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

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.

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