Abstract LB-411: A phase II study of combination epigenetic therapy in advanced non-small cell lung cancer
Notice bibliographique
Résumé
Abstract Background: Epigenetic gene silencing is a key contributor to carcinogenesis. Pre-clinical studies suggest that combined inhibition of DNA methyltransferase and of histone deacetylase activity can synergistically re-express aberrantly silenced genes. Clinical studies combining 5-azacitidine (5AC) and entinostat have shown activity in leukemia. We hypothesized that a similar effect might be seen in patients with solid tumors. As a first test of this hypothesis, we conducted a phase II study in patients (pts) with advanced, recurrent non-small cell lung cancer (NSCLC). This was just completed under the aegis of a Stand up to Cancer (SU2C) project. Methods: Subjects included adults with recurrent metastatic NSCLC and progressive disease after ≥1 prior chemotherapy regimen. Pts were given 5AC 40 mg/m2 SQ days 1–6 and 8–10, and entinostat 7 mg days 3 and 10, on a 28 day cycle. A standard Simon two stage design was used. Results: 42 pts were enrolled on study, of whom, 32 completed 2 cycles and were evaluable for response. Mean # of previous therapies was 3. Treatment was well tolerated, with local injection site reactions being the most common toxicity. A complete response was observed in a pt with 3 prior therapies that also had the highest 5AC exposure by pharmacokinetic analysis. She remained on therapy for 14 months (m) and discontinued due to what proved to be a genetically distinct second primary lung cancer. This was resected, and she remained disease free off treatment for 12 m. A second pt with 3 prior therapies and metastases to the liver had a partial response for 8 m, including complete resolution of his liver disease. He also developed an independent primary, treated with chemoradiotherapy, and has been progression-free for over 18 m off epigenetic therapy. 9 pts had disease stabilization (SD) over multiple cycles, including 2 with SD for 14 m and 18 m, respectively, with marked symptomatic improvement. Median time to progression was 8 weeks and median overall survival was 8 m, comparing favorably with currently FDA approved drugs for this clinical context. Biomarker assessments included serial analysis of circulating tumor DNA methylation in plasma (loci: APC, RASSF1A, HCAD). 17 pts had ≥ 2 methylated loci detectable. 8 pts (47%) showed decreasing signal at all detectable loci of which 6 had SD or better, including both pts with RECIST criteria response. Conclusions: The combination of 5AC and entinostat is safe and well tolerated in advanced NSCLC pts. Durable patient benefit has been observed in this extensively pretreated population, including major objective responses. Correlative analyses are ongoing to identify characteristics of pts benefitting from this novel therapy. Based on these data, related studies are being initiated in colon, breast, and early stage NSCLC pts under the aegis of the SU2C. Supported by NCI, FAMRI, and AACR/SU2C. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-411. doi:10.1158/1538-7445.AM2011-LB-411
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».