دورية أكاديمية
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).
| العنوان: | 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). |
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| المؤلفون: | Rosen, Ezra, Silverman, Ian M., Fontana, Elisa, Lee, Elizabeth Katherine, Spigel, David R., Højgaard, Martin, Lheureux, Stephanie, Mettu, Niharika B., Carneiro, Benedito A., Carter, Louise, Plummer, Elizabeth Ruth, Schonhoft, Joseph D., Ulanet, Danielle, Manley, Peter, Reis-Filho, Jorge S., Xu, Yi, Rimkunas, Victoria, Koehler, Maria, Yap, Timothy A. |
| المصدر: | Rosen , E , Silverman , I M , Fontana , E , Lee , E K , Spigel , D R , Højgaard , M , Lheureux , S , Mettu , N B , Carneiro , B A , Carter , L , Plummer , E R , Schonhoft , J D , Ulanet , D , Manley , P , Reis-Filho , J S , Xu , Y , Rimkunas , V , Koehler , M & Yap , T A 2022 , ' Circulating tumor DNA (ctDNA) determinants of improved outcomes in patients (pts) with .... |
| سنة النشر: | 2022 |
| المجموعة: | The University of Manchester: Research Explorer - Publications |
| الوصف: | 3082Background: 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. ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1200/jco.2022.40.16_suppl.3082 |
| الإتاحة: | https://doi.org/10.1200/jco.2022.40.16_suppl.3082Test https://research.manchester.ac.uk/en/publications/6911c799-4520-46d4-ab4a-6a0cedd8d4b3Test https://www.mendeley.com/catalogue/e0eed99f-985d-3bd1-8328-8d8b02db3508Test/ |
| حقوق: | info:eu-repo/semantics/restrictedAccess |
| رقم الانضمام: | edsbas.3DE7196B |
| قاعدة البيانات: | BASE |
| DOI: | 10.1200/jco.2022.40.16_suppl.3082 |
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