Circulating tumor DNA (ctDNA) determinants of improved outcomes in patients (pts) with advanced solid tumors receiving the ataxia telangiectasia and Rad3-related inhibitor (ATRi), RP-3500, in the phase 1/2a TRESR trial (NCT04497116).
Notice bibliographique
Résumé
3082 Background: RP-3500 is a selective and potent oral ATRi in development for advanced solid tumors harboring loss-of-function (LOF) alterations in genes associated with ATRi sensitivity. We determined whether ctDNA can facilitate enrollment/monitoring of pts treated with RP-3500. Methods: Serial plasma samples collected at baseline (BL, 99 pts) and early timepoints on therapy (89 pts, 3-9 weeks [wks]) were profiled for ctDNA (Tempus xF or Guardant360). Targeted next generation sequencing (NGS) (SNiPDx panel) was performed on matched peripheral blood mononuclear cells and tumor samples collected at BL. Molecular ctDNA response (MR) was defined as ≥50% reduction in mean variant allele frequency (VAF) from BL to any timepoint ≤9 wks on-therapy. Clonal hematopoiesis (CH) or germline alterations were excluded from the analysis. Efficacy was assessed in pts treated with > 100 mg RP-3500/day with ≥1 post-BL response assessment. Endpoints included progression-free survival (PFS) and clinical benefit rate (CBR; CR/PR by RECIST1.1 or PSA/CA-125, or > 16 wks on treatment). Results: BL ctDNA was detected in 82% (81/99) of pts. Eligibility alterations were evaluable by the ctDNA panel in 61% (60/99) of pts, excluding structural/copy number variants and genes/exons not on the panel. Percent agreement between BL ctDNA and local eligibility NGS test was 93% (56/60). CH variants were identified in 26 pts (1-14 per pt); median VAF was 0.4% (0.1-12.4%). Two pts with pathogenic ataxia-telangiectasia mutated ( ATM) alterations were determined to be from CH. MRs were observed in 44% (24/55) of pts with median time to MR of 3.3 wks and were across tumors harboring ATM (10/20), BRCA2 (7/10), BRCA1 (4/15), CDK12 (1/3), PALB2 (1/3) and RAD51C (1/1) pathogenic alterations. Four pts with BRCA1 mutant tumors had MRs, 2 of whom (breast cancer) had received prior PARPi and had confirmed BRCA1 reversion mutations and clinical benefit (CB). One pt with g ATM pancreatic cancer with CB had > 90% reduction in KRAS mutant VAF at 3 wks. MR was associated with longer mPFS (29 vs 12 wks, p = 0.0002) and significantly higher CBR (17/22 (77%) vs. 8/28 (29%); p = 0.001) than those without MR. Pts with MRs not achieving CB (N = 5) included 4 with RP-3500 dose interruptions/reductions and 1 who discontinued early (10 wks) due to clinical progression but with decreased target lesions and stable disease. Conclusions: ctDNA testing is a reliable method to detect DNA damage repair LOF alterations but is limited to alterations and genes/exons covered by the ctDNA test. CH alterations are frequent, especially for ATM, thus matched normal analysis is preferred. Changes in ctDNA as early as 3 wks were associated with improved outcomes and may be useful for evaluating drug activity in heterogenous tumors outside of traditional efficacy endpoints. Clinical trial information: NCT04497116.
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 | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| 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) | 0,002 | 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 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 ».