The treatment landscape for chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) has undergone a paradigm shift within the last decade, transitioning toward a targeted inhibitor-based treatment approach for most patients.1 The two most successful classes of targeted inhibitors include Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 inhibitors (BCL2i). The first-generation BTK inhibitor ibrutinib has largely been supplanted by the next-generation inhibitors acalabrutinib and zanubrutinib, based on improved safety and efficacy in recent clinical trials; however, all currently available BTK inhibitors target the BTK protein through a similar mechanism and are therefore subject to similar pharmacologic pitfalls.2-4 All currently available BTK inhibitors covalently (irreversibly) bind the BTK protein at its C481 residue, blocking the ATP-binding pocket and abrogating catalytic activity.2 As BTK inhibitors are administered continuously, many patients will ultimately cease to derive a clinical benefit, possibly through acquired resistance to covalent inhibition due to mutations in the C481 protein or downstream effectors, and many experience dose-limiting long-term toxicity.1
Noncovalent (reversible) BTK inhibitors have been in development to improve upon the pharmacologic limitations of covalent BTK inhibitors, with a focus on maintaining clinical activity in C481-mutated BTK and increasing on-target specificity to limit toxicity.1 Pirtobrutinib is the first noncovalent BTK inhibitor developed for use in B-cell malignancies, having gained accelerated FDA approval for use in patients with relapsed/refractory (r/r) mantle cell lymphoma in 2023 based on safety and clinical efficacy data from a subset analysis of the phase I/II BRUIN study.1,5,6 The BRUIN investigators recently published the efficacy results for the inhibitor-exposed CLL/SLL cohort, as well as safety results for all patients with CLL/SLL, discussed herein.7
The BRUIN study is a multicenter, international, phase I/II clinical trial designed to evaluate the safety and efficacy of pirtobrutinib in patients with r/r B-cell malignancies, reporting partial results in 2021.6 In the phase I portion, patients received oral pirtobrutinib monotherapy in increasing doses to determine the recommended phase II dose (RP2D) of 200 mg once daily given in continuous, 28-day cycles. Treatment continued until disease progression, toxicity, or patient withdrawal. The primary endpoint for the CLL/SLL cohort was the overall response rate (ORR) based on the International Workshop on CLL (iwCLL) criteria, with additional endpoints of ORR including partial response with lymphocytosis (PR-L), progression-free survival (PFS), overall survival (OS), safety, and exploratory biomarker analyses.7
From March 21, 2019, to July 29, 2022, a total of 317 patients with r/r CLL/SLL were enrolled and evaluable for safety; 247 had previously received at least one BTK inhibitor and were included in the efficacy cohort.7 The median age was 69 years (range: 36-88 years), and patients were heavily pretreated, having received a median of three previous therapies (range: 1-11).7 Among patients who had been exposed to BTK inhibitors, 40.5% had also previously progressed on a BCL2i, rendering them so-called “double refractory” to the best available therapies.7 A small minority of patients had received cellular therapies including chimeric antigen receptor (CAR) T-cell therapy (5.7%) and allogeneic hematopoietic stem cell transplant (2.4%).7 Most patients had progressed on prior BTK inhibitor therapy (76.9%), with a minority discontinuing due to toxicity (23.1%).7 Most patients also had high-risk molecular features including TP53 aberrancy (46.6%), complex karyotype (42%), and an unmutated immunoglobulin heavy chain variable region gene (IGHV, 84.8%).7
Among patients exposed to BTK inhibitors, the ORR was 73.3%, (95% CI 67.3-78.7), and most responses were partial (71.3%); when PR-L was considered, the ORR increased to 82.2% (95% CI 76.8-86.7).7 An ORR of 70.0% (95% CI 60.0-78.8) was observed in the subgroup of patients with double-refractory disease.7 The majority of patients (96.9%) demonstrated a decrease in the size of target lesions based on computed tomography (CT) evaluations, regardless of prior acquired resistance to BTK inhibitors and/or BCL2i treatment. Median PFS was 19.6 months (95% CI 16.9-22.1) over a median follow up of 19.4 months.7 Among a heavily refractory subgroup of patients who had received all five classes of currently available CLL/SLL-directed therapy, the median PFS was 13.8 months (95% 10.3 to inestimable).7
Among the 317 patients treated with pirtobrutinib, 277 (87.4%) had received at least one dose of pirtobrutinib at the RP2D of 200 mg orally once daily, with a median treatment duration of 16.5 months (range: 0.2 to 39.9 months).7 The most common adverse events (AEs) were infections (any grade: 71.0% of patients, grade 3 or higher: 14.8%), bleeding (42.6%), and neutropenia (32.5%).7 As a class, BTK inhibitors share common AEs of interest thought to occur secondary to off-target effects. Notably, pirtobrutinib demonstrated a tolerable safety profile for treatment-related AEs of interest at any grade when compared with that for historical BTK inhibitors, including rates for atrial fibrillation (1.3%), bleeding (23.7%), hemorrhage (6.9%), hypertension (3.8%), infections (12.3%), and neutropenia (19.6%).7 No sudden cardiac deaths were observed. In total, 16 patients included in the study died due to causes other than disease progression, including coronavirus disease 2019 (COVID-19)-related fatalities (n=8), pneumonia (n=2), septic shock (n=2), and others (n=4).7
Within its limitations as a phase II study lacking a randomized control arm with limited long-term follow-up data, the BRUIN trial demonstrates the promising efficacy and tolerable safety of continuous, oral pirtobrutinib monotherapy for CLL/SLL. The reversible binding of pirtobrutinib circumvents the need for covalent modification of the C481 residue of the BTK protein, thereby maintaining potent activity in both wild-type and C481-mutated BTK and allowing for sequential treatment within the same class of drug, even in patients previously exhibiting progression despite treatment with a covalent BTK inhibitor. Furthermore, the BRUIN trial provides prospective evidence on pirtobrutinib activity in patients with double-refractory CLL/SLL, a high-risk group with traditionally poor outcomes and limited treatment options. Several ongoing phase III trials are evaluating pirtobrutinib in patients with CLL/SLL, and longer-term data will be needed to clarify the durability of responses, long-term safety, and mechanisms of resistance to covalent BTK inhibition.
Dr. Islam indicated no relevant conflicts of interest. Dr. Usmani has received research funding from Amgen, BMS/Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, and Takeda, and reported consulting/advisory board activity for Abbvie, Amgen, BMS, Celgene, Genentech, Gilead, GSK, Janssen, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.