{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:56:11Z","timestamp":1792036571667,"version":"4.4.0"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: There are multiple effective treatment options for patients diagnosed with chronic lymphocytic leukemia and small lymphocytic lymphoma (hereafter, simply CLL). In 2025, two phase 3 randomized clinical trials of pirtobrutinib, a non-covalent BTK inhibitor, were reported, demonstrating improved outcomes versus comparator therapies in the treatment-na\u00efve setting (NCT05254743 and NCT05023980). Methods: A systematic literature review was conducted to identify RCTs in the first-line setting for CLL. A Bayesian NMA was performed to compare overall response rate (ORR) and progression-free survival (PFS) of pirtobrutinib versus treatments recommended by the National Comprehensive Cancer Network in the first-line setting, with a focus on BTKi monotherapy. Results: Eight unique trials were identified for comparison versus pirtobrutinib. Eligible RCTs formed two disconnected networks (pirtobrutinib, ibrutinib and zanubrutinib were in Network 1; acalabrutinib was in Network 2). Results from Network 1 for ORR showed an odds ratio (OR) = 0.56 (95% credible interval [CrI], 0.28, 1.12) for ibrutinib versus pirtobrutinib and OR = 0.50 (95% CrI, 0.20, 1.27) for zanubrutinib versus pirtobrutinib. The PFS of ibrutinib was inferior to pirtobrutinib (hazard ratio (HR) = 1.89, 95% CrI, 1.13, 3.19); the PFS HR comparing zanubrutinib with pirtobrutinib was 1.51 (95% CrI, 0.84, 2.72). Conclusions: This NMA shows that pirtobrutinib has better PFS outcomes than ibrutinib. While PFS outcomes suggest that pirtobrutinib is comparable to second-generation covalent BTKi monotherapies, uncertainty exists in the interpretation of the treatment effect, as evidenced by wide credible intervals. These findings suggest the value of pirtobrutinib as a future treatment option for patients in the first-line setting.<\/jats:p>","DOI":"10.3390\/cancers18040660","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T07:50:30Z","timestamp":1771401030000},"page":"660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Efficacy of Pirtobrutinib Monotherapy in Treatment-Na\u00efve Chronic Lymphocytic Leukemia: A Bayesian Network Meta-Analysis of Randomized Controlled Trials"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6631-9749","authenticated-orcid":false,"given":"Toby A.","family":"Eyre","sequence":"first","affiliation":[{"name":"Oxford University Hospitals NHS Trust, London OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3631-3941","authenticated-orcid":false,"given":"Lisa M.","family":"Hess","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Indianapolis, IN 46285, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehsan","family":"Masoudi","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, 61352 Bad Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4916-0107","authenticated-orcid":false,"given":"Min-Hua","family":"Jen","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Basingstoke RG21 4FA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarang","family":"Abhyankar","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Indianapolis, IN 46285, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peita L.","family":"Graham-Clarke","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Sydney 2000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4452-8021","authenticated-orcid":false,"given":"Naleen Raj","family":"Bhandari","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Indianapolis, IN 46285, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Maguire","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Basingstoke RG21 4FA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine B.","family":"Winfree","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Indianapolis, IN 46285, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marsha","family":"Tracey","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, T4D KD39 Cork, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaisa-Leena","family":"Taipale","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Basingstoke RG21 4FA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S.","family":"Davids","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"ref_1","unstructured":"The Surveillance, Epidemiology, and End Results (SEER) National Cancer Institute (2025, November 14). Leukemia\u2014Chronic Lymphocytic Leukemia (CLL), Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/clyl.html."},{"key":"ref_2","first-page":"e14258","article-title":"Epidemiology, treatment patterns and survival of chronic lymphocytic leukaemia\/small lymphocytic lymphoma (CLL\/SLL) in Taiwan, 2006\u20132015","volume":"75","author":"Ko","year":"2021","journal-title":"Int. J. Clin. Pr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1007\/s12272-025-01546-0","article-title":"BTK inhibitors and next-generation BTK-targeted therapeutics for B-cell malignancies","volume":"48","author":"Kim","year":"2025","journal-title":"Arch. Pharmacal Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13045-021-01054-w","article-title":"Current and future treatment strategies in chronic lymphocytic leukemia","volume":"14","author":"Patel","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.12688\/f1000research.11618.1","article-title":"Recent therapeutic advances in chronic lymphocytic leukemia","volume":"6","author":"Bose","year":"2017","journal-title":"F1000Research"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1001\/jama.2023.1946","article-title":"Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review","volume":"329","author":"Shadman","year":"2023","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"175","DOI":"10.6004\/jnccn.2024.0018","article-title":"Chronic Lymphocytic Leukemia\/Small Lymphocytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology","volume":"22","author":"Wierda","year":"2024","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_8","first-page":"e19033","article-title":"Real-world treatment utilization patterns, discontinuation and healthcare resource utilization of first-line (1L) bruton tyrosine kinase inhibitor (BTKi) therapy in chronic lymphocytic leukemia (CLL): Age-related disparity","volume":"43","author":"Yang","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1200\/JCO-25-00166","article-title":"Phase III Trial of Pirtobrutinib Versus Idelalisib\/Rituximab or Bendamustine\/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor-Pretreated Chronic Lymphocytic Leukemia\/Small Lymphocytic Lymphoma (BRUIN CLL-321)","volume":"43","author":"Sharman","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_10","unstructured":"Woyach, J.A., Qiu, L., Grosicki, S., Wrobel, T., Capra, M., Czyz, J., Yi, S., Eom, K.S., Panovska, A., and Jurczak, W. (2025). Pirtobrutinib Versus Ibrutinib in Treatment-Naive and Relapsed\/Refractory Chronic Lymphocytic Leukemia\/Small Lymphocytic Lymphoma. J. Clin. Oncol., JCO2502477."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Jurczak, W., Kwiatek, M., Czyz, J., de Mattos, E.R., Eom, K., Egle, A., Panovsk\u00e1, A., Grudeva-Popova, Z., Shih, H.-J., and Montero, L.F.C. (2025). Pirtobrutinib vs bendamustine plus rituximab (BR) in patients with CLL\/SLL: First results from a randomized phase III study Examining a non-covalent BTK inhibitor in untreated patients. J. Clin. Oncol.","DOI":"10.1182\/blood-2025-LBA-3"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"n160","DOI":"10.1136\/bmj.n160","article-title":"PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_14","unstructured":"NICE (2025, December 03). Appendix C: Methodology Checklist: Randomised Controlled Trials. Available online: https:\/\/www.nice.org.uk\/process\/pmg6\/resources\/the-guidelines-manual-appendices-bi-2549703709\/chapter\/appendix-c-methodology-checklist-randomised-controlled-trials#checklist-2."},{"key":"ref_15","unstructured":"Dias, S., Welton, N.J., Sutton, A.J., and Ades, A.E. (2011). NICE DSU Technical Support Document 2: A Generalised Linear Modelling Framework for Pairwise and Network Meta-Analysis of Randomised Controlled Trials, University of Sheffield. Available online: https:\/\/sheffield.ac.uk\/nice-dsu\/tsds\/evidence-synthesis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Woods, B.S., Hawkins, N., and Scott, D.A. (2010). Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: A tutorial. BMC Med. Res. Methodol., 10.","DOI":"10.1186\/1471-2288-10-54"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Rucker, G., and Schwarzer, G. (2015). Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med. Res. Methodol., 15.","DOI":"10.1186\/s12874-015-0060-8"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.jclinepi.2010.03.016","article-title":"Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: An overview and tutorial","volume":"64","author":"Salanti","year":"2011","journal-title":"J. Clin. Epidemiol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Carlin, B.P., and Louis, T.A. (2008). Bayesian Methods for Data Analysis. Psychometrika, Cambridge University Press. [3rd ed.].","DOI":"10.1201\/b14884"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1093\/aje\/kwab278","article-title":"Introducing the Treatment Hierarchy Question in Network Meta-Analysis","volume":"191","author":"Salanti","year":"2022","journal-title":"Am. J. Epidemiol."},{"key":"ref_21","unstructured":"Plummer, M., Stukalov, A., and Denwood, M. (2025, December 12). rjags: Bayesian Graphical Models Using MCMC. Available online: https:\/\/cran.r-project.org\/web\/packages\/rjags\/index.html."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1056\/NEJMoa2213093","article-title":"First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia","volume":"388","author":"Eichhorst","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1182\/blood-2024-200701","article-title":"Fixed-Duration Acalabrutinib Plus Venetoclax with or without Obinutuzumab Versus Chemoimmunotherapy for First-Line Treatment of Chronic Lymphocytic Leukemia: Interim Analysis of the Multicenter, Open-Label, Randomized, Phase 3 AMPLIFY Trial","volume":"144","author":"Brown","year":"2024","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1056\/NEJMoa2409804","article-title":"Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia","volume":"392","author":"Brown","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1200\/JCO-24-02265","article-title":"Zanubrutinib Versus Bendamustine and Rituximab in Patients with Treatment-Naive Chronic Lymphocytic Leukemia\/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up of SEQUOIA","volume":"43","author":"Shadman","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/S1470-2045(22)00293-5","article-title":"Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): A randomised, controlled, phase 3 trial","volume":"23","author":"Tam","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1182\/blood.2023021959","article-title":"Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL","volume":"143","author":"Woyach","year":"2024","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1056\/NEJMoa1812836","article-title":"Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL","volume":"379","author":"Woyach","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1182\/bloodadvances.2021006434","article-title":"Up to 8-year follow-up from RESONATE-2: First-line ibrutinib treatment for patients with chronic lymphocytic leukemia","volume":"6","author":"Barr","year":"2022","journal-title":"Blood Adv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/S0140-6736(20)30262-2","article-title":"Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): A randomised, controlled, phase 3 trial","volume":"395","author":"Sharman","year":"2020","journal-title":"Lancet"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1056\/NEJMoa1815281","article-title":"Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions","volume":"380","author":"Fischer","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1056\/NEJMoa1313984","article-title":"Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions","volume":"370","author":"Goede","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e19031","DOI":"10.1200\/JCO.2025.43.16_suppl.e19031","article-title":"A network meta-analysis (NMA) of efficacy of Zanubrutinib versus fixed-duration acalabrutinib plus venetoclax in treatment-na\u00efve (TN) chronic lymphocytic leukemia (CLL)","volume":"43","author":"Shadman","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"99","DOI":"10.2147\/PPA.S289139","article-title":"Oncologist and Patient Preferences for Novel Agents in First-Line Treatment for Chronic Lymphocytic Leukemia: Commonalities and Disconnects","volume":"15","author":"Le","year":"2021","journal-title":"Patient Prefer. Adherence"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/4\/660\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:11:21Z","timestamp":1771564281000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/4\/660"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,18]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cancers18040660"],"URL":"https:\/\/doi.org\/10.3390\/cancers18040660","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,18]]}}}