INTERIM REPORT FROM A PHASE 2 MULTICENTER STUDY OF TAZEMETOSTAT, AN EZH2 INHIBITOR, IN PATIENTS WITH RELAPSED OR REFRACTORY B‐CELL NON‐HODGKIN LYMPHOMAS
Notice bibliographique
Résumé
Background: New treatments with novel mechanisms of action are needed for patients with relapsed/refractory (R/R) DLBCL and FL. Because tumor cells may depend on the histone methyltransferase EZH2 to perpetuate a less-differentiated state, and activating mutations may be oncogenic drivers, tazemetostat, a potent, selective EZH2 inhibitor was developed. Tazemetostat shows antitumor activity in preclinical models and in a phase 1 study in patients (pts) with mutated or wild-type (wt) EZH2 tumours. This open-label, multicentre phase 2 study enrolled pts with either mutated or wt EZH2 R/R DLBCL or FL to determine efficacy and safety in 6 separate cohorts. Methods: Tazemetostat 800 mg is administered po BID. Tumour tissue is analysed prospectively to guide cohort assignment based on EZH2 hot spot activating mutations (Y646X, A682G, A692V) using a cobas® EZH2 Mutation Test (Roche Molecular Systems, in development). A 62-gene panel is used to assess tissue DNA and circulating tumour DNA (ctDNA) for biomarkers of tazemetostat sensitivity. Key inclusion criteria include: ≥18 yrs old; ≥2 prior treatment regimens; measurable disease; and adequate organ function. The primary endpoint is overall response rate (ORR). Secondary endpoints include progression-free survival and safety/tolerability. Enrolment for monotherapy has been completed in 3 cohorts with wt EZH2 and is ongoing in 2 cohorts of mutant EZH2. Enrolment for a tazemetostat combination with prednisolone in wt EZH2 DLBCL was recently initiated. Results: As of Feb. 28, 2017, interim safety data are summarized from 165 DLBCL or FL pts with documented tazemetostat dosing. Grade ≥ 3 treatment-emergent adverse events related to tazemetostat were reported in 18% of pts. The most common (>10%) adverse events across all grades were: nausea; thrombocytopenia; cough; diarrhoea; fatigue; and asthenia. Interim efficacy results are summarized from 149 pts (median: 3 prior therapies) and exclude ongoing pts who lack an on-study tumor assessment. The ORR (CR + PR) was 40% in pts with DLBCL with EZH2 mutations (N = 10), 18% in pts with DLBCL with wt EZH2 (N = 85), 63% in FL pts with EZH2 mutations (N = 8), and 28% in FL pts with wt EZH2 (N = 46). In the cohorts of EZH2 mutant FL and EZH2 wt FL, 38% and 30% of pts, respectively, remained on study with stable disease. Safety and efficacy data will be further updated at the conference. The genetic analysis of tumor biomarkers will be reported separately. Conclusion: This phase 2 interim assessment shows preliminary clinical activity of tazemetostat with a favourable safety profile in pts with R/R DLBCL and FL, with preferential benefit in pts whose tumours bear activating EZH2 mutations. Pts continue to be followed for tazemetostat treatment outcomes in light of previously reported observations that the onset of clinical response may be delayed and evolve over time from SD to PR and from PR to CR. Keywords: diffuse large B-cell lymphoma (DLBCL); EZH2; follicular lymphoma (FL).
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 | 0,000 |
| 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 ».