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PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

2561 Background: Some cancers, including breast, ovarian, pancreatic, and prostate cancers, are traditionally considered “cold” tumors, less likely to trigger an immune response and/or respond to immune checkpoint inhibitors (ICIs). However, some patients with these cancer types may benefit from ICIs. Here we investigate if a high blood tumor mutational burden (bTMB-H) may predict benefit to ICIs in such tumor types. Methods: We retrospectively queried the Guardant Health database for patients with advanced breast (n = 8531), ovarian (n = 1106), upper GI/pancreatic (n = 5110), and prostate (n = 7153) cancer who had ctDNA next-generation sequencing (Guardant360, Redwood City, CA) as part of routine clinical care from 2020-2022. Mutation profiles were evaluated for patients with bTMB-H (based on previously reported 80th percentiles for each tumor type, breast ≥15.31mut/Mb, ovarian ≥14.98mut/Mb, pancreatic ≥11.36mut/Mb, prostate ≥13.4mut/Mb) vs those with bTMB below this threshold (bTMB-L). A subset of cases were analyzed in a multi-institutional clinical cohort with a bTMB of ≥10mut/Mb (n = 35). Results: bTMB-H was observed in 9.5% of patients with breast cancer, 5.1% ovarian, 2.0% pancreatic, and 4.4% prostate. Genes more often mutated in patients with pTMB-H vs pTMB-L in each cancer type included TP53 and PIK3CA in breast cancer; TP53 and CHEK2 in ovarian; ATM and CHEK2 in pancreatic; TP53 and AR in prostate (all p values < 0.01). Patients in the clinical cohort (n = 35) had a median age of 74 (range: 40-85) 29/35 White / 4/35 Black, 27 prostate, 1 breast, 3 upper GI. Patients underwent first ctDNA analysis after a median of 3 (range 0-11) lines of therapy. The median bTMB detected was 16.59 mut/Mb (range: 10.02-152.85); six patients (6/35) were MSI-H. Twenty-three patients received ICI after a median of 6 (range: 0-8) lines of therapy, either alone (9, 39%) or in combination with hormonal therapy (5, 22%), chemotherapy (3, 13%) or targeted therapy (6, 26%). The median time to progression on ICI was 5.0 (95% CI, 3.6-6.4) months and median duration of response was 19.8 months (12.1-20.2). The ORR for evaluable patients was 13% and 74% of patients had progressed on therapy at time of data cut-off. Conclusions: "Cold” tumors represent a meaningful portion of patients with advanced cancer in which ICIs are not typically leveraged, and ctDNA was a feasible tool for identifying patients with bTMB-H who achieved durable responses from ICI-based therapy. The efficacy in this clinical cohort of traditionally “cold” tumors approaches other pan-cancer cohorts that include more traditionally immunoresponsive tumor types; further research is warranted to explore predictive value of bTMB, including potential tumor-specific thresholds, for optimizing patient selection for ICIs.

165 Background: A prior study of patients with advanced cancers treated with immune checkpoint inhibitors (ICI) associated improved overall survival with tissue tumor mutational burden above the 80th percentile in each histology (tTMB-H). TMB can also reliably be calculated via liquid biopsy (bTMB), and trends higher than tTMB in analogous tumors. Here, we generate a plasma-informed benchmark for bTMB-H in advanced prostate cancer and report preliminary data from an ongoing multi-institutional case series of patients treated with ICI. Methods: Circulating tumor DNA (ctDNA) next generation sequencing (NGS) results from 3,504 patients with advanced prostate cancer who received a Guardant360 liquid biopsy within a 12-month period were analyzed. The 80th percentile of TMB was defined as the benchmark for bTMB-H in this cohort, and prevalence of microsatellite instability (MSI-H) was determined. Subsequently, clinical data were collected from patients across five institutions who received pembrolizumab based on bTMB scores or other tumor characteristics (i.e. CDK12 mutation). Results: Overall, mean and median bTMB were calculated as 12.34 mut/Mb and 8.61 mut/Mb, respectively (range: 0 – 1164.75 mut/Mb). The 80th percentile of bTMB was 13.4 mut/Mb and the 90th percentile was 16.6 mut/Mb. 2.6% of patients were both MSI-H and bTMB-H. No patients with bTMB < 13.4 mut/Mb (TMB-L) were found to be MSI-H. Ten patients from five institutions received pembrolizumab (8 monotherapy) after a median of 4.5 lines of prior therapy (Table). Four patients were MSI-H. The 3 patients in the cohort with PSA decreases > 50% had both MSI-H and bTMB ≥ 13.4 mut/Mb. Per RECIST criteria, disease was controlled (CR, PR, SD) in 6 of 7 (86%) patients with bTMB scores ≥ 13.4 mut/Mb. Conclusions: These data continue to affirm that ctDNA NGS is a practical and cost-effective means of assessing potential predictors of ICI activity in patients with advanced prostate cancer. Preliminary data from this growing cohort of patients who have received ICI guided by bTMB scores and other molecular parameters identified via ctDNA NGS, including MSI-H, demonstrate a clinical benefit from therapy. Further studies are warranted for contextualizing individual tumor bTMB scores with established, pathology-specific benchmarks.[Table: see text]

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

5077 Background: Several ICIs are used in first and subsequent lines of therapy for mRCC, either alone or in combination with another ICI or targeted therapy (TT). There are no data on the efficacy and safety of using an ICI in patients who have already received an ICI in a prior line of therapy. Methods: We reviewed patients with mRCC at 8 institutions who received 2 separate lines of ICI therapy (ICI-1, ICI-2), including as a single-agent and/or combination with other agents. The primary outcomes were overall response rate (ORR) and time to progression (TTP) with ICI-1 and ICI-2. Immune-related adverse events (irAEs) were graded using CTCAEv5.0. Results: 65 patients were included. Median age at diagnosis of mRCC was 60 years (range 30-86) and the majority had clear cell RCC (n=56, 86%). Median follow-up was 3.5 years (95% CI 2.9-4.4). Median lines at which ICI-1 and ICI-2 were received were 1 (1-6) and 3 (2-8) respectively. Reasons for discontinuing ICI-1 were disease progression (n=47, 72%), toxicity (n=15, 23%) or other (n=3, 5%). Therapies received at ICI-2 were single-agent ICI (n=26, 40%), or combinations of ICI with another ICI (n=20, 31%), TT (n=11, 17%) or other agent (n=8, 12%). Responses to ICI-1 and ICI-2 are shown in the Table; ORR to ICI-2 was significantly lower than to ICI-1 (23% vs. 36%, p=0.044). Amongst those who responded to ICI-2 (n=14), 7 (50%) received single-agent ICI, and the remainder received ICI in combination with another ICI (n=4, 29%) or TT (n=3, 21%); 7 patients (50%) had previously responded to ICI-1. The ORR to ICI-2 was higher in responders to ICI-1 (32%) compared to those with SD (17%) or PD (15%) to ICI-1. Median TTP (mTTP) at ICI-2 was shorter compared to ICI-1 (5.3 months vs. 8.5 months, Wilcoxon p=0.024). 29 patients (45%) experienced an irAE with ICI-2; 8 (12%) and 3 (5%) had a grade 3 or 4 irAE respectively, with 3 (30%) of these patients having previously had ≥grade 3 irAE to ICI-1. There were no treatment-related deaths. Conclusions: The ORR to ICI-2 was 23%, which is comparable to that seen with ICI after prior TT. Responses were seen even amongst those receiving single-agent ICI at ICI-2 and the likelihood of response to ICI-2 was higher if a patient had previously responded to ICI-1. No increase in toxicity with ICI-2 was apparent. Additional data from prospective studies are needed to determine whether sequential ICI has a role in treatment of mRCC. [Table: see text]

Abstract Abstract 852 Adult acute lymphoblastic leukemia (ALL) is an aggressive disease with <30% long-term survival. This relatively poor outcome can be explained in part by an increased frequency of high-risk molecular subtypes compared to childhood ALL, such as BCR/ABL (20%-40% in adults vs 2%-5% in children). We hypothesized that aberrant epigenetic gene regulation contributes to the pathogenesis and clinical features of adult ALL. We therefore performed genome-wide DNA methylation and gene expression microarray studies of 215 adult patients with B-lineage ALL enrolled in the ECOG E2993 phase III trial. Patients had a median follow-up 4.75 years (3.5 months to 13 years) and median age 39 years (17 to 63 years). BCR/ABL(+) cases (n=83) had a worse overall survival (OS, p=0.08) than BCR/ABL(-) cases (n=132). The smaller difference in survival in this series between BCR/ABL(+) and (-) cases is likely due to the use of imatinib in some of these patients. The HELP microarray assay was used to measure DNA methylation at 50,000 CpGs annotated to ∼22,000 RefSeq promoters. The accuracy of HELP was confirmed by extensive quantitative single locus validation studies. Supervised analysis revealed the presence of a markedly aberrant DNA methylation signature (166 genes) in BCR/ABL(+) ALL with the cutoff values of p<0.001 (FDR<0.002) and log fold change>1, and a differential gene expression profile of 416 genes at p<0.001 (FDR<0.004) and log fold change>1. Integrative analysis of expression and DNA methylation indicated that many of these genes are functionally connected within a gene network centered around IL8, which was over expressed and hypomethylated in BCR/ABL(+) cases, along with IL2RA(CD25), CEBPB, ABL1, ID1, IL15, BCL2L13, CD69, NOV, S100A8 and S100A9. KEGG and BioCarta pathway analysis also showed enrichment for IL8 signaling, NF-kB Activation, B Cell Development and Antigen Presentation pathways, suggesting these cytokine networks might play central and distinct roles in BCR/ABL(+) ALL. To identify a core set of functionally relevant genes, we explored the overlap of the DNA methylation and gene expression signatures. The overlap consisted of 13 genes, among which 11 showed inverse correlation, including CD200, GAB1, HLA-DQA1, HLA-DQB1, IL2RA (CD25), LST1, LTB, NOV, ROB04, S100A9, and CD38. Consistent with previous ECOG findings, CD25 positivity was a more dominant predictor than BCR/ABL, and could further stratify BCR/ABL(+) patients into a favorable (CD25-) and a poor (CD25+) outcome group (OS, p=0.07). When comparing CD25(+) and CD25(-) groups among BCR/ABL(+) cases, we found RhoH and UBE2J1 as the top differentially methylated and IL2RA(CD25) as the top differentially expressed genes, and all three genes showed concordant corresponding changes in expression and methylation. The aberrant DNA methylation signature of MLL/AF4 cases was even more dramatic, with 469 identified as differentially methylated (p<0.001 (FDR<0.015), log fold change>1) and 1108 genes differentially expressed (p<0.001 (FDR<0.009), log fold change>1). Integrated analysis of DNA methylation and expression implicated gene pathways centered around TNFA and MYC, respectively. A core set of 44 genes were identified overlapping between the methylation and gene expression signatures, among which 34 showed inverse correlation, including ANXA5, BRE, CAPG, CEBPA, FAIM, FLT3, FUT4, IGFBP7, IL1R2, ITGA7, ITGAE, MAP1A, MAP7, MRPL33, PARP8, RBKS, SLITRK4 and TFR2 with overexpression and hypomethylation, and BTBD3, CCR6, FYN, GAB1, GYPC, HPS4, IL2RA, KCNK3, LCK, LST1, LTB, PRKCH, QPCT, S100A13, SGPL1 and ZAP70 with underexpression and hypermethylation in MLL/AF4(+) ALL. All signatures were independent of B-ALL differentiation stage. Using univariate Cox Hazard Regression model adjusted by age, WBC, CD25 and BCR/ABL status, we furthermore identified 259 expression and 115 methylation markers which were significantly correlated with patient OS risk (p<0.01). Molecularly or immunophenotypically defined poor prognosis adult B- ALLs thus feature specific aberrant DNA methylation profiles with associated inversely correlated gene expression. These gene sets delineate specific biological functions that may contribute to disease phenotype and offer an opportunity for development of targeted therapy. Aberrantly methylated genes in adult B-ALL correlate with clinical risk independent of other clinical or molecular risk factors. Disclosures: No relevant conflicts of interest to declare.

Abstract Genetic lesions such as BCR–ABL1, E2A–PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR–ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR–ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A–PBX1-positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A–PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A–PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLLr B-ALLs. Significance: We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA(CD25), which is linked with BCR–ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survival of primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr. Cancer Discov; 2(11); 1004–23. ©2012 AACR. Read the Commentary on this article by Cimmino and Aifantis, p. 976. This article is highlighted in the In This Issue feature, p. 961