Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study.
Notice bibliographique
Résumé
LBA1000 Background: Vepdegestrant, an oral PROTAC (PROteolysis TArgeting Chimera) ER degrader, showed encouraging clinical activity and was well tolerated in a phase 1/2 study in pretreated patients (pts) with aBC, and is the first PROTAC to be evaluated in a phase 3 trial (VERITAC-2). Methods: Eligible pts (aged ≥18 y) had ER+/HER2- aBC, 1 prior line of a cyclin-dependent kinase (CDK)4/6 inhibitor plus endocrine therapy (ET) and ≤1 additional line of ET (most recent ET given for ≥6 mo before disease progression); pts with prior chemotherapy in the advanced setting or prior fulvestrant were excluded. Pts were randomized 1:1 to vepdegestrant 200 mg orally once daily continuously or fulvestrant 500 mg intramuscularly (days 1 and 15 of cycle 1; day 1 of subsequent cycles); pts were stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in pts with ESR1 mutations ( ESR1m ) and all pts. Overall survival (OS) was a key secondary endpoint. PFS was tested by stratified 1-sided log-rank. Median PFS (mPFS) was estimated by Kaplan-Meier method and hazard ratio (HR) by a stratified Cox proportional hazard model; study was designed to detect HR<0.60 with 88% power in pts with ESR1m and HR<0.67 with 92.5% power in all pts (1-sided α=0.01875). Results: 624 pts (median age: 60.0 y [range 26–89]) were randomized (n=313 vepdegestrant; 311 fulvestrant); 43.3% had ESR1m tumors (n=136 vepdegestrant; 134 fulvestrant). PFS by BICR was significantly longer with vepdegestrant vs fulvestrant among pts with ESR1m (174 events, HR=0.57 [95% CI 0.42–0.77]; P =0.0001); mPFS (95% CI) was 5.0 mo (3.7–7.4) vs 2.1 (1.9–3.5). PFS by BICR in all pts was not significantly different (384 events, HR=0.83 [95% CI 0.68–1.02]; P =0.0358); mPFS (95% CI) was 3.7 mo (3.6–5.3) vs 3.6 (2.2–3.8). OS data are immature (20% of targeted events in all pts). In 619 treated pts, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. Grade ≥3 TEAEs occurred in 23.4% of pts in the vepdegestrant arm (vs 17.6% fulvestrant). The most common TEAEs in the vepdegestrant arm were fatigue (26.6% vs 15.6% fulvestrant), increased ALT (14.4% vs 9.8%), increased AST (14.4% vs 10.4%) and nausea (13.5% vs 8.8%). TEAEs led to discontinuation of vepdegestrant in 2.9% of pts (vs 0.7% fulvestrant). Conclusions: Vepdegestrant demonstrated statistically significant and clinically meaningful improvement in PFS vs fulvestrant in the ESR1m population. No statistically significant improvement in PFS was observed in the all-pt population. Vepdegestrant was generally well tolerated with low discontinuation rates due to TEAEs. Results support vepdegestrant as a potential oral treatment option for previously treated pts with ESR1m ER+/HER2- aBC. Clinical trial information: NCT05654623 .
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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 | 0,003 | 0,005 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| 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 ».