Serial ctDNA Research Articles

Abstract B019: Clinical and molecular correlates of circulating tumor DNA (ctDNA) dynamics in breast tumors resistant to neoadjuvant therapy (NAT)

Abstract Purpose: We examined the utility of serial ctDNA testing for refining risk stratification of NAT- resistant tumors (RTs, defined as residual cancer burden, RCB-II/III) and predicting early treatment response. We also characterized the molecular correlates of ctDNA dynamics in RTs to elucidate the mechanisms associated with increased metastatic potential. Methods: We performed serial ctDNA testing using a tumor-informed personalized assay (SignateraTM, Natera Inc.) in 723 patients (pts) with high-risk early-stage breast cancer receiving NAT (I-SPY2). Tumors were stratified according to RCB class and ctDNA dynamics (clearance patterns), and the distant recurrence-free survival (DRFS) between groups was compared. We examined the predictive value of ctDNA dynamics using the RCB index (the continuous measure of RCB) as the response endpoint. Serial whole exome sequencing (WES), gene expression profiling (GEP), and reverse-phase protein analysis (RPPA) data were analyzed to elucidate the molecular biology of RTs. Results: Of the 723 pts, 300 (41%) had hormone receptor (HR)+HER2-, 237 (33%) triple-negative (TN), and 186 (26%) HER2+ breast cancers with pretreatment ctDNA-positivity rates of 76%, 92%, and 77%, respectively. 321 (45%) pts had responding tumors (RCB-0/I), and 55% had RTs: RCB-II (n=255) and RCB-III (n=132). CtDNA dynamics revealed heterogeneity in the metastatic potential of RTs, including tumors with a reduced propensity to metastasize (persistent ctDNAneg and early clearance). Failure to clear ctDNA after NAT was associated with an increased risk of metastatic recurrence and death (3-yr DRFS rates: no clearance=35% vs. persistent ctDNAneg=98%, p<0.001). Early clearance of ctDNA, 3 weeks after treatment initiation, skewed the distributions toward lower RCB indices (favorable response), including in arms containing immune checkpoint inhibitors. Of the 387 RTs, 316 had ctDNA data post-NAT, of which only 51 (16%) were ctDNA+. We hypothesized that changes in the mutational landscape during NAT could have impacted the detection of patient-specific ctDNA targets selected from WES of pretreatment tumors. However, serial WES (n=100) of RTs showed that these targets remained detectable in solid tissue over time, even in persistent ctDNAneg. To investigate the biology of persistent ctDNA positivity, we used logistic regression to analyze serial GEP (n=174) and RPPA (n=98) data in RTs that were ctDNA+ at pretreatment, comparing those with ctDNA clearance by surgery vs. those that remained ctDNA+. We found subtype- specific associations: In HR+HER2-, failure to clear ctDNA during NAT was associated with low pretreatment ER/AR, high early on-treatment proliferation, and low HER2-signaling after NAT, while in TN, fewer associations were observed; these included high pretreatment levels of MYC and proliferation. Conclusions: ctDNA dynamics refined risk stratification of RTs and enabled early prediction of treatment response. Understanding the molecular profiles of RTs based on ctDNA dynamics could aid treatment selection to overcome resistance to NAT. Citation Format: Mark Jesus M. Magbanua, Denise M. Wolf, Samuel Rivera-Hinojosa, Ziad Ahmed, Nayelis A. Manon, Rosalyn Sayaman, Antony Tin, Ekaterina Kalashnikova, Lamorna Brown Swigart, Gillian L. Hirst, Christina Yau, Wen Li, Claudine Isaacs, Rebecca A. Shatsky, Amy L. Delson, Charuta C. Palsuledesai, Angel Rodriguez, Minetta C. Liu, Paula R. Pohlmann, Laura J. Esserman, Hope S. Rugo, Angela DeMichele, Laura van 't Veer. Clinical and molecular correlates of circulating tumor DNA (ctDNA) dynamics in breast tumors resistant to neoadjuvant therapy (NAT) [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B019.

Abstract B039: Clinical liquid biopsy testing for detecting actionable genomic alterations in children and young adults with advanced solid tumors

Abstract Introduction: Given the paucity of data regarding circulating tumor DNA (ctDNA) as a modality to guide diagnosis and treatment for children with solid tumors, we conducted a prospective study to determine the frequency of diagnostic and targetable genomic variants identified by clinical ctDNA testing. Methods: GAIN is a prospective, multi-center molecular profiling study that was amended to include clinical ctDNA testing starting in January 2022. Patients were eligible if they were <30 years old with a refractory, recurrent, newly diagnosed with 2-year EFS <50%, or rare solid tumor and had measurable or evaluable disease. Paired tumor and blood samples underwent next generation sequencing (NGS) in CLIA-certified laboratories, with return of results to clinicians. Serial ctDNA samples were analyzed by F1LCDx (FoundationOne® Liquid Companion Diagnostic), an FDA-approved clinical ctDNA test that includes hybrid capture sequencing of a 300+ gene panel, comprehensive multi-omics ctDNA tumor fraction (TF) assessment, tumor mutational burden, and microsatellite instability status. We analyzed comprehensive NGS tissue-based and F1LCDx sequencing data for each participant to compare findings from each sample. The detection of alterations was stratified by ctDNA burden as assessed by ctDNA TF. We calculated the prevalence of ctDNA in our cohort, overall and by disease type. Chart review provided additional patient characteristic, diagnostic, therapeutic, and disease assessment data. The clinical impact of ctDNA results was qualitatively described. Results: The cohort included 35 patients, with a total of 70 F1LCDx samples (range 1-6 samples per patient). There were 16 unique tumor types represented, most commonly osteosarcoma (n = 8), neuroblastoma (n = 8), and Ewing sarcoma (n = 4). 77% of patients had metastatic disease at time of first ctDNA sample collection. 51% of patients had detectable ctDNA TF in at least one sample. Overall, 60% of patients had at least one actionable genomic alteration (range 0-14 variants per patient) identified in liquid biopsy samples, including 3 patients with actionable variants identified with undetectable ctDNA TF. We observed case vignettes in which ctDNA results informed clinical decisions, including disease assessment and treatment guidance. An illustrative example was the identification of ALK variants in relapse blood samples of two patients with neuroblastoma that were not identified in baseline tissue, which were targeted in both instances. Data collection and analyses as described in the methods are ongoing. Conclusion: In this prospective cohort of children and young adults with advanced solid tumors, ctDNA was detectable across a wide range of diagnoses and 60% of patients had at least one diagnostic or potentially targetable alteration identified. These data demonstrate that liquid biopsy yields actionable genomic variants, particularly when ctDNA burden is elevated. We will determine the association of these variants with those identified in tissue samples and their clinical implications in ongoing analyses. Citation Format: Holly J Roberts, Hannah Comeau, Steven G Dubois, Katerina Hoskova, Douglas I Lin, Brian D Crompton, Katherine A Janeway, David S Shulman. Clinical liquid biopsy testing for detecting actionable genomic alterations in children and young adults with advanced solid tumors [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B039.

First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors

Oncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).

Genomic landscape of circulating tumor DNA and real-world outcomes in advanced endometrial cancer.

ctDNA is a novel technique extensively studied in solid tumors, although not currently well defined in endometrial cancer (EC). A de-identified retrospective analysis of 1988 patients with advanced/recurrent EC was performed. In addition, an analysis of a real-world evidence (RWE) cohort was completed (n=1266). Patients underwent ctDNA testing using Guardant360 during routine clinical care. The objective was to describe and assess molecular landscape using ctDNA. Among 1988 ctDNA samples, at least one somatic alteration was detected in 91.6% (n=1821). Most frequently altered genes were TP53 (64%), PIK3CA (29%), PTEN (25%), ARID1A (20%) and KRAS (14%). Overall, 18.5% had amplifications, with the majority identified in CCNE1 (40.9%), PIK3CA (22%) and EGFR (19.3%). From the RWE cohort, those with TP53 mutations had a worse overall survival (OS) vs those without TP53 mutations (p=0.02) and those with TP53 co-mutations had an inferior OS in comparison to TP53-mutated only (p=0.016). Amongst these, patients with a PIK3CA co-mutation (p=0.012) and CCNE1 amplification (p=0.01) had inferior OS compared to those with only TP53 mutations. 57 patients with newly diagnosed EC had at least 2 serial ctDNA samples showing evolution in detected variants compared to baseline samples, with TP53 being the most frequent change. This study is one of the largest cohorts of ctDNA currently reported in EC. The presence of TP53 mutation and other co-mutations detected by ctDNA have a negative effect on outcomes. This report suggests that ctDNA analysis is feasible and could become a useful biomarker for EC.

639P Serial ctDNA profiling as a catalyst for tailored therapeutics in advanced cancer: Analysis of two precision medicine studies

639P Serial ctDNA profiling as a catalyst for tailored therapeutics in advanced cancer: Analysis of two precision medicine studies

CORRECT-MRD I: A clinical validation study to predict recurrence in stage II-III colorectal cancer (CRC) using a bespoke circulating tumor DNA (ctDNA) assay to detect molecular residual disease (MRD).

TPS98 Background: Despite standard of care management with surgery ± adjuvant chemotherapy treatment (ACT), >30% of patients (pts) with resectable CRC recur. The presence of ctDNA in plasma after resection and after ACT, has been shown to be a strong prognostic factor for the risk of recurrence, suggesting that the presence of ctDNA in blood is molecular evidence of residual disease. As such, ctDNA analysis may enable post-surgical risk stratification for ACT decision-making, as well as detection of molecular recurrence during surveillance and subsequent early intervention. The CORRECT-I study aims to validate the association of post-definitive therapy and pre-recurrence follow-up ctDNA positivity with recurrence-free interval (RFI) in pts who have undergone complete surgical resection for stage II or III CRC. Methods: This study is a prospective, observational, multicenter study, which is open in Israel, Italy, Japan, Spain, and the UK. Pts must have pathologically confirmed stage II or III CRC, have undergone complete surgical resection, and have tissue available from the primary resection. Pts may not have started ACT prior to baseline blood draw post-surgery. Pts are asked to provide serial whole blood specimens for ctDNA analysis at a) post-surgical baseline, b) pre-recurrence follow-up visits (max 15 blood draws over max 5 years), and c) clinical recurrence. ctDNA will be analyzed with an NGS-based tumor-informed MRD assay that identifies somatic genomic alterations from DNA derived from the patient’s tumor tissue and detects a selected subset of tumor-specific (bespoke) ctDNA in their blood. The primary objective of this study is to validate the association of post-definitive therapy and serial pre-recurrence follow-up ctDNA positivity with RFI, using a Cox proportional hazards regression analysis. Further objectives include the assessment of sensitivity and specificity of the ctDNA assay, the association between ctDNA at individual timepoints and RFI, ctDNA dynamics and RFI, and the time from ctDNA positivity to clinical recurrence. A multivariable model, including ctDNA, clinicopathological risk features, serial serum CEA assessments, and recurrence risk as determined by the Oncotype Colon Recurrence Score will be fit with RFI as endpoint. The primary analysis will be conducted when ≥30 histologic and/or radiographic confirmed cases of clinical recurrence have been observed. As of April 2, 2024, 158 pts of 400 have been enrolled.

Circulating Tumor DNA Dynamics Reveal KRAS G12C Mutation Heterogeneity and Response to Treatment with the KRAS G12C Inhibitor Divarasib in Solid Tumors.

To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. Plasma samples were collected for serial ctDNA profiling at baseline (cycle 1 day 1 prior to treatment) and multiple on-treatment time points (cycle 1 day 15 and cycle 3 day 1). KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as cycle 1 day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.

A phase 1 trial evaluating the safety, tolerability, PK, and preliminary efficacy of QTX3034, an oral G12D-preferring multi-KRAS inhibitor, in patients with solid tumors with KRASG12D mutation.

TPS3172 Background: KRAS is one of the most mutated driver oncogenes across solid tumors, and KRAS G12D missense mutations have high prevalence in pancreatic, colorectal (CRC), and endometrial cancers. QTX3034 is a highly-selective, non-covalent, orally bioavailable, multi-KRAS inhibitor with potent activity across several KRAS variants, particularly G12D. QTX3034 binds to GDP-bound forms of mutant and wild-type KRAS with (sub)nanomolar affinities, allosterically inhibiting its conversion to the active state. QTX3034 inhibits KRAS signaling in in vitro studies and displays synergy with EGFR inhibitors. In vivo evaluation of QTX3034 resulted in significant tumor growth inhibition across various tumor models, with tumor regressions observed in 100% of animals in both HPAC pancreatic and GP2D colorectal KRAS G12D xenograft models. QTX3034 exhibits brain penetration in preclinical studies, including an orthotopic model of intracranial efficacy. This clinical trial is now enrolling patients with advanced solid tumors harboring a KRASG12D mutation. Methods: This is a first-in-human, multicenter, open-label phase 1 study in adult patients with advanced solid tumors with KRASG12D mutations, without prior direct KRAS inhibitor treatment (NCT06227377). The primary objectives are to evaluate the safety and tolerability and to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of QTX3034 alone, and in combination with cetuximab. Secondary objectives are characterization of the PK profile and preliminary antitumor activity. Part 1 consists of two dose-escalation arms: QTX3034 monotherapy (advanced solid tumors) and QTX3034 plus cetuximab (CRC) and will enroll 3-4 subjects per cohort in a Bayesian Logistic Regression Model (BLRM) design. QTX3034 will be administered orally in 21-day cycles until disease progression, intolerable toxicity, or withdrawal from treatment. Exploratory paired biopsies will be collected in Cycle 2 in a group of patients in the dose-escalation phase. Serial ctDNA will be collected in all patients. Following identification of a RP2D, QTX3034 will be evaluated in dose-expansion cohorts of up to 30 patients with various KRASG12D mutated tumor types to determine preliminary activity: pancreatic cancer, CRC, non-small cell lung cancer and endometrial cancer. To further optimize the recommended dose, patients will be randomized between two dose levels in the pancreatic cancer cohort. QTX3034 plus cetuximab will be explored following identification of a recommended combination dose in patients with CRC. Clinical trial information: NCT06227377 .

Serial Postoperative Circulating Tumor DNA Assessment Has Strong Prognostic Value During Long-Term Follow-Up in Patients With Breast Cancer.

Here, we report the sensitivity of a personalized, tumor-informed circulating tumor DNA (ctDNA) assay (Signatera) for detection of molecular relapse during long-term follow-up of patients with breast cancer. A total of 156 patients with primary breast cancer were monitored clinically for up to 12 years after surgery and adjuvant chemotherapy. Semiannual blood samples were prospectively collected, and analyzed retrospectively to detect residual disease by ultradeep sequencing using ctDNA assays, developed from primary tumor whole-exome sequencing data. Personalized Signatera assays detected ctDNA ahead of clinical or radiologic relapse in 30 of the 34 patients who relapsed (patient-level sensitivity of 88.2%). Relapse was predicted with a lead interval of up to 38 months (median, 10.5 months; range, 0-38 months), and ctDNA positivity was associated with shorter relapse-free survival (P < .0001) and overall survival (P < .0001). All relapsing triple-negative patients (n = 7/23) had a ctDNA-positive test within a median of 8 months (range, 0-19 months), while the 16 nonrelapsed patients with triple-negative breast cancer remained ctDNA-negative during a median follow-up of 58 months (range, 8-99 months). The four patients who had negative tests before relapse all had hormone receptor-positive (HR+) disease and conversely, five of the 122 nonrelapsed patients (all HR+) had an occasional positive test. Serial postoperative ctDNA assessment has strong prognostic value, provides a potential window for earlier therapeutic intervention, and may enable more effective monitoring than current clinical tests such as cancer antigen 15-3. Our study provides evidence that those with serially negative ctDNA tests have superior clinical outcomes, providing reassurance to patients with breast cancer. For select cases with HR+ disease, decisions about treatment management might require serial monitoring despite the ctDNA-positive result.

Plasma ctDNA biomarker study in patients with non-small cell lung cancer with EGFR exon 20 insertion mutation treated with sunvozertinib.

8563 Background: There are limited reports on biomarker studies of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutation (exon20ins). Sunvozertinib (DZD9008), an oral, potent, irreversible and selective EGFR tyrosine kinase inhibitor (TKI), has been granted conditional approval in China for the treatment of NSCLC with EGFR exon20ins in the ≥ second-line setting. Here we report biomarker analysis of EGFR exon20ins in large sample size, by pooling data from WU-KONG series of studies. Methods: Serial plasma ctDNA samples were collected from baseline until progressive disease (PD). Next generation sequencing was used to assess EGFR exon20ins in baseline plasma ctDNA, and to analyze genetic alterations in baseline and PD plasma ctDNA to identify potential resistance mechanisms to sunvozertinib. Droplet digital PCR was used to dynamically monitor the quantity of EGFR exon20ins during treatment. In addition, association between baseline EGFR exon20ins and disease characteristics as well as antitumor activity of sunvozertinib was analyzed. Furthermore, in vitro and in vivo experiments were performed to explore potential approach which may overcome the resistance to sunvozertinib. Results: A total of 121 patients were included in this biomarker analysis, among them 81 out of 121 (66.9%) had detectable EGFR exon20ins in baseline plasma ctDNA. There was a positive correlation between detectable EGFR exon20ins and higher number of metastasis sites. In addition, higher EGFR exon20ins abundance was positively correlated with more metastasis sites and brain metastasis. Patients with EGFR exon20ins negative in plasma ctDNA achieved a higher objective response rate (ORR) (68.0% vs. 45.8%) and longer median progression free survival (PFS) (7.4 months vs. 5.5 months) with sunvozertinib treatment. In patients with baseline detectable EGFR exon20ins, the mutant allele decreased over time with treatment in majority of patients (12/14, 85.7%), and the earliest clearance of EGFR exon20ins occurred after one week of treatment. In patients who developed disease progression, 12 of 18 (66.7%) maintained EGFR exon20ins at PD, and among them, 3 concurrently acquired EGFR C797S, all in cis with exon20ins. In addition, EGFR G724S and other genetic aberrations in EGFR downstream signaling pathway, were also detected. Exploratory work on overcoming resistance to sunvozertinib suggests that combination of golidocitinib, a selective JAK1 inhibitor, with chemotherapy could be a potential approach. Conclusions: This study showed that positive EGFR exon20ins in plasma ctDNA is associated with advanced disease characteristics. Sunvozertinib can effectively clear EGFR exon20ins in plasma ctDNA, confirming its direct effect on EGFR pathway. The resistance to sunvozertinib can be through EGFR-dependent and EGFR-independent mechanisms.

Plasma mutational burden in PIK3CA and TP53 independently predicts early progression in patients with HR+/HER2- metastatic breast cancer (MBC) enrolled in the GEICAM/2014-12 FLIPPER trial.

1029 Background: There is an unmet need for molecular diagnostics to predict therapy outcomes using blood-based biomarker monitoring to guide treatments in HR+/HER2- MBC patients. Here, we report initial results of serial ctDNA analyses in a trial of Fulvestrant (F) + CDK4/6 inhibitor (CDK4/6i) Palbociclib (Pa) vs. F + Placebo (Pl). Endocrine therapy + CDK4/6i are currently the cornerstones of treatment for HR+/HER2- MBC. However, between 10–30% of patients suffer primary resistance. Thus, early identification of HR+/HER2- MBC patients that progress during CDK4/6i treatment is required. Methods: The GEICAM FLIPPER trial (NCT02690480) is a multicenter, double-blind, randomized, phase II study comparing F+Pa vs F+Pl in postmenopausal women with HR+/HER2- MBC. Sequential plasma was collected from 187 patients at baseline, 12, 24, 36, and 48 weeks on treatment and at progression. In total, 903 samples were analyzed using the Plasma-SeqSensei BC IVD kit (Sysmex Inostics) that identifies and quantifies ctDNA mutations in six BC-related genes. The mutant allele frequency (MAF) of PIK3CA and TP53 variants was assessed in baseline samples (median value as cutoff). These variants, identified as the most prevalent, were used as surrogate markers for mutational burden. The Kaplan-Meier method was used to estimate median (m) PFS and overall survival (OS). Hazard ratio (HR) and odds ratio (OR) were calculated with 95% confidence interval (CI) using Cox proportional hazards regression model and logistic regression respectively, unadjusted or adjusted by age, site of disease, disease presentation at study entry and clinical subtype. Results: Previously we showed that F+Pa improved 1-year PFS (83.5% vs. 71.9%, p=0.064) and mPFS (31.8 vs. 22.0 months, p=0.001) vs F+Pl. Here, ctDNA analyses revealed that having ≥1 mutation in PIK3CA + TP53 was prognostic of early (≤12 months) progression (OR 2.37; 95% CI 1.1-5.12, p=0.0274) independent of treatment arm. Furthermore, having ≥2 mutations was associated with treatment resistance (not achieving objective response; OR 3.55; 95% CI 1.28-9.87, p=0.0151). Additionally, worse mPFS and mOS were seen in patients with ≥2 mutations in PIK3CA + TP53 (PFS: HR 3.6; 95% CI 2.25-5.76, p&lt;0.0001; OS: HR 2.92; 95% CI 1.66-5.12, p=0.002) and in patients with high MAF (PFS: HR 2.43; 95% CI 1.6-3.68, p&lt;0.0001; OS: HR 2.83; 95% CI 1.75-4.58, p&lt;0.0001). Finally, having ≥2 mutations in PIK3CA + TP53 was predictive of early progression (OR 22.32; 95% CI 4.12-120.9, p&lt;0.0001) and worse mOS (61.8 vs. 34.79 months) in the F+Pl arm (HR 5.91; 95% CI 2.65-13.16, p&lt;0.0001) but not in the F+Pa arm. Conclusions: Baseline plasma mutational burden in both PIK3CA and TP53 genes was significantly associated with Fulvestrant +/- Palbociclib treatment outcome in HR+/HER2- MBC and appeared to be predictive of Palbociclib benefit. Clinical trial information: NCT02690480 .

Clinical validation of Northstar response: A novel methylated ctDNA therapy response monitoring assay in patients with advanced gastrointestinal cancers.

e16000 Background: Circulating tumor DNA (ctDNA) offers a non-invasive method to comprehensively assess tumors. While most assays for therapy response monitoring rely on variant allele frequencies, methylated ctDNA has shown promise. However, accuracy has been limited by quantification precision. The CLIA-approved Northstar Response assay quantifies over 550 hyper-methylated loci and has demonstrated a 10-fold increase in detection signal over tissue-informed assays. Methods: We present an interim analysis from an ongoing prospective, observational study designed to assess the clinical validity of Northstar Response as a tool to monitor therapeutic response without prior tumor tissue. Our study aims to include 100 advanced GI cancer patients undergoing systemic therapies for advanced disease. Serial ctDNA measurements are collected at baseline, approximately every 30 days post-treatment initiation, and with imaging assessments. The primary endpoint is concordance between ctDNA and RECISTv1.1 criteria for disease response until progression or death. Results: Baseline ctDNA characteristics were examined from 44 patients, with 23 undergoing at least two longitudinal blood collections and subsequent imaging. The median age in this cohort was 65.5 years, with a male predominance (70.5%) and a majority identifying as White (79.5%). Cancers included esophageal (18.2%), hepatocellular (29.5%), biliary (15.9%) and colorectal (15.9%), among others. A majority (59.1%) had both primary and metastatic lesions. Baseline methylation scores ranged from 280 in biliary cancers to 100,000 in colorectal cancers. Those on second-line treatments had lower scores than first or third-line therapies. Methylation scores decreased in patients responding to treatment, indicating that these scores have the potential to serve as indicators of therapeutic efficacy. Conclusions: Baseline methylation scores differ across GI tumor types, disease burdens, and treatment lines, reflecting the complexity of using methylation as a biomarker. Northstar Response has shown initial promise in monitoring therapy response in GI cancers. More mature data, which will further elucidate the assay's clinical utility, will be presented at the meeting.

Personalized circulating tumor DNA for minimal residual disease and dynamic assessment in patients undergoing neoadjuvant chemotherapy for breast cancer: Preliminary analysis from MSK-LINC.

3049 Background: Identification of minimal residual disease (MRD) with circulating tumor DNA (ctDNA) in pts with early-stage breast cancer holds promise to identify risk of relapse. MSK-LINC is prospective ctDNA plasma analysis of breast cancer pts. This pilot study evaluated the utility of serial ctDNA assessment as a biomarker for monitoring MRD and recurrence prediction in clinical stage II-III breast cancer pts undergoing neoadjuvant chemotherapy (NAC). Methods: 30 pts who underwent NAC across all subtypes were identified from MSK-LINC. The ctDNA analysis was performed at baseline, on-NAC, post-NAC/pre-surgery, within 8 weeks post-surgery, and during follow-up. Personalized ctDNA RaDaR assays were designed using whole exome sequencing data of paired primary tumor and germline samples from each pt. ctDNA levels were quantified as an estimated variant allele fraction (eVAF). Results: ctDNA panels were successfully designed for 29/30 pts (16 Stage II, 13 Stage III), including 6 HR+/HER2-, 12 HER2+, and 11 TNBC, with a median follow up of 4.2 years. The bespoke ctDNA assays targeted a median of 48 variants (21-51), with a median of 43 variants (11-48) passing quality control. A total of 175 plasma samples were analyzed, including 24 baseline and 24 post-surgery. A 100% ctDNA detection rate was observed at baseline in the 24 pts for whom a baseline sample was available (median eVAF 0.33%, range 0.0083% - 8.91%). Pathologic complete response (pCR) was achieved in 11 pts who remained disease free; and of the 18 pts without a pCR, 5 recurred. All patients with a pCR were ctDNA negative post treatment. In 3/5 patients who recurred, MRD detection was achieved, including one patient with persistent ctDNA positivity throughout all timepoints. For the other two pts, ctDNA was first detected in follow-up plasma collected at 4.4 and 9.8 months prior to clinical recurrence. Conclusions: This study demonstrates the potential of ctDNA as a dynamic biomarker for monitoring disease burden in pts with high-risk early-stage breast cancer, highlighting its remarkable sensitivity at baseline and its capability for MRD detection preceding clinical recurrence. These findings suggest the need for further research to fully understand the relationship between ctDNA dynamics during and after NACT with prediction of breast cancer outcomes. ctDNA detection rates in plasma samples across collection timepoints. [Table: see text]

Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with KRAS G12C-mutant advanced solid tumors.

3007 Background: Olomorasib is a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, which preclinically delivers &gt;90% sustained target occupancy. Here, we report updated results from LOXO-RAS-20001, a phase 1/2 study of olomorasib in patients with KRAS G12C-mutant advanced solid tumors (NCT04956640). Methods: Patients (pts) with advanced solid tumors positive for KRAS G12C (tissue or plasma) were eligible. Dose escalation used a mTPI-2 method, followed by expansion cohorts in NSCLC (with/without prior G12Ci), CRC, and other solid tumors. Safety was evaluated across all pts dosed. Antitumor activity per RECIST v1.1 was studied in all pts who had ≥1 post-baseline response assessment (PBRA) or had discontinued before the first PBRA. Serial ctDNA analysis was performed using FoundationOne Liquid CDx. Results: As of 30 October 2023, 157 pts (58 NSCLC, 32 CRC, 24 PANC, 43 other solid tumors) received single agent olomorasib (50-200 mg BID PO); 29 pts with NSCLC had received a prior KRAS G12Ci. Median age was 65 yrs (range, 36-85), median number of prior systemic therapies was 3 (range, 0-11). Any grade TRAEs were 62%; TRAEs ≥10% were diarrhea (24%), fatigue (10%), and nausea (10%); grade ≥3 TRAEs were 5%. TRAEs led to dose hold in 10% of pts, dose reduction in 3%, and discontinuation in 2%. Among 10 pts treated after discontinuing prior G12Ci due to toxicity (5/10 due to LFT increase), 1 pt (10%) required olomorasib dose reduction and none discontinued due to toxicity. 68 pts are ongoing and 89 discontinued treatment. 146 pts were efficacy evaluable (120 G12Ci-naïve; 26 with prior G12Ci) with a median follow-up of 10 months (95% CI, 7-13). As anticipated, ORR was lower in 32 pts with CRC (9%, 3 PR; DCR 84%)1 and higher in 88 pts with non-CRC tumors (40%, 30 PR and 5 uPR pending/ongoing in 13 unique tumor types; DCR 90%). mPFS ranged across tumor types from 4 months (CRC, 95% CI, 3-7) to 9 months (NSCLC, 95% CI, 3-NE). In the 26 efficacy evaluable NSCLC pts with prior KRAS G12Ci treatment (16 discontinued due to PD, 9 due to AE), the ORR was 39% (9 PR, 1 uPR pending/ongoing; DCR 73%); mPFS was 6 months (95% CI, 3-NE). In 37 pts with ctDNA results at baseline and ongoing, ctDNA response (&gt;50% KRAS G12C VAF reduction) was seen in pts with PR (11/11), SD (17/22), and PD (1/4). Conclusions: Olomorasib demonstrates efficacy across a range of KRAS G12C-mutant solid tumors with a favorable safety profile including in pts with prior G12Ci intolerance. Activity of the second-generation G12Ci olomorasib after prior exposure to G12Ci demonstrates the increased potency and target coverage these agents can deliver compared to first generation inhibitors. Phase 2 expansion is currently enrolling pts with PANC, and a global registrational study investigating olomorasib in combination with pembrolizumab in first-line NSCLC is ongoing (NCT06119581). 1. Hollebecque A. et al. ASCO-GI 2024. Clinical trial information: NCT04956640 .

Circulating tumor DNA (ctDNA) to predict response to neoadjuvant chemotherapy (NAC) and prognosis in patients (pts) with early breast cancer (BC).

e12642 Background: pCR to NAC is an important predictor of clinical recurrence. Up to 16% of patients with pCR may experience disease recurrence, 45% of patients with RD do not. Longitudinal ctDNA testing offers a minimally invasive approach for monitoring treatment response EBC patients receiving NAC. We evaluated whether ctDNA status and dynamics can predict the tumor response to NAC and the risk of recurrence in patients with EBC. Methods: We conducted an observational, retrospective, single-center study to investigate whether ctDNA can predict tumor response to NAC and prognosis in BC patients. 74 pts received standard of care NAC;g 4 patients were treated in the adjuvant setting. Blood samples were collected at diagnosis from 44 pts (baseline) and longitudinally during treatment from 34 patients. Tumor response and progression outcomes were reported. A clinically validated, tumor-informed ctDNA assay (Signatera). ctDNA status and dynamics were correlated with pathologic and radiologic outcomes. Results: 29 TNBC pts were ctDNA+ at baseline, 6 were ctDNA- Of the 29 pts, early ctDNA clearance by week 6 of NAC was observed in 10 pts, weeks 7-16 in 9 pts, clearance post-surgery in 1, 3 pts remained ctDNA+ after surgery, serial ctDNA testing is underway for the remaining 6 pts. All TNBC patients who had radiological complete response (CR) had early clearance of ctDNA . All pts with persistent ctDNA positivity levels after completion of NAC had radiological partial response (PR). Of the 9 TNBC pts with undetectable baseline ctDNA, 33% achieved CR on MRI and 43% achieved pathologic CR. Of the 19 TNBC pts with ctDNA clearance in response to NAC, 89% (17/19) remained ctDNA- and with no evidence of disease (NED) (length of follow up). 1 pt initially cleared their ctDNA on NAC, turned ctDNA+ 4 weeks prior to radiological recurrence. 1 pt with ctDNA clearance on NAC remained ctDNA post-surgery but experienced recurrence. All (n=3) TNBC pts with persistent ctDNA-positivity levels after curative treatment (NAC and surgery) had disease recurrence. The remaining 6 pts ctDNA are ongoing NAC. Of the 6 pts with undetectable baseline ctDNA, 6/6 continued to be ctDNA- regardless of their disease status. At diagnosis, 8/9 ER+ ps were ctDNA+. 3/8 (38%) ER+ pts with positive baseline ctDNA had early clearance of ctDNA after NAC. All 3 had residual disease on pathology. 2/8 (25%) remained ctDNA+ after surgery and neither achieved radiologic CR or pCR. The remaining 3 pts are ongoing NAC. Conclusions: In early TNBC, ctDNA monitoring can be used to predict tumor response to NAC and tailor therapeutic regimens. ctDNA persistence can predict early recurrence and helps identify patients in which treatment escalation or enrollment on clinical trials is necessary. In ER positive breast cancer, and despite the small number of patients, ctDNA clearance does not predict response to NAC.

Use of baseline and serial ctDNA dynamics to predict outcomes in patients treated with first-line tebentafusp, including those who were and were not treated beyond progression.

9536 Background: Tebentafusp (tebe), a bispecific soluble T cell receptor specific for a gp100 peptide, is licensed for the treatment of metastatic uveal melanoma (mUM) in HLA-A*02:01+ individuals. As part of the pivotal, Phase 3 IMCgp100-202 study, 378 mUM pts were randomized to receive tebe or investigators choice. Approximately 60% of patients (pts) with metastatic UM in the IMCgp100-202 study had detectable baseline ctDNA. We have reported the strong relationship between change in ctDNA at 9 weeks (wks) and overall survival (OS). Additionally, radiographic treatment response is a poor predictor of who is benefitting from therapy. We hypothesized that ctDNA dynamics would help identify those patients (pts) who benefit from treatment beyond progression (TBP). Methods: Sera (n=202 pts) collected at baseline and wk 9 on tebe were analyzed for ctDNA using a targeted mPCR-NGS assay for 15 genes including GNAQ, GNA11, SF3B1, PLBC4, EIF1AX, and CYSLTR2. RECISTv1.1 was assessed by investigators; TBP was allowed per protocol. OS was analyzed in subsets of pts who were not TBP, and those who were TBP and treated with tebe for &lt; or &gt; 16 wks; the approximate time point where TBP pts would have had confirmatory imaging, although confirmatory scan data is not available. At baseline, pts were determined to be ctDNA detectable or undetectable. At wk 9, pts were determined to have cleared ctDNA, &lt; or ≥ 68% (0.5 log-fold) reduction, &lt; or ≥ 50% reduction. Data cut-off was July 2023. Results: Of 202 pts randomized to tebe and with ctDNA at baseline and wk 9, 126 (62%) received TBP (80 &lt;16 wks, 46 ≥ 16 wks). Undetectable ctDNA at baseline was associated with improved OS regardless of TBP, while TBP was associated with improved OS in those with baseline detectable ctDNA (hazard ratio, HR, 0.59, 95% confidence interval, CI, 0.4-0.88). Subgroup analysis of those with baseline detectable ctDNA demonstrated improved OS in only those who received TBP for ≥ 16 wks (HR 0.33; 95% CI 0.21-0.51). Clearance of ctDNA at wk 9 was associated with better OS than in those who did not have clearance. TBP was associated with better OS in pts who did not have clearance (HR 0.48, 95% CI 0.30-0.79), but not in those with clearance (HR 0.87, 95% CI 0.43-1.78). Finally, TBP was associated with improved outcomes in pts with ≥50% and ≥68% reduction, compared to those without reduction, HR 0.63 (95% CI 0.4-0.97) and 0.62 (95% CI 0.39-0.99), respectively. Conclusions: Baseline and wk 9 ctDNA detection predicts OS in mUM pts treated with first line tebe. The utility of ctDNA predicting pts most likely to benefit from TBP is less clear, although TBP seems to be more beneficial in those with reduction of ctDNA at wk 9. Optimization of time points, assay, and integration of ctDNA data with radiomics are necessary to understand the true utility of ctDNA in helping select which pts should receive TBP. Clinical trial information: NCT03070392 .

Pan-tumor circulating tumor DNA testing in the community oncology setting.

e14556 Background: Circulating tumor DNA (ctDNA) technology allows for monitoring the genomic profile of cancer over time non-invasively, and in a way that is more representative of existing tumor clones than tissue sampling. The clinical and research applications of this new technology are numerous, and they are potentiated through serial ctDNA testing of individual patients. It is important to identify and characterize real-world data sets that will permit the development of both ctDNA’s clinical and research applications. Methods: This is an observational study of breast, non-small cell lung cancer (NSCLC), colorectal and prostate cancer patients who had ctDNA testing in The US Oncology Network from August 2014 to August 2023. All unique ctDNA reports per patient were collected, along with the report dates and patient characteristics. Rate of change in number of unique reports per month through time was evaluated as well as frequencies of serial testing and median time lapse between diagnosis and date of first ctDNA test by cancer type. Results: Number of new unique ctDNA testing reports per month increased for The US Oncology Network from 2014 through 2018 at a rate of 0.86 (95% CI [0.70, 1.02]). From 2018 to 2023 this rate increased to 5.87 (95% CI [5.16, 6.59]) new reports per month. The total number of unique patients with one of the 4 cancer indications and at least one ctDNA test during the study time period was 10,852. The cancer indication with greatest number of patients with ctDNA testing is NSCLC with 5,503 patients, followed by breast with 2,408, and colorectal and prostate with 1,544 and 1,397 respectively. Black patients were equally represented across all 4 cancers at rates of 13.6% for colorectal, 12.7% for breast, and 12% for NSCLC and prostate. Patients over 65 made up 66% for prostate and NSCLC but only 38% and 32% for colorectal and breast respectively. Most patients presented with a single ctDNA test (n = 9482), but an important proportion presented with 2 serial ctDNA tests or more (n = 1370, 12.6%).The median time between either cancer diagnosis date or date of first visit in The Network and the date of the first ctDNA test report was 39 days for NSCLC, 1,690 days for breast, 377 days for colorectal and 772 days for prostate, and presented with a skewed, long right tailed distribution. Median times were similar for Black and White patients across all cancers. Conclusions: The number of patients with ctDNA testing data available is increasing through time without evidence of plateauing. Although the total number of patients represented is still a very small fraction of the total patient population, the rate of increase in number of new reports through time is equivalent to an exponential increase in the total number of reports. 12.6% of patients presented with two tests or more, potentially allowing for pre and post treatment assessments. There’s an opportunity to better align cancer research and cancer treatment paradigms with this new technology.

Longitudinal circulating tumor DNA monitoring for detection of molecular residual disease in patients with advanced germ cell tumors.

e17022 Background: Germ cell malignancies, commonly manifesting as testicular cancer, is one of the most common malignancies in men 15 to 45 years of age, with the incidence doubling over the past 40 years. When identified promptly and treated with a multidisciplinary approach, germ cell tumors have an excellent prognosis with cure rate &gt;90% and 5-year survival rate &gt;95%. Treatment involves radical orchiectomy for diagnostic and therapeutic purposes. Further management includes active surveillance, adjuvant chemotherapy, retroperitoneal lymph node dissection (RLND), and radiation therapy. While AFP, B-HCG, and LDH are good biomarkers, they are not sensitive or specific for detecting molecular residual disease (MRD). B-HCG is detected in &lt;30% of individuals with seminoma and B-HCG and AFP are detected in 50–60% of patients with non-seminomatous tumors. We describe the use of circulating tumor DNA (ctDNA) for detection of MRD in advanced germ cell malignancy, especially when baseline biomarkers are negative. Methods: This is a retrospective analysis of 20 patients with testicular cancer treated at Rush University Medical Center who monitored closely for MRD. Signatera (Natera Inc.), a personalized tumor-informed ctDNA assay, was utilized for detection and quantification of ctDNA in patients’ plasma samples, measured at MRD (1-12 weeks post-orchiectomy) and regular intervals thereafter, regardless of treatment modality. Event free survival (EFS) was determined, defined as the period from radical orchiectomy to date of radiographic progression of disease. Results: There was a total of 20 patients (35% seminoma, 65% non-seminoma) with 2 of the patients having extragonadal disease. The mean age was 32.2 years old with IQR (28-36). Post operatively, 20% underwent RLND, 10% were on surveillance, 53% received post-orchiectomy chemotherapy, 6.7% of patients underwent autologous stem cell transplant. The median follow up time is 1.14 years. Two patients had positive ctDNA despite negative baseline traditional biomarkers. There were 23.3% (7/30) of patients that had evidence of radiographic progression. Of the patients with progression, serial ctDNA monitoring had high rates of concordance (85%, 6/7) of ctDNA positivity with biomarker positivity and radiographic progression. Conclusions: Overall, ctDNA correlated with, and sometimes even preceded, traditional biomarkers and radiographic findings of disease progression. The ctDNA positivity of 2 patients in this cohort despite negative baseline AFP, B-HCG, and LDH, highlights the sensitivity and specificity of ctDNA for MRD compared to more traditional biomarkers. Serial monitoring of ctDNA offers valuable insights into germ cell tumor disease status, including presence of MRD, and there is a need for prospective studies to guide treatment escalation and de-escalation in germ cell tumors.

A first-in-human (FIH), phase 1/2, dose-escalation, dose-optimization, and dose-expansion study of PARP1-selective inhibitor IMP1734 in participants with advanced solid tumors.

TPS3191 Background: PARP inhibitors (PARPi) selectively kill tumor cells harboring genetic mutations in critical DNA repair genes (e.g., BRCA1/2). While several approved nonselective PARPi have provided robust anti-tumor activity, they are associated with significant hematologic toxicities that limit dose intensity and clinical benefit. Drugs that selectively inhibit PARP1 but spare PARP2 may improve the risk-benefit profile for this class of therapies by retaining anti-tumor activity while avoiding PARP2-related toxicities. IMP1734 (EIK1003) is a potent PARP1-selective inhibitor that inhibits tumor growth in nonclinical models and may widen the therapeutic index in tumors where non-selective PARPi have demonstrated efficacy. Methods: Study EIK1003-001 (IMP1734-101) is a global, multi-center, Phase 1/2 study evaluating the safety and potential antitumor activity of IMP1734 in participants with advanced solid tumors. The study has 3 parts: Part 1 (FIH; Dose Escalation), Part 2 (Dose Optimization), and Part 3 (Dose Expansion at the recommended dose for expansion [RDE]). Part 1 of this study is currently enrolling and consists of dose escalation of IMP1734 in study participants with advanced/recurrent/metastatic ovarian, breast, or prostate cancer with suspected deleterious/deleterious mutations in a pre-specified panel of homologous recombination repair (HRR) genes (n = 70). Eligible participants must be ≥ 18 years of age, have histologically or cytologically confirmed tumors as indicated in each study part, and at least 1 RECIST v1.1-measurable lesion and/or pre-specified serum tumor-specific marker. All participants must have a deleterious or suspected deleterious mutation in select HRR genes. Primary endpoints include safety and tolerability (evaluation of dose-limiting toxicities and determining the maximum tolerated dose, maximum achievable dose, and RDE). Secondary endpoints include evaluation of the pharmacokinetic parameters of IMP1734 and measures of efficacy, including overall response rate, duration of response, progression-free survival, and overall survival. Exploratory endpoints include analysis of pharmacodynamic biomarkers, serial ctDNA measurements, and patient quality-of-life measures. This study opened on 11 Dec 2023. Clinical trial information: NCT06253130 .

Abstract B027: The MAT2A inhibitor IDE397: a novel combination backbone for urothelial cancer subjects with MTAP deficiency

Abstract Methylthioadenosine phosphorylase (MTAP) loss, due to focal homozygous deletions in chromosome 9 (9p21.3), occurs in over 25% of urothelial carcinoma and is an adverse prognostic factor for overall survival. Furthermore, MTAP-deleted tumors are associated with a “cold” tumor immune microenvironment and are resistant to immune checkpoint inhibitor therapy. Loss of MTAP confers a dependency on methionine adenosyltransferase 2A (MAT2A), which catalyzes the production of the primary methyl donor for all cellular methyltransferase reactions, S-adenosyl methionine (SAM). IDE397, a potent small molecule inhibitor of MAT2A, was developed to selectively exploit this synthetic lethal vulnerability in MTAP −/− tumors. The accumulation of the metabolite MTA in MTAP −/− tumors combined with a reduction of SAM by MAT2A inhibition results in selective inhibition of PRMT5, a methyltransferase that governs spliceosome fidelity. This triggers pre-mRNA splicing defects that may induce RNA polymerase stalling and can cause R-loop accumulation. Furthermore, due to essential roles in 1-carbon metabolism, MAT2A inhibition together with MTAP loss leads to depletion of metabolites required for both de novo and salvage nucleotide biosynthesis, thus preventing effective management of DNA replication and DNA damage repair. Notably, R-loops must be resolved by topoisomerase activity (TOP1) to prevent replication conflict and mitotic catastrophe. These combinatorial mechanistic relationships underpin a hypothesis that dual inhibition of MAT2A and TOP1 will fully capitalize on the synthetic lethal vulnerabilities associated with MTAP loss in urothelial cancers (replication stress, genomic instability). Consistent with this, IDE397 in combination with TOP1 inhibitors demonstrated synergistic combination benefit in MTAP −/− bladder cancer cell lines in vitro and in cell-line derived xenograft (CDX) models in vivo. IDE397 exposure was associated with heavily disordered methionine metabolism and accumulation of DNA damage response intermediates. In the ongoing Phase 1 dose escalation/expansion study of IDE397 in MTAP −/− solid tumors (NCT04794699), measurable tumor shrinkage has been observed in urothelial cancers (including a CR per RECIST 1.1) along with molecular responses on serial ctDNA measurements. Supported by our preclinical data, and the clinical observation that MTAP −/− urothelial cancers may be more sensitive to sacituzumab govitecan (SG); a TROP-2-targeting TOP1 ADC (UNITE study; JCO.2023.41.16_suppl.4572), a combination of SG+IDE397 could represent a novel early-line therapy for these patients with high unmet need. We plan to evaluate the combination of SG+IDE397 in MTAP-/- urothelial cancers in the next stage of the ongoing IDE397 trial (NCT04794699). Citation Format: Claire L. Neilan, Marcus M. Fischer, Damien Garbett, Arjun A. Rao, Mili Mandal, Michael A. White, Jasgit C. Sachdev. The MAT2A inhibitor IDE397: a novel combination backbone for urothelial cancer subjects with MTAP deficiency [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B027.