1 september 2023: zie ook dit artikel: https://kanker-actueel.nl/pirtobrutinib-loxo-305-krijgt-versnelde-goedkeuring-van-fda-voor-gebruik-bij-zwaar-voorbehandelde-patienten-met-recidief-of-refractair-mantelcellymfoom.html

Update 24 juni 2026:

Een nieuwe tussenanalyse van de BRUIN-studie, een open label gerandomiseerde fase III studie met totaal 638 deelnemende patiënten (PVR, n=321; VR, n=318) met gevorderde voorbehandelde Chronische Lymfatische Leukemie (CLL) en met een kleincellig Lymfatisch Lymfoom (SLL) blijkt pirtobrutinib (Jaypirca) een zogeheten niet-covalente BTK-remmer, na ten minste drie andere behandelingen waaronder systemische therapie (chemokuren), plus een andere covalente BTK-remmer een betere ziekteprogressievrije overleving (PFS) te geven vergeleken met een vaste behandelingsduur boven venetoclax plus rituximab, met een ziekteprogressievrije overleving van 86,9% versus 71,8% op 2-jaars meting bij een mediane follow-up van 27,3 maanden.

Ook het aantal complete remissies was beter 31,8% versus 23,3% voor pirtobrutinib (Jaypirca) en de analyse liet ook aanzienlijk hogere percentages ondetecteerbare minimale restziekte zien.

Het behandelingseffect was consistent in risicogroepen en bij patiënten die eerder waren blootgesteld aan covalente BTK-remmers, inclusief patiënten bij wie de ziekte was voortgeschreden tijdens BTK-therapie (HR, 0,444 in de subgroep met stopzetting van de BTK-therapie).
De toxiciteitsprofielen waren vergelijkbaar tussen de behandelingsgroepen; graad ≥3 bijwerkingen kwamen voor bij 78,8% versus 73,0% van de patiënten, de frequentie van atrium fibrillatie bleef laag en het tumorlysissyndroom kwam minder vaak voor bij de drievoudige therapie.

Zie verder meer over deze studie verderop in dit artikel en nieuwe abstract staat onderaan in dit artikel zoals gepresenteerd tijdens EHA congres 2026.

1 september 2023: Bron: N Engl J Med 2023; 389:33-44, juli 2023

Voor patiënten met gevorderde zwaar voorbehandelde Chronische Lymfatische Leukemie (CLL) en met een kleincellig Lymfatisch Lymfoom (SLL) blijkt pirtobrutinib (Jaypirca) een zogeheten niet-covalente BTK-remmer, na ten minste drie andere behandelingen waaronder systemische therapie (chemokuren), plus een andere covalente BTK-remmer alsnog een effectieve behandeling te zijn. Mediaan bereikte 73,3 procent een complete remissie. De ziektevrije tijd was mediaan 19,6 maanden en slechts 9 van de 317 patiënten stopte de behandeling wegens ernstige bijwerkingen. Blijkt uit de BRUIN-studie, een fase I/II studie met totaal 317 patiënten.

De resultaten:

In totaal kregen 317 patiënten met CLL of SLL pirtobrutinib, waaronder 247 die eerder een BTK-remmer hadden gekregen. Onder deze 247 patiënten was het mediane aantal eerdere therapielijnen 3 (variërend van 1 tot 11), en 100 patiënten (40,5%) hadden ook een B-cellymfoom 2 (BCL2)-remmer zoals venetoclax gekregen.
Het percentage patiënten met een algehele respons op pirtobrutinib was 73,3% (95% betrouwbaarheidsinterval , 67,3 tot 78,7), en het percentage was 82,2% (95% BI, 76,8 tot 86,7) wanneer de gedeeltelijke respons met lymfocytose werd meegerekend.
De mediane progressievrije overleving was 19,6 maanden (95% BI: 16,9 tot 22,1).

Bijwerkingen:

Van alle 317 patiënten met CLL of SLL die pirtobrutinib kregen, waren de meest voorkomende bijwerkingen infecties (bij 71,0%), bloedingen (bij 42,6%) en neutropenie (bij 32,5%).
Bij een mediane behandelingsduur van 16,5 maanden (variërend van 0,2 tot 39,9) traden sommige bijwerkingen die doorgaans geassocieerd worden met BTK-remmers relatief zelden op, waaronder hypertensie (bij 14,2% van de patiënten), atriumfibrilleren of flutter (bij 3,8%) en ernstige bloedingen (bij 2,2%).
Slechts 9 van de 317 patiënten (2,8%) stopten met pirtobrutinib vanwege een behandelingsgerelateerde bijwerking.

CONCLUSIES
In dit onderzoek bleek pirtobrutinib werkzaam bij patiënten met zwaar voorbehandelde CLL of SLL die eerder een covalente BTK-remmer hadden gekregen. De meest voorkomende bijwerkingen waren infecties, bloedingen en neutropenie.

Het abstract van de studie is gepubliceerd in NEJM, juli 2023. Voor het volledige studierapport moet er betaald worden:

Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia

Anthony R. Mato, M.D., M.S.C.E.,
Jennifer A. Woyach, M.D.,
Jennifer R. Brown, M.D., Ph.D.,
Paolo Ghia, M.D., Ph.D.,
Krish Patel, M.D.,
Toby A. Eyre, M.B., Ch.B., M.D.,
Talha Munir, M.B., B.S.,
Ewa Lech-Maranda, M.D., Ph.D.,
Nicole Lamanna, M.D.,
Constantine S. Tam, M.D.,
Nirav N. Shah, M.D.,
Catherine C. Coombs, M.D.,

Abstract

BACKGROUND

Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton’s tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition.

METHODS

We conducted a phase 1–2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety.

RESULTS

A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval , 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event.

CONCLUSIONS

In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529. opens in new tab.)

EDITORIALJUL 6, 2023Inhibiting BTK in Chronic Lymphocytic LeukemiaA.P. Kater and B. Eichhorst

Supported by Loxo Oncology, a wholly owned subsidiary of Eli Lilly.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Mato and Woyach contributed equally to this article.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the BRUIN trial patients and their caregivers, without whom this work would not be possible; the trial staff; and Declan O’Dea, Ph.D., and Alyson Essex, Ph.D., employees of Eli Lilly, who provided medical writing assistance with an earlier version of the manuscript.

Author Affiliations

From Memorial Sloan Kettering Cancer Center (A.R.M.), and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center (N.L.), New York, the Donald and Barbara Zucker School of Medicine, Northwell–Hofstra, Uniondale (J.M.R.), Northwell Health Cancer Institute at Lake Success, North New Hyde Park (J.M.R.), and the Lymphoma Section, Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo (F.H.-I.) — all in New York; the Ohio State University Comprehensive Cancer Center, Columbus (J.A.W.), and Cleveland Clinic, Cleveland (D.J.) — both in Ohio; Dana–Farber Cancer Institute and Harvard Medical School — both in Boston (J.R.B.); Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan (P.G.), and IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seràgnoli” (P.L.Z.), and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Università di Bologna (P.L.Z.), Bologna — all in Italy; the Center for Blood Disorders and Cellular Therapy, Swedish Cancer Institute (K.P.), and the Fred Hutchinson Cancer Center, University of Washington (C.S.U.) — both in Seattle; Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Centre, Oxford (T.A.E.), and the Department of Haematology, St. James’s University Hospital, Leeds (T.M.) — both in the United Kingdom; the Institute of Hematology and Transfusion Medicine, Warsaw (E.L.-M.), and Maria Sklodowska-Curie National Research Institute of Oncology, Krakow (W.J.) — both in Poland; Peter MacCallum Cancer Centre, Royal Melbourne Hospital and the University of Melbourne, Melbourne, VIC (C.S.T., J.F.S.), and Linear Clinical Research and Sir Charles Gairdner Hospital (C.Y.C.), and the Medical School, University of Western Australia (C.Y.C.), Perth, WA — all in Australia; Medical College of Wisconsin, Milwaukee (N.N.S.); University of North Carolina at Chapel Hill, Chapel Hill (C.C.C.); the University of California, San Francisco, San Francisco (B.F.); Florida Cancer Specialists, Sarah Cannon Research Institute, Sarasota (M.R.P.), and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami (A.J.A.) — both in Florida; Winship Cancer Institute, Emory University, Atlanta (J.B.C.); the Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia (J.N.G.); Sarah Cannon Research Institute, Nashville (I.W.F.); Robert H. Lurie Comprehensive Cancer Center, Division of Hematology–Oncology, Northwestern University Feinberg School of Medicine, Chicago (S.M.); Loxo@Lilly (M.B., B.N., P.A., D.W., D.E.T.) and Eli Lilly (C.W., A.S.R.) — both in Indianapolis; and M.D. Anderson Cancer Center, Houston (W.G.W.).

Dr. Woyach can be contacted at jennifer.woyach@osumc.edu or at the Ohio University Comprehensive Cancer Center, 460 W. 10th Ave., Columbus, OH 43210.

A complete list of the BRUIN investigators is provided in the Supplementary Appendix, available at NEJM.org.

FIXED-DURATION PIRTOBRUTINIB PLUS VENETOCLAX–RITUXIMAB VERSUS VENETOCLAX–RITUXIMAB FOR PATIENTS WITH PREVIOUSLY TREATED CLL/SLL: A PHASE 3, RANDOMIZED TRIAL (BRUIN CLL-322)

Faculty / Presenters

Author(s): Matthew Davids, Toby A. Eyre, Jennifer Woyach, Lindsey Roeker, Alessandra Ferrajoli, Yucai Wang, Constantine S. Tam, Wojciech Jurczak, Pier Luigi Zinzani, Martin Simkovic, Jianyong Li, Francisco Bosch Albareda, Damien Roos-Weil, Paula Cramer, Anders Österberg, Prioty Islam, Ryan Jacobs, Alan Skarbnik, Seema Ali Bhat, Suhyun Kang, Bastien Nguyen, Samuel Clark McNeely, Karen Chung, Joana Oliveira, Rodrigo Ito, Paolo Ghia, William Wierda

(Abstract release date: 06/02/26) EHA Library. Presenters F. 06/02/2026; 4214968; LB5001;

This abstract is embargoed until the start of the Late-Breaking Oral Session on Sunday, June 14, 2026, 09:15 CEST.

Presentation during EHA2026: The Late-Breaking Oral Session will be held on Sunday, June 14, 2026, 09:15 CEST and will be accessible for on-demand viewing from June 17 to October 15, 2026 on the Congress platform

Abstract: EHA-7224 Short: LB5001

Title: FIXED-DURATION PIRTOBRUTINIB PLUS VENETOCLAX–RITUXIMAB VERSUS VENETOCLAX–RITUXIMAB FOR PATIENTS WITH PREVIOUSLY TREATED CLL/SLL: A PHASE 3, RANDOMIZED TRIAL (BRUIN CLL-322)

Type: Oral Presentation

Session title: Late-Breaking Oral Session

Background:
Venetoclax-rituximab (VR) is the current standard of care (SOC) fixed-duration therapy for relapsed/refractory (R/R) CLL; however, prospective data are limited in patients (pts) previously treated with covalent BTK inhibitors (cBTKis), the most commonly used first-line SOC. Pirtobrutinib, a highly selective noncovalent (nc) BTKi, has demonstrated efficacy in first-line, second-line, and more heavily pretreated R/R CLL, including in pts with prior cBTKi exposure, leading to global regulatory approvals. The synergy of dual inhibition of BTK and BCL2 combined with anti-CD20 therapy provides rationale for adding pirtobrutinib to VR (PVR) to deepen responses and improve outcomes in R/R CLL, particularly in the post-cBTKi setting.

Aims:

To compare the efficacy and safety of fixed-duration PVR v VR in pts with R/R CLL.

Methods:

Pts were randomized 1:1 to PVR or VR, stratified by del(17p) status and prior cBTKi exposure. Pts with prior ncBTKi or BCL2i exposure were excluded. Both arms received venetoclax (25 cycles [C]) and rituximab (6C); the PVR arm also received fixed-duration pirtobrutinib (28C), with a 3C pirtobrutinib-rituximab lead-in before venetoclax initiation. The primary endpoint was IRC-assessed PFS (iwCLL 2018). Secondary endpoints included INV-assessed PFS, OS, TTNT, ORR, and safety. MRD analyses (clonoSEQ®) were exploratory. This planned interim analysis tested PVR superiority in IRC-PFS using a group sequential approach to control type I error. Data cutoff: 2Feb2026.

Results:

639 pts were randomized (PVR, n=321; VR, n=318). Median age was 68 years (range, 32-87); median number of prior line of therapies was 2 (range, 1-9). 510 (79.8%) pts had prior cBTKi exposure of whom 362 (71.0%) had discontinued cBTKi due to progressive disease (PD). PVR demonstrated superiority in IRC-PFS v VR in the ITT population (HR, 0.547; 95% CI, 0.400-0.748; P=0.0001; Figure); median follow-up 27.3 months (95% CI, 25.49-29.86). Twenty-four-month PFS was 86.9% with PVR v 71.8% with VR. The PFS benefit with PVR was consistent across prespecified subgroups, including pts with prior cBTKi exposure, those who discontinued prior cBTKi due to PD, and pts with del(17p)/TP53 mutation. TTNT favored PVR (HR, 0.498; 95% CI, 0.352-0.704). OS data are immature (HR, 0.891; 95% CI, 0.568-1.398). Peripheral blood undetectable (u) MRD4 rates at end of treatment were higher with PVR in pts with evaluable samples (101/117 [86%] v 71/117 [61%]; P<0.0001). Rates of any grade (G) AEs (PVR v VR: 99.7% v 98.1%) and G≥3 AEs (78.8% v 73.0%) were similar between arms, including low rates of any G atrial fibrillation/flutter (3.5% v 2.6%), hypertension (12.0% v 7.4%), and hemorrhage (14.2% v 10.6%). G≥3 clinical AEs of interest included neutropenia (50.3% v 43.7% [febrile neutropenia 2.2% v 3.5%]) and tumor lysis syndrome (0.9% v 3.9%). Discontinuation rates due to treatment-related AEs were similar for PVR v VR (5.4% v 5.1%).

Summary/Conclusion:

PVR showed a statistically significant and clinically meaningful improvement in IRC-PFS compared with VR in previously treated CLL, with higher uMRD rates and a similar safety profile. BRUIN CLL-322 provides the first randomized phase 3 data for any BTKi as part of a fixed-duration regimen in R/R CLL, including in pts previously treated with cBTKi, and establishes fixed-duration PVR as a potential new SOC for R/R CLL.

References

Davids MS, Eyre TA, Woyach JA, et al. Fixed-duration pirtobrutinib plus venetoclax–rituximab versus venetoclax–rituximab for patients with previously treated CLL/SLL: a phase 3, randomized trial (BRUIN CLL-322). Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract LB5001.
Jaypirca (pirtobrutinib) now approved by U.S. FDA for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. News release. Eli Lilly and Company. December 1, 2023. Accessed June 14, 2026. https://investor.lilly.com/news-releases/news-release-details/jaypircar-pirtobrutinib-now-approved-us-fda-treatment-adult
FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 3, 2025. Accessed June 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic

CLL, chronische lymfatische leukemie, SLL, Pirtobrutinib, niet-covalente BTK remmer, covalente BTK remmer, progressievrije ziekte, complete remissie, kleincellig lymfatisch lymfoom