Abstract B169: Retrospective baseline biomarker analyses in a first-in-human Phase 1 trial of the PKMYT1 inhibitor lunresertib (RP-6306) in pts with advanced solid tumors harboring <i>CCNE1</i> amplification and/or deleterious alterations in <i>FBXW7</i> or <i>PPP2R1A</i>
Notice bibliographique
Résumé
Abstract Background: Lunresertib (RP-6306) is a first-in-class membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase (PKMYT1) inhibitor that disrupts the G2/M checkpoint leading to premature mitosis and catastrophic DNA damage in cells harboring synthetic lethal genomic alterations. The safety and tolerability of lunresertib alone and in combination with camonsertib (RP-3500) is being investigated in the Phase 1 MYTHIC study in patients with advanced solid tumors with either CCNE1 amplifications (amp) or deleterious alterations in FBXW7 or PPP2R1A (NCT04855656). Here, we present a comprehensive retrospective biomarker analysis aimed at understanding concordance between local vs. central and tissue- vs. plasma-based next generation sequencing (NGS). The correlation between CCNE1 copy number assessment by NGS and fluorescence in situ hybridization (FISH), as well as the relationship between CCNE1 amp and Cyclin E1 protein levels, was investigated. Methods: Patients were enrolled based on results from sponsor-approved local tumor NGS and plasma circulating tumor DNA (ctDNA) tests. To ensure molecular eligibility criteria were met, local NGS reports were centrally reviewed and functionally annotated prior to enrollment. Tumor tissue and plasma samples collected at screening were retrospectively analyzed by SNiPDx™ and Tempus xF(+), respectively. Tissue samples were further evaluated by FISH and immunohistochemistry. Results: As of June 1, 2023, 145 patients were screened with uterine (23%), colorectal (CRC, 15%), ovarian (13%), and upper GI (6%) as the most frequent cancers. Ninety-four percent (137/145) of patients screened had local NGS results available (98% tissue, 2% plasma). CCNE1 amp (40.1%) were most frequently observed in ovarian, uterine, and upper GI malignancies. FBXW7 (39.4%) and PPP2R1A (16.0%) alterations were enriched in CRC and uterine cancer, respectively. TP53 alterations were frequent across all biomarker groups (76% CCNE1, 54% FBXW7, and 88% PPP2R1A). Central tissue NGS confirmed 94% (47/50) of the enrollment alterations. Central plasma ctDNA confirmed 83.0% (39/47) of FBXW7 and PPP2R1A mutations and had high positive predictive value (100%, 17/17) but low sensitivity (42.5%; 17/40) for CCNE1 amp. CCNE1 amp call and copy number estimation by tissue NGS and FISH were highly correlated (Spearman ρ=0.65, p=0.006). Seventy-five percent of tumors with CCNE1 amp had Cyclin E1 overexpression (H-score ≥100; mean=168; range [0, 300]). Conclusion: In this study, local NGS tests were an efficient and robust strategy for directing patients into a molecularly defined Phase 1 trial. Plasma ctDNA reliably detected alterations in all 3 genes, but caution should be taken when interpreting CCNE1 amplification negative results due to a high false negative rate. FISH and genomics are appropriate methods to estimate CCNE1 amp copy number. These retrospective analyses enable the testing of the synthetic lethal hypothesis of lunresertib and CCNE1, PPP2R1A and FBXW7, assuring reliable interpretation of the clinical data. Citation Format: Elia Aguado-Fraile, Sunantha Sethuraman, Adam Petrone, Emeline Bacque, Alison Schram, Stephanie Lheureux, Elizabeth K Lee, Maria Koehler, Ian M Silverman, Victoria Rimkunas, Timothy A Yap. Retrospective baseline biomarker analyses in a first-in-human Phase 1 trial of the PKMYT1 inhibitor lunresertib (RP-6306) in pts with advanced solid tumors harboring CCNE1 amplification and/or deleterious alterations in FBXW7 or PPP2R1A [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B169.
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) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 ».