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 machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".