Advanced Colorectal Adenocarcinoma Research Articles

Abstract 5977: A first-in-human, open-label, multi-center phase 1 study of TST003, a GREM 1 inhibitor, in subjects with locally advanced or metastatic solid tumors

Abstract Background: Gremlin-1 (GREM1), a member of the TGF-β superfamily, plays a key role in EMT, and cancer cell proliferation by binding to BMPs. GREM1 is widely expressed in various human cancers and TME stromal cells. Overexpression of GREM1 is correlated with poor prognosis. TST003 is a novel humanized IgG1 monoclonal antibody targeting GREM1 with high affinity and selectivity, and it blocks GREM1 binding to BMP2/4 resulting in enhanced BMP signaling. This study will investigate TST003’s safety, tolerability, and preliminary anti-tumor activity in patients with advanced solid tumors. Objectives: The primary objectives are to evaluate the safety and tolerability and determine the maximum tolerated dose and/or optimal biologic dose(s) of TST003. Secondary objectives include pharmacokinetic, pharmacodynamic and preliminary anti-tumor activity of TST003. A comprehensive biomarker plan will be implemented to analyze GREM1 expression, BMP signaling pathway, and tumor microenvironment with tumor tissues (including tumor cells, CAFs, Teff, Treg, MDSCs and TAMs), as well as circulating tumor DNA to explore the correlation among drug exposure, pharmacodynamic markers and clinical outcomes. Method: This is a first in human Phase 1 study in locally advanced or metastatic solid tumor subjects having tumor progression during or after prior therapies and have no standard therapy that could confer clinical benefit. It comprises of the Part 1 Dose Escalation and the Part 2 Pharmacodynamic Cohorts. Part 1 will evaluate sequential dose levels of 1, 3, 10, 20 and 30 mg/kg TST003 iv., every three weeks as a single agent. The traditional “3+3” design were used for dose escalation of the first two cohorts (1 and 3 mg/kg), and Bayesian Optimal Interval (BOIN) Design with prespecified cohort size of 3 is used in the following cohorts. Part 2 will include 2 pharmacodynamic cohorts to evaluate the pharmacokinetic (PK) profile, pharmacodynamic (PD) markers, preliminary tumor response, as well as safety of TST003 as monotherapy in locally advanced or metastatic colorectal adenocarcinoma (CRC) subjects. The 2 doses used in the pharmacodynamic cohorts will be chosen from Part 1 and are expected to be within the pharmacologically active range based on nonclinical PK/PD modeling and available clinical PK/PD data from the ongoing study. Baseline GREM1 expression will be analyzed by immunohistochemistry. In each pharmacodynamic cohort, around 13-18 subjects will be enrolled to ensure at least 7 GREM1 positive subjects. Eligible subjects will receive TST003 until unacceptable toxicity or disease progression by RECIST v1.1. The enrollment is ongoing in clinical centers in the US and China. No significant safety signals were reported in the first few patients treated with TST003. Clinical Trial Information: NCT05731271. Study Sponsor: Suzhou Transcenta Therapeutics Co., Ltd. Citation Format: Ismael Rodriguez Rivera, Lin Shen, Shivaani Kummar, Minal Barve, Caroline Germa, Chuan Qi, Lei Chen, Jenny Milata, Jenny Yao, Li Shen, Xuelian Zhu. A first-in-human, open-label, multi-center phase 1 study of TST003, a GREM 1 inhibitor, in subjects with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5977.

Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE

Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. Patients (n= 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n= 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage2. NCT03812796 (registered 23rd January 2019).

Serum angiopoietin-like protein 2 level in patients who received bevacizumab-containing chemotherapy for metastatic colorectal cancer.

209 Background: Anti-angiogenic agents are important for treating patients with advanced colorectal adenocarcinoma, however, their efficacy is not long-lasting and survival benefits are modest. Reliable biomarkers and novel targets for angiogenesis are still required in this era. Angiopoietin-like protein 2 (AGLP-2) is an emerging biomarker for angiogenesis in cardiovascular disease, but its role in the oncology area is yet to be elucidated. Methods: Serum samples from patients with advanced colorectal carcinoma treated with bevacizumab-containing chemotherapy were retrospectively studied. Blood samples at baseline and at disease progression of the first line systemic therapy were selected. Serum angiopoietin-like protein 2 (AGLP-2) concentrations were measured using ELISA kit, serial changes, and the relationship with progression-free survival and overall survival on the systemic therapy were statistically analyzed. Results: 68 patients were enrolled. Their median age was 66 years old (range, 38-82), and 14 (20.6%) patients had metastatic lesions at 3 or 4 organs. The median serum AGLP-2 levels at baseline and at disease progression (PD) were 41,618 pg/ml (95% confidence interval (CI) 34,560-40,713), and 49,706 pg/ml (95% CI 39,853-49,017), respectively. There was a tendency of difference between AGLP-2 levels at baseline and at PD ( p=0.057). Patients whose baseline serum AGLP-2 levels with 40,000 pg/ml or above showed relatively shorter overall survival (median 31.4 months with 95% CI, 14.4-38.6) compared with patients with serum AGLP-2 level below 40,000 pg/ml at baseline (median 38.6 months with 95% CI, 23.6-127.3), but not statistically significant ( p=0.0946). There was no survival difference observed according to serum AGLP-2 levels at disease progression on the first line bevacizumab-containing chemotherapy. Conclusions: Serum angiopoietin-like protein-2 has potential as a new target for novel anti-angiogenic therapy in metastatic colorectal cancer.

The genomic landscape of patients with advanced colorectal adenocarcinoma with PIK3CA mutations using comprehensive cell free tumor DNA next generation sequencing.

181 Background: PIK3CA mutations ( PIK3CAm) are highly prevalent in advanced CRC but the prognostic value is unclear. PIK3CAm are associated with advanced stage disease, tumor aggressiveness, resistance to therapy, and a poorer prognosis. In some cases, PIK3CAm co-occur with other genetic alterations leading to complex signaling networks. Understanding these genetics are crucial to devise effective treatments. In this study, evaluated the genomic landscape of PIK3CAm in advanced CRC using cell free tumor DNA (ctDNA) next generation sequencing. Methods: This analysis assessed advanced CRC samples between 2020-2022 from the Guardant360 database using plasma-based ctDNA (~15000 patients, ~17000 samples). PIK3CAm were assessed by patient demographics, MSI-H status, TMB score, and frequency of co-occurring alterations via cbioportal. A sub analysis was collected between 2021-2022 (~8000 samples) to examine the frequency of PIK3CA exon 9 vs. 20 mutations between BRAF V600E and non- V600E BRAF mutations, and separately between KRAS G12C and G13D. Comparisons were analyzed by two-sided Fisher’s exact test. Results: PIK3CAm were detected in ~21% (~3500) of mCRC samples. Of these samples, the median age was 63 years old and the sex distribution was 56% males. MSI-H was reported in 3.3% of samples. PIK3CAm included 25% E545 (Exon 9), 13% E542 (Exon 9), 5% Q546 (Exon 9), and 10% H1047 (Exon 20). PIK3CAm had increased median alterations per sample to PIK3CA not detected (8 vs. 5) and a significant increase in co-occurrence with most genes in the panel. Relevant clinical co-occurrences were APC (73.7% vs. 57.4%), BRAF (19.9% vs. 13.0%), EGFR (34.7% vs. 24.9%), ERBB2 (9.2% vs. 6.0%), and KRAS (62.9% vs. 41.2%). Additionally, PIK3CAm samples had higher median TMB scores (13.4 vs. 9.8 mut/Mb), with >25% of PIK3CAm reporting a TMB score above the 80th percentile (20.19 mut/Mb). In a sub analysis, there were significantly greater frequencies of PIK3CAm in exon 20 in BRAF V600E samples vs. non-V600E BRAFm samples (p=0.0003) with no significant differences in exon 9 or 20 mutations in KRAS G12C vs. G13D. Conclusions: Our study shows the frequency of PIK3CAm and distribution of exons 9 and 20 are similar to those found previously in the literature by Tan (Xie) et al., 2022. Our results demonstrate PIK3CA having a low frequency of MSI-H co-occurrence, higher TMB scores, and increased co-occurring alterations with notable increased in APC, BRAF, EGFR, ERBB2 and KRAS, which may suggest higher genomic instability. Our findings underscore the clinical significance of PIK3CAm in the context of CRC, emphasizing their role as key drivers of oncogenesis, and supports the development of tailored therapeutic strategies such as combining PIK3CAi with immunotherapy or other targeted therapies.

DKN-01 plus bevacizumab and chemotherapy as second-line (2L) investigational therapy in advanced microsatellite stable (MSS) colorectal adenocarcinoma (CRC): DeFianCe trial.

104 Background: CRC is characterized by hyperactivation of the Wnt pathway where DKK1 plays a critical regulatory role. DKN-01 is an IgG4 monoclonal antibody that potently neutralizes DKK1. DKN-01 has immunomodulatory activity and stimulates a pro-inflammatory tumor microenvironment. Elevated DKK1 expression has been shown to correlate with fluorouracil (5FU) resistance in CRC tumors. 5FU-based combination therapies have demonstrated promising clinical activity in combination with DKN-01 in gastric cancer. In pre-clinical models of 5FU-resistant CRC, DKN-01 showed potent anti-tumor effects. Methods: DeFianCe (NCT05480306) is a Phase 2 randomized, open-label, two-part, multicenter study to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as 2L treatment of advanced MSS CRC patients (pts). The primary endpoint of the single arm Part A (DKN-01 + SOC) was safety and tolerability with secondary endpoints including overall response rate (ORR), progression-free survival (PFS) and overall survival. Retrospective analysis of tumoral DKK1 mRNA expression was measured centrally by in situ hybridization. Results: Thirty-three pts enrolled in Part A between Sept 2022-April 2023. As of 21 Aug 2023, median age 56 years (35, 84); 20 males. 29 pts had tumors with evaluable baseline DKK1 expression; 55% were DKK1-expressing (≥1% tumor cells). All patients had received prior 5FU-based therapies, 30 pts (91%) with oxaliplatin in combination and 17 pts (52%) had prior bevacizumab. 24 pts (73%) had RAS mutations (22 KRAS, 2 NRAS) and 23 pts (70%) had liver metastasis. 30 pts (91%) received DKN-01 + bevacizumab + FOLFIRI. 17 pts (52%) had ≥grade 3 treatment related adverse events (TRAE) with neutrophil count decreased, anemia and fatigue representing the most common. No pt discontinued DKN-01 due to a TRAE. Of the 27 response evaluable pts the ORR was 30% and the DCR was 93%: 8 PR, 17 SD and 2 PD. The median PFS has not been reached. Conclusions: DKN-01 in combination with SOC was well tolerated with promising preliminary activity (ORR 30% and DCR 93%) in the single arm Part A. PFS has not been reached and survival follow up is ongoing. Part B randomized expansion phase has begun and is enrolling an additional 130 pts. Tumoral DKK1 expression and correlation with clinical outcomes will be evaluated as an exploratory efficacy endpoint. Clinical trial information: NCT05480306 .

Chemokine- and chemokine receptor-based signature predicts immunotherapy response in female colorectal adenocarcinoma patients

The clinical significance and comprehensive characteristics of chemokines and chemokine receptors in female patients with advanced colorectal adenocarcinoma have not ever been reported. Our study explored the expression profiles of chemokines and chemokine receptors and constructed a chemokine- and chemokine receptor-based signature in female patients with advanced colorectal adenocarcinoma. Four independent cohorts containing 1335 patients were enrolled in our study. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were performed to construct the signature. CIBERSORT was used to evaluate the landscape of immune cell infiltration. Thirty-two pairs of tissue specimens of female advanced colorectal cancer (CRC) patients and two CRC cell lines were used to validate the signature in vitro. Quantitative real-time PCR and western blotting were performed to validate the mRNA and protein expression levels of signature genes. EdU and colony formation assays were performed to examine proliferative ability. Transwell and wound healing assays were used to evaluate cell invasion and migration capacity. During the signature construction and validation process, we found that the signature was more applicable to female patients with advanced colorectal adenocarcinoma. Hence, the subsequent study mainly focused on the particular subgroup. Enrichment analyses revealed that the signature was closely related to immunity. The landscape of immune cell infiltration presented that the signature was significantly associated with T cells CD8 and neutrophils. Gene set enrichment analysis (GSEA) confirmed that the high-risk group was chiefly enriched in the tumor-promoting related pathways and biological processes, whereas the low-risk group was mainly enriched in anti-tumor immune response pathways and biological processes. The signature was closely correlated with CTLA4, PDL1, PDL2, TMB, MSI, and TIDE, indicating that our signature could serve as a robust biomarker for immunotherapy and chemotherapy response. ROC curves verified that our signature had more robust prognostic power than all immune checkpoints and immunotherapy-related biomarkers. Finally, we used 32 pairs of tissue specimens and 2 CRC cell lines to validate our signature in vitro. We first provided a robust prognostic chemokine- and chemokine receptor-based signature, which could serve as a novel biomarker for immunotherapy and chemotherapy response to guide individualized treatment for female patients with advanced colorectal adenocarcinoma.

Overexpression of VSNL1 Enhances Cell Proliferation in Colorectal Carcinogenesis

Introduction: We have previously reported that overexpression of visinin-like protein 1 (VSNL1) is frequently observed in advanced colorectal adenocarcinomas and correlates with poorer prognosis. In this study, we determined the levels of VSNL1 expression in the earlier stages of colorectal tumors including adenomas and adenocarcinomas, and attempted to clarify the functional significance of VSNL1 overexpression in colorectal carcinogenesis. Methods: Levels of VSNL expression in colorectal tumor tissues were analyzed using immunohistochemistry. The effects of VSNL1 downregulation and overexpression on cell proliferation, resistance to apoptosis, and invasiveness were determined using two VSNL1-overexpressing colorectal cancer cell lines, CW-2 and HCT-116 and VSNL1 inducibly expressing SNU-C5, respectively. Gene expression signatures in VSNL1-downregulated CW-2 and HCT-116 were identified using transcriptome and gene set enrichment analyses. Results: VSNL1 expression was restricted to only a few crypt cells in the non-tumorous epithelium, whereas it became enhanced in adenomas and adenocarcinomas with the progression of tumorigenesis. Downregulation of VSNL1 in CW-2 and HCT-116 cells suppressed their proliferation through induction of apoptosis. Conversely, overexpression of VSNL1 in SNU-C5 cells enhanced resistance to anoikis. Transcriptome and gene set enrichment analyses revealed that downregulation of VSNL1 altered the expression level of the apoptosis-related gene set in CW-2 and HCT-116 cells. Conclusion: VSNL1 plays a role in both the development and progression of colorectal tumors by enhancing cell viability.

Adult sigmoid intussusception as a rare presentation of advanced adenocarcinoma: a case report

Adult bowel intussusception is a rare clinical entity resulting in 1-5% of intestinal obstructions. It occurs more often in the small intestine and it’s secondary to a pathologic condition in 90% of cases. Its clinical picture can be unspecific, and the diagnosis is often made intraoperatively. We describe an uncommon clinical presentation of this rare clinical entity. A 69-year-old female presented in our emergency room with severe abdominal pain and rectorrhagia. The abdomen computed tomography scan revealed a colonic intussusception and a mass suggestive of a malignancy, as confirmed by rectosigmoidoscopy. The patient underwent the Hartmann procedure. A histopathological examination revealed an advanced colorectal adenocarcinoma as the lead point of the intussusception. Adult sigmoid intussusception is a rare cause of bowel obstruction, and it is often cancer-related. Symptoms can be nonspecific, and diagnosis is best made by CT imaging and endoscopic investigations which allow for planning surgery.

A 5-hydroxymethylcytosine-based noninvasive model for ultrasensitive early detection of colorectal advanced adenoma and adenocarcinoma: The METHOD-2 study.

3042 Background: Detection of colorectal tumors at a time when there are more treatment options is associated with better outcomes. This prospective case-control study (NCT03676075) assessed the performance of 5-hydroxymethycytosine (5hmC) biomarkers in circulating cell-free DNA (cfDNA) to detect advanced colorectal adenomas (ADA) or adenocarcinomas (CRC). Methods: This multi-center study enrolled 2,576 participants, including patients with newly diagnosed CRC (n=1,074), ADA (n=356), other solid tumors (n=80), and healthy individuals (HEA) (n=1,066), followed by genome-wide 5hmC profiling using the 5hmC-Seal, a highly sensitive chemical labeling approach. A weighted diagnostic model for CRC (stage I-III) and ADA was developed using the elastic net regularization in a training set of age-, sex-, region-matched samples and validated in independent samples. Results: Distribution of 5hmC in cfDNA reflected gene regulatory relevance and tissue of origin. In an independent validation set of 482 samples, a 96-gene model trained in stage I-III CRC, ADA, and HEA achieved an AUC (area under the curve) of 92.6% (95% CI [confidence interval], 90.7-94.5%) for distinguishing CRC from HEA, regardless of primary location or mutation. This model also showed high capacity for distinguishing ADA from HEA with an AUC of 87.9% as well as cancer-type specificity. Model performance was further confirmed in samples from multiple centers. Functionally, differential 5hmC features associated with CRC and ADA demonstrated relevance to CRC biology, including pathways such as calcium and MAPK signaling. Conclusions: Genome-wide mapping of 5hmC in cfDNA shows promise as a highly sensitive and specific approach to be integrated in a screening program for improving early detection of CRC and high-risk ADA. Clinical trial information: NCT03676075 .

High frequency of colorectal neoplasia in patients with sporadic adenomas or adenocarcinomas of the papilla of Vater: The same adenoma-carcinoma sequence?

Data on the frequency of colorectal neoplasia in sporadic ampullary tumors remains scarce. We retrospectively reviewed 135 patients undergoing endoscopic ampullectomy from January 2018 to July 2021, and identified 95 patients with sporadic ampullary adenoma who underwent total colonoscopy. Colonoscopy findings were compared with 380 asymptomatic controls using the chi-squared test. Whole-exome sequencing (WES) was performed on one patient with synchronous adenomas of the ampulla of Vater and ascending colon. Colorectal polyps were present in 60% of Cases vs. 34.7% of Controls (P=0.001), advanced adenoma in 20% vs. 5.5%, and adenocarcinoma in 4.2% vs. 0.8%. Cases tended to have larger polyps than Controls (P<0.001), while there was no difference in polyp location and histology between the two groups. The odds ratio of all the colorectal lesions, advanced colorectal adenoma and adenocarcinoma in Cases was 1.7, 4.2, and 4, respectively. WES in one patient revealed that both of ampullary adenoma and colonic adenoma shared somatic ABCB1 mutation. The frequency of colorectal polyps or neoplasia was significantly higher in Cases than Controls. We proposed that ampullary neoplasia is analogous to colon lesions and warrants total colonoscopy screening in patients diagnosed with ampullary tumors.

Malignant polyps in the COVID-19 era: a population-based analysis.

Malignant polyps represent the early development of colorectal adenocarcinoma. During 2020, there was widescale rationing of health-care resources in response to the COVID-19 pandemic. In particular there was deferral of some colonoscopy procedures required for timely malignant polyp detection. This study sought to assess how these deferrals affected the diagnosis of malignant polyps. A population wide analysis was performed of 2079 malignant polyps, diagnosed in Queensland, Australia from 2011 to 2020. A regression analysis, with 95% prediction intervals, was produced to determine whether there was a significant impact on the number of malignant polyps diagnosed in 2020 compared to previous years. Univariate statistical analysis of patient, procedural, and pathological variables was also performed. In 2020 there were 211 malignant polyps diagnosed, which was significantly lower than was predicted by the univariate regression analysis (r2 = 0.85, 95% prediction interval: 255.07-323.91, P< 0.001). These malignant polyps were less likely to be diagnosed in a private setting (P< 0.001), and exhibited significantly less depth of submucosal invasion (P= 0.017). There was no significant difference in the management strategy (polypectomy, resection or trans-anal resection) between 2011 and 2019 and 2020. Because of the significant decrease in the number of malignant polyps, and the natural history of the disease, it is expected that there will be an increase in more advanced colorectal adenocarcinomas presenting in 2021 and beyond. This has implications for healthcare resources, particularly in light of the ongoing strain on health departments as a result of the COVID-19 pandemic.

Abstract B019: APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer

Abstract Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally, with the majority of cases initiated by inactivation of the APC tumor suppressor. This results in the constitutive transcriptional activation of the canonical WNT signal transduction pathway effector b-Catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM. Here, we show that NOTUM retains cell-autonomous tumor suppressive activity in APC-null adenomatous lesions despite constitutive b-Catenin activation. Strikingly, we find that NOTUM becomes an obligate oncogene upon subsequent P53 inactivation during the adenoma-adenocarcinoma transition, and that these phenotypes are WNT-independent, resulting from differential activity of NOTUM upon its enzymatic targets Glypican 1 and 4 in early vs. late-stage disease, respectively. Ultimately, preclinical mouse models of CRC and human tumoroid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonization of distal organs. The finding that a single agent targeting an extracellular enzyme is effective in treating highly aggressive tumors make NOTUM a novel therapeutic vulnerability in advanced colorectal adenocarcinomas. Citation Format: Christopher Lengner. APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B019.

Major vascular reconstruction in colorectal adenocarcinoma and retroperitoneal sarcoma: A retrospective study of safety and margins in a tertiary referral centre

BackgroundThe role of en bloc vascular resection and reconstruction (EVRR) is controversial in colorectal adenocarcinoma (CRC), but well-established in retroperitoneal sarcoma (RPS). Sparse data exists regarding these complex procedures. MethodsPatients undergoing curative intent EVRR for advanced CRC and RPS between 2014 and 2021 at a tertiary centre were included. Morbidity, margins, recurrence, and survival were evaluated. Results24 patients underwent EVRR with 48 reconstructions (11 CRC and 13 RPS). For CRC, 100% of patients underwent Iliac system reconstructions. For RPS, inferior vena cava reconstructions were the most common (69.2%). There were 2 arterial and 1 venous graft thromboses. Primary graft patency was 89.4% arterial and 93.1% venous, while secondary patency was 100% arterial and 96.5% venous at last follow up. 1 venous and 1 arterial graft required reoperation for bleeding. There were no compromised limbs. Major complications occurred in 6 patients (25.0%) with no observed difference between CRC and RPS (OR 0.43 95%CI[0.60,3.19], P = 0.41). R1 margins occurred 1 CRC (90.9%) and 3 RPS (76.9%), with no R2 resections. All vascular resection margins were clear. There were 6 CRC (50%) and 4 RPS (33.3%) recurrences. Median recurrence time was 20.9 months for CRC and ‘not yet reached’ for RPS. Median follow-up was 19.4 months for CRC and 21.4 months for RPS. ConclusionEVRR for locally advanced CRC or RPS is safe and achieves favorable R0 resection rates. CRC patients with major vascular invasion can still be considered for curative intent surgery. Larger cohorts with longer follow up are needed to assess oncologic outcomes.

S131 Clinical Application of Circulating Tumor DNA in Gastrointestinal Cancer Patients

Introduction: Circulating tumor DNA (ctDNA) derived from apoptotic tumor cells is rapidly emerging as a non-invasive biomarker to detect the presence of tumor at a molecular level and guide therapy. In this study, we present our experience with this novel marker in gastrointestinal malignancy (GIM) patients. Methods: We included all patients with GIM for whom ctDNA was ordered from January 2020 to July 2021 at our center. Patient demographics, tumor type, pathology, stage, and radiographic findings were collected. Descriptive statistics were employed to report findings. Results: We identified 62 GIM patients for whom ctDNA was ordered. Results for 6 patients were not reported due to insufficient tumor tissue. Of the 56 patients for whom ctDNA results were available, 46 (82%) had colorectal adenocarcinoma (CRC) and the rest had other GI malignancies. Of the overall cohort of 56 evaluable patients, 21 (37.5%) had metastatic disease. Imaging findings paralleled ctDNA levels and correlated with tumor burden in 30 patients (53.5%). In 13 patients (23.2%), undetectable CT DNA levels influenced decisions regarding systemic therapy in addition to acting as a surrogate for treatment response. We discontinued maintenance therapy in 5 metastatic CRC patients with negative ctDNA and imaging. These patients have been off treatment for > 12 months without evidence of recurrence. We also truncated or skipped adjuvant treatment in 6 Stage III CRC patients with negative ctDNA and imaging who had significant post-operative complications or were otherwise considered high risk for severe toxicity. In one CRC patient, ctDNA was found to be undetectable post neoadjuvant therapy which corroborated with pathological complete response on surgical pathology report. 5 patients (9.09 %) had false-negative results and 1 patient had falsely elevated levels. In 6 other patients, we could not draw significant conclusions due to the availability of only a single value. Conclusion: Our experience suggests that ctDNA is not only a sensitive tool to assess tumor burden, but can also help guide therapy in locally advanced and metastatic CRC patients. However, further prospective studies are needed to improve the accuracy of test results and integrate ctDNA in day-to-day clinical practice.

PD-2 EMERGE: A multi-centre, non-randomised, single-arm phase II study investigating domatinostat plus avelumab in patients with previously treated advanced mismatch repair-proficient oesophagogastric and colorectal adenocarcinoma

Mismatch repair proficient (MMRp) oesophagogastric (OG) and colorectal cancers (CRC) respond less frequently to checkpoint inhibition. Epigenetic modulation of tumours using HDAC inhibitors can increase the chance of response to immunotherapy. We previously reported dose escalation (EMERGE phase IIA) and the established recommended phase II dose (RP2D) of domatinostat (selective class I HDAC inhibitor) 200mg BID continuously plus avelumab 10mg/kg q2w.

Evaluation of tyrosine kinase inhibitors combined with antiprogrammed cell death protein 1 antibody in tyrosine kinase inhibitor-responsive patients with microsatellite stable/proficient mismatch repair metastatic colorectal adenocarcinoma: protocol for open-label, single-arm trial

IntroductionThe prognosis of patients with advanced metastatic colorectal adenocarcinoma (mCRC) after multiple-line therapy remains poor due to the high tumour load, high level of malignancy and strong drug resistance. The...

A multi-modular phase I/II study of UCB6114, a first-in-class, fully human IgG4P anti-Gremlin-1 monoclonal antibody, as monotherapy and in combination with mFOLFOX6 or trifluridine/tipiracil, for patients with advanced gastrointestinal (GI) tumors.

TPS221 Background: Despite recent advances, effective treatment for GI cancers remains a significant unmet medical need. Gremlin-1 is secreted by the peri-tumoral stroma and down-regulates bone morphogenetic proteins (BMP) -2, -4, and -7 (members of the transforming growth factor-β superfamily), thereby allowing malignant cell expansion, renewal, and a more treatment-resistant mesenchymal phenotype. Gremlin-1 mRNA is highly expressed in multiple solid tumors including &gt;60% of colorectal, pancreatic and esophageal cancers. UCB6114 is a first-in-class, fully human IgG4P monoclonal antibody optimized for neutralizing the activity of human Gremlin-1 thereby restoring BMP signaling. Preclinical studies have demonstrated that UCB6114 binds to Gremlin-1, inhibits its pharmacological activity, and has antitumor activity in several in vivo mouse models (including several GI cancers). Methods: ONC001 (clinicaltrials.gov: NCT04393298) is an ongoing multi-part, multicenter, nonrandomized, open-label, Phase I/II study evaluating the safety, pharmacokinetics (PK) and antitumor activity of UCB6114 administered intravenously as monotherapy or in combination with selected standard of care (SOC) regimens. Eligible patients (pts) are: aged ≥18 years; resistant or refractory to standard therapy; ECOG performance status 0/1; and have adequate renal, hepatic and bone marrow function. In the Phase I monotherapy dose escalation and adaption part (part A and A1; modified rolling 6 design), up to 66 pts with advanced solid tumors associated with high levels of Gremlin-1 mRNA expression will be recruited. In parts B and C (modified toxicity probability interval design), up to 54 pts with locally advanced or metastatic colorectal, gastric or gastroesophageal junction adenocarcinomas will receive UCB6114 in escalating doses in combination with either mFOLFOX6 (5-fluorouracil, leucovorin and oxaliplatin) or trifluridine/tipiracil, given at SOC dosing and schedules. The overarching objective of the phase I parts of the study (Parts A‒C) is to identify the recommended phase II dose of UCB6114 either as monotherapy or in combination. The primary objective is to characterize the safety profile of UCB6114; secondary and exploratory objectives include PK, antitumor activity (RECIST v1.1), and pharmacodynamics (including circulating Gremlin-1). Enrollment in ONC001 began in July 2020; as of Sept 2021, four dose escalation levels in the monotherapy dose-escalation module (Part A) have been completed without DLT. Recruitment to parts B and C is due to commence in Q4 2021. Clinical trial information: NCT04393298.

Comparison of Treatment Outcomes between Right- and Left-sided Colorectal Adenocarcinoma after Adjuvant Chemotherapy

Objective: The survival outcomes of patients with metastatic colorectal adenocarcinoma based on tumor laterality has already been established based on large-scale retrospective studies. As for the non-metastatic disease, the data is much more conflicting. Local data in this population is also scarce. In this study, we determined the difference in survival of right-sided versus left-sided colorectal cancer patients after surgery and adjuvant chemotherapy. Patients and Methods: This retrospective study analyzed a total of 124 patients who were diagnosed with early to locally advanced (stage I to IVA) colorectal adenocarcinoma and underwent definitive surgery and adjuvant systemic treatment per physician’s preference. The patients were stratified according to the primary tumor laterality: Right-Sided Colon cancer (RCC) and Left-sided Colon cancer (LCC). The primary outcome being investigated is the disease-free survival (DFS) at 3 years and 5 years. Secondary outcomes are overall survival (OS) at 3 years and 5 years, and site of disease recurrence across laterality.Results: The findings did not show a significant difference in the 3-year and 5-year DFS between RCC and LCC after surgery and adjuvant chemotherapy (3-year DFS: 50.0% in the RCC group and 54.3% in the LCC group; P=.671; 5-year DFS: 36.7% in the RCC group and 36.2% in the LCC group, P=.474). The OS difference was also not significant at 3 years and 5 years (3-year OS: 68.8% in the RCC group and 73.9% in the LCC group, P=.572; 5-year OS: 31.3% in the RCC group and 26.1% in the LCC group, P=.474). The overall recurrence rate was not significantly different in both groups (65.6% in the RCC group and 66.3% in the LCC group; P=.944). Majority of the recurrences were at a distant site in both groups (61.1% in the RCC group and 69.6% in the LCC group; P=.501) and the most common were in the lungs, and liver. Conclusion: The survival outcome of non-metastatic colorectal adenocarcinoma was not significantly different between RCC and LCC after surgery and adjuvant chemotherapy. The outcome was also similar after stratification of the population into early and locally advanced disease. More diverse clinical characteristics other than tumor location may be prognostic of disease-free and survival outcomes in the non-metastatic setting of colorectal cancer. Further studies with a larger sample size are needed to validate the correlation of survival to the specific stage and anatomic location.

P-98 A single-arm study of apatinib plus neoadjuvant chemotherapy followed by resection in patients with locally advanced colorectal adenocarcinoma

There is insufficient evidence for the treatment of neoadjuvant chemotherapy combined with apatinib in locally advanced colorectal cancer. We conducted this clinical study to evaluate whether neoadjuvant chemotherapy combined with apatinib was effective in the treatment of locally advanced colorectal cancer.

Outcomes and applicability of a deep learning virtual tumor board (DLVTB) in community-dwelling colorectal cancer (CRC) patients.

e18635 Background: With almost 85% of patients treated outside NCI-designated cancer centers, providing comprehensive, state-of-the-art cancer care to millions of patients in the U.S. remains a significant challenge. We aimed to combine cutting edge AI based technology of DLVTB with high value-added services to provide evidence-based care management recommendations and implementation support to the patients and physicians in the community. To further demonstrate the feasibility, reproducibility, scalability, and benefits of DLVTB, we evaluated key outcomes from incorporating DLVTB in a cohort of 35 patients with advanced colorectal adenocarcinoma (CRC). Methods: Our core-enabling technology is a deep learning based Natural Language Understanding Engine that employs (1) natural language processing for medical text digestion and structuring, (2) decision trees and multilayer perception models to produce evidence-based treatment protocols, and (3) natural language based report generation. The technology platform is combined with human support from oncology sub-specialists to deliver a comprehensive Interpretive Report with a prioritized list of recommendations for each patient. These recommendations are operationalized by a case management team to ensure care implementation and monitoring of outcomes. Results: Thirty-five patients with CRC were referred for incorporation of DLVTB into clinical practice. Median age of patients was 57 years with 68.6% males. About 88.6% of the patients were Stage IV and 82.9% were treated by community practice oncologists. Median time since diagnosis was 17 months (1-73 months). Overall, DLVTB-cohort demonstrated an increase in median Overall Survival of 12 months per patient in comparison with historical cohorts. More specifically, DLVTB recommended initial and/or additional biomarker testing for 71% of the patients with further precision oncology-guided treatment recommendation (e.g. an EGFR inhibitor) for 80% of the patients. 63% of the patients were eligible for at least one clinical trial. 58% of the trials identified were within proximity (≤50 miles) of the patient’s primary residence. Thus, DLVTB was able to identify a trial that did not require extensive travel, provided eligibility and actionability closer to the point-of-care. 14% of the DLVTB evaluated patients subsequently enrolled in the recommended clinical trial, far surpassing the national average (3%). Moreover, DLVTB recommended treatments achieved on average savings of $39,194 per patient which is 35% of the average drug cost per patient. Conclusions: Our results demonstrate the feasibility and benefits of incorporating DLVTB into clinical practice. The utilization of DLVTB as a clinical trial enrollment tool and an engine for development of pathways resulting in improved clinical outcomes, in a cost-effective, and innovative care delivery model.