INTRODUCTION:Adjuvant chemotherapy can improve recurrence-free survival (RFS) in gastrointestinal malignancies. Previous review of phase III randomized controlled trials (RCTs) for colorectal cancer observed that RFS improvements were driven by early divergences during active chemotherapy; late recurrences were not influenced by adjuvant therapy. The broader applicability of this finding is unknown. METHODS:PubMed, Cochrane Library (CENTRAL), Embase, Scopus, and Web of Science were queried from database inception to December 31, 2025, for phase III RCTs including pancreatic, gastroesophageal, hepatocellular, and biliary tract malignancies. Trials where significant differences in RFS were observed between experimental (adjuvant chemotherapy) and control (resection alone) arms were included. Summary data were extracted from Kaplan-Meier curves using DigitizeIT, and absolute differences in RFS were compared at matched intervals using Wilcoxon matched-pairs signed rank tests. RESULTS:A total of 14 RCTs were identified, investigating periampullary (n = 4), gastroesophageal (n = 5), hepatocellular (n = 4), and biliary tract (n = 1) carcinomas. Across pooled RCTs, the highest rates of recurrence were observed in the first year following resection. Median RFS event rate was significantly higher with resection alone (0-0.5 y: resection alone 44.9 [IQR 14.2-84.1] versus adjuvant chemotherapy 26.4 [IQR 7.7-41.9], P < 0.001; 0.5-1 y: resection alone 33.2 [22.7-42.1] versus adjuvant chemotherapy 25.0 [13.8-44.5]; P = 0.007). No difference was observed during later intervals from postoperative randomization (1-2 y: P = 0.952; 2-3 y: P = 0.191; 3-4 y: P = 0.999; 4-5 y: P = 0.110). For the subset of trials where ≤6 mo of adjuvant chemotherapy was used (n = 10), improvements in RFS event rates were observed only during and immediately following the treatment interval (0-6 mo: P = 0.001; 6-12 mo: P = 0.037). CONCLUSIONS:Across multiple gastrointestinal malignancies, improvements in RFS associated with active adjuvant chemotherapy regimens are driven by early changes in recurrence dynamics. These data may provide in vivo understanding of residual tumor cell populations after curative-intent resection and how chemotherapy can be best used to prevent recurrence.

2506 Background: TP53 is the most frequently mutated tumor suppressor gene across various tumor types, but no approved targeted therapies exist. NT-175 is an autologous engineered T-cell receptor (eTCR) T-cell therapy expressing an HLA-A*02:01-restricted TCR that targets the TP53 R175H tumor neoantigen. Methods: This open-label Phase 1 study (NCT05877599) enrolled HLA-A*02:01-positive adults with advanced/metastatic, TP53 R175H-mutated solid tumors. NT-175 was manufactured from autologous T cells modified by CRISPR/Cas9 gene-editing to delete endogenous TGFβR2 and replace the TCRα locus with the A*02:01-restricted R175H specific TCR. Patients (pts) received lymphodepletion with fludarabine and cyclophosphamide followed by a single NT-175 infusion along with subcutaneous recombinant IL-2. NT-175 was administered at 3 escalating dose levels (DLs) of eTCR+ T-cells. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus definitions. Response was determined by investigator assessment per RECIST v1.1. The primary objective was safety; secondary and exploratory objectives included preliminary antitumor activity and pharmacokinetics (PK), respectively. Results: As of Oct 31, 2025, 26 pts were enrolled and 21 were infused with NT-175 (median age 58 years, [range 43–77] across all DLs (DL1, n = 3; DL2, n = 4; DL3, n = 13; other, n = 1). Pts had a median of 3 prior lines of systemic therapy. Median time from apheresis to NT-175 infusion was 36 days and median follow-up was 6.0 (range: 0.9–9.5) months. Pts had colorectal adenocarcinoma (CRC, n = 10), pancreatic adenocarcinoma (PDAC, n = 6), breast cancer (BC, n = 2), and other solid tumors (n =3). There were no DLTs or Grade 5 events. CRS occurred in 11 (52.4%) pts (Grade ≥3 in 2 [9.5%]); ICANS occurred in 1 pt (Grade 3, 4.8%). Across all dose levels, objective response rate (ORR, including 7 confirmed and 3 unconfirmed responses) was 47.6% (95% CI, 25.7–70.2); in DL3, ORR was 53.8% (95% CI, 25.1–80.8). Partial responses (PR) were observed in 10 pts including 5/6 pts (83%) with PDAC and 5 pts across various tumor histologies (2/10 CRC, 2/2 BC, 1 other), and stable disease in 4 pts. Of 7 evaluable PR pts with ≥6 months of follow up, 5 remain in PR (2 PDAC, 1 leiomyosarcoma, and 2 CRC). Overall, disease control rate was 66.7% (95% CI, 43.0–85.4). Peripheral blood PK analyses (n =21) showed dose-dependent NT-175 expansion, peaking at Week 1 post-infusion, and persistence > 300 days. Conclusions: Manufacturing and treatment with autologous NT-175 eTCR T cells was safe and feasible in pts with heavily pre-treated metastatic TP53-mutated malignancies. Further, NT-175 demonstrated encouraging preliminary antitumor activity across multiple histologies, with most notable early signals in PDAC and may offer a prolonged treatment-free interval in pts with refractory solid tumors. Clinical trial information: NCT05877599 .

4194 Background: Mucin 5AC (MUC5AC) is aberrantly expressed in pancreatic ductal adenocarcinoma (PDAC) and associated with tumor progression; however, its role in altering the tumor immune microenvironment (TIME) and immunotherapy-relevant pathways is poorly understood. Thus, we evaluated whether MUC5AC expression delineates PDAC into distinct transcriptional and immunologic subtypes based on TIME. Methods: Bulk RNA-seq data from 730 PDAC tumors (Oncology Research Information Exchange Network, ORIEN) and 360 normal pancreatic tissues (GTEx) were analyzed. Differential gene expression and pathway enrichment were assessed using Gene Ontology and KEGG analyses. Immune infiltration and stromal states were inferred using multiple complementary deconvolution algorithms (CIBERSORT and xCell). Tumors in the lowest quartile of MUC5AC expression (≤25th percentile; MUC5AC-low, MUC5AC-L) were compared with the remaining samples (MUC5AC-high, MUC5AC-H). Associations between MUC5AC expression and immune cell populations and immunomodulatory genes were evaluated by using correlations and group-based analyses with false discovery rate (FDR) corrections. Results: Principal component analysis demonstrated clear separation between PDAC tumors and normal pancreas and revealed distinct transcriptional programs between MUC5AC-H (N = 544) and MUC5AC-L (N = 186) tumors. MUC5AC-H tumors exhibited a profoundly immunosuppressive and stromal-remodeled TIME, including enrichment of M2 macrophages, regulatory T cells, activated natural killer ells, fibroblast-associated signatures, and significantly higher immune and stromal scores (multiple FDR ≤10⁻⁶ to ≤10⁻²⁸). In contrast, MUC5AC-L tumors showed relatively enrichment of immune-activating populations, including naïve B cells, dendritic cell subsets, resting CD4⁺ memory T cells, and CD8⁺ T cells (multiple FDR < 10⁻¹⁵). MUC5AC expression strongly correlated with immune checkpoint genes CD274 (PD-L1) and TIGIT , and with multiple suppressive immune populations (p < 0.01 to < 10⁻¹⁰). Conclusions: MUC5AC defines a transcriptionally distinct, immunosuppressive PDAC subtype characterized by stromal activation, macrophage/Treg enrichment, and immune checkpoint engagement. MUC5AC may serve as a biomarker for immune stratification and supports rational combination strategies integrating stromal targeting with immune checkpoint modulation in PDAC.

BACKGROUND:Colorectal cancer (CRC) can be effectively treated with fluoropyrimidine chemotherapy doublets. The triplet chemotherapy program, FOLFOXIRI, is more effective than a doublet in randomized trials. We combined this triplet with the anti-epidermal growth factor receptor (EGFR) antibody, panitumumab, as first-line therapy in the appropriately targeted population: left-sided, RAS wild-type metastatic CRC. METHODS:A multicenter trial was conducted with the AGICC (Academic GI Cancer Consortium) group. Patients with stage IV or unresectable, left-sided, Rat Sarcoma Virus oncogene (RAS) wild-type CRC were eligible if they had measurable disease, adequate organ function, and Perfromance Status (PS) 0-1. Consented patients were treated with modified FOLFOXIRI and panitumumab every 2 weeks until progression or toxicity. CT scans were performed every 8 weeks. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECiST) v1.1, with an expectation of an RR ≥85%. RESULTS:Twenty-nine patients were enrolled and 27 were treated. A total of 430 cycles were given, including 7 patients with the maximum of 24 cycles (median 18, range 3-24). Best response included 2 CR, 18 PR, and 6 SD (RR 74%). One patient progressed at the time of first assessment. Grade 3+ toxicity included neutropenia, diarrhea, rash, hypomagnesemia, and hypokalemia, similar to prior reports. No patient had grade 5 toxicity. Median progression-free survival (PFS) was 17.0 months, and overall survival was not reached but exceeded 36 months. CONCLUSION:In this small US multicenter study, utilizing FOLFOXIRI with an anti-EGFR antibody for appropriately selected patients, we note that the response rates and PFS values are among the highest reported in stage IV colon cancer. CLINICALTRIALS.GOV IDENTIFIER:NCT04169347.

1533 Background: Colorectal cancer is now the leading cause of cancer-related death in people under 50, and young adults living in poverty have increased mortality. Despite younger age being associated with higher clinical trial enrollment, young adults face distinct social and structural barriers that may impede participation. This study examines how neighborhood social vulnerability is associated with clinical trial participation for colon cancer in young and older adults. Methods: Patients diagnosed with colon cancer were identified in the nationally representative Vizient Clinical Database from January 2022 – June 2025 and stratified into young adult (age 18-49) and older adult (50 and above) cohorts. The outcome of interest was clinical trial enrollment, identified by billing codes. Social vulnerability was defined by the Vizient Vulnerability Index in quartiles at the census tract level. Multivariable analyses were performed in both cohorts. An interaction analysis was performed between age and social vulnerability. Results: Of 234,047 patients, 15% were young adults, of which 5.1% enrolled in a clinical trial. Eighty-five percent were older adults, of which 3.0% enrolled in clinical trials. Most young adults had private insurance (73.1%) while most (56.6%) of the older patients were enrolled in Medicare. Non-Hispanic (NH) Black patients were less likely to enroll than NH White patients in both the young adult (OR 0.72, p=0.0001) and older adult cohorts (OR 0.79, p<.0001), as were young and older patients with Medicaid vs. private insurance (OR 0.75, p=0.0001 and OR 0.71, p<.0001, respectively). Diagnosis at an academic medical center vs. community hospital increased the odds of enrollment for both groups: young (OR 2.79, p<.0001) and older (OR 2.04, p<.0001), as did being married vs. single: OR 2.31, p=0.0016 for younger and OR 1.85, p<.0001 for older adults. Among older adults only, Hispanic patients (OR 0.87, p=0.0056; ref NH White) and female patients (OR 0.91, p=0.0002; ref male) were less likely to enroll. Living in the most vs. least socially vulnerable neighborhoods impacted trial enrollment more for young adults (OR 0.75, p<.001) than for older adults (OR 0.91, p<.0001), p= 0.0042 for interaction. Conclusions: Many factors that influence trial enrollment, including insurance, social support, diagnosis at an academic center, and race/ethnicity, are similar among young and older adults with colon cancer. However, the negative impact of neighborhood disadvantage on trial enrollment is more pronounced among young adults, highlighting the need for practical trial design, targeted navigation, and strategic recruitment of young adults living in socially vulnerable areas.

e16313 Background: Well-differentiated GEP-NETs comprise a heterogenous group of malignancies with variable behavior. While existing grading structures attempt to predict these behaviors, significant variability remains. The ORIEN database contains complementary clinical, genomic, and transcriptomic profiling, providing a novel source for correlating molecular data with clinical characteristics. Methods: mRNA expression profiles were assessed for correlation the presence (M1) or absence (M0) of metastatic disease at diagnosis. The workflow consisted of: (1) Data preparation: RSEM gene expression data were processed, quality-controlled, and mapped to clinical metadata. (2) Differential gene expression: DESeq2 was used to identify significantly differentially expressed genes (FDR < 0.05). (3) Pathway enrichment analysis: Gene Ontology (GO), KEGG, and Reactome enrichment analyses were performed on all differentially expressed genes to identify biological pathways associated with metastatic status. Results: Across all GEP-NETs, 112 genes had significantly different expression levels for M1 (n = 5) vs. M0 (n = 24) stage, including 35 genes expressed at higher levels in M1 disease. In analysis limited to pNETs, 708 genes showed significantly different expression levels between M1 (n = 3) and M0 (n = 20) stages, including 155 genes expressed at higher levels in in M1 disease. In both the entire GEP-NET cohort and pNET subgroup analysis, the most frequently overexpressed Reactome pathways associated with M1 stage were related to the regulation of metaphase transition and DNA-protein (histone) interactions. Cancer testis antigen (CTA) genes were also frequently upregulated (Table 1). Conclusions: Differential mRNA expression data provides a novel means for better characterizing the molecular underpinnings of GEP-NETs. Specifically, cell cycle, histone-related, and CTA gene expression profiles may provide actionable findings on which to base downstream drug development for the prevention and/or treatment of metastatic disease. Most upregulated mRNA profiles by magnitude in metastatic GEP-NETs. Gene Log 2 Fold ∆ a Description / Function GAGE2A 7.41 CTA, chromatin regulator, anti-apoptosis RNF17 5.89 CTA, DNA damage response GTSF1 5.76 CTA, DNA methylation, retrotransposon regulation NBEAP1 5.19 Also called BCL8, little known normal physiologic function ORM1 4.53 Acute phase reactant, angiogenesis, immune evasion HIST2H3C 4.18 Histone H3 regulation, chromatin regulator LYZ 4.12 Lysozyme production, TME inflammation, immune evasion PBK 4.02 CTA, cell cycle regulation, histone phosphorylation, anti-apoptosis HIST2H3A 3.71 Histone H3 regulation, chromatin regulator a All p-values <0.0001.

125 Background: Tovecimig is a recombinant bispecific antibody that simultaneously blocks the delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A) signaling pathways. In a Phase 1 study of tovecimig, two patients with metastatic colorectal cancer (CRC) had confirmed partial responses (PRs) prompting the further exploration of tovecimig in patients with CRC treated in the third- or fourth-line setting. Methods: COMPANION-003 (NCT05513742) was a multi-center, single arm Phase 2 study with a Simon Two Stage design. Eligible patients had metastatic CRC with primary tumor resection and had progressed after receiving two or three prior systemic therapies, which must have included oxaliplatin, irinotecan, a fluoropyrimidine, an anti-VEGF therapy, and, if indicated, an anti-EGFR therapy. Patients with both KRAS wild type and KRAS mutated tumors were eligible. Tovecimig was given as a monotherapy intravenously at 10 mg/kg every two weeks, and tumor response was assessed every eight weeks based on RECIST v1.1. DLL4 expression assessed in tumor tissue from archived biopsy specimens was analyzed by immunohistochemistry (IHC) retrospectively. Results: Of the 49 patients enrolled in Stage 1 of the study, there were 40 response evaluable patients. 23 out of the 40 patients (58%) were treated in the fourth-line setting. 16 of the 40 patients (40%) had KRAS mutated tumors. Final analysis shows an objective response rate (ORR) of 5% (2 out of 40 patients), median progression free survival (PFS) of 3.9 months, disease control rate (DCR) of 68% (27 out of 40 patients with a partial response or stable disease as the observed best overall response), and median overall survival (OS) of 10.2 months. Treatment emergent adverse events (TEAEs) were reported in 98.0% of subjects and TEAEs of ≥ Grade 3 were reported in 65.3% of subjects. The most frequently reported TEAEs were hypertension (44.9%), proteinuria (36.7%), nausea (28.6%), and fatigue (26.5%). The most frequently reported TEAEs of ≥ Grade 3 were hypertension (32.7%) and proteinuria (6.1%). Archived biopsy specimens were obtained from 25 patients in the study. IHC analysis suggested a trend toward longer PFS in patients with DLL4 high tumors compared to patients with DLL4 low tumors. Conclusions: The results from the Phase 2 COMPANION-003 study demonstrated clinically meaningful anti-tumor activity with a manageable safety profile, which supports further development of tovecimig in patients with advanced, metastatic CRC. Clinical trial information: NCT05513742 .

3516 Background: ICIs produce durable benefit in MSI-H CRC, yet optimal treatment duration and monitoring strategies remain unclear. ctDNA enables minimally invasive assessment of molecular response during and after ICI. We evaluated real-world treatment patterns, outcomes, and longitudinal ctDNA dynamics in pts with MSI-H CRC treated with ICI. Methods: Pts with MSI-H mCRC treated with first-line ICI were identified from Natera’s Real-World Database with linked longitudinal ctDNA results (Signatera, Natera, Inc.) and commercial claims data (Forian’s Hybrid data ecosystem, CHRONOS). Overall survival (OS) was estimated using available mortality data (Veritas Data Research, Fact of Death Mortality Data Index). ctDNA status was assessed pre-ICI when available and longitudinally following ICI initiation. Outcomes included OS and time to next trmt (TTNT); ctDNA dynamics following ICI discontinuation were descriptively evaluated. Results: Among 559 pts treated with first line ICI (pembrolizumab [70.1%], ipilimumab+nivolumab [15.7%], and nivolumab [11.8%]), the median duration of ICI was 266 days. Baseline (pre-ICI) ctDNA results were available for 180 pts, including 38% who were treated with chemotherapy, and most pts (71.7%, 129/180) were ctDNA-positive (ctDNA(+)) prior to ICI initiation. Of these, 89.9% (116/129) had ctDNA-timepoints after the start of ICI, and 81.0% (94/116) achieved anytime ctDNA clearance (from ctDNA(+) to negative), while 19.0% (22/116) remained ctDNA(+). ctDNA(+) at anytime after the start of ICI (HR: 8.0, p < 0.0001) or on first result after the start of ICI (HR: 3.4, p < 0.0001) was associated with inferior OS compared ctDNA-negativity (ctDNA(-)) at these time points. Among pts whose first post-ICI test was ctDNA(+), 32% switched treatments, with a median TTNT of 302 days, compared to only 6.6% of pts (median TTNT 683 days) whose first post-ICI test was ctDNA(-). First post-ICI ctDNA status was associated with longer ICI duration (median 192 days for ctDNA(+) vs 303 days for ctDNA(-)), and ctDNA(+) was predictive of inferior OS (HR: 4.9; p < 0.001). ctDNA after the end of ICI was available for 392 patients; it was persistently negative in 77.2% (303/392), persistently positive in 12.8% (50/392), cleared after the end of ICI (positive to persistently negative) in 4.1%, and the remaining 5.9% had variable patterns (e.g. positive to negative to positive). Conclusions: In this large real-world cohort of MSI-H mCRC treated with ICI, longitudinal ctDNA dynamics strongly correlated with treatment durability, time to subsequent therapy, and OS. These findings support further evaluation of ctDNA to inform treatment duration and surveillance strategies in MSI-H mCRC.

Immunotherapy with checkpoint inhibitors targeting the PD1/PD-L1 and CTLA4 pathways has limited activity in patients with microsatellite stable (MSS) colorectal adenocarcinoma (CRC). In a prior study, the combination of cetuximab and pembrolizumab failed to improve outcomes for patients with advanced RAS wild-type (RAS(wt)) CRC. In this post hoc secondary analysis, we show that the cetuximab and pembrolizumab-treated patients with TP53 mutant (p53(mt)) tumors had significantly higher progression-free survival (PFS) and a decrease in tumor burden compared to patients with TP53 wild-type (p53(wt)) tumors but no difference in overall survival compared to patients with p53(wt) tumors. The gene set enrichment analysis showed a uniform upregulation of multiple metabolic and immune gene sets, including NK-mediated immunity and IL-12 pathway, while the IL6 pathway was downregulated. There were no overlapping transcriptional alterations between the p53(mt) and p53(wt) groups with treatment that remain constant despite the therapeutic intervention. Functional overlap with treatment in both groups in the proliferative, immune, and metabolic pathways were identified. In the baseline tumor samples, the number of PD-L1(+) tumor cells was significantly higher in p53(mt) tumors while the number of OX40(-)/AE1_AE3(-)/PD-L1(-) non-tumor cells, positive for either LAG3, CTLA4 or TIM3, was significantly higher in p53(wt) tumors. In conclusion, TP53 status was prognostic of improved PFS with cetuximab plus pembrolizumab in RAS(wt) CRC. Future studies evaluating immune-oncology agents in patients with MSS, RAS(wt) CRC should include TP53 as an integrated biomarker and evaluate its performance as a positive predictive biomarker (ClinicalTrials.gov NCT02713373).

e15710 Background: Traditionally, research on the epidemiology and outcomes in minorities in the United States has primarily focused on differences between Non-Hispanic White (NHW) and Non-Hispanic Black (NHB) and Hispanic populations, with a lower emphasis on Asians, a gradually increasing demographic in the US. Recent literature suggests the rate of colorectal cancer (CRC) screening among Asian Americans remains low, despite an increasing rate of CRC diagnoses within this population. The differences between the disease courses of Asian and NHW patients are not well-characterized. In this study, we aimed to examine the diagnosis, treatment, and survival of Asian and NHW patients diagnosed with CRC. Methods: This was a retrospective, observational IRB-approved study of Asian and NHW patients treated for CRC at a single NCI-designated comprehensive cancer center. Descriptive variables were collected including demographics (age at diagnosis, gender, race/ethnicity), disease characteristics (stage at diagnosis, anatomical site of primary cancer, mutations), treatment (surgery, radiation, neo-adjuvant/adjuvant therapy, lines of treatment for advanced disease), and survival. The primary outcome was overall survival (OS) from time of stage IV diagnosis to death or last follow-up. Statistical analysis was performed using R software and GraphPad Prism, and Log-Rank tests were used to determine differences in OS between the two cohorts; patients were considered dead or censored if alive or status was unknown. Results: 122 patients were included in the study: Asian (n = 60) and NHW (n = 62). The overall survival data included 68% (n = 83) alive at last follow up, 28.7% (n = 35) deceased, and 3.3% (n = 4) unknown; this was consistent across both cohorts. Median age at initial diagnosis (years) of Asians was younger, but not significantly different [Asian 61, NHW 66; p = 0.279]; the same was observed for the median age (years) at stage IV diagnosis [Asian 60, NHW 68; p = 0.222]. Asian patients had a lower proportion of stage IV disease at initial diagnosis [Asian 30%, NHW 45%; p = 0.123]; however, NHW patients were significantly more likely to have stage IV CRC at any time during their disease course [Asian 37%, NHW 61%; p = 0.011]. There was no statistically significant difference in median OS (years) to death or last follow up from time of initial diagnosis [Asian 4.89, NHW 4.79; HR 0.88, p = 0.72], and for the primary outcome of median OS (years) from time of stage IV diagnosis to death or last follow up [Asian 3.03, NHW 2.87; HR 0.91, p = 0.934]. Conclusions: Asian and NHW patients have similar overall survival and ages at initial and stage IV diagnosis, but NHW are significantly more likely to have stage IV disease. Given their increasing presence in US society, more in-depth analysis of Asian populations with CRC is warranted to determine any disparities in screening, treatments, and outcomes.

e15152 Background: In comparison to the prior studies with eniluracil (6422) and 5-FU, 6422 + Cap uses a novel schedule of a single dose of 6422 followed the next 7 days with capecitabine (Cap) at a dose approximately one-tenth that of present monotherapy Cap (Mono-Cap). 6422 irreversibly inhibits dihydropyrimidine dehydrogenase (DPD), the enzyme that metabolizes 5-FU to catabolites which cause side effects while providing no therapeutic benefit. Inhibition of DPD not only eliminates these catabolites but also exposes cancer cells to more 5-FU and more cancer killing 5-FU anabolites. The objectives of this Phase 1B study in gastrointestinal cancer patients were to: evaluate the safety and efficacy, evaluate exposure to Cap, 5-FU, and FBAL (major catabolite of 5-FU), determine the Maximum Tolerated Dose (MTD), and determine the Recommended Phase 2 Dose Range (RP2DR) for the optimal dosage regimen studies. Methods: The 3+3 design trial included patient cohorts who received ascending Cap doses given 7 days on/7 days off preceded 16-24 hours by a single dose of 6422 before the start of every Cap cycle. 5-FU and FBAL exposure (AUC) were calculated. All patients were refractory or intolerant to available cancer therapies. Radiological tumor response evaluation (RECIST 1.1) was performed every 8 weeks. Results: PK Results: 18 patients were enrolled in 4 dose levels from 75 mg qd to 225 mg BID of Cap. All 6422 + Cap BID dosing had 5-FU AUC exposure greater than reported for Mono-Cap. The AUC for the 150 mg BID and 225 mg BID cohorts were approximately 5-10 times the previously reported AUC for the typical 2,250 mg BID Mono-Cap treatment. The 5-FU T1/2 of approximately 3 hrs for these two cohorts was also much longer than 0.84 hrs reported for Mono-Cap. Efficacy-Safety Results: 36.4% (4/11) of the patients in the 150 mg BID and 225 mg BID cohorts had grade 3-4 adverse events (AEs) (eg, neutropenia) associated with anabolites, similar to the incidence reported for Mono-Cap. The extremely low FBAL catabolite formation/exposure across all 6422 + cap doses resulted in only 1 out of 18 patients (5.6%) having mild Grade 1 HFS, a much lower incidence and severity than Mono-Cap. For the 13 RECIST evaluable patients, partial response (PR) was 15.4% (2/13) and stable disease (SD) was 46.2% (6/13). The median Progression-Free Survival (PFS) for the evaluable patients was 93 days (ranging from 53 to 332 days). For all 18 patients, PR was 11.1% (2/18 – the 2 PR patients in the highest Cap dose) and SD was 33.3% (6/18). Conclusions: Although 5-FU exposure was up to 5-10x greater than for Mono-Cap, AEs from 5-FU catabolites were minimal while anabolite associated AEs for the highest dose cohorts were similar to those reported for Mono-Cap. In these evaluable refractory or intolerant cancer patients, 6422 + Cap efficacy occurred with a PR of 15.4%, SD of 46.2%, and median PFS of 93 days. The MTD was 225 mg BID and RP2DR was 75 mg BID to 225 mg BID. Clinical trial information: NCT04861987 .

Indocyanine green fluorescence angiography (ICGFA) during colorectal surgery either reassures surgeons regarding intestinal perfusion sufficiency or prompts changed surgical strategy by indicating unsuspected insufficiency. This study describes existing evidence supporting ICGFA use in colorectal surgery, particularly regarding impact on intraoperative decisions. Searches were performed on PubMed, ScienceDirect, Scopus, Web of Science, Cochrane Collaboration databases on 5th December 2023, updated to 19th August 2024. Full English language publications of clinical studies in human patients undergoing colorectal resection with primary anastomosis with the use of ICGFA to assess bowel perfusion intraoperatively, with a control group, were included. Pooling of anastomotic leak (AL) rates was performed for primary outcome analysis with odds ratio (OR) and number-needed-to-treat (NNT) calculated regarding leak reduction. 45 studies comprising 14,333 patients were included, with 7 randomised controlled trials (2911 patients). Overall, AL rate was 6.8

BACKGROUND:Mutational landscape is prognostic in colorectal cancer (CRC). Rat sarcoma (RAS) oncogenes, such as KRAS and NRAS, with driver mutations, portend poor survival outcomes, whereas pathologic mutations in HRAS are extremely rare, and their prognostic value remains uncertain. METHODS:This retrospective study analyzed the Oncology Research Information Exchange Network (ORIEN) alliance tumor RNA-Seq data in Stages II and III CRC to investigate the association between RAS gene expression and survival outcomes. RESULTS:High transcript levels of HRAS were associated with superior overall survival (OS). The high HRAS-associated OS benefit was most pronounced in patients with right-sided primary expressing low KRAS transcript levels in the absence of pathologic KRAS mutations. CONCLUSIONS:Contrary to the notion that RAS family genes are proto-oncogenic, this study demonstrates that high HRAS transcript levels are associated with superior OS in Stages II and III CRC. The potential of HRAS as a prognostic biomarker should be explored further.

189 Background: TAS102 (trifluridine/tipiracil hydrochloride) is approved for use alone or with bevacizumab in late line metastatic colorectal cancer (mCRC), with overall survival benefit in phase 3 trials (RECOURSE and SUNLIGHT). Oxaliplatin is frequently reintroduced after progression, resolution of limiting neuropathy, or disease recurrence post adjuvant therapy. In preclinical studies, oxaliplatin combined with TAS102 has shown synergism. We hypothesized TASOX may be an option for patients who have progressed/recurred after FOLFOX. Methods: We assessed safety and efficacy of TAS102 with oxaliplatin, enrolling patients with metastatic CRC progressed on ≥2 lines of therapy including 5FU, oxaliplatin and irinotecan. Patients with recurrence during or within 6 months of adjuvant chemotherapy were allowed. Exclusion: Prior TAS102 exposure, functional impairing peripheral neuropathy, ≥Grade 3 hypersensitivity to oxaliplatin, or uncontrollable grade 1-2 hypersensitivity to oxaliplatin. Treatment continued until disease progression or unacceptable toxicity. Patients received oxaliplatin 85 mg/m2 and TAS-102 35 mg/m2 bid days 1-5 every two weeks, and bevacizumab per MD choice. The primary endpoint was overall response rate (ORR) by RECIST (by independent radiologists). Secondary endpoints included disease control rate (DCR), safety and tolerability. Results: 54 patients enrolled; 53 received treatment on study and 48 had ≥1 disease assessment (median age 59, 58 % male, tumor RAS mutated 69%). Median time on study was 4 months (8 cycles; range 1-37 cycles). ORR was 6% (n=3), with average change in target lesions -45% (range -35 to -67%). 71% (n=34) had SD defined on study, with average change in target lesions -3% (range -29% to +20%). In those treated with bevacizumab (59%; n=28 ), 79% (n=22) had disease control vs. 75% (n=15). The most common reason for study discontinuation was progressive disease (23%, n=11). 68% (n=36) had a treatment-related adverse event (TRAE) ≥Grade 3 at any point during therapy. The most common G3 TRAEs were anemia 19% (n=10) and leukopenia 28% (n=15) at any time. Two (4%) developed grade 3 neuropathy. Conclusions: TASOX is effective as a 3rd line therapy for patients with mCRC. In our study, overall disease control rate was 77% with up to 19 months on study. Anemia and leukopenia are common but manageable. Bevacizumab did not seem to have as great an effect in our trial as observed in SUNLIGHT. Future studies would warrant TASOX in combination to bevacizumab in randomized trials in candidates for oxaliplatin retreatment. Clinical trial information: NCT02848079 .

TPS313 Background: Currently, pembrolizumab is one of the front-line therapies for patients with MSI-H CRC. However, approximately 40% of patients who received pembrolizumab experienced disease progression early in the course of disease (KEYNOTE 177). Therefore, there is still an unmet need to enhance the efficacy of checkpoint inhibitors in MSI-H CRC. MSI-H CRC has a higher level of expression of VEGF in blood compared to patients compared to its MSS counterpart (Hansen et al. Colorectal Dis. 2011). Consistently, exploratory analysis of CALBG-80405 and PARADIGM trial showed that patients with MSI-H CRC were more likely to benefit from anti-VEGF therapy than anti-EGFR therapy regardless of the side of the tumor. NSABP C-08 also suggested that anti-VEGF therapy may have biological activity even in as adjuvant therapy for patients with MSI-H colon cancer. Regorafenib is a potent VEGF inhibitor, with preclinical evidence showing its immune modulatory effect in the tumor microenvironment. In this trial, we hypothesize that adding low-dose regorafenib to pembrolizumab may induce synergistic activity beyond their independent clinical efficacy and create deep and durable responses for patients with MSI-H CRC. Methods: In the lead arm of this prospective randomized study, 22 patients will be enrolled through Hoosier Cancer Research Network (HCRN-GI23-643). Patients with treatment naïve MSI-H CRC will be enrolled in this front-line trial. One cycle of pembrolizumab and up to 3 cycles of chemotherapy prior to determination of MMR-D/MSI-H is allowed. Patients will receive regorafenib 60 mg daily in combination with pembrolizumab 200mg IV in cycle 1, followed by regorafenib 90mg in subsequent cycles to improve treatment tolerance. The primary outcome that will be measured is ORR, defined as the percentage of partial or complete response to the treatment within 12 months. ORR will be measured using RECIST 1.1. criteria. A formal one-sided hypothesis test will be conducted for futility, assuming that we will reject the null hypothesis of a target ORR only if we have strong evidence. In this study, we assume a null hypothesis that ORR is 0.60, which would reflect significant clinical improvement over the current standard of ORR = 0.43 from KEYNOTE 177. The alternative hypothesis is that ORR is less than 0.60. For the lead-in phase of the study, the emphasis is on controlling Type I error to be small, approximately 0.05. The test statistic will be the number of ORRs in the 22 patients, which we assume to follow a binomial distribution. Clinical trial information: NCT06006923 .

e15605 Background: Actionable biomarkers have a prominent role in frontline decision-making for pts with metastatic colorectal cancer (CRC). Strategies targeting the EGFR/HER2, KRAS/BRAF, and PD-1/PD-L1 pathways are now being combined with chemotherapy with new approvals and active trials. Here, we explore relationships between actionable biomarkers and molecularly-matched therapies versus other therapies given in 1st line and how actionability evolves in later lines. Methods: We analyzed outcomes and NGS results across 533 pts from the Know Your Biomarker initiative and Perthera’s real-world evidence database. Actionability in a 1st line context was analyzed retrospectively and prospectively in multiple settings via the Perthera Report. Progression-free survival (PFS) was evaluated from initiation of 1st line for advanced disease until discontinuation due to disease progression. Hazard ratios and p-values were computed via Cox regression when comparing PFS on subsets (n=161) who received either a 1st line regimen including any biomarker-based molecularly-targeted agent versus a standard triplet (FOLFOXIRI) or doublet (FOLFOX or FOLFIRI). Frequencies of other genomic alterations with actionability for later lines of therapy were analyzed in the context of prospectively ranked therapy options. Results: Overall actionability for upfront biomarkers in CRC was 54% (287 / 533) including MSI-high (4%), HER2-positive (4%), KRAS G12C (4%), BRAF V600 (4%), and RAS/RAFwt (38%). Median PFS on a biomarker matched therapy was significantly longer than either FOLFOX or FOLFIRI (p<0.05) but not FOLFOXIRI (Table). Ranked therapy options were prospectively provided at any line of therapy and 33 pts who initiated a new therapy post-report often received the #1 (58%), #2 (18%), #3 (6%) or lower (18%) ranked options based on actionability guidance. Conclusions: Upfront biomarker testing is increasingly important in CRC and the initial results from this real-world initiative further support the clinical utility of molecularly-matched therapies; however, the rapidly evolving treatment landscape for chemotherapy combinations (+/- other agents) is a challenge for trial design. Median PFS (months) on 1st line therapies in CRC for actionable biomarker-matched therapies versus typical chemotherapy (+/- VEGFi) triplets or doublets. Therapy Subgroup mPFS [95% CI] on 1st line (# pts) Biomarker Matched 28.4m [18.7-N/R] (n=32) FOLFOXIRI 30.6 [15.2-N/R] (n=22) FOLOX or FOLFIRI 11.0 [8.0-20.9] (n=107)

Supplementary Figure S10. Serial peripheral blood mass cytometry by patient.

Supplementary Table 1. Flow cytometric Abs and Reagents