Abstract CT053: Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase 1 clinical trial of the anti-PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced NSCLC and MSI-H endometrial cancer
Notice bibliographique
Résumé
Abstract Introduction: TSR-042 is a humanized monoclonal antibody targeting programmed death (PD)-1, effectively blocking interaction with its ligands PD-L1 and PD-L2. TSR-042 is being evaluated in patients (pts) with advanced solid tumors in the ongoing phase 1 GARNET trial (NCT02715284). Weight based dose escalation (Part 1) and fixed-dose safety studies (Part 2A) have been completed,1 and the study is currently enrolling pts with specific tumor types into expansion cohorts. Here, we present safety and efficacy data from the microsatellite instability-high (MSI-H) endometrial cancer (EC) and non-small cell lung cancer (NSCLC) cohorts, as well as pharmacokinetic (PK) and receptor occupancy (RO) characterization at the recommended phase 2 dose (RP2D). Methods/Procedures: 30 NSCLC pts and 19 MSI-H EC pts with previously treated recurrent or advanced disease were enrolled; median number of prior lines of therapy for metastatic disease was 1.0 for both cohorts. MSI status for EC pts was determined centrally using a next generation sequencing-based assay. Key exclusion criteria included prior therapy with agents targeting anti-PD-1, PD-L1, or PD-L2, and uncontrolled CNS metastases. Pts were treated at the R2PD of TSR-042: 500 mg Q3W for the first 4 cycles and 1000 mg Q6W thereafter. Serum and PBMCs were collected for PK and RO analyses, respectively. Antitumor activity was assessed by investigators using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). RO was assessed using a CD3+ binding assay (direct receptor occupancy).1 Results: Among the 30 NSCLC and 19 MSI-H EC pts, 42 (85.7%) pts reported ≥1 adverse event (AE), with grade ≥3 AEs reported in 13/49 (26.5%) pts. The most common AEs were diarrhea and nausea (11 pts each), arthralgia and fatigue (9 pts each), and cough, decreased appetite, and dyspnea (7 pts each). 25/49 (51.0%) pts reported treatment-related AEs; 11/49 (22.4%) pts had serious AEs; 1 case of grade 3 fatigue and 1 case of grade 3 leukopenia and grade 3 neutropenia were deemed treatment-related. 21 NSCLC and 11 MSI-H EC pts had at least 1 tumor assessment. Among NSCLC pts, 7/21 (33.3%) had a partial response (irPR; confirmed and unconfirmed), and 6/21 (28.6%) had stable disease (irSD); among MSI-H EC pts, 4/11 (36.4%) had irPR, and 2/11 (18.2%) had irSD. TSR-042 demonstrated dose-proportional PK. The maximal achievable RO was observed in pts treated at the RP2D, consistent with the results reported for Parts 1 and 2A.1 Conclusions: These results indicate clinical benefit of TSR-042 in previously treated NSCLC and MSI-H EC patients, with a safety profile similar to other PD-1 inhibitors. PK results were consistent across all patients evaluated and show that maximal achievable receptor occupancy was attained at the RP2D. 1. Sachdev JC et al. Ann Oncol. 2017(suppl 5):28:420;1185P Citation Format: Victor Moreno, Maria-Pilar Barretina-Ginesta, Wei Guo, Sharon Lu, David Jenkins, Kristen McEachern, Vienna Reichert, Steven Dunlap, Ellie Im, Lucy Gilbert, Ana Oaknin, Charles Leath, III, Janakiraman Subramanian. Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase 1 clinical trial of the anti-PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced NSCLC and MSI-H endometrial cancer [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 CT053.
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 | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 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 ».