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
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».