Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type abstract
PMID
Authors Timothy A. Yap, Ian M. Silverman, Elisa Fontana, Elizabeth Lee, David Spigel, Martin Højgaard, Stephanie Lheureux, Niharika Mettu, Benedito A. Carneiro, Louise Carter, Ruther Plummer, Joseph D. Schonhoft, Danielle Ulanet, Parham Nejad, Peter Manley, Jorge S. Reis-Filho, Yi Xu, Victoria Rimkunas, Maria Koehler, Ezra Rosen
Title Abstract CT030: Genomic and pathologic determinants of response to RP-3500, an ataxia telangiectasia and Rad3-related inhibitor (ATRi), in patients (pts) with DNA damage repair (DDR) loss-of-function (LOF) mutant tumors in the Phase 1/2 TRESR trial
Journal Cancer Res
Vol 82
Issue 12_supplement
Date 2022
URL https://aacrjournals.org/cancerres/article/82/12_Supplement/CT030/701936/Abstract-CT030-Genomic-and-pathologic-determinants
Abstract Text Background: RP-3500 is a potent, oral ATRi developed to treat tumors with LOF gene alterations predicted to exhibit synthetic lethality with ATRi (STEP2 genes). Biomarker analyses from TRESR (NCT04497116) identified predictors of sensitivity to RP-3500. Methods: Biomarker data were centrally assessed from: Tumor/normal sequencing including zygosity analysis (SNiPDx targeted NGS panel), ctDNA, and ATM IHC. Correlations with clinical outcomes: Overall Response (OR: RECIST 1.1 confirmed/unconfirmed CR/PR, PSA or CA125 response), PFS, and CBR (OR or therapy duration >16 weeks [w]) were assessed. Results: 120 pts (ovarian [n=22], prostate [n=22], breast [n=17], pancreatic [n=12], other [n=47]) with LOF alterations (ATM [n=44], BRCA1 [n=25], BRCA2 [n=15], CDK12 [n=9], RNASEH2 [n=5], PALB2 [n=5], SETD2 [n=5], other [n=12]) were enrolled based on local tumor NGS (n=71), germline testing (n=29), ctDNA (n=13), or IHC (n=7). Prior therapies included PARPi (39/120) and platinum (81/120). Locally and centrally assessed biomarker status were concordant for tumor NGS (45/46), germline (20/20) and ctDNA (7/8). Alterations were germline in 50/88 (57%) and somatic in 36/88 (41%) pts; clonal hematopoiesis was the source of ATM LOF in 2/88 (2%) pts. Gene zygosity was biallelic in 49/68 (72%) and monoallelic in 19/68 (28%) tumors. ATM protein loss was detected in 11/13 (85%) biallelic (discordance explained by missense mutations) and 5/8 (63%) monoallelic ATM LOF. Reversions were detected at baseline in 6 pt tumors (BRCA1 [n=3], BRCA2 [n=1], PALB2 [n=1], NBN [n=1]). In pts receiving RP-3500 >100mg and ≥1 response evaluation, OR was 13% (13/98; responses in tumors with ATM, BRCA1, BRCA2, CDK12, RAD51C, SETD2 genotypes); CBR was 47% in 77 pts with follow-up >16w , mPFS was 15w; 40/98 pts remain on RP-3500 (up to 50+w). CBR was >60% and mPFS not reached on 17 pts with ovarian tumors. Compared with monoallelic loss, tumors with biallelic loss had significantly higher CBR (20/34 [59%] vs 1/10 [10%], p=0.01) and trend for longer mPFS (19w vs 6w, p=0.08). CBR was 64% (7/11) vs 0% (0/3) in biallelic vs monoallelic tumors with ATM LOF (p=0.19), and 64% (7/11) vs 0% (0/2) in tumors with BRCA1 LOF (p=0.19). Two pts with post-PARPi BRCA1 reversions had treatment durations of 17w and 29w. Conclusions: RP-3500 has clinical activity across STEP2 genotypes including those pretreated with PARPi and with BRCA1 reversions. IHC is an imperfect surrogate for ATM zygosity. ATM alterations originating from clonal hematopoiesis of indeterminate potential (CHIP) can be misdiagnosed as tumor derived. High concordance of local and central testing supports the use of local NGS to identify LOF alterations. Improved CBR with RP-3500 therapy in tumors with biallelic LOF supports the use of gene zygosity as a predictor of benefit.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM inact mut Advanced Solid Tumor predicted - sensitive RP-3500 Phase Ib/II Actionable In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a response rate of 13% (13/98), clinical benefit rate (CBR) of 47% (36/77), and median progression-free survival (mPFS) of 15 weeks in solid tumor patients with inactivating mutations in DNA damage repair genes, including ATM, with a CBR of >60% and mPFS not reached in 17 ovarian tumor patients, and with biallelic ATM inactivation CBR was 64% (7/11) vs 0% (0/3) with monoallelic inactivation (Cancer Res 2022;82(12_Suppl): CT030, NCT04497116). detail...
RAD51C inact mut Advanced Solid Tumor predicted - sensitive RP-3500 Phase Ib/II Actionable In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a response rate of 13% (13/98), clinical benefit rate (CBR) of 47% (36/77), and median progression-free survival (mPFS) of 15 weeks in solid tumor patients with inactivating mutations in DNA damage repair genes, including RAD51C, with a CBR of >60% and mPFS not reached in 17 ovarian tumor patients (Cancer Res 2022;82(12_Suppl): CT030, NCT04497116). detail...