Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase I clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-H endometrial cancer
Notice bibliographique
Résumé
Background: TSR-042, a humanized monoclonal antibody, targets programmed death (PD)–1 effectively blocking interaction with its ligands PD-L1 and PD-L2. TSR-042 is being evaluated in patients with advanced solid tumors in the ongoing phase 1 GARNET trial (NCT02715284).1 We present safety and efficacy data from the microsatellite instability-high (MSI-H) endometrial cancer (EC) cohort, pharmacokinetics (PK) and receptor occupancy (RO) at the recommended phase 2 dose (RP2D), as well as biomarker analyses. Methods: Patients with previously treated MSI-H EC were evaluated. Patients received the RP2D of TSR-042: 500 mg Q3W for the first 4 cycles and 1000 mg Q6W thereafter. Antitumor activity was assessed by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Serum and peripheral blood mononuclear cells were collected for PK and RO measurements, respectively.1 Results: Twenty-five patients with MSI-H EC were enrolled and treated; median age was 66 years old and 56% had received prior therapy for metastatic/recurrent disease (median=1.0 line of treatment). Seventeen patients had at least 1 tumor assessment (week 12) and also underwent biomarker profiling. Partial responses (confirmed and unconfirmed) occurred in 9 patients (53%), 1 (6%) had stable disease, and 6 (35%) had progressive disease; one patient was not evaluable. Duration of response data for this cohort is not mature yet. Of the 25 patients, 18 (72%) had ≥1 adverse event (AE) with grade ≥3 AEs reported in 11 patients (44%). Treatment-emergent AEs (TEAEs) occurred in 18 patients (72%) with grade ≥3 TEAEs in 1 patient (4%) who experienced grade ≥3 leukopenia and grade ≥3 neutropenia. TSR-042 PK was dose-proportional. Maximal RO was observed at RP2D consistent with results in Parts 1 and 2A.1 Conclusions: TSR-042 demonstrated robust clinical activity in patients with previously treated recurrent or advanced MSI-H EC and an acceptable toxicity profile. PK was consistent across patients. Maximal RO was attained at RP2D. 1. Sachdev JC et al. Ann Oncol. 2017(suppl 5):28:420;1185P. Clinical trial identification: NCT02715284. Editorial acknowledgement: Editorial support, funded by Tesaro, Inc. (Waltham, MA, USA) and coordinated by Ted Paunescu, PhD of Tesaro, Inc., was provided by Dena McWain of Ashfield Healthcare Communications (Middletown, CT, USA). Legal entity responsible for the study: Tesaro, Inc. Funding: Tesaro, Inc. Disclosure: A. Oaknin: Advisory boards: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inc.; Support for travel or accommodation: Roche, AstraZeneca, PharmaMar. S.L. Ellard: Advisory boards: AstraZeneca, Astellas; Honoraria: AstraZeneca. C. Leath, III: Advisory boards: Mateon, Celsion. W. Guo, S. Lu, D. Jenkins, K. McEachern, K. Yu Jen, S. Dunlap, E. Im: Employment and stock and other ownership interests: Tesaro, Inc. L. Gilbert: Advisory boards: AstraZeneca, Roche. All other authors have declared no conflicts of interest.
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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 | 0,001 |
| 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 ».