All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the Lymphoma Coalition.
An expert panel hosted by
Customizing first-line BTK inhibitors for CLL
with Gilles Salles, Paolo Ghia, and Francesc Bosch
Wednesday, October 23, 2024
18:30-19:30 BST
This independent educational activity is supported by Pharmacyclics LLC, an AbbVie Company and Janssen Biotech. All content is developed independently by the faculty. The funder is allowed no influence on the content of this activity.
The Lymphoma Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the Lymphoma Hub cannot guarantee the accuracy of translated content. The Lymphoma Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.
When treating B cell-malignancies, covalent inhibitors correspond to the most frequently used drug class to target Bruton’s tyrosine kinase (BTK) pathway. These irreversible BTK inhibitors (BTKi) have low oral bioavailability, short half-lives, and high protein binding affinity, which results in incomplete target inhibition towards the end of the dosing interval, ultimately leading to drug resistance. Currently, up to 40% of patients treated with first-generation BTKi will discontinue the treatment due to drug resistance. Frequently, these patients harbor BTK C481 mutations.
Pirtobrutinib (also known as LOXO-305), an orally available, highly selective, reversible BTKi that can sequentially bind in a covalent and noncovalent way to its target, has been recently evaluated by Mato et al., in a first-in-human phase I/II trial in pretreated B-cell malignancies.1
For phase I
For phase II
Patient characteristics are summarized in Table 1. Median age across the study was 68 years. Previous BTK inhibition therapy was received by 76% of all 323 patients treated with pirtobrutinib. Other previously received therapies included anti-CD20 antibody (94%), chemotherapy (87%), BCL-2 inhibitor (25%), PI3K inhibitor (16%), lenalidomide (14%), autologous stem-cell transplant (7%), allogeneic stem-cell transplant (3%), and CAR T-cell therapy (7%).
Table 1. Patient demographics*
Characteristic |
ALL (n = 323) |
CLL/SLL (n = 170) |
MCL (n = 61) |
WM (n = 26) |
Other (n = 66) |
---|---|---|---|---|---|
Male, % |
66 |
64 |
77 |
69 |
61 |
ECOG PS, % |
|
|
|
|
27 65 6 |
Number of previous lines of systemic therapy (all patients) |
3 (2–5) |
3 (2–5) |
3 (2–4) |
3 (2–4) |
4 (3–5) |
Number of previous lines in BTK pretreated |
3 (2–5) |
4 (2–5) |
3 (2–4) |
3 (3–4) |
5 (3–7) |
Reasons for previous BTKi discontinuation |
|||||
Progressive disease, % |
71 |
67 |
77 |
67 |
79 |
Toxicity or other, % |
29 |
33 |
23 |
33 |
21 |
BCL2, B-cell lymphoma-2; BTKi, Bruton’s tyrosine kinase inhibitor; CLL, chronic lymphocytic leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; SLL, small lymphocytic lymphoma; MCL, mantle cell lymphoma; WM, Waldenström’s macroglobulinemia. *Adapted from Mato et al.1 †Patients with diffuse large B-cell lymphoma/DLBCL (n = 26), follicular lymphoma/FL (n = 12), marginal zone lymphoma/MZL (n = 13), Richter’s transformation (n = 9), other transformation (n = 3), B-cell prolymphocytic leukemia/B-PLL (n = 2), and hairy cell leukemia/HCL (n = 1). |
During this study, 87% of adverse events (AEs) were Grade 1 or 2. Dose interruptions were recorded in 8% of patients, dose reduction in 2%, and 1% discontinued permanently due to drug-related adverse events. Nevertheless, a longer follow-up is needed to describe the safety profile of pirtobrutinib fully.
Grade ≥3 neutropenia was observed in 10% of the overall patient population, but it was not dose-dependent. Of note, less than 1% of patients experienced atrial arrhythmias and were considered not related to pirtobrutinib. A similar safety profile was observed in patients with various tumor types and those who received at least one dose of 200 mg pirtobrutinib. Treatment-related AEs of any grade are listed in Table 2.
Table 2. TRAEs reported in the overall population (N = 323)*
TRAEs of any grade occurring in ≥3% of patients, % |
|
---|---|
Diarrhea |
9 |
Contusion |
9 |
Fatigue |
8 |
Neutropenia |
6 |
Headache |
4 |
Nausea |
3 |
Anemia |
3 |
Maculopapular rash |
3 |
Dizziness |
3 |
Hyperuricemia |
3 |
Pruritus |
3 |
TRAEs of special interest, % |
|
Bruising |
12 |
Rash |
6 |
Arthralgia |
2 |
Hemorrhage |
2 |
Hypertension |
1 |
TRAEs, treatment-related adverse events. |
ORRs achieved with pirtobrutinib in the different types of malignancies are presented in Figure 1. Response distribution, median follow-up time, and patients still on treatment in every cohort at the time of data cutoff are summarised in Table 3.
Figure 1. ORR with pirtobrutinib in all efficacy-evaluable patients across all dose levels by disease*
CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; ORR, overall response rate; WM, Waldenström’s macroglobulinemia.
*Adapted from Mato et al.1
Table 3. Depth of response achieved at data cutoff by patients with CLL/SLL, MCL, and WM treated with pirtobrutinib*
B-cell malignancy |
CR, % |
PR, % |
SD, % |
PD, % |
Median follow-up, |
Patients still on treatment, |
---|---|---|---|---|---|---|
CLL/SLL |
|
|
|
|
|
|
MCL |
25 |
27 |
18 |
21 |
6 |
57 |
WM |
— |
47 |
37† |
16 |
5 |
77 |
CLL, chronic lymphocytic leukemia; CR, complete response, MCL, mantle cell lymphoma; PD, progressive disease; PR, partial response; SD, stable disease; SLL, small lymphocytic lymphoma; WM, Waldenström’s macroglobulinemia |
Responses recorded in other malignancies were:
Pirtobrutinib shows a favorable safety profile and promising efficacy in multiple B-cell neoplasms. This novel reversible BTKi can be safely administered at full dose without the requirement of a ramp-up period. Moreover, there was no maximum tolerated dose identified.
Pirtobrutinib enables the sequential use of inhibitors that bind to the BTK receptor through covalent and noncovalent mechanisms, offering a new therapeutic alternative for patients with B-cell malignancies refractory to first- and second-generation BTKi.
With these positive preliminary results of the BRUIN study, phase III trials are ongoing to evaluate pirtobrutinib in patients previously exposed to BTKi to treat CLL/SLL (BRUIN CLL-321, NCT04666038), or MCL (BRUIN MCL-321, NCT04662255).
Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. DOI: 10.1016/S0140-6736(21)00224-5
Understanding your specialty helps us to deliver the most relevant and engaging content.
Please spare a moment to share yours.
Please select or type your specialty
Your opinion matters
Subscribe to get the best content related to lymphoma & CLL delivered to your inbox