Abstract CT016: First-in-human (FIH) phase 1 trial of the oral first-in-class covalent Werner helicase (WRN) inhibitor RO7589831 in patients with microsatellite instable (MSI) and/or mismatch repair deficient (dMMR) advanced solid tumors
Notice bibliographique
Résumé
Abstract Background: WRN is an enzyme critical for DNA repair and genome stability and is a promising synthetic lethal target for MSI cancers. 40-70 % of patients (pts) with MSI/dMMR solid tumors do not respond to immune checkpoint inhibitors (ICI) or develop resistance, representing an unmet need in MSI cancers. RO7589831 is a novel first-in-class covalent, irreversible WRN inhibitor that induces dose-dependent DNA damage and tumor growth inhibition in MSI preclinical models, supporting its clinical evaluation in MSI pts. Methods: This open-label, multi-center, FIH study assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of RO7589831 in pts with MSI and/or dMMR advanced solid tumors (NCT06004245). The primary objective is to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). 14 paired tumor biopsies were collected for translational analysis. Results: As of Nov 25, 2024, 44 pts (24 F, 20 M; median age 62y (32-77y)) were enrolled in six dose cohorts at RO7589831 daily doses from 150 mg to 2000 mg. Based on clinical first dose PK data (rapid absorption, mean Tmax 2.6 h [± 1.3h] and half-life 4.4 h [±1.8h], n=41), RO7589831 was dosed orally once (QD) or twice (BID) daily. Among the 44 pts (22 colorectal (CRC) and 22 non-CRC), median prior treatment lines were 3 (range 1-12); 89% had received ICIs. 35 pts had MSI tumors (18 CRC and 17 non-CRC). No dose-limiting toxicities (DLTs) have been reported and the MTD has not been reached. The most common treatment-emergent AEs across all doses were nausea (52.3%), diarrhea (34.1%), and vomiting (31.8%). Grade (G)3 treatment related AEs (TRAE) were nausea and increased AST/ALT in 2 pts each (4.3%) as well as fatigue and anemia in 1 pt each (2.1%). No G4 or worse TRAEs were observed. Of the efficacy evaluable MSI pts (n= 32), four RECISTv1.1 partial responses (PRs) (2 confirmed and 2 ongoing unconfirmed PRs) were observed in post-ICI-treated MSI CRC (n=1), ovarian (n=1), and endometrial cancer (n=2) for up to 9.5+ mths. Disease control rate (DCR) was 68.8% (95%CI 51.13, 86.37) and 20 (62.5%) pts achieved RECISTv1.1 stable disease (SD). 48.4% (15/31) of FDG-PET scan evaluable pts across all dose levels showed metabolic responses to RO7589831. All pts with RECIST PR showed pronounced metabolic responses (-50% to -90%). ctDNA molecular responses were observed in 2/2 pts with RECISTv1.1 PR, 8/9 pts with SD and 0/5 pts with disease progression. Conclusions: RO7589831 is generally safe and well tolerated, with promising DCR, durable RECISTv1.1, FDG-PET metabolic and ctDNA molecular responses in pts with advanced MSI cancers, including ICI-treated pts, providing the first early clinical proof-of-concept for effectively drugging WRN. Dose optimization cohorts are ongoing to establish the RP2D. Citation Format: Timothy A. Yap, Natalie Cook, Elisa Fontana, Erica S. Tsang, Oliver Bechter, Marwan Fakih, Kristoffer S. Rohrberg, Emiliano Calvo, Elena M. Elez, Meredith Pelster, John H. Strickler, Ignacio Matos, Adam Sharp, Sophia Blake, David Dejardin, Stephen Fowler, Nina Henkel, Michael Hettich, Angelika Lahr, Ting Liu, Christophe Meille, Piergiorgio Pettazzoni, Denise Reeves, Barbara Romagnoli, Sotirios Sotiriou, Daniel Waterkamp, Yali Fu, Sophie Postel-Vinay. First-in-human (FIH) phase 1 trial of the oral first-in-class covalent Werner helicase (WRN) inhibitor RO7589831 in patients with microsatellite instable (MSI) and/or mismatch repair deficient (dMMR) advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT016.
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) | 0,002 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,008 | 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 ».