Single agent activity of ZW25, a HER2-targeted bispecific antibody, in heavily pretreated HER2-expressing cancers.
Bibliographic record
Abstract
2500 Background: ZW25, a novel Azymetric bispecific antibody, targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated mechanisms of action including increased tumor cell binding, blockade of ligand-dependent and independent growth, and improved receptor internalization and downregulation relative to trastuzumab (T). In vivo studies demonstrate anti-tumor activity in HER2-low to high expressing models. This Phase 1 study evaluated ZW25 single agent safety and anti-tumor activity. Methods: Part 1 (P1) evaluated ZW25 5, 10 and 15 mg/kg weekly and 20 mg/kg biweekly using a 3+3 design to identify a recommended dose (RD) for further study. Part 2 (P2) is ongoing and evaluating safety and efficacy in separate expansion cohorts, including HER2-high (IHC 3+ or 2+/FISH+) breast (BC), gastric/esophageal (GE), and other cancers. Pts had to have progressive disease after standard of care, including HER2-targeted agents. Adverse events (AE), PK, and response per RECIST 1.1 (every 8 wks in pts with measurable disease) were assessed. Results: 33 pts have been treated in P1 and P2: 17 BC, 11 GE and 5 other cancers. HER2-high BC pts had prior T and T-DM1 (100%), pertuzumab (82%) and lapatinib (53%), with a median of 6 HER2-targeted regimens for metastatic disease. All GE pts had received prior T, with a median of 4 systemic tx. Safety and anti-tumor activity were similar across dose levels with no DLTs. The RD for Part 2 was 10 mg/kg weekly or 20 mg/kg biweekly. The most common AEs were diarrhea and infusion reaction, all Gr 1 or 2, with no tx-related discontinuations. Time on study is 14-348 days with 9 pts still active. 23 pts are response evaluable, with 3 pts not yet restaged. Conclusions: ZW25 has been well tolerated with promising single agent anti-tumor activity in pts with heavily pretreated HER2-expressing cancers that have progressed after standard of care, including multiple HER2-targeted regimens. These data support the therapeutic potential of ZW25 and suggest that its unique MOA may overcome mechanisms of resistance to other HER2-targeted agents. Clinical trial information: NCT02892123.Partial response (PR) and disease control rates DCR = PR or SD anytime on study. PR DCR BC n=13 46% 54% GE n=7 43% 57% Other n=3 — 33% Total n=23 39% 52%
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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 | 0.005 | 0.005 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 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".