First interim analysis of a phase 1 study of zanubrutinib (zanu) + lenalidomide (len) in patients with relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL)
Bibliographic record
Abstract
Introduction: Effective therapies for R/R DLBCL are limited in China, especially for patients (pts) who are ineligible for high-dose therapy/stem cell transplantation (HDT/SCT). Preclinical data suggest synergy of len and zanu, a potent and selective Bruton tyrosine kinase inhibitor approved for various B-cell malignancies (Guo et al. J Med Chem 2019). Here, we present the interim analysis of an ongoing phase 1, open-label, dose-escalation/expansion study of zanu + len in R/R DLBCL in China (NCT04436107). Methods: Pts with R/R DLBCL ineligible for HDT/SCT with ≥1 prior line of adequate systemic therapy were enrolled. Dose escalation (part 1): Len 15 mg, 20 mg, or 25 mg orally once daily on days 1–21 of each 28-day cycle. Dose expansion (part 2): Len 25 mg. Zanu 160 mg was given orally twice daily continuously in parts 1 and 2. Primary endpoints were safety and recommended phase 2 dose (RP2D) of len (part 1) and overall response rate (ORR) by investigator based on Lugano classification (part 2). Interim analysis was performed when the 19th pt in part 2 completed first tumor assessment. Pts who received len 25 mg (RP2D) in parts 1 and 2 were analyzed separately. Results: As of 8 November 2022, 46 pts were treated and included in the analysis (27 in part 1; 19 in part 2; 30 at RP2D). Median age was 60 years (range, 29–82), 83% had stage III-IV disease, 37% had refractory disease, 70% had non-germinal center B-cell (non-GCB)-like disease; and median number of prior systemic therapies was 1 (range, 1–5). Median exposure to zanu and len was 3.9 months (range, 0.4–24.9), median follow-up was 6.6 months (range, 0.5–25.5). ORR was 46% overall (95% CI: 30.9, 61.0; complete response [CR]: 24%) and 57% at RP2D (95% CI: 37.4, 74.5; CR: 30%). At RP2D, ORR was 61% (95% CI: 38.5, 80.3; CR: 35%) for pts with non–GCB-like disease and 50.0% (95% CI: 11.8, 88.2; CR: 17%) for GCB. At RP2D, median duration of response was not reached and 6-month event-free rate was 59% (95% CI: 23.8, 82.8). The 9-month progression-free survival rate was 37% (95% CI: 17.6, 57.4). Overall, 46 (100%) pts experienced ≥1 treatment-emergent adverse event (TEAE). At RP2D, grade ≥3 TEAEs occurred in 60% of pts, most commonly neutrophil count decreased (43%), white blood cell count decreased (23%), and pneumonia (13%). One patient (2%) had febrile neutropenia (grade 3) but recovered within 2 days. TEAEs led to discontinuation of both len and zanu in 2 pts (cardiopulmonary failure unrelated to treatment [part 1, len 20 mg], pulmonary embolism [part 1, len 25 mg]) and discontinuation of len in 2 pts (platelet count decreased [part 1, len 20 mg], rash [part 2]). Two TEAEs leading to death were assessed as unrelated to treatment. Conclusions: Zanu 160 mg + len 25 mg combination showed an acceptable safety profile with promising efficacy. Further evaluation of the combination in a larger sample size is planned in future analysis. Encore Abstract - previously submitted to ASCO 2023 and EHA 2023 The research was funded by: BeiGene Keywords: Aggressive B-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. Y. Guo Employment or leadership position: Shanghai East Hospital, Tongji University Consultant or advisory role: Merck Serono, MSD, Bayer, Roche, GSK Honoraria: Merck Serono, Roche, MSD, BMS S. Huang Employment or leadership position: BeiGene (Shanghai) Co., Ltd Stock ownership: BeiGene Ltd Z. Liang Employment or leadership position: BeiGene Ltd Stock ownership: BeiGene Ltd Educational grants: BeiGene Ltd J. Lyu Employment or leadership position: BeiGene Y. Fang Employment or leadership position: BeiGene A. Cohen Employment or leadership position: BeiGene Stock ownership: BeiGene
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".