Pirtobrutinib in the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma

ABSTRACT

Pirtobrutinib, a novel noncovalent Bruton’s tyrosine kinase (BTK) inhibitor (BTKi) has demonstrated significant potential in overcoming treatment resistance characterized by BTK mutations in chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL). Unlike currently approved covalent BTKi (cBTKi) such as ibrutinib, acalabrutinib, and zanubrutinib that irreversibly bind to the cysteine 481 (C481) residue of BTK, pirtobrutinib’s non-covalent binding enables it to maintain efficacy even in the presence of cysteine 481 serine (C481S) mutations which are the most common form of acquired resistance. This current review seeks to demonstrate the mechanism of action as well as the clinical efficacy of pirtobrutinib in treating patients with relapsed/refractory CLL/SLL and to describe ongoing studies of pirtobrutinib in combination with other agents and in earlier lines of therapy.

1. Introduction

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) arise from malignant transformation of B cells. CLL is considered to be the most common form of leukemia in the Western hemisphere [1,2]. In 2025, there were an estimated 23,690 new cases of CLL/SLL with a resultant 4,460 deaths, with the disease accounting for 1 in 3 new cases of leukemia diagnosed in the United States (US) [3]. Standard of care treatment regimens for CLL/SLL have changed dramatically in the past few decades. Although chemoimmunotherapy is still used globally, in the United States a shift has been made toward novel agents which are both safer and more effective for the management of this disease [4].

BTKi’s have shown impressive efficacy and safety for the treatment of CLL/SLL, and are now the most commonly prescribed agents in the frontline setting in the US [5]. The first approved BTKi, ibrutinib heralded a new treatment paradigm for management of this disease [6–17]. Second-generation cBTKi, such as acalabrutinib and zanubrutinib, however, have shown improved clinical and safety outcomes for treatment of CLL/SLL, in the frontline and relapsed/refractory setting [18–26]. Another first or subsequent line treatment option for CLL/SLL is the B-cell lymphoma 2 (BCL2) inhibitor, venetoclax, most typically combined with an anti-CD20 monoclonal antibody, which has also demonstrated excellent efficacy and safety [27–29].

Despite these advances, there are still patients who are failed by these targeted therapies, whether through resistance or intolerance [30–32]. After progression on BCL2 and cBTKi, therapeutic options for these patients previously had been limited to chemoimmunotherapy and phosphatidylinositol 3-kinase (PI3K) inhibitors, both of which only provided modest durable responses while subjecting patients to significant adverse effects [33,34]. With the recent Food and Drug Administration (FDA) approval for lisocabtagene maraleucel and pirtobrutinib, however, this has provided CLL/SLL patients with novel treatment options to more effectively control their disease in the third line and beyond [35–38].

Pirtobrutinib, formerly known as LOXO-305, is a selective, noncovalent, oral inhibitor of BTK that acts by inhibiting both wild-type and C481S mutant BTK protein in a reversible fashion [39,40]. In doing so, it can overcome the acquired resistance that develops from prior cBTKi. In 2023, the FDA granted accelerated approval to pirtobrutinib for patients with CLL/SLL who have been failed by both a cBTKi and venetoclax [41]. In this review, we will discuss the pharmacology, clinical efficacy data, toxicity profile, and future considerations for the use of pirtobrutinib in the management of CLL/SLL.

2. Pharmacology

In B-cell malignancies, such as CLL/SLL, BTK plays a critical role in the B cell receptor (BCR) signaling pathway [42]. The BCR recruits BTK to the cell membrane, where it is activated and subsequently activates PLCγ2 [43]. As downstream signaling continues, the activation of PLCγ2 results in calcium influx from the endoplasmic reticulum and for the transduction of NF-κB, a survival mechanism that inhibits programmed cell death, aiding in anti-apoptosis and the maintenance of B-cells (Figure 1) [44,45].

Figure 1.

Schematic depicting how pirtobrutinib binds non-covalently to BTK as opposed to the currently approved covalent BTK inhibitors. Pirtobrutinib is shown to bind in the ATP binding pocket without directly interacting with the CYS481 residue which allows pirtobrutinib to remain effective alongside CYS481 mutations. Covalent bound BTK inhibitors bind active BTK which is depicted by phosphorylation at TYR551. Whereas, pirtobrutinib binds the inactive form of BTK, inhibiting downstream substrates and activity. Created in BioRender.

cBTKi, such as ibrutinib bind to cysteine 481 (C481) irreversibly in the ATP-binding pocket to block its enzymatic function. More selective cBTKi such as acalabrutinib and zanubrutinib similarly bind C481 irreversibly, with a largely shared mechanism of resistance between all cBTKi, via acquisition of C481S mutations [46].

Pirtobrutinib overcomes the C481 mutation resistance by reversibly binding BTK without direct interaction with the C481 residue, allowing inhibition in both C481 mutant and C481 wildtype BTK (Figure 1) [47]. X-ray structures demonstrate that pirtobrutinib binds in the ATP-binding pocket of BTK with both hydrogen bonds and pi-stacking engagement with non-C481 residues of BTK [47]. Furthermore, pirtobrutinib binds BTK in the inactive form and inhibits phosphorylation at tyrosine 551 (Y551), which may inhibit kinase-independent scaffolding interactions. In contrast, cBTKi bind BTK in the activated conformation which does not inhibit Y551 phosphorylation [47,48].

When testing effectiveness in BTK wild-type and BTK C481 mutant mouse xenograft models using both ABC-DLBCL cell lines (OCI-Ly-10 and TMD8) and an MCL cell line (REC-1), pirtobrutinib promoted dose-dependent tumor growth inhibition in all 3 models [47]. Clinical and preclinical investigations show that the mechanism in which pirtobrutinib inhibits BCR signaling is via suppression of BTK downstream signaling pathways via ERK and PLCγ2. Pirtobrutinib also reduces the secretion of cytokines CCL3 and CCL4, biomarkers associated with tumor burden in both wild-type and C481S-mutant CLL [40].

At the recommended 200 mg daily dose schedule, plasma concentrations of pirtobrutinib reach their peak at the two-hour point and a steady state within 5 days. Pirtobrutinib is metabolized by CYP3A4; therefore, strong inhibitors and strong/moderate CYP3A4 inducers should be avoided when possible. Otherwise, pirtobrutinib dose can be adjusted based on the package insert instructions when coadministration cannot be avoided. Pirtobrutinib is also a P-gp inhibitor, a moderate inhibitor of CYP2C8 and BCRP, and a weak inhibitor of CYP2C19 and CYP3A inhibitor so coadministration may lead to an increase in the concentration of these substances and consequent adverse effects [49].

3. Clinical efficacy data

3.1. Phase 1/2 BRUIN trial (NCT03740529)

The phase 1/2 BRUIN trial provided the first experience on both the safety and efficacy of pirtobrutinib in CLL in addition to other B-cell malignancies [37,38]. Focusing on the CLL patients who had been pre-treated with at least a prior cBTKi, at a median follow-up of 27.5 months, pirtobrutinib demonstrated an overall response rate (ORR) of 81.6%, in this heavily pre-treated cohort of 282 CLL patients with 4 median prior lines of therapy. The median progression-free survival (PFS) was 19.4 months, with a longer PFS of 23.0 months for patients who were naïve to a BCL2 inhibitor compared to those with prior exposure with median PFS 15.9 months [50]. Patients with CLL showed similar ORR rates regardless of a number of clinical or biologic features such as age, performance status, number of prior lines of therapy, reason for discontinuation of prior cBTKi, and high risk biologic features such as unmutated IGHV and 17p deletion/TP53 mutation [50]. Pirtobrutinib led to a favorable safety profile, with few grade 3 or higher AEs and low rates of severe bleeding or atrial fibrillation, with only 2.5% of patients discontinuing due to treatment-related adverse events (AE) [50]. The safety of pirtobrutinib continues with longer-term use, as evidenced by the safety experience for patients on the drug for 1 year or more [51].

While most patients in this trial discontinued prior cBTKi for intolerance, 23.6% of patients discontinued due to toxicity or other reasons. The experience of 127 cBTKi intolerant patients who accrued to the phase 1/2 BRUIN trial was recently reported, including 78 patients with CLL/SLL [52]. The most common AE leading to prior BTKi discontinuation was cardiac disorders in 31.5%, atrial fibrillation in 23.6%. With a median follow-up of 17.4 months, the ORR among the patients with CLL/SLL was 76.9% with median PFS of 28.4 months. Pirtobrutinib was well tolerated in this intolerant population with no patients discontinuing due to the reason that they discontinued the prior cBTKi. Cardiac disorders recurred in 25% of treated patients [52]. These data suggest that pirtobrutinib may be another option in the setting of cBTKi intolerance, similar to data from patients who switch to acalabrutinib and zanubrutinib from ibrutinib and/or acalabrutinib [53,54].

The promising results from this study led to the accelerated approval of pirtobrutinib by the FDA for patients with CLL/SLL who have received at least two prior therapies including a cBTKi and venetoclax on 1 December 2023. Pirtobrutinib, along with lisocabtagene maraleucel, which received accelerated approval on 14 March 2024, are both listed as preferred regimens in this third-line setting by the National Cancer Care Network (NCCN) guidelines. In weighing the risks and benefits of these two potential third-line (or beyond) options, especially among double refractory patients, pirtobrutinib’s strengths include its high ORR and excellent safety profile, whereas lisocabtagene maraleucel offers the opportunity for deep and long-lasting remissions following a one-time therapy, albeit in a minority of patients (CR/CRi rate of 20%) and potential for toxicities including cytokine release syndrome, neurologic events, and delayed cytopenias [36]. We suggest employing shared decision-making to help assist patients in deciding which therapy is the best approach based on underlying comorbidities and preferences (Figure 2).

Figure 2.

Algorithm for how to choose most appropriate therapy in the third-line setting, which should first consider whether the patient is double exposed or double refractory. For double exposed patients, third-line options include an alternate BTKi for patients with prior cBtki intolerance, or venetoclax retreatment. In patients who are double refractory, both pirtobrutinib or lisocabtagene maraleucel may be considered. Though prospective data are lacking, use of pirtobrutinib as a bridge to patients prior to lisocabtagene may be a reasonable approach to improve disease bulk which has been a predictor for outcomes.

3.2. Pirtobrutinib in Richter’s transformation

Among patients enrolled to the phase 1/2 BRUIN trial, pirtobrutinib was also used to treat patients with Richter’s transformation (RT) [55–57]. The RT cohort of 82 patients were either treatment-naïve (8 patients) or previously treated for their disease (2 median prior lines of therapy for both CLL/SLL and RT, 4 median prior lines total, with 34% patients having had a prior cBTKi for the RT and 62% had prior cBTKi for the CLL/SLL). The ORR for this entire group was 50.0%, with 13.4% of them achieving CR and 36.6% achieving partial response (PR). In patients previously treated with cBTKi, the ORR was 45.9%. Among those who discontinued cBTKi due to disease progression, the ORR was 42.0%. The median duration of response (DOR) was 7.4 months with an estimated 12-month DOR rate of 45.9%. Notably, eight patients who responded to pirtobrutinib proceeded to allogeneic stem cell transplantation (alloSCT), underscoring its potential as a bridge to a more definitive therapy. Median PFS was 3.7 months. The median OS was 12.5 months after a median follow-up of 18.3 months, with the 18-month OS rate being 44.3% [56,57]. These survival results may be partly attributed to the proportion of patients receiving alloSCT. These results highlight pirtobrutinib’s capacity to achieve durable clinical benefits even in heavily pretreated RT patients, including those who had prior therapy with and resistance to cBTKi.

Pirtobrutinib demonstrated a manageable safety profile in this high-risk patient population. The most common treatment-emergent AEs (TEAEs) included neutropenia (29.3%), fatigue (24.4%), diarrhea, dyspnea, thrombocytopenia, and pyrexia (each occurring in 18.3% of patients). Among grade ≥3 TEAEs, neutropenia was the most frequent (23.2%), followed by thrombocytopenia (11.0%), anemia, and sepsis (9.8% each). None of these patients discontinued pirtobrutinib due to TEAEs [56,57].

3.3. Phase 1b BRUIN Substudy (NCT03740529)

In a substudy from the phase 1/2 BRUIN trial, the combination of pirtobrutinib with venetoclax (PV) or with venetoclax and rituximab (PVR) was examined in previously treated patients with CLL who had not been exposed to BCL2 inhibitor. Fifteen patients were treated with PV and ten with PVR for a total of 25 cycles. Patients had two median prior lines of therapy, 68% with prior cBTKi. The ORR was 93.3% for PV and 100% for PVR, with complete remission (CR) of 46.7% and 30%, respectively. Notably, undetectable minimal residual disease (uMRD) was achieved during treatment in 85.7% of patients treated with PV and 90.0% with PVR, with 70.8% uMRD following completion of cycle 12 for both cohorts. The MRD results compare favorably to what was seen in the MURANO phase 3 trial of venetoclax with rituximab that enrolled primarily cBTKi naïve patients [58,59].

With a median follow-up of 22.1 months, the PFS at 18 months was 92.9% for the PV group and 80.0% for the PVR group. No dose limiting toxicities were observed and the overall safety outcomes were as expected based on the known safety profiles of the agents. Neutropenia (46.7%) and infections (26.7%) were the most common all-cause grade > 3 AEs. The promising results from this study support further investigation of the combination of pirtobrutinib with venetoclax, leveraging the synergistic effects of BTK and BCL2 inhibition to overcome resistance mechanisms and achieve sustained disease control [59].

The BRUIN phase 1/2 trial and the phase 1b substudy have served as a strong foundation for several phase 2 studies and a phase 3 pirtobrutinib program in CLL, which seek to validate pirtobrutinib both alone and in combination in a variety of clinical settings as described below and in Tables 1 and 2. Of the phase 3 trials, only one (BRUIN CLL-321) has reported results at the time of this review.

Table 1.

Description of phase 3 trials using pirtobrutinib in CLL with description of eligible patient population, relevant endpoints, and enrollment status.

Trial name and NCT number (if available)	Comparison groups	Eligible patient population	Primary endpoint	Key secondary endpoints	Enrollment status
BRUIN CLL-321 NCT04666038	Pirtobrutinib vs. investigator’s choice of idelalisib/rituximab or bendamustine/rituximab	Previously treated with at least a prior covalent BTKi	PFS	ORR, OS, TTNT	Active, not recruiting; results have been presented
BRUIN CLL-314 NCT05254743	Pirtobrutinib vs. ibrutinib	Covalent BTKi naïve patients	ORR	EFS, PFS, DOR, OS, TTNT	Active, not recruiting
BRUIN CLL-313 NCT05023980	Pirtobrutinib vs. bendamustine/rituximab	Previously untreated patients, excludes 17p deletion	PFS	OS, TTNT, ORR, DOR	Active, not recruiting
BRUIN CLL-322 NCT04965493	Pirtobrutinib plus venetoclax/rituximab vs. venetoclax/rituximab	Previously treated with at least 1 line of therapy	PFS	OS, TTNT, EFS, ORR	Active, not recruiting
CLL18 [83]	Pirtobrutinib plus venetoclax (fixed duration) vs. pirtobrutinib plus venetoclax (MRD guided duration) vs. venetoclax/obinutuzumab	Previously untreated patients	PFS	Not available	Planned, not yet enrolling

Table 2.

List of current phase 2 clinical trials investigating the use of pirtobrutinib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.

Clinical trial ID	Title	Comparison groups	Eligible patient populations	Primary endpoints	Key secondary endpoints	Enrollment status
NCT05536349	Time-limited Triplet Combination of Pirtobrutinib, Venetoclax, and Obinutuzumab for Patients With Treatment-naïve Chronic Lymphocytic Leukemia (CLL) or Richter Transformation (RT)	Single arm study	Previously untreated CLL/SLL patients or previously untreated RT (but must have received prior therapy for CLL) or relapsed/refractory RT arising from CLL	uMRD	Combined response rate (defined as CR/CRi/PR), PFS, OS, uMRD	Actively recruiting; first datapoint results have been presented
NCT05317936	Pirtobrutinib (LOXO-305) Consolidation for MRD Eradication in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated With Venetoclax	Single arm study	Previously treated CLL/SLL patients, including may have received covalent BTKi and BCL-2 inhibitors	uMRD	CR, CRi, uMRD at different sensitivities, Safety profiles	Active, not recruiting
NCT06466122	Pirtobrutinib (LOXO-305) and Venetoclax for the Treatment of Patients With CLL or SLL Resistant to Covalent BTKi	Single arm study	Previously treated CLL/SLL patients who have been exposed to covalent BTKi	uMRD	ORR, PFS, OS, Incidence of AE	Actively recruiting
NCT06588478	A Study Evaluating the Efficacy and Safety of Pirtobrutinib in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma	Comparingpirtobrutinib at three dose levels	Previously treated CLL/SLL patients who have been exposed to 1–3 prior lines of therapy, including a covalent BTKi	ORR	DOR	Actively recruiting
NCT06333262	Fixed Duration Pirtobrutinib and Obinutuzumab in Chronic Lymphocytic Leukemia	Single arm study	Previously untreated CLL/SLL patients	CR	ORR, PR, EFS, PFS, OS, Time to next line of therapy, Rate of re-treatment with pirtobrutinib	Actively recruiting
NCT04849416	A Study of LOXO-305 in Chinese Participants With Blood Cancer (Including Lymphoma and Chronic Leukemia)	Single arm study	Previously treated CLL/SLL patients who have been exposed to covalent BTKi	ORR Assessed byIndependent Review Committee	ORR Assessed by Investigator, Best overall response rates, DOR, PFS, OS, Pharmacokinetics (AUC), Disease-Related Symptoms and Health-Related Quality of Life Measures	Active, not recruiting
NCT05677919	Pirtobrutinib and Venetoclax with MRD Detection for Previously Untreated Chronic Lymphocytic Leukemia	Single arm study	Previously untreated CLL/SLL patients	uMRD	ORR, CR, DOR, Time to next treatment, PFS, OS, Incidence of AE	Actively recruiting

Abbreviations: CLL = Chronic lymphocytic leukemia; SLL = Small lymphocytic leukemia; RT = Richter transformation; BTKi = Bruton tyrosine kinase inhibitor; BCL-2 = B-cell Lymphoma 2; PFS = Progression free survival; OS = Overall survival; ORR = Overall response rate; CR = Complete response; CRi = Complete remission with incomplete marrow recovery; PR = Partial response; uMRD = Undetectable measurable residual disease; DOR = Duration of response; EFS = Event free survival, AE = Adverse events.

3.4. Ongoing phase 2 trials

Pirtobrutinib is currently being evaluated in several phase 2 studies for the treatment of CLL/SLL, in a variety of clinical settings (Table 2). At the time of this review, preliminary results from NCT05536349 have been reported. This investigator-initiated trial evaluates the combination of pirtobrutinib, venetoclax, and obinutuzumab in treatment naïve patients with CLL/SLL. At the time of presentation, 74 patients have been treated with a median age of 64 years (range: 38–79). Seventy-seven percent had unmutated IGHV and 12% had del(17p)/TP53 mutation. Patients received pirtobrutinib 200 mg daily for 13 cycles, obinutuzumab for 6 cycles, and venetoclax ramp-up started on cycle 2 until reaching target dose of 400 mg that was continued till cycle 13. The primary objective of MRD negativity by next-generation sequencing was assessed in both bone marrow (BM) and peripheral blood (PB) at the end of cycle 7 (C7) and cycle 13 (C13). Those with detectable MRD (≥10⁻⁵ in either PB or BM) at end of C13 could continue pirtobrutinib and venetoclax for another 12 cycles. At the end of C7, reached by 43 patients at the time of presentation, BM and PB uMRD (10⁻⁶ sensitivity) was reached in 28/43 (65%) and 34/43 (79%) patients, respectively, with 91% and 93% of patients achieving uMRD to 10⁻⁴, respectively. At the end of C13, reached by 27 patients, BM and PB uMRD (10⁻⁶ sensitivity) was achieved in 22/27 (81%) and 24/27 (89%) patients, respectively (98% and 100% at 10⁻⁴). Of patients who reached C13, 24/27 patients discontinued all therapy while the remaining three patients were continuing pirtobrutinib and venetoclax as permitted by the study. The most notable grade 3/4 AE reported were neutropenia and thrombocytopenia, occurring in 58% and 18% of patients, respectively, similar to what has been reported with these agents [60].

3.5. Phase 3 BRUIN CLL-321 (NCT04666038)

BRUIN CLL-321 trial is a pivotal phase 3, randomized study that evaluated the efficacy and safety of pirtobrutinib monotherapy compared to investigator’s choice (IC) of idelalisib and rituximab (IdelaR) or bendamustine and rituximab (BR) combinations. The study exclusively enrolled patients with CLL/SLL who had previously been treated with at least one cBTKi. Stratification was based on del(17p) and prior treatment with venetoclax. Crossover to pirtobrutinib was permitted for patients with IRC-confirmed progression on both arms. The trial’s primary endpoint was PFS by independent review committee (IRC) assessment with secondary endpoints including overall survival (OS), event-free survival (EFS), and time to next treatment (TTNT). Importantly, this was the first randomized phase 3 trial to focus specifically on post-cBTKi treatment for heavily pretreated CLL/SLL patients, thus providing essential insights into the relative performance of pirtobrutinib in this difficult clinical setting [61,62].

In total, 238 patients were randomized in a 1:1 ratio to receive either pirtobrutinib or IC. Patients treated with IC included 77 (70.6%) with idela-R and 32 with BR (29.4%). Prior median lines of therapy were 3 and 50.4% of patients had received venetoclax previously. At a median follow-up of 17.2 months, the median PFS of 14.0 months for pirtobrutinib compared to 8.7 months for IC was observed (hazard ratio [HR] = 0.58; p = 0.01) based on Independent Review Committee (IRC) assessments. Investigator-assessed results showed a median PFS of 15.3 months for pirtobrutinib versus 9.2 months for IC (HR = 0.48; p < 0.0001). EFS with pirtobrutinib was 14.1 months compared to 7.6 months for IC (HR = 0.39; p < 0.0001). Perhaps most impressively, TTNT was 24.0 months for pirtobrutinib versus 10.9 months for IC (HR = 0.37, p < 0.0001). In venetoclax-naïve patients, TTNT was even longer at 29.5 months, underscoring its potential in optimizing treatment sequences. There was no difference in OS, likely related to the crossover element of the trial, with 50 of 66 patients crossing over to receive pirtobrutinib Pirtobrutinib demonstrated consistent efficacy across high-risk stratified subgroups, including those with del(17p), TP53 mutations, unmutated IGHV, or complex karyotypes.

Pirtobrutinib showed a more favorable safety profile compared to IC, with fewer treatment-related discontinuations (5.2% vs. 21.1%). TEAEs were also less frequent, notably diarrhea (16.4% vs. 31.2%), fatigue (11.2% vs. 20.2%), and nausea (11.2% vs. 20.2%). Severe AE (Grade ≥3) were also less common, such as lower rates of neutropenia (20.7% vs. 27.5%). The overall AE profile was similar to what was seen in the phase 1/2 BRUIN trial with no unexpected safety signals. Additionally, the median treatment duration for pirtobrutinib was significantly longer at 15.1 months compared to 7.1 months for idelaR and 4.7 months for BR, emphasizing its tolerability and suitability for long-term management [62].

This trial likely will lead to approval of pirtobrutinib in the post-cBTKi setting, though it does not address an important question: whether pirtobrutinib or venetoclax-based regimens should be used in the second line following progression on a cBTKi in the frontline? The data supporting both approaches are strong [63,64]. A matching-adjusted indirect comparison suggests similar PFS for pirtobrutinib and venetoclax monotherapy; however, venetoclax is frequently combined with an anti-CD20, limiting the applicability of these results to modern practices [65]. Venetoclax-based approaches offer the benefit of time-limited administration when paired with an anti-CD20, with longer follow-up. Prospective data are limited in the post-cBTKi setting, though real-world data have provided support for venetoclax efficacy both alone and in combination with anti-CD20 in the post-cBTKi setting [66–69]. Venetoclax also carries the downside of administration hurdles (tumor lysis syndrome monitoring and intravenous administration for the anti-CD20). Pirtobrutinib offers ease of administration and an excellent safety profile, though long-term responses are uncommon [66–69]. Assuming an FDA approval occurs, it would be reasonable to discuss both options with patients and select which therapy fits best with the patient’s preferences and ultimate goals of therapy.

3.6. Ongoing phase 3 trials

BRUIN CLL-322 (NCT04965493) seeks to evaluate the efficacy of pirtobrutinib in combination with venetoclax and rituximab in patients with relapsed/refractory disease, approximately 80% of whom were previously treated with a cBTKi. Approximately 600 patients were enrolled into this study and randomized 1:1 to the trial arm vs the control arm of venetoclax plus rituximab (MURANO regimen). Patients were stratified by del(17p) status and prior BTKi exposure. There were no restrictions on how many lines of therapy the patient previously received, except for no prior use of BCL2 or non-covalent BTKi. Primary endpoint is PFS. The study seeks to establish that the addition of pirtobrutinib to the MURANO regimen in a heavily BTKi-pretreated CLL/SLL patient population will prolong PFS as compared to using the MURANO regimen alone [70].

BRUIN CLL-314 (NCT05254743) seeks to evaluate pirtobrutinib in both the frontline and later-line settings in CLL/SLL patients. The study includes CLL/SLL patients who were BTKi-naïve. Approximately 650 patients enrolled in trial and were stratified based on del(17p) status and the number of prior lines of therapy received. Patients were randomized 1:1 to either pirtobrutinib 200 mg daily or ibrutinib 420 mg daily. The primary endpoint is to establish non-inferiority with respect to ORR for pirtobrutinib compared to ibrutinib in this patient population, though a key secondary endpoint is to test superiority of pirtobrutinib versus ibrutinib in addition to comparison of safety [71].

BRUIN CLL-313 (NCT05023980) is a randomized trial comparing pirtobrutinib monotherapy to BR in treatment naïve CLL/SLL patients without 17p deletion. Approximately 250 patients were randomized 1:1, stratified based on IGHV status and Rai stage. Patients in the BR arm can crossover to the pirtobrutinib monotherapy arm in the setting of IRC-confirmed progressive disease. The primary endpoint is PFS [72,73].

3.7. Acquired resistance mechanisms to Pirtobrutinib

As noted, a particular advantage of pirtobrutinib is that it reversibly binds to the C481 residue of BTK, thus overcoming the most common resistance mutation that emerges with prolonged use of cBTKi. As is inevitable with any targeted therapy, alternate mechanisms of resistance to pirtobrutinib have since been described among patients with CLL.

Reports have shown that patients who progressed on pirtobrutinib have developed on-target resistance mutations in the form of non-C481 BTK mutant clones and downstream PLCγ2 mutations [74–77]. The most common resistance mutations seen include the gatekeeper T474I/F and kinase-impaired L528W mutations. Both mutations are within the kinase domain of BTK, causing sidechain point substitutions and inhibiting the binding of pirtobrutinib and other BTK inhibitors [78]. The T474I mutation causes steric interference with pirtobrutinib and other BTK inhibitors through the modification from Thr474 to an isoleucine side chain, preventing the drugs from binding [79]. BTK L528W is a kinase-impaired mutation and decreases the catalytic activity of BTK rendering it inactive [74]. However, downstream signaling is maintained by activating the SRC kinase HCK, thus conferring resistance to covalent and noncovalent BTK inhibitors [80]. Other BTK mutations included D539A/G/H, V416L, M437R, Y545N, and A428D [75]. Some of these mutations may cause resistance to both cBTKi and noncovalent BTKi therapies [74]. It remains to be seen whether these acquired resistance mutations will become either more or less prevalent if pirtobrutinib is used in earlier lines of therapy or in combination with other treatments.

3.8. Looking into the future: CLL18, broader use of pirtobrutinib in the frontline

The CLL18 trial is designed to compare the standard-of-care fixed-duration venetoclax and obinutuzumab regimen with two pirtobrutinib-containing regimens: first, a fixed-duration combination of pirtobrutinib and venetoclax and second, an MRD-guided combination of pirtobrutinib and venetoclax. As this trial has not yet begun accrual at the time of this review, one can conclude it will take many years to see the results [81]. However, should CLL18 be positive, either a fixed-duration or MRD-guided duration of pirtobrutinib with venetoclax may offer many benefits compared to venetoclax and obinutuzumab given the all-oral administration schema and potential for improved efficacy and/or safety compared to previously studied BTKi and BCL2 regimens [14,17,82]. The ongoing trials which have both met accrual targets, BRUIN CLL-313 and BRUIN CLL-314 May lead to registrational approval of pirtobrutinib in the frontline as well, if positive. However, these studies will not be able to answer an important question related to pirtobrutinib’s positioning in the frontline as a continuous monotherapy: namely, does the use of pirtobrutinib before a covalent BTKi have the potential to lead to cross-resistance with the covalent BTKi class [83,84]? This stresses the importance of longer-term follow-up and prospective collection of progression samples and data on sequential lines of therapy and response, to better understand for which patients’ frontline pirtobrutinib may be considered.

4. Conclusion

Pirtobrutinib has demonstrated impressive efficacy as a monotherapy in heavily pre-treated patients with CLL, including in the phase 1/2 BRUIN trial and the phase 3 BRUIN 321 trial. Despite its notable efficacy, long-term treatment with pirtobrutinib may face challenges due to the emergence of resistance mechanisms. Extrapolating from frontline data of covalent BTKi, emergence of resistance mutations is either rare or significantly delayed compared to patients with heavily relapsed disease, likely owing to the greater degree of genomic instability among the latter group [9,85]. Time will tell if pirtobrutinib resistance follows a similar path. This underscores the importance of molecular testing following progression on pirtobrutinib therapy, especially for the ongoing clinical trials with this agent. As has been observed with time-limited combination of ibrutinib and venetoclax, one would expect a potential benefit of similar pirtobrutinb-based combination treatments to limit development of resistance mutations [85,86]. Future trials on the horizon will further expound on the efficacy of pirtobrutinib in earlier lines of therapy and shed light on the clinical safety and efficacy of pirtobrutinib in combination with other therapies. At the time of this review, pirtobrutinib has been established as a preferred third-line treatment option for patients with prior cBTKi and venetoclax, though it may soon be employed in earlier lines of therapy, based on the results of completed and ongoing trials (Figure 3). Pirtobrutinib’s favorable pharmacokinetic profile, with a prolonged half-life and safety profile, supports its promise as a combination partner when compared to other BTKi. This allows it to be a valuable addition to the therapeutic armamentarium of CLL/SLL, especially in cases where resistance to cBTKi limits treatment options.

Figure 3.

Schematic of therapeutic sequences involving pirtobrutinib both based on the current accelerated FDA approval and based on whether selected completed and ongoing trials in the relapsed setting lead to earlier FDA approvals. Lisocabtagene maraleucel is not incorporated in this schematic for simplicity and is discussed in Figure 2.

Funding Statement

No funding received.

Article highlights

• Pirtobrutinib has demonstrated excellent efficacy and safety in CLL patients treated with at least a prior covalent BTK inhibitor based on the BRUIN phase 1/2 trial.

• Pirtobrutinib has demonstrated activity and safety in patients with covalent BTKi intolerance in a subset analysis from the BRUIN phase 1/2 trial.

• Similar safety has been demonstrated in the phase 3 BRUIN CLL-321 trial, with comparable efficacy considering differences in patient populations.

• Pirtobrutinib shows early efficacy and good safety when combined with venetoclax (with or without obinutzumab) in phase 1b trial.

• Pirtobrutinib has high rates of both response and undetectable MRD when combined with venetoclax and obinutuzumab in the frontline setting in a phase 2 trial.

• Pirtobrutinib has also demonstrated efficacy in patients with Richter’s transformation.

• Resistance to pirtobrutinib is most typically via the acquisition of mutations at non-C481 residues of BTK, including at T474 and L528.

• Pirtobrutinib has additional ongoing studies both in the investigator-initiated setting and in the phase 3 setting.

Author contribution

Syed Ibrahim, Nghia Pham, Aarushi Sahni, Samantha Sekeres, Allison Cool, and Justin Taylor drafted and substantially revised the article.

Catherine C. Coombs substantially revised and critically reviewed the article.

All authors agreed on the journal to which this article was submitted, reviewed and agreed on all versions of the article before submission, during revision, and the final version accepted for publication, and any significant changes introduced at the proofing stage. All authors agree to take responsibility and be accountable for the contents of the article and to share responsibility to resolve any questions raised about the accuracy or integrity of the published work.

Disclosure statement

C.C.C. has received honoraria/served as a consultant for AbbVie, Allogene, AstraZeneca, Beigene, BMS, Genentech, Janssen, Lilly, Octapharma, Pharmacyclics, have served on speaker’s bureaus for AbbVie, AstraZeneca, Beigene, Genentech, Lilly, have stock in Bluebird Bio, Geron, Pfizer, and have received research funding (paid to institution) from AbbVie, AstraZeneca, Beigene, CarnaBio, Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Writing disclosure

No writing assistance was utilized in the production of this manuscript.