Abstract CT180: Preliminary phase 1 profile of BMS-986179, an anti-CD73 antibody, in combination with nivolumab in patients with advanced solid tumors
Notice bibliographique
Résumé
Abstract Background: CD73 is an ectonucleotidase that converts adenosine monophosphate to adenosine, a potent immunosuppressive soluble mediator that inhibits the cytotoxic function of CD8+ T cells and natural killer cells while promoting proliferation of immunosuppressive cells. BMS-986179 is a high-affinity antibody that inhibits CD73 enzymatic activity and downregulates its expression on tumor cells. Blockade of CD73 enhanced the antitumor activity of anti-PD-1 in preclinical models (Barnhart BC, et al. Cancer Res. 2016;76(14 suppl) [abstract 1476]). Here we describe preliminary results of the first-in-human phase 1/2a study of BMS-986179 + nivolumab (NIVO) in patients (pts) with advanced solid tumors (NCT02754141). Methods: Pts with ≥ 1 prior therapy were treated in this open-label, dose-escalation and -expansion study. Escalation began with a 2-week monotherapy lead-in, in which pts received BMS-986179 150-1600 mg IV QW followed by BMS-986179 (same dose) IV QW + NIVO 240 mg IV Q2W. Pharmacokinetics (PK), pharmacodynamics (PD), safety, and preliminary antitumor activity were evaluated. PD analyses included immunohistochemistry, enzyme activity assays in tumor biopsies, and evaluation of receptor occupancy and soluble CD73 in peripheral blood. Results: As of the Dec 19, 2017, data cutoff, 59 pts were treated with BMS-986179 ± NIVO during dose escalation. PK of BMS-986179 was nonlinear at lower doses due to target-mediated drug disposition, and exposure increased proportionally from 1200 to 1600 mg. BMS-986179 demonstrated complete and persistent CD73 target engagement in the tumor and periphery at all doses. Treatment-related AEs (TRAEs) were observed in 30 of 52 pts (58%) who received the combination, with no clear dose relationship. Only 8 pts (15%) experienced grade 3 TRAEs, and 1 discontinued treatment due to a TRAE (grade 3 increased ALT). Both the monotherapy lead-in and the combination were well tolerated, with no grade 4 TRAEs and no treatment-related deaths. BMS-986179 efficiently inhibited CD73 enzyme activity in the tumor vasculature and tumor cells at all doses, without dose dependency. Overall, 7 pts with head and neck, pancreatic, prostate, anal, and renal cancer achieved confirmed partial responses and 10 pts had stable disease. Conclusions: BMS-986179 + NIVO was well tolerated, with CD73 target engagement in the tumor and periphery and a safety profile similar to that of NIVO monotherapy. The combination demonstrated preliminary antitumor activity. These data support the ongoing evaluation of this combination in pts with advanced solid tumors. Citation Format: Lillian L. Siu, Howard Burris, Dung T. Le, Antoine Hollebecque, Neeltje Steeghs, Jean-Pierre Delord, John Hilton, Bryan Barnhart, Emanuela Sega, Kinjal Sanghavi, Anke Klippel, Cyrus Hedvat, Ed Hilt, Mark Donovan, Adrianna Gipson, Paul Basciano, Jennifer Postelnek, Yue Zhao, Raymond P. Perez, Richard D. Carvajal. Preliminary phase 1 profile of BMS-986179, an anti-CD73 antibody, in combination with nivolumab in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT180.
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 | 0,000 |
| 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 ».