Jaypirca (pirtobrutinib) / Eli Lilly, Innovent Biologics, Nippon Shinyaku - LARVOL DELTA

Cases and Conversations: Sequencing Strategies in Relapsed and Refractory CLL (ASH 2026) - "Pivotal phase 3 readouts — AMPLIFY (acalabrutinib + venetoclax ± obinutuzumab), CLL17, BRUIN CLL-313/-314 (pirtobrutinib), CELESTIAL-TN (sonrotoclax + zanubrutinib), and MAJIC — have reshaped both the treatment armamentarium and the decision framework around fixed-duration vs continuous therapy. Real-world data show persistent gaps in molecular testing, treatment selection, and toxicity management. This Medical Crossfire® session uses focused didactic primers paired with moderated expert debate to examine the frontline decision points clinicians face every day, with attention to molecular testing, fixed-duration vs continuous therapy, MRD-guided approaches, and proactive AE management."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia

COMBINED PIRTOBRUTINIB, VENETOCLAX, AND OBINUTUZUMAB IN FIRST-LINE TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A PHASE 2 TRIAL (EHA 2024) - P2 | "Background: Treatment with combined covalent BTK-inhibitor (cBTKi such as ibrutinib, acalabrutinib, zanubrutinib) withBCL2-inhibitor, venetoclax +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectableMRD (U-MRD) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). We report the first results for first-line combined pirtobrutinib, venetoclax, and obinutuzumab in pts with CLL. Avery high rate of bone marrow U-MRD at 10-6 sensitivity was noted at 6-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents."

Clinical • P2 data • Chronic Lymphocytic Leukemia • Febrile Neutropenia • Head and Neck Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • TP53

Pirtobrutinib, Venetoclax, and Obinutuzumab Treatment in First-Line CLL (PIVOT-CLL) (SOHO 2026) - P2 | "Combined pirtobrutinib, venetoclax, and obinutuzumab leads to a very high U-MRD6 remission rate in patients with previously untreated CLL. BCL2: B-cell leukemia/lymphoma 2, CD: cluster of differentiation, CLL: chronic lymphocytic leukemia, IGHV: immunoglobulin heavy variable, iwCLL: International Workshop on Chronic Lymphocytic Leukemia, MRD: measurable residual disease, NGS: next-generation sequencing, OS: overall survival, PFS: progression-free survival, TP53: tumor protein p53."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Head and Neck Cancer • Lymphoma • Oncology • Solid Tumor • IGH • TP53

Combined Pirtobrutinib, Venetoclax, and Obinutuzumab As First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL) (ASH 2024) - P2 | "Introduction : Combined treatment with covalent BTK-inhibitor (cBTKi), such as ibrutinib, acalabrutinib, or zanubrutinib with BCL2-inhibitor, venetoclax, +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectable MRD (U-MRD4, 10-4 sensitivity) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). Adverse event profile was similar to what was noted in previous studies with these agents. Updated data will be presented."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Head and Neck Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • TP53

Efficacy of pirtobrutinib monotherapy in treatment-naïve chronic lymphocytic leukemia: A Bayesian network meta-analysis of randomized controlled trials (ASH 2025) - P3 | "Background BRUIN CLL-314 (NCT05254743) is a global phase 3 open-label randomized controlled trial (RCT)comparing pirtobrutinib with ibrutinib (ibr) in both treatment-naïve (TN) and relapsed/refractory patients(pts) with CLL/SLL and no prior BTKi exposure...Thisresulted in two disconnected networks of NCCN-recommended therapies: Network1 includedpirtobrutinib, ibr, and zanubrutinib (zanu); Network2 included venetoclax (ven) + obinutuzumab (obi), ven+ ibr, acala (acala), acala + obi, acala + ven, and acala + obi + ven.In Network1, pirtobrutinib had an 87.5% probability of being ranked first for ORR (surface under thecumulative ranking curve [SUCRA]=96.8%), followed by zanu (5.7% probability of being first,SUCRA=64.2%)...While the efficacy of pirtobrutinib as measured by ORR andpreliminary PFS generate favorable point estimates relative to currently available therapy (i.e., ORs > 1and HRs < 1), caution is needed when interpreting the data due to the wide..."

Monotherapy • Retrospective data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia

Pirtobrutinib, venetoclax, and obinutuzumab for patients with richter transformation: A phase 2 trial (ASH 2025) - P2 | "Threepts had no response (1 pt with previously untreated RT who received venetoclax +obinutuzumab for CLL; 1 pt with prior BR and Ibrutinib + obinutuzumab for CLL, and prior atezolizumab + venetoclax +obinutuzumab, and R-CHOP + venetoclax for RT; 1 pt with no prior CLL therapy and R-EPOCH forRT).Two of the responding pts underwent consolidative allo-SCT. We report results of combined pirtobrutinib, venetoclax, and obinutuzumab in ptswith untreated or R/R RT. We observed an ORR rate of 67% and a 12-month EFS and OS rates of73% and 82%, respectively."

Clinical • IO biomarker • P2 data • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Richter's Syndrome • TP53

Time-limited pirtobrutinib, venetoclax, and obinutuzumab combination in first-line chronic lymphocytic leukemia (ASH 2025) - P2 | "We report results of combined pirtobrutinib, venetoclax, and obinutuzumab in pts withpreviously untreated CLL. We observed a very high rate of BM and blood U-MRD6 remission after 6-months and 12-months of combined treatment."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Head and Neck Cancer • Hematological Malignancies • Leukemia • Neutropenia • Solid Tumor • Thrombocytopenia • CD20 • TP53

Pirtobrutinib Monotherapy for First-Line Chronic Lymphocytic Leukemia: A Non-Anchored Indirect Comparison Using Reconstructed Patient-Level Data. (PubMed, Hematol Rep) - "Compared with pirtobrutinib monotherapy, HRs for PFS were 0.5544 (95%CI, 0.2696-1.1397) versus venetoclax plus obinutuzumab, 0.4583 (95%CI, 0.2066-1.0200) versus venetoclax plus ibrutinib, and 1.4453 (95%CI, 0.6684-3.1240) versus acalabrutinib plus obinutuzumab... This exploratory non-anchored analysis suggests that pirtobrutinib monotherapy may provide PFS outcomes broadly comparable to current first-line combination regimens for CLL. Given the methodological limitations inherent to indirect comparisons, prospective head-to-head studies are needed to clarify the optimal positioning of pirtobrutinib in treatment-naïve CLL."

Journal • Monotherapy • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Recent advances and future perspectives in the treatment of chronic lymphocytic leukemia (PubMed, Rinsho Ketsueki) - "Current recommended first-line treatment options include covalent BTK inhibitor (cBTKi: ibrutinib, acalabrutinib±obinutuzumab, and zanubrutinib)-based regimens and BCL2 inhibitor (BCL2i: venetoclax)-containing regimens (venetoclax+obinutuzumab and venetoclax+ibrutinib). The non-covalent BTK inhibitor pirtobrutinib has recently been approved for patients with relapsed or refractory CLL who have previously been treated with a cBTKi. The durability of responses to initial and subsequent treatment of CLL has greatly extended life expectancy, and newer agents including BTK degraders, next-generation BCL2 inhibitors, novel antibodies (antibodies against BAFF, CD19, or ROR1, along with CD3×CD20 bispecific antibodies), and chimeric antigen receptor T-cell therapies should further improve quality of life for all patients."

Journal • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ROR1

Complete Metabolic Response to Pirtobrutinib in Refractory Richter Transformation (SOHO 2026) - "Venetoclax and obinutuzumab (VO) therapy was initiated...Acalabrutinib was stopped, and zanubrutinib was started 2 months later...He is now being started on epcoritamab as a bridge to ASCT... This case highlights the very uncommon finding of RT presenting as isolated splenomegaly. SF3B1 mutations have not been well characterized in RT; this case could contribute to the evolving understanding of the mutational landscape of RT. It was impressive to see a complete response (CR) with pirtobrutinib in RT in a patient refractory to chemoimmunotherapy, although only 13% achieved CR in the BRUIN study."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • ATM • SF3B1

Comparative Efficacy and Safety of Pirtobrutinib vs Covalent BTK Inhibitors in Treatment-Naïve Chronic Lymphocytic Leukemia: A Systematic Review and Bayesian Network Meta-Analysis (SOHO 2026) - "In the NMA (random-effects model), SUCRA rankings were: pirtobrutinib, 75.4%; acalabrutinib-obinutuzumab, 73.7%; zanubrutinib, 60.0%; acalabrutinib, 52.2%; and ibrutinib, 51.3%, with all BTKis ranking substantially above chemotherapy. This independent NMA, the first to connect pirtobrutinib with all approved covalent BTKis in a unified network, shows directionally favorable but nonsignificant PFS comparisons against covalent BTKis under the random-effects model. These findings are limited by indirect estimation and short pirtobrutinib follow-up. A favorable cardiovascular safety profile was observed in direct comparison."

Retrospective data • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Real-World Overall Survival, Richter's Transformation, and Secondary Primary Malignancy Rates in CLL Treated With Fixed-Duration Venetoclax-Based Therapy Versus Indefinite BTK Inhibitor Monotherapy: A TriNetX Propensity-Matched Analysis (SOHO 2026) - "Background: The chronic lymphocytic leukemia (CLL) treatment landscape is defined by two dominant targeted therapy paradigms: fixed-duration venetoclax-based combinations (venetoclax and obinutuzumab or venetoclax and ofatumumab [Ven-O/Ofa]) and indefinite Bruton tyrosine kinase inhibitor (BTKi) monotherapy (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib). In this propensity-matched real-world analysis of 2546 patients with CLL, fixedduration venetoclax-based therapy was associated with improved 5-year OS and lower RT rates compared with indefinite BTKi monotherapy. SPM rates were largely comparable, although higher skin cancer incidence with Ven-O/Ofa warrants further investigation and highlights the importance of dermatologic surveillance in this population."

Clinical • Monotherapy • Real-world • Real-world evidence • Acute Myelogenous Leukemia • Basal Cell Carcinoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Non-melanoma Skin Cancer • Oncology • Richter's Syndrome • Skin Cancer • Squamous Cell Carcinoma

GOLDILOX: FIRST EXPERIENCE OF TWO DOSING STRATEGIES OF PIRTOBRUTINIB AND GLOFITAMAB FOR MANTLE CELL LYMPHOMA PREVIOUSLY TREATED WITH COVALENT BTK INHIBITORS (ICML 2025) - P2 | "Cohort 1 and 2 (C1, C2) consisted of a 7-day pre-phase of pirto 200 mg daily and obinutuzumab IV pre-treatment of 2g in 2–3 divided doses over 1 week IV (dGPT), followed by pirto and either standard 2.5 mg/10 mg/30 mg step-up glo (SSG) IV or 1.25 mg/5 mg/10 mg/30 mg weekly. 16 pts were enrolled across C1–3, with 13 evaluable for the primary endpoint. Median age was 74 (range 67–77) yrs; 19% had blastoid/pleomorphic morphology, 81% had int-high MIPI, 62.5% had 17p deletion. Median number of prior therapies was 3 (range 2–3), all with prior cBTKi, 38% prior ASCT and 31% prior CAR-T."

Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology

Population pharmacokinetic analysis of pirtobrutinib, a non-covalent BTK inhibitor, in patients with hematological malignancies from the Phase 1/2 BRUIN study. (PubMed, Cancer Chemother Pharmacol) - P1/2 | "With the proposed starting dose of 200 mg QD, most patients (96%) were expected to exceed 90% BTK inhibition, across the entire dosing interval, indicating extensive and durable engagement of the drug target. No dose adjustments based on body weight, serum albumin or renal function were recommended."

Journal • P1/2 data • PK/PD data • Hematological Disorders • Hematological Malignancies • Hepatology • Oncology

Mosunetuzumab in Combination With Pirtobrutinib in Patients With Relapsed or Refractory Waldenstrom Macroglobulinemia (MPOWER) (clinicaltrials.gov) - P2 | N=25 | Not yet recruiting | Sponsor: University of Utah | Trial completion date: Jun 2035 ➔ Nov 2035 | Initiation date: Jun 2026 ➔ Nov 2026 | Trial primary completion date: Jun 2034 ➔ Nov 2034

Trial completion date • Trial initiation date • Trial primary completion date • Hematological Disorders • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Waldenstrom Macroglobulinemia

A Study of Pirtobrutinib in Participants With Immune Thrombocytopenia (clinicaltrials.gov) - P1/2 | N=68 | Recruiting | Sponsor: Eli Lilly and Company | Trial primary completion date: May 2028 ➔ Feb 2028

Trial primary completion date • Hematological Disorders • Immune Thrombocytopenic Purpura • Thrombocytopenia • Thrombocytopenic Purpura

BRUIN-MCL-321: Study of BTK Inhibitor LOXO-305 Versus Approved BTK Inhibitor Drugs in Patients With Mantle Cell Lymphoma (MCL) (clinicaltrials.gov) - P3 | N=500 | Active, not recruiting | Sponsor: Loxo Oncology, Inc. | Trial completion date: Apr 2028 ➔ Jun 2030 | Trial primary completion date: Jan 2027 ➔ Nov 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology

Real-World Outcomes of Pirtobrutinib Versus Venetoclax After Covalent BTK Inhibitor Exposure in CLL/SLL (SOHO 2026) - "Adults with CLL/SLL previously exposed to a covalent BTK inhibitor, including ibrutinib, acalabrutinib, or zanubrutinib, were identified...Propensity score matching included demographics; prior BTK inhibitor exposure; prior rituximab and antineoplastic therapy; and baseline creatinine, hemoglobin, neutrophil count, platelet count, and albumin levels... In this large real-world matched analysis of patients with CLL/SLL previously exposed to covalent BTK inhibitors, pirtobrutinib showed comparable 12-month survival, infection risk, and early hematologic safety relative to venetoclax. In evolving treatment algorithms that now include noncovalent BTK inhibition after covalent BTK inhibitor exposure, these findings support pirtobrutinib as a practical sequencing option with outcomes similar to an established venetoclax-based approach. Rather than identifying a single preferred strategy, these data support individualized treatment selection based on prior therapy, comorbidity..."

Clinical • Real-world • Real-world evidence • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Generational safety profiles of BTK inhibitors: adverse reaction signals and real-world evidence from the FAERS database. (PubMed, Front Med (Lausanne)) - "However, safety concerns remain regarding treatment-associated adverse events: first-generation ibrutinib has been associated with off-target adverse event profiles, second-generation agents (acalabrutinib and zanubrutinib) require further validation of long-term safety patterns, and the real-world safety characteristics of third-generation pirtobrutinib continue to be evaluated. This descriptive pharmacovigilance study identified distinct disproportionality reporting signal patterns for four BTK inhibitors based on FAERS data, providing potential signals for post-marketing safety surveillance. These findings should be interpreted as differences in reporting patterns."

HEOR • Journal • Real-world evidence • Atrial Fibrillation • Cardiovascular • Hematological Malignancies • Immunology • Infectious Disease • Oncology • Pain • Pneumonia • Respiratory Diseases

Discovery of BTK degraders for the treatment of B-cell malignancies (ACS-Fall 2026) - "Covalent BTK inhibitors (e.g., ibrutinib, acalabrutinib) have demonstrated efficacy across diseases including CLL, MCL, MZL, and WM, but long-term benefit is frequently limited by resistance mutations, most commonly at BTKC481, that abrogate covalent binding and drive progression, and additional mutations may also reduce the activity of emerging noncovalent inhibitors, such as pirtobrutinib. Together, these data support BTK degraders as a promising modality to overcome BTK inhibitor resistance and broaden therapeutic impact, including in CNS disease. This presentation will describe the discovery of NX-2127 and NX-5948, pre-clinical characterization and translation to clinical effects in lymphoma and leukemia patients."

Chronic Lymphocytic Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Lymphoma • Marginal Zone Lymphoma • Oncology • Targeted Protein Degradation • CRBN • IKZF1 • IKZF3

Genomic Evolution and Resistance during Pirtobrutinib Therapy in Covalent BTK-Inhibitor (cBTKi) Pre-Treated Chronic Lymphocytic Leukemia Patients: Updated Analysis from the BRUIN Study (ASH 2023) - P1/2 | "BTK Cysteine 481 substitution is known to contribute to cBTKi acquired resistance to ibrutinib, acalabrutinib, and zanubrutinib. Despite this cohort representing the first relapsing CLL patients from BRUIN and presenting with frequent baseline BTK mutations, response to pirtobrutinib was high, with an ORR of 83%, and substantial clearance of BTK C481 clones. At progression, the majority of pts (56%) either acquired non-BTK mutations or did not acquire any resistance mutations in this targeted panel, suggesting alternative resistance mechanisms. A smaller group of patients (44%) displayed emergence of non-C481 clones, particularly gatekeeper T474 and kinase-impaired L528W mutations."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • NOTCH1 • PIK3CA • PLCG2 • SF3B1 • TP53

Fixed-Duration Pirtobrutinib Plus Venetoclax–Rituximab Vs. Venetoclax–Rituximab For Patients With Previously Treated CLL/SLL (BRUIN CLL-322): An Open-Label, Multicenter, Randomized, Controlled, Phase 3 Trial (SOHO 2026) - "This activity is sponsored by Eli Lilly USA, LLC"

Clinical • P3 data • Chronic Lymphocytic Leukemia • Oncology • Small Lymphocytic Lymphoma

Real-World Pharmacovigilance Assessment of Hematologic Safety Signals Among Bruton Tyrosine Kinase Inhibitors, Including Pirtobrutinib: Insights From the Food and Drug Administration Adverse Event Reporting System (SOHO 2026) - " A disproportionality analysis was conducted using the FDA Adverse Event Reporting System (FAERS) database from 2023 to 2026, including reports associated with ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib. BTK inhibitors showed heterogeneous reporting signal profiles. Ibrutinib exhibited the broadest signal distribution, whereas pirtobrutinib demonstrated fewer overall signals. Certain findings, including the pure red cell aplasia signal observed with pirtobrutinib, warrant further evaluation in larger data sets and prospective studies."

Adverse events • Clinical • Real-world • Real-world evidence • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • ROR1

Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. (PubMed, N Engl J Med) - P1/2 | "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.)."

Journal • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Hypertension • Infectious Disease • Leukemia • Lymphoma • Neutropenia • Oncology • Small Lymphocytic Lymphoma

BRUIN CLL-321: Randomized Phase III Trial of Pirtobrutinib Versus Idelalisib Plus Rituximab (IdelaR) or Bendamustine Plus Rituximab (BR) in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (ASH 2024) - P3 | "Methods : Eligible CLL/SLL pts previously treated with cBTKi were randomized 1 : 1 to receive pirtobrutinib monotherapy (200mg QD) or IC of IdelaR or BR and stratified by prior use of venetoclax and del(17p) status. Summary/Conclusion : BRUIN CLL-321 is the first randomized study conducted exclusively in cBTKi pretreated CLL/SLL pts. In this heavily pretreated patient population with poor prognosis, pirtobrutinib treatment led to a significant improvement in PFS compared to IC, along with a more favorable safety profile."

Clinical • P3 data • Anemia • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Hypertension • Infectious Disease • Leukemia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Respiratory Diseases • Small Lymphocytic Lymphoma • IGH • TP53