Abstract B057: BMS-986148, an anti-mesothelin antibody-drug conjugate (ADC), alone or in combination with nivolumab demonstrates clinical activity in patients with select advanced solid tumors
Notice bibliographique
Résumé
Abstract Background: Mesothelin, a GPI-anchored cell surface protein, is highly expressed in several tumor types and can be targeted for antibody (ab)-based cancer therapy. BMS-986148 is a fully human IgG1 anti-mesothelin monoclonal ab conjugated to tubulysin to promote selective cytotoxic delivery to tumor cells. In preclinical models, combination of anti–mesothelin-tubulysin with anti–PD-1 promoted a synergistic antitumor response and influx of tumor-infiltrating lymphocytes. Here, we present initial data for BMS-986148 ± nivolumab (NIVO; anti–PD-1) from a phase 1/2a trial in a biomarker-defined population of patients (pts) with select advanced solid tumors (NCT02341625). Methods: During dose escalation (ESC), pts received BMS-986148 0.1 to 1.6 mg/kg IV Q3W, BMS-986148 0.4 or 0.8 mg/kg IV Q1W, or BMS-986148 0.8 mg/kg + NIVO 360 mg IV Q3W. During monotherapy (mono) dose expansion (EXP), pts with mesothelin-selected mesothelioma (ie, H score ≥ 100 for tumor mesothelin expression), non-small cell lung cancer (NSCLC), or ovarian cancer received BMS-986148 1.2 mg/kg mono IV Q3W, and during combination (combo) dose EXP, pts with mesothelin-selected mesothelioma or pancreatic cancer received BMS-986148 0.8 mg/kg + NIVO 360 mg combo IV Q3W. The primary endpoint was safety. Secondary endpoints included pharmacokinetics (PK) and antitumor activity. Results: As of April 1, 2019, 126 pts have been treated in this trial; 96 pts received BMS-986148 mono (Q3W, n = 84; Q1W, n = 12), and 30 pts received BMS-986148 + NIVO combo. PK analysis in pts treated during ESC demonstrated that total antibody and active ADC exposures increased in a dose-proportional manner. Unconjugated tubulysin concentrations were low but sustained over the dosing interval. The maximum tolerated dose (MTD) for mono was 1.2 mg/kg Q3W, and the 0.8 mg/kg dose was determined to be tolerable for the combo. Across all cohorts, any-grade and grade 3/4 treatment-related AEs (TRAEs) were reported in 87% and 44% of all pts, respectively. Overall, the most common TRAEs (any grade; grade 3-4) reported in ≥ 15% of pts were AST increased (43%; 17%), ALT increased (41%; 16%), fatigue (37%; 5%), nausea (29%; 0%), decreased appetite (22%; 1%), and blood alkaline phosphatase increased (18%; 4%). The frequency of TRAEs and dose-limiting toxicities related to liver function tests increased with increasing dose of BMS-986148. Most TRAEs resolved with dose interruption, dose reduction, or treatment discontinuation. Serious TRAEs were reported in 18% of pts with mono and 23% of pts with combo. Fifteen percent of pts discontinued due to TRAEs, and 1 pt died due to a TRAE (pneumonitis; 1.2 mg/kg Q3W mono). The ORR was 6% (0 CR, 3 PR) with mono in EXP and 20% (0 CR, 6 PR) with the combo in ESC and EXP. Among pts with mesothelioma, the ORR was 4% with mono in EXP and 31% with combo in ESC and EXP. Among pts with ovarian carcinoma, the ORR was 9% with mono in EXP. Of note, durable responses lasting up to ≈ 20 mo in pts with ovarian cancer with mono and ≈ 9 mo in pts with mesothelioma with mono and combo were observed. Conclusions: BMS-986148 ± NIVO was tolerable and demonstrated a clinically manageable safety profile. Preliminary clinical activity was observed with BMS-986148 ± NIVO in select patient populations, including pts with mesothelioma. Citation Format: Jeffrey Clarke, Siu-Chung Chu, Lillian L Siu, Jean-Pascal Machiels, Benjamin Markman, Kimberley Heinhuis, Michael Millward, Martijn Lolkema, Sandip Pravin Patel, Paul de Souza, Giuseppe Curigliano, Armando Santoro, Michelle Brown, Ronald Fleming, Heather Vezina, Chunsheng He, Sylvie Rottey. BMS-986148, an anti-mesothelin antibody-drug conjugate (ADC), alone or in combination with nivolumab demonstrates clinical activity in patients with select advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B057. doi:10.1158/1535-7163.TARG-19-B057
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 ».