was 16.8 months. In a small number of patients (N = 18) with a phospholipase C gamma 2 mutation, another mutation responsible for acquired resistance to covalent BTK inhibitors, the response rate was 56%.
Safety
Across all 7 dose levels investigated in the phase 1/2 BRUIN trial, from 25 to 300 mg, no dose-limiting toxicities were observed, and therefore, no maximum tolerated dose was identified. 4 In the BRUIN trial, adverse events were reported regardless of attribution and subsequently categorized as treatment-related adverse events. Most adverse events were grade 1 or 2 (87%). The most common grade 3 or higher adverse event reported was neutropenia which occurred in 32 of 323 patients (10%). 4 Other commonly observed adverse events of any grade were fatigue (20%), diarrhea (17%), and contusion (13%). Dose interruptions occurred for 26 patients (8%), dose reductions for 7 (2%), and permanent discontinuation for 5 (1%) patients. 4
Two of the major safety concerns with BTK inhibitors are atrial fibrillation or flutter and hemorrhage as they often result in treatment discontinuation. Notably, the BRUIN trial included patients with controlled atrial fibrillation and/or concomitant anticoagulant (except warfarin) or antiplatelet therapy. 4 Out of all 323 patients in the BRUIN trial, atrial fibrillation or flutter was observed in 2 patients (1%), and both were considered grade 2 adverse drug events. Both patients had a history of atrial fibrillation; therefore, their atrial arrhythmias were deemed unrelated to pirtobrutinib. One patient experienced a grade 3 hemorrhage due to a bicycle accident. Bruising was observed in 53 (16%) patients and was unrelated to dose or exposure. Interestingly, 18 patients discontinued a previous BTK inhibitor for cardiovascular toxicity or hemorrhage, but none had a reoccurrence of these adverse events with pirtobrutinib. For further information regarding cardiac effects of interest, including updates to the BRUIN trial in the CLL and MCL population, see Table 3.4-6,16-24
Blanks in table indicate that the adverse effect was not reported.
Abbreviations: BTK, Bruton’s tyrosine kinase; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma.
Bleeding used interchangeably with hemorrhage in ELEVATE-RR. Bleeding in BRUIN, SEQUOIA, and ACE-LY-004 included both bruising or contusion and hemorrhage. Major hemorrhage defined as any serious hemorrhage or grade 3 or higher hemorrhage or central nervous system hemorrhage of any grade.
BRUIN, ASPEN, ALPINE, ELEVATE-TN, ELEVATE-RR, and ASCEND trials reported incidence of atrial fibrillation/atrial flutter, while RESONATE-2 and ACE-LY-004 described atrial fibrillation.
Median follow-up reported in BRUIN and ACE-LY-004.
All-grade major hemorrhage, hypertension, and atrial fibrillation by time of follow-up: years 5 to 6 = 0%, 25%, and 9%; years 6 to 7 = 0%, 23%, and 7%; years 7 to 8 = 3%, 25%, and 7%, respectively.
In the update of the BRUIN trial in the CLL/SLL population, the most common all-grade adverse effects reported were infections (71%), bleeding (43%), and neutropenia (33%). 5 Grade 3 or higher neutropenia occurred in 85 patients (27%). A similar safety profile was observed compared with the entire population of B-cell malignancies in the BRUIN trial, but the incidence of infections was considerably higher in the CLL population (71% vs 56%). Of note, the reason for previous BTK discontinuation was toxicity or other reason in 23%, but treatment-related adverse effects caused only 9 patients (2.8%) to permanently discontinue pirtobrutinib in this population of patients with CLL. In the update of the BRUIN trial in the MCL population, the most common all-grade adverse effects were fatigue (30%), diarrhea (21%), and dyspnea (17%), while the most common grade 3 or higher adverse effect was infection (17%). 6 Grade 3 or higher neutropenia occurred in 13%, substantially lower than the 27% observed in the CLL population. Among those with MCL, 9% discontinued therapy due to adverse effects.
Warnings and Precautions
According to the FDA-approved labeling for pirtobrutinib, there are no boxed warnings or absolute contraindications to this medication. 3 However, concerns related to adverse effects are clearly noted. Patients receiving pirtobrutinib are at risk of cardiovascular adverse effects including hypertension, atrial fibrillation, and bleeding (Table 3). To monitor for hypertension, providers should assess blood pressure at each clinic visit. 3 In addition, a baseline electrocardiogram (ECG) should be obtained to rule out an atrial arrhythmia at the start of therapy and repeat ECGs should be completed in patients with signs or symptoms of an arrhythmia. Hemorrhage, although rare, has occurred both with and without concurrent antithrombotic therapy; therefore, a risk-benefit evaluation is important prior to initiating therapy. 3 Of note, anticoagulant (except warfarin) and antiplatelet use was permitted in the BRUIN trial. 4 Due to the risk for bleeding, it is reasonable to consider withholding pirtobrutinib for 3 to 7 days perioperatively to reduce bleeding risk. Grade 3 or 4 cytopenias, including neutropenia, anemia, and thrombocytopenia, have also been observed with pirtobrutinib; therefore, it is important to monitor blood counts regularly throughout therapy. 3 Fatal and serious infections including opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP) have occurred with BTK inhibitors.2,25,26 Antimicrobial prophylaxis is not routinely recommended; however, National Comprehensive Cancer Network (NCCN) guidelines for the prevention and treatment of cancer-related infections recommend varicella zoster/herpes simplex virus and PCP prophylaxis be considered in patients at increased risk of infection (eg, history of opportunistic infection, heavily pretreated patients). 27 Secondary malignancies have developed in a small percentage of patients with the most common being nonmelanoma skin cancer; therefore, patients should be advised to use sun protection by wearing protective clothing, using broad-spectrum sunscreen, or by limiting sun exposure while taking pirtobrutinib. 3 Finally, due to a risk of fetal harm observed in animal studies of pirtobrutinib, patients of reproductive potential should verify pregnancy status before initiation and use effective contraception during therapy and for 1 week after their last pirtobrutinib dose. 3
Drug Interactions
As a result of pirtobrutinib’s metabolism via CYP 3A, drug interactions may occur. 3 Strong CYP 3A inhibitors resulted in a 49% increase in pirtobrutinib AUC and moderate 3A inhibitors increased AUC by 20% to 30%. 3 Likewise, strong CYP3A inducers decreased pirtobrutinib AUC by 71% and moderate CYP3A inducers decreased AUC by 27% to 49%. 3 Gastric acid-reducing agents and P-glycoprotein inhibitors did not have any effect on pirtobrutinib kinetics. 3 It is recommended that strong 3A inhibitors and moderate or strong 3A inducers be avoided. If concomitant use of strong 3A inhibitors or moderate 3A inducers cannot be avoided, a reduced or increased pirtobrutinib dose should be considered, respectively. Pirtobrutinib FDA-approved labeling recommends to decrease the pirtobrutinib dose by 50 mg if a CYP3A inhibitor cannot be avoided and to increase the dose to a maximum of 300 mg daily if the patient is receiving 200 mg daily or by 50 mg if the patient is receiving 50 mg or 100 mg daily in the presence of an inducer. 3 Pirtobrutinib is an inhibitor of CYP 3A4 (70% increase in oral midazolam AUC, no effect on IV midazolam kinetics), CYP 2C8 (130% increase in repaglinide AUC), CYP 2C19 (56% increase in omeprazole AUC), P-glycoprotein (35% increase in digoxin AUC), and BCRP (140% increase in rosuvastatin AUC). 3 If concomitant therapy with interacting medications cannot be avoided, additional monitoring and/or dose modifications may be necessary for the affected medication.
Compared with other BTK inhibitors, all are susceptible to interactions via CYP 3A and P-glycoprotein (as the inhibitors/inducers, substrates, or both) (Table 1). Similar to ibrutinib and zanubrutinib, acid suppression does not affect absorption of pirtobrutinib, whereas acalabrutinib absorption is decreased in the presence of acid suppressive therapy. 1
Dosing and Administration
Pirtobrutinib is available commercially as 50- or 100-mg oral tablets and the recommended dose is 200 mg once daily until disease progression or unacceptable toxicity. 3 Pirtobrutinib should be taken whole (not cut, crushed, or chewed) at the same time each day, with or without food, and if a dose is missed for more than 12 hours, dosing should be resumed the next day. Dosage modifications are recommended for grade 3 or greater nonhematologic adverse reactions and myelosuppression. 3 In addition, patients with severe renal impairment (eGFR of 15-29 mL/min) should receive a reduced dose of 100 mg of pirtobrutinib once daily. 3 No adjustments are necessary for hepatic dysfunction or mild to moderate renal impairment. Dosing modifications may be necessary if pirtobrutinib is concomitantly used with CYP3A inducers or inhibitors (see “Drug Interactions” section). 3 Compared with other BTK inhibitors, the ease of use (2 tablets, once daily) of pirtobrutinib is similar to the other products based on their recommended starting dose and dosage forms (ibrutinib 420 mg [1 tablet] daily, acalabrutinib starting dose 100 mg [1 tablet] every 12 hours, and zanubrutinib 160 mg [2 capsules] every 12 hours or 320 mg [4 capsules] daily).3,8-10 All BTK inhibitors listed above may be administered with or without food; however, ibrutinib was the only agent demonstrating an impact on overall AUC (2-fold increase in AUC) when administered with a high-fat meal. 8
Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs
Current NCCN guidelines for the treatment of B-cell lymphoma recommend BTK inhibitors (preferably acalabrutinib or zanubrutinib due similar efficacy and a more favorable toxicity profile compared with ibrutinib) as options for second-line treatment for MZL and MCL. 28 Pirtobrutinib is recommended as third-line or subsequent therapy for the treatment of MCL. 28 Insertion of pirtobrutinib into the MCL treatment scheme for patients progressing on second-line treatment with a covalent BTK inhibitor may potentially delay the necessity of further cytotoxic chemotherapy. Comparative efficacy data are not yet available; therefore, it is unclear if pirtobrutinib offers improved outcomes relative to other available treatment regimens. Likewise, it is unclear if pirtobrutinib possesses properties to improve outcomes compared with covalent BTK inhibitors when used earlier in the treatment scheme. A phase 3 study (BRUIN MCL-321, NCT04662255) is currently underway comparing pirtobrutinib with investigator choice covalent BTK inhibitor in patients with BTK inhibitor-naïve MCL, evaluating the impact of moving pirtobrutinib to the second-line treatment of MCL (Table 2). 15
Similar to MCL, NCCN guidelines for the treatment of CLL/SLL have incorporated the use of pirtobrutinb. 29 The recommendation to utilize pirtobrutinib in the second-line or third-line setting after failing or becoming intolerant to a covalent BTK inhibitor is based on demonstrated efficacy in the large proportion of patients with CLL in the BRUIN study.4,5 A confirmatory phase 3 trial (BRUIN CLL-321, NCT04666038) is underway comparing pirtobrutinib with idelalisib/rituximab or bendamustine/rituximab in patients receiving prior treatment with a covalent BTK inhibitor. 11 Pirtobrutinib is also being investigated in combination with venetoclax as a second-line treatment of CLL (BRUIN CLL-322, NCT04965493). 14 Moreover, a phase 3, comparative trial is underway in the first-line treatment of CLL where pirtobrutinib is being compared with bendamustine/rituximab (BRUIN CLL-313, NCT05023980) in patients with untreated CLL. 13 In an effort to clarify pirtobrutinib’s place in therapy compared with covalent BTK inhibitors, another phase 3 trial is underway to compare pirtobrutinib with ibrutinib in patients who are BTK inhibitor naïve (BRUIN CLL-314, NCT05254743). 12 See Table 2 for a description of ongoing clinical trials in the development of pirtobrutinib. Despite these ongoing comparative trials, comparative efficacy data are overall lacking to date for pirtobrutinib.
While pirtobrutinib’s place in therapy is being established in both MCL and CLL, as well as other potential B-cell malignancies, an understanding of the medication’s adverse effect profile is paramount to the ideal management of patients receiving this medication. Despite the selective nature of pirtobrutinib for BTK, it nonetheless carries a risk for bleeding and atrial fibrillation, similar to other BTK inhibitors. When comparing across the multiple studies of BTK inhibitors, pirtobrutinib appears to have a similar risk for bleeding compared with the covalent BTK inhibitors (Table 3). Hypertension and atrial fibrillation incidence appear to be on the lower end of the spectrum of incidences associated with the covalent BTK inhibitors and appear to be similar in incidence to that seen with acalabrutinib and zanubrutinib. The comparative trials BRUIN MCL-321 and BRUIN CLL-314 described above will provide comparative safety data among the available BTK inhibitors.12,15 Of note, many of the studies of BTK inhibitors excluded patients with significant cardiovascular disease. Due to the common risk factors for CLL, MCL, and cardiovascular disease (ie, increased age), it is likely that patients treated in routine clinical care will have comorbid cardiovascular diseases; therefore, the incidence of these cardiovascular adverse events may be more frequent outside of the controlled clinical trial setting.
A dilemma often encountered by those managing patients on BTK inhibitors is the management of atrial fibrillation, particularly related to the use of anticoagulation. Due to the presence of both pharmacodynamic (increased bleeding risk) and pharmacokinetic (CYP enzyme/P-glycoprotein) interactions, utilization of anticoagulants is complicated in the presence of BTK inhibitors. Many of the trials, including the BRUIN trial of pirtobrutinib, excluded patients receiving warfarin.4,16,18,19,24 The BRUIN trial allowed the use of anticoagulants (except warfarin) and antiplatelets. 4 Pirtobrutinib is a weak CYP 3A4 inhibitor and moderate P-glycoprotein inhibitor (Table 1); therefore, dabigatran and edoxaban should be avoided due to their susceptibility to P-glycoprotein counter transport. Although apixaban and rivaroxaban are metabolized by CYP 3A4, their susceptibility to P-glycoprotein is minor, resulting in less of a potential interaction with pirtobrutinib compared with dabigatran and edoxaban. Despite the limited pharmacokinetic interaction with apixaban and rivaroxaban, a pharmacodynamic interaction still exists due to the increased bleeding risk with pirtobrutinib. Compared with other BTK inhibitors, an in vitro analysis demonstrated similar impacts on platelet function when pirtobrutinib was compared with ibrutinib and acalabrutinib; however, due to the reversible, noncovalent nature of pirtobrutinib binding, platelet dysfunction was rapidly reversible which may decrease bleeding risk. 30 To mitigate the increased bleeding risk, some have recommended utilizing a lower dose of apixaban or rivaroxaban for 7 to 10 days followed by titration to usual maintenance doses to assess tolerability when coadministered with ibrutinib. 31 Despite a lack of data to support such a strategy, especially with the limited pirtobrutinib data available, it may be reasonable to consider starting an anticoagulant at a lower dose in patients at high risk of bleeding (HAS-BLED score >3). 31
Conclusion
Pirtobrutinib is a noncovalent BTK inhibitor FDA approved for the treatment of R/R MCL and CLL. Trials are ongoing to confirm the results of the initial phase 1/2 BRUIN trial and potentially expand use in MCL/CLL, as well as expand use in other B-cell malignancies. Its unique reversible, noncovalent binding properties that do not involve binding at Cys481 allow for activity in patients with a mutated BTK enzyme (C481 mutation) that no longer respond to covalent BTK inhibitors. Cardiac adverse events, including atrial fibrillation and hemorrhage, are a class effect of BTK inhibitors; however, the observed incidence of these events with pirtobrutinib may be lower than those of other available agents. Data from ongoing clinical trials evaluating pirtobrutinib’s use in B-cell malignancies will help clarify its place in the therapy of these malignancies.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
