Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer Res	82	12_supplement	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.

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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