Abstract PS11-11: Targeted safety events from a phase I/Ib study evaluating GDC-0077 alone and in combination with endocrine therapy (ET) ± palbociclib (palbo) in patients (pts) with <i>PIK3CA</i>-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)
Notice bibliographique
Résumé
Abstract Background Activating mutations in PIK3CA, encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3K) occur in ~40% of HR+/HER2- BCs. GDC-0077, a PI3Kα-selective inhibitor and mutant PI3Kα degrader, is being developed as an anticancer agent. A phase I/Ib study of GDC-0077 alone and combined with other therapies is ongoing in pts with locally advanced or metastatic PIK3CAmut, HR+/HER2- mBC (NCT03006172). Targeted safety events are presented here. Methods Safety was assessed via NCI-CTCAE v4 for GDC-0077 administered alone (Arm A), with letrozole and palbo (Arm B), with letrozole (Arm C), with fulvestrant (Arm D), or with fulvestrant and palbo (Arm E, plus metformin in Arm F for pts with body mass index ≥ 30 and/or HbA1c ≥ 5.7%), in 28-day cycles until intolerable toxicity or disease progression. GDC-0077 was administered orally daily at 3, 6, 9, or 12 mg; letrozole, at 2.5 mg orally daily; palbo, at 125 mg orally 21/28 days; and fulvestrant, at 500 mg intramuscularly every 4 weeks. Targeted adverse events (AEs) included hyperglycemia, diarrhea, stomatitis (includes stomatitis, mucosal inflammation, mouth ulceration, glossitis, lip ulceration, palatal ulcer, and tongue ulceration), rash (includes rash, maculopapular rash, dermatitis acneiform, erythema, and erythematous rash), neutropenia (includes neutropenia and neutrophil count decreased), thrombocytopenia, and pneumonitis. Results As of clinical data cutoff (03/20/2020), 157 pts were enrolled and treated (Arm A: 20; Arm B: 33; Arm C: 37; Arm D: 39; Arm E: 13; Arm F: 15). Median cumulative dose intensity was 97.2% for GDC-0077, 90.6% for palbo, 99.9% for letrozole, and 100% for fulvestrant. Pneumonitis was reported in 2 pts, both in palbo-containing arms (grade 1 in Arm B; grade 2 in Arm F). Hyperglycemia required antihyperglycemic treatment in 69 pts (44%), and the most frequent agents used were metformin (39%; except Arm F where this was required as part of study treatment), empagliflozin (16%), and sitagliptin (15%). Fifteen pts (10%) required GDC-0077 dose reductions due to hyperglycemia. Stomatitis treatment was administered in 51 pts (32%), with dexamethasone mouthwash used most frequently (22%). Neutropenia and thrombocytopenia were managed with palbo dose reduction in 13 pts (21%) and 1 pt (2%), respectively. Overall, treatment-related AEs led to GDC-0077 discontinuation in 2 pts (1%) (grade 3 hyperglycemia in Arm B; grade 2 panniculitis in Arm F). Conclusion Targeted safety events with GDC-0077 alone and in combination ET ± palbo were manageable and required minimal GDC-0077 dose modifications or discontinuations. No unexpected safety events were reported in combination with palbo. A phase III study of GDC-0077 in combination with palbo and fulvestrant is enrolling currently (NCT04191499). Pts, n (%)Treatment-related AEsTreatment-related grade ≥ 3 AEsAll arms;All arms;N = 157N = 157Hyperglycemia98 (62)36 (23)Stomatitis (grouped terms)69 (44)2 (1)Diarrhea68 (43)0Rash (grouped terms)19 (12)1 (1)Palbo arms (B/E/F);Palbo arms (B/E/F);N = 61N = 61Neutropenia45 (74)36 (59)Stomatitis (grouped terms)41 (66)2 (3)Thrombocytopenia19 (31)4 (7) Citation Format: Mafalda Olivera, Komal Jhaveri, Dejan Juric, Philippe L Bedard, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Peter Schmid, Nicolas Turner, Andrea Varga, Guiyuan Lei, Stephanie Royer-Joo, Piia Thomas, Jennifer L Schutzman, Cristina Saura. Targeted safety events from a phase I/Ib study evaluating GDC-0077 alone and in combination with endocrine therapy (ET) ± palbociclib (palbo) in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-11.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,002 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,001 |
| 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 ».