Abstract CT184: First-in-human trial of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with advanced solid unresectable tumors
Notice bibliographique
Résumé
Abstract Introduction: M6223 is an intravenous (IV), fully human, antagonistic, anti-TIGIT antibody with an Fc-mediated effector region. In preclinical studies, M6223 combined with BA (a bifunctional fusion protein that simultaneously targets the TGF-β and PD-(L)1 pathways) enhanced antitumor efficacy compared to either agent alone. Methods: This first-in-human, dose escalation study of M6223 as monotherapy (M6223; Part 1A) or in combination with BA (M6223+BA; Part 1B) included pts with advanced solid tumors (aged ≥18 years, ECOG PS ≤1) (NCT04457778). In Part 1A, pts received M6223 at 10 mg, 30 mg, 100 mg, 300 mg, 900 mg, 1600 mg, 2400 mg (all Q2W) or M6223 2400 mg Q3W. In Part 1B, pts received M6223 at 300 mg, 900 mg, or 1600 mg, all in combination with BA 1200 mg (both Q2W, IV). Dose escalation decisions by the Safety Monitoring Committee were assisted by a Bayesian 2-parameter logistic regression model. Primary objectives were safety, tolerability, maximum tolerated dose (MTD), and recommended dose for expansion (RDE). Additional objectives included pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity. Results: At final analysis, 40 pts (21 male, age range 24-79 years) had received M6223 (Q2W: n=32; Q3W: n=8), and 18 pts (7 male, age range 34-80 years) had received M6223+BA. Overall, two dose-limiting toxicities were observed: a grade 3 adrenal insufficiency (M6223, 900 mg) and a grade 3 anemia (M6223+BA, 300 mg; unrelated to M6223). In the M6223 group, grade ≥3 TEAEs were observed in 14 (35.0%) pts and M6223-related grade ≥3 TEAEs in 2 (5.0%) pts. In the M6223+BA group, grade ≥3 TEAEs were observed in 14 (77.8%) pts and M6223-related grade ≥3 TEAEs in 4 (22.2%) pts. No MTD was identified. RDEs were 1600 mg Q2W or 2400 mg Q3W for M6223 monotherapy, and 1600 mg+1200 mg Q2W for M6223+BA. Half-life for the two monotherapy RDEs were 9.0 and 14.6 days, respectively, with moderate accumulation at the selected RDEs. Linear PK was observed for M6223 at 100-2400 mg Q2W and at 2400 mg Q3W; co-administration with BA did not change the PK profile of M6223. PD analyses in blood showed full and sustained TIGIT target occupancy, and depletion of suppressive Tregs at M6223 ≥900 mg. Paired biopsies in the M6223 group (900 mg Q2W, 1600 mg Q2W, 2400 mg Q3W; n=12) showed a trend of decrease in TIGIT+ and increase in CD226+ cells. Median overall survival was 7.6 months (95% CI: 4.9, 12.0) and median progression-free survival was 1.4 months (95% CI: 1.3, 1.8). No pt achieved an objective response (per RECIST v1.1); stable disease as the best response was observed in 13 (32.5%) pts in M6223 and 5 (27.8%) pts in M6223+BA. Conclusion: M6223 monotherapy and in combination with BA had a manageable safety profile, and RDEs for both mono- and combination therapy were defined. Further evaluation of M6223 is ongoing in combination with PD-L1 inhibitor avelumab (JAVELIN Bladder Medley; NCT05327530). Citation Format: Aung Naing, Meredith McKean, Anthony Tolcher, Anja Victor, Ping Hu, Keyvan Tadjalli Mehr, Thomas Kitzing, Daniel Holland, Emilia Richter, Lillian Siu. First-in-human trial of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with advanced solid unresectable tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT184.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 tête enseignante, 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 ».