COMBINING CD19‐4‐1BBL (RO7227166) WITH GLOFITAMAB IS SAFE AND SHOWS EARLY EFFICACY IN PATIENTS SUFFERING FROM RELAPSED OR REFRACTORY B‐CELL NON‐HODGKIN LYMPHOMA
Notice bibliographique
Résumé
Introduction: The antibody-like fusion protein RO7227166 simultaneously targets CD19 on B-cells and 4-1BB (CD137) on T cells. RO7227166 activity is strictly dependent on CD19 crosslinking and exhibits no single-agent activity. RO7227166 plus glofitamab shows strong synergy in preclinical models and is being developed for patients (pts) with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). Methods: This first-in-human trial BP41072 (NCT04077723) evaluated the safety, tolerability, pharmacokinetics/dynamics and preliminary activity of RO7227166 in combination with glofitamab. After a single obinutuzumab dose (1000 mg), pts started glofitamab step up dosing receiving the first target dose of 30 mg on C2D1. On C2D8 RO7227166 dose was given intravenously. From C3D1 both drugs were administered Q3W for a maximum of 12 cycles. Dose escalation was conducted using an mCRM EWOC model with overdose control. Response rates were assessed using Lugano criteria. Results: As of 15 December, 57 pts with aggressive (aNHL) and 23 pts with indolent NHL (iNHL) out of a total of 104 enrolled (all histologies) were evaluable. Aggressive NHL include 42 DLBCL (diffuse large B-cell lymphoma) and 15 trFL (transformed follicular lymphoma). RO7227166 doses ranging from 360 ug up to 75 mg were assessed and the maximum tolerated dose was not reached. Pts (aNHL/iNHL) had median age of 63/62, 39% female, ECOG 0 (56%/74%) or 1 (44%/26%), and stage IV (54%/56%). Patients were heavily pre-treated (median 3 for both [1–8]; 46%/4% had prior CAR-T and 19.7%/9% were primary refractory. Across the 84 safety evaluable pts (all histologies) who received both glofitamab and RO7227166 at least once, the most common adverse events (>15% of pts) were cytokine release syndrome (CRS, 58.3%), neutropenia (28.6%), COVID-19 (25.0%), anemia (22.6%), diarrhea and rash (19.0% each), fatigue (17.9%) and pyrexia (16.7%). Grade 5 events were reported in 5 pts (6%), related to study treatment in 2 pts. A Grade 5 pneumocystis jiroveci pneumonia, related to glofitamab qualified as dose-limiting toxicity (n = 1). CRS was grade 1 in 50.0%, grade 2 in 16.7% and grade 3 in a single patient, mostly confined to the first two cycles of glofitamab. CRS was considered related to only RO7227166 in 6 pts and were all grade 1. Across all doses investigated, best ORR (aNHL/iNHL) was 70%/ 95.7% with CRR of 53%/74%. The aNHL pts with prior CAR-T had 68% BORR and 42% CRR. RO7227166 exposure increased in an almost dose proportional manner for doses ≥22 mg. Furthermore, pharmacodynamic analysis showed expansion of primed and activated CD8, and effector memory T-cells, with a reduction of exhausted T cell phenotypes. Conclusions: Glofitamab can be safely combined with a costimulatory bispecific antibody (RO7227166) in R/R B-NHL. The safety profile of the combination was mainly driven by glofitamab and we did not detect an additive safety signal from RO7227166. Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract M. Hutchings Consultant or advisory role: Genmab, Roche, Takeda Honoraria: Genmab, Roche, Takeda Research funding: Celgene, Daiichi-Sankyo, Genmab, Janssen, Novartis, Roche, Sanofi, Takeda M. Dickinson Consultant or advisory role: Roche, Abbvie Honoraria: Roche, Abbvie Research funding: Roche Educational grants: Roche C. Carlo-Stella Employment or leadership position: Humanitas University, Milano (Italy) Consultant or advisory role: Sanofi, ADC Therapeutics, Bristol-Myers Squibb, Celgene, Karyopharm Therapeutics, Roche Honoraria: AstraZeneca, Bristol-Myers Squibb, Incyte, Janssen Oncology, Takeda, ADC Therapeutics Research funding: ADC Therapeutics, Roche, Sanofi Educational grants: Roche, Janssen Oncology, Takeda F. Morschhauser Consultant or advisory role: Roche, Gilead, Genmab, Novartis, Abbvie Honoraria: Chugai (scientific lectures) F. Bosch Research funding: Roche G. Gritti Consultant or advisory role: Roche, Takeda, Kite-Gilead, Ideogen, Genmab Educational grants: Janssen, Beigene, Sandoz W. Townsend Consultant or advisory role: Roche, Takeda, Gilead, Incyte Honoraria: Roche, Takeda, Gilead, Incyte Educational grants: Roche and Takeda N. L. Bartlett Consultant or advisory role: tbd Honoraria: tbd Research funding: tbd G. Cartron Consultant or advisory role: ROCHE, BMS, Abbvie, MedXcell, MabQi, Ownards Therapeutics Honoraria: GILEAD, BMS, Roche, Abbvie, Jansen, Novartis Educational grants: Roche H. Ghesquieres Consultant or advisory role: tbd Honoraria: tbd Research funding: tbd R. Houot Consultant or advisory role: Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte, Miltenyi Honoraria: Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, Roche A. Christiansen Consultant or advisory role: Roche N. Dimier Employment or leadership position: Roche Stock ownership: Roche C. Jamois Employment or leadership position: Roche Stock ownership: Roche E. Harrop Employment or leadership position: Roche Stock ownership: Roche S. Herter Employment or leadership position: Roche Stock ownership: Roche G. Hölzlwimmer Employment or leadership position: Roche Stock ownership: Roche A. Keelara Employment or leadership position: Roche Stock ownership: Roche K. Korfi Employment or leadership position: Roche Stock ownership: Roche J. Luong Employment or leadership position: Roche Stock ownership: Roche C. Mueller Employment or leadership position: Roche Stock ownership: Roche S. Mycroft Employment or leadership position: Roche Stock ownership: Roche M. Whayman Employment or leadership position: Roche Stock ownership: Roche I. Prieto Employment or leadership position: Roche Stock ownership: Roche D. Rukina Consultant or advisory role: Roche K. Lechner Employment or leadership position: Roche Stock ownership: Roche
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) | 0,001 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».