Abstract CT109: A phase I/Ib study evaluating GDC-0077 plus fulvestrant in patients with <i>PIK3CA</i>-mutant, hormone receptor-positive/HER2-negative breast cancer
Notice bibliographique
Résumé
Abstract Background: PIK3CA encodes the PI3K p110α subunit, and dysregulating mutations are widely seen in breast cancer (BC) and other solid tumors. GDC-0077 (G) is a potent p110α-selective inhibitor that degrades mutant p110α and demonstrates antitumor activity in PIK3CA-mutant BC xenograft models, either as a single agent, or combined with anti-estrogen therapy. From an ongoing, open-label, phase I/Ib dose-escalation study of G alone and combined with endocrine + targeted therapies (NCT03006172), we present data of G + fulvestrant (F) in postmenopausal patients (pts) with PIK3CA-mutant, hormone receptor-positive/HER2-negative BC, including a food-effect assessment on the pharmacokinetics (PK) of G. Methods: Safety (NCI-CTCAE v4), PK, and preliminary antitumor activity (clinical benefit rate [CBR]: RECIST v1.1 stable disease for ≥24 weeks, partial response [PR], or complete response) of 9 mg oral once-daily G + 500 mg intramuscular F on Day 1 (and Day 15 of Cycle 1) of 28-day cycles were assessed until intolerable toxicity/disease progression. The effect of a standard high-fat meal on the PK of G was evaluated after a single dose and at steady state. Relevant signaling and pharmacodynamic (PD) biomarkers were assessed using circulating tumor (ct) DNA samples. Results: At clinical cutoff (Jul 19, 2019), 20 pts were enrolled in the food-effect portion of the G + F arm. Fifteen (75%) had received ≥2 prior lines of therapy for metastatic BC. Median G treatment duration was 5.9 months (range 1.7-17.8); cumulative dose intensity, 98%. Adverse events (AEs) led to dose reduction in 3 pts (15%). The most common treatment-related (TR) AEs (≥4 pts, 20%) were hyperglycemia (11, 55%), diarrhea (10, 50%), stomatitis (grouped term; 9, 45%), nausea (8, 40%), decreased appetite (7, 35%), dysgeusia, fatigue, and muscle spasms (4 each, 20%). Grade ≥3 TRAEs were hyperglycemia, nausea, lymphopenia, hyperamylasemia, and hyperlipasemia (1 each, 5%). The PK of G in combination with F was similar to single-agent PK. Comparable G exposures (Cmax and AUC0-24) were observed following administration in fasted or fed states. Seventeen pts (85%) discontinued treatment, all due to radiographic/clinical disease progression. Overall, 5/14 pts with measurable disease had a PR (36%; 2 received prior F; 4, prior CDK4/6i), of whom 2 pts (14%) had a confirmed PR. CBR was 60% (12/20 pts). Most pts showed decreased ctDNA PIK3CA-mutant allele frequency during treatment. Conclusion: G + F demonstrated a manageable safety profile, similar PK to G alone, preliminary antitumor activity, and PD modulation of PIK3CA-mutant allele frequency in ctDNA. The presence of food did not significantly impact the rate or extent of G absorption following single or multiple doses. Additional pts are being enrolled in the G + F arm to further inform the safety and efficacy of this combination. Citation Format: Kevin Kalinsky, Dejan Juric, Philippe L. Bedard, Mafalda Oliveira, Andres Cervantes, Erika Hamilton, Ian E. Krop, Nick Turner, Peter Schmid, Andrea Varga, Antoine Italiano, Zachary Veitch, Cristina Saura, Valentina Gambardella, Sravanthi Cheeti, Naoki Kotani, Guiyuan Lei, Katherine E. Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer L. Schutzman, Komal Jhaveri. A phase I/Ib study evaluating GDC-0077 plus fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive/HER2-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT109.
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 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».