Abstract B130: Phase 1 study of Zanidatamab Zovodotin (ZW49): Safety Profile and Recommended Dose (RD) in patients with Human Epidermal Growth Factor 2 (HER2)-positive solid cancers
Bibliographic record
Abstract
Abstract Background ZW49 is a novel, humanized, antibody-drug conjugate comprised of a bispecific antibody directed against 2 non-overlapping HER2 epitopes and attached to a proprietary auristatin toxin with a protease-cleavable linker. Here we present data supporting the selection of the ZW49 RD in an ongoing, first-in-human, dose escalation (DE) and dose expansion (DX) study (NCT03821233).1 Methods The 3+3 DE phase evaluated safety and tolerability of ZW49 IV (1-1.75 mg/kg QW; 1-2 mg/kg Q2W; and 2-3 mg/kg Q3W) in pts with HER2+ cancers. The DX phase further evaluated safety and antitumor activity of ZW49 IV (1.25 and 1.5 mg/kg QW; 2.5 mg/kg Q3W) in pts with centrally confirmed HER2+ (IHC 3+ or IHC 2+/FISH+) cancers. Primary endpoints are safety, tolerability, and maximum tolerated dose/RD. Secondary endpoints are pharmacokinetics (PK) parameters and response per RECIST1.1. Analyses of data for 66 pts treated with ZW49 at select cohorts/regimens in DE and DX are herein presented. Results As of 19 Dec 2022, 66 pts (n = 18, 1.25 mg/kg QW; n = 18, 1.5 mg/kg QW; and n = 30, 2.5 mg/kg Q3W; male, 52%; median age, 60.5 years [range, 32 – 83]) were treated with ZW49 in the selected population. The most common cancer types were gastric (35%) and breast (15%); 67% of pts had received prior HER2-targeted therapy; median number of prior metastatic therapies was 3 (range, 1 – 13). The overall incidence of treatment-related adverse events (TRAEs) was 91% (100% [18/18 pts] in 1.5 mg/kg QW, 93% [28/30 pts] in 2.5 mg/kg Q3W, and 78% [14/18 pts] in 1.25 mg/kg QW regimens). Overall, the most common (≥ 20%) TRAEs were keratitis (44%), alopecia (26%), and diarrhea (24%); the majority were Grade (Gr) 1 or 2 in severity; Gr 3 or 4 TRAEs occurred in 14 (21%) pts. Serious TRAEs occurred in 4 (6%) pts. Eight pts discontinued (D/C) due to TRAEs, including 1 pt D/C due to a serious TRAE (Gr 4 infusion-related reaction [IRR]; 2.5 mg/kg Q3W). No interstitial lung disease or TR-deaths were reported. Seven dose-limiting toxicities (DLTs) occurred, including 4 DLTs in 1.5 mg/kg QW (3 Gr 2 keratitis events and 1 Gr 3 diarrhea), 2 DLTs in 1.25 mg/kg QW (Gr 3 blurred vision and Gr 3 IRR), and 1 DLT in 2.5 mg/kg Q3W (Gr 2 keratitis) regimens. The 1.5 mg/kg QW regimen was closed due to the frequency of DLTs and dose modifications observed. The safety profile was comparable between the 1.25 mg/kg QW and 2.5 mg/kg Q3W regimens. Preliminary PK analyses indicated that the half-life was similar across these dose/regimens. The confirmed objective response rate and disease control rate in HER2+ response-evaluable pts were 6% (1/17 pt) and 53% (9/17 pts) in 1.25 mg/kg QW regimen; and 31% (9/29 pts) and 72% (21/29 pts) in 2.5 mg/kg Q3W regimen, respectively. Based on these results, 2.5 mg/kg Q3W regimen was chosen as the RD. Conclusions ZW49 2.5 mg/kg Q3W IV was well tolerated, showed encouraging antitumor activity in heavily pretreated pts with advanced HER2+ cancers, and has been identified as the RD for further clinical development. References 1 Jhaveri K, et al.; ESMO; Sep 09 -13 2022 Citation Format: Do-Youn Oh, Philippe L Bedard, Keun-Wook Lee, Hyo Sook Han, Yoon-Koo Kang, Wilson H Miller, Sun Young Rha, Jwa Hoon Kim, Efrat Dotan, Chih-Yi Liao, Anthony Tolcher, Alexander Spira, Erika Hamilton, Christos Karapetis, Lisa Boyken, Charles Chen, Joseph Woolery, Komal Jhaveri. Phase 1 study of Zanidatamab Zovodotin (ZW49): Safety Profile and Recommended Dose (RD) in patients with Human Epidermal Growth Factor 2 (HER2)-positive solid cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B130.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.000 |
| 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".