Advanced Gastrointestinal Malignancies Research Articles

Minnelide suppresses GVHD and enhances survival while maintaining GVT responses.

Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by graft-versus-host disease (GVHD). Minnelide, a water-soluble analog of triptolide, has demonstrated potent antiinflammatory and antitumor activity in several preclinical models and has proven both safe and efficacious in clinical trials for advanced gastrointestinal malignancies. Here, we tested the effectiveness of Minnelide in preventing acute GVHD as compared with posttransplant cyclophosphamide (PTCy). Strikingly, we found Minnelide improved survival, weight loss, and clinical scores in an MHC-mismatched model of aHSCT. These benefits were also apparent in minor MHC-matched aHSCT and xenogeneic HSCT models. Minnelide was comparable to PTCy in terms of survival, GVHD clinical score, and colonic length. Notably, in addition to decreased donor T cell infiltration early after aHSCT, several regulatory cell populations, including Tregs, ILC2s, and myeloid-derived stem cells in the colon were increased, which together may account for Minnelide's GVHD suppression after aHSCT. Importantly, Minnelide's GVHD prevention was accompanied by preservation of graft-versus-tumor activity. As Minnelide possesses anti-acute myeloid leukemia (anti-AML) activity and is being applied in clinical trials, together with the present findings, we conclude that this compound might provide a new approach for patients with AML undergoing aHSCT.

Abstract B114: A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies

Abstract Background:KAZ954 (KAZ), a humanized immunoglobulin G1 monoclonal antibody, is a potent, selective inhibitor of anti-ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2). Preclinical data show that KAZ blocks the hydrolysis of adenosine triphosphate, enhances immune activation in the tumor microenvironment, and augments the efficacy of PDR001 (PDR, anti-PD-1), and NIR178 (NIR, adenosine A2aR inhibitor). Methods: This is an open-label, multicenter, dose-escalation (ESC)/expansion study (NCT04237649). We present the dose-ESC results of KAZ single-agent (SA) and with PDR or NIR in patients (pts) with advanced gastrointestinal (GI) malignancies. Dose ESC was guided by Bayesian logistic regression models and comprised 3 arms: (1) SA KAZ administered intravenously (IV) at 30, 50, 100, and 150 mg biweekly (Q2W) flat dosing; KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose; (2) KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose with PDR 400 mg IV every 4 weeks; and (3) KAZ 100 mg priming dose followed by 300 and 600 mg experimental dose with NIR 160 and 240 mg twice daily orally. Primary objectives were to evaluate safety and tolerability and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Secondary objectives were to assess antitumor activity and pharmacokinetics (PK). Tumor biopsies and blood samples were taken for biomarker analysis. Results: As of March 20, 2023, 77 pts were enrolled in ESC KAZ (n=43), KAZ+PDR (n=18), and KAZ+NIR (n=16) arms. Tumor types enrolled were microsatellite-stable colorectal cancer (37, 48%), pancreatic ductal adenocarcinoma (27, 35%), cholangiocarcinoma (10, 13%), and esophageal cancer (3, 4%). At data cutoff, 43 (100%), 15 (83.3%), and 11 (68.8%) pts discontinued treatment, and treatment-related adverse events (TRAEs) were reported in 37 (86%), 12 (66.7%), and 13 (81.3%) pts in KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. KAZ had an acceptable and manageable safety profile. Given the occurrence of cytokine release syndrome (CRS) observed with cycle 1 day 1 (C1D1), prophylactic premedication with acetaminophen, antihistamine, and corticosteroid, together with a priming dose on C1D1, was established as the recommended regimen to administer KAZ. Grade ≥3 TRAEs were reported in 9 pts(20.9%) in KAZ, most commonly CRS and decreased lymphocyte count (n=2 each); 7 pts(38.9%) in KAZ+PDR, most commonly lymphopenia and increased aspartate aminotransferase (n=2 each); and 2 pts(12.5%) in KAZ+NIR (asthenia and lymphopenia [n=1 each]). No MTDs were reached in any treatment arm explored. Although no objective responses were observed, 12(27.9%), 2(11.1%), and 2(12.5%) pts showed stable disease in the KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. Conclusions: KAZ was considered to be safe and well tolerated at all doses, and PK/PD analysis suggest effective ENTPD2 inhibition from a dose range of 150 to 1200 mg Q2W. Although a biologically active dose range was established, further dose-exploration studies are required to establish an RDE. Citation Format: Devalingam Mahalingam, Chia-Chi Lin, Philippe L. Bedard, Massimo Di Nicola, Zev Wainberg, Patricia LoRusso, Shubham Pant, Brigette B.Y. Ma, Wei-Peng Yong, Mia C. Weiss, Alessio Amatu, Kentaro Yamazaki, Lisa Nardi, Jong Bong Lee, Mike Roy, Anhthu Dang, Shu Yang, Bernard Pereira, Javier A. Otero, Teresa Macarulla. A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B114.

Trajectory of Healthcare Contact Days for Veterans With Advanced Gastrointestinal Malignancy.

How and where patients with advanced cancer facing limited survival spend their time is critical. Healthcare contact days (days with healthcare contact outside the home) offer a patient-centered and practical measure of how much of a person's life is consumed by healthcare. We retrospectively analyzed contact days among decedent veterans with stage IV gastrointestinal cancer at the Minneapolis Veterans Affairs Healthcare System from 2010 to 2021. Among 468 decedents, the median overall survival was 4 months. Patients spent 1 in 3 days with healthcare contact. Over the course of illness, the percentage of contact days followed a "U-shaped" pattern, with an initial post-diagnosis peak, a lower middle trough, and an eventual rise as patients neared the end-of-life. Contact days varied by clinical factors and by sociodemographics. These data have important implications for improving care delivery, such as through care coordination and communicating expected burdens to and supporting patients and care partners.

Phase 1A, first-in-human study of ARB202, bispecific antibody to CDH17 and CD3, in advanced gastrointestinal malignancies expressing CDH17.

25 Background: Cadherin-17 (CDH17) is a highly specific therapeutic cancer target, of which aberrant expression has been reported in 50-95% in GI tumor samples (including stomach, pancreas, liver/bile duct, rectum, and colon). Normal CDH17 expression is primarily in the water-tight junction between mucosal epithelial cells which is potentially “masked” from the immune system (Feng, Z., et al., Nat Cancer, 2022). A bispecific T-cell engager ARB202 using CD3 to aid the formation of an immunological synapse CDH17 tumor cells and T-cells is being studied. Methods: In an ongoing dose-escalation phase IA part of a continuous study, patients with advanced CD17+ solid tumors are being given up to 3 doses of ARB202 bispecific. In part 1, 28 pts can be treated at dose levels from 0.0003 mg/kg to 10 mg/kg; Based on clinical response intra-dosing of tolerated (higher) doses can occur in for the 2nd and 3rd doses. Second and 3 doses are planned at the 4th cohort starting at a dose of 0.010 mg/kg when tissue levels are likely physiologically active. Minimum anticipated biological effect level (MABEL) dosing which is based on the most sensitive in vitro assay is being used to set the initial 3 doses to ensure safety of any T-cell engagement at low levels in circulation. Data cutoff 10.04.23. Results: Colorectal, gastric, pancreatic and cholangiocarcinoma patients have screened positive for CDH17 by semi-automated tissue immunostaining. Seven patients have completed dosing in the first 3 cohorts and have shown tolerability to 0.0003 to 0.003 mg/kg single IV doses. The Cmax measured within 1 hour of dosing has confirmed the circulating PK range of 10-20 ng/ml for the 2nd cohort and 40-50 ng/ml in the 3rd cohort consistent with the expected PK of antibody-like volume of distribution. The safety review committee has approved the dose escalation to proceed to the 4th cohort Identifier: NCT05411133. Conclusions: ARB202 a bispecific T-cell engager has shown tolerability up to 40ng/ml Cmax in circulation suggesting no clinically significant CD3 only binding cell activation at these levels. These data allow for higher dosing to achieve tissue ARB202 concentrations where anti-CDH17/CD3 aided synapse formation between tissue tumor cells and T-cells can lead to clinical evidence of bispecific target engagement and their expected effects. Clinical trial information: NCT05411133 .

High-throughput drug screening (HTDS) of patient-derived tumor organoids (PTDO) from advanced gastrointestinal malignancies: Response and identification of novel therapeutic options.

e16019 Background: Most patients with advanced GI cancers lack predictive biomarkers to determine response to systemic therapies. HTDS of PDTOs allows automated screening of large numbers of compounds to identify novel therapeutic options for refractory GI cancer patients in a rapid clinically meaningful way. Our objective was to determine the feasibility of HTDS on refractory GI PDTOs and to identify the concordance of ex-vivo sensitivity with clinical response to establish a new pipeline to reveal novel therapeutic options for GI cancer patients. Methods: Tumor tissues were obtained from advanced GI cancer patients anytime during their systemic therapies from needle biopsies or surgical specimens. PDTOs were established from these tumors at Englander Institute of Precision Medicine of Weill Cornell Medicine. Successful establishment of PDTOs occurs when they can be viably expanded beyond their initial plating in Matrigel for at least 5 passages and bio-banked. Whole exome sequencing and RNA sequencing confirmed genomic similarities between PDTOs and their originating tumors. PDTOs were screened for 156 drugs by using an integrative robotic HTDS system to examine drug sensitivity and validate patients’ clinical response. To determine clinical correlation, PDTOs ex-vivo response to FOLFOX, FOLFIRI, and docetaxel/paclitaxel (taxanes) were compared with their matching patients’ clinical response. Results: 30 PDTOs were established from 25 patients (11 colorectal, 14 gastroesophageal). Dose response curves for all 156 drugs were generated and subsequently AUC and IC50s were calculated. The concordance between PDTOs and patient’s response to FOLFOX, FOLFIRI and Taxane was determined for 31 PDTO-drug treatment iterations in which the patients also received same drug. 16/31 times the tissue was collected before the patient received the corresponding therapy and 15/31 times, afterwards. 2 patients were clinically non-evaluable. The overall concordance was 59% (17/29). Concordance was 64% (9/14) for specimens collected before patient receiving the therapy and 53% (8/15) for after. Concordance for FOLFOX was 71% (10/14), FOLFIRI 86% (6/7), Paclitaxel 14% (1/7) and Docetaxel 0% (0/1). Combined concordance for FOLFOX and FOLFIRI was 76%, and for specimens collected prior to clinical drug use, 80 % (8/10). Approx. 10% of drug screens revealed potential sensitive new treatment options such as Selinexor, Crizotinib, or Osimertinib for advanced GI cancer patients. Conclusions: We successfully demonstrated feasibility of an automated, end-to-end high-throughput screening of PTDOs in patients with refractory GI malignancies. PDTOs response highly correlated with clinical response, especially for FOLFOX and FOLFIRI. The HTDS identified several novel therapeutic options for advanced GI cancer patients.

Preliminary results from ERAS-007 plus palbociclib (palbo) in patients (pts) with KRAS/NRAS mutant (m) colorectal cancer (CRC) or KRASm pancreatic ductal adenocarcinoma (PDAC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers).

3558 Background: The RAS/MAPK pathway is dysregulated in a broad range of cancers including CRC and PDAC, resulting in downstream activation of ERK1/2. ERAS-007 is a novel, orally bioavailable inhibitor of ERK. Palbo is an oral CDK4/6 inhibitor that inhibits cellular proliferation, an essential feature of tumor growth. Both in vitro & in vivo data exploring the combination of ERAS-007 and palbo in a panel of CRC and pancreatic CDX and/or PDX models have shown promising activity to support the potential combinatorial clinical benefit in RASm CRC and PDAC pts. Methods: HERKULES-3 is a Phase 1b/2 study to assess safety, tolerability, PK, and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety, tolerability, and PK of escalating doses of ERAS-007 twice daily-once a week (BID-QW) (75, 100 mg) in combination with palbo once daily (QD) (75, 100, 125 mg) in pts with KRASm/NRASm CRC or KRASm PDAC. Results: As of 30 November 2022, 30 pts were dosed with the combination of palbo and ERAS-007. Treatment emergent AEs (TEAEs) occurring in ≥20% pts were diarrhea (40%), nausea (40%), anemia (33%), vision blurred (27%), fatigue (23%), and neutrophil count decreased (20%). ERAS-007 treatment related AEs (TRAEs) were reported in 19 pts (63%), with the most frequently reported as diarrhea (40%), nausea (33%), and vision blurred (27%). Grade (Gr) ≥3 TEAEs were reported in 12 pts (40%), including 3 related to ERAS-007 (neutrophil count decreased, diarrhea and dermatitis acneiform). Neutrophil count decreased and anemia were the only Gr 3 events reported in ≥2 pts. No Gr 4 events were reported. Two Gr 5 events unrelated to any drugs (hemorrhage intracranial and malignant pleural effusion) and one Gr 5 event (anemia) related to palbo were reported. Two pts discontinued ERAS-007 due to TEAEs (Gr 5 malignant pleural effusion and Gr 2 neutrophil count decreased). Three pts reported 4 DLTs: 1 pt at 75mg ERAS-007 & 125mg palbo (Gr 3 maculopapular rash & Gr 4 sepsis), 1 pt at 100mg ERAS-007 & 100mg palbo (Gr 3 dermatitis acneiform), and 1 pt at 100mg ERAS-007 & 125mg palbo (Gr 3 thrombocytopenia). Based on preliminary PK, no clinically relevant PK interactions were identified between ERAS-007 and palbo. The evaluation of clinical activity is ongoing. Conclusions: ERAS-007 in combination with palbo in pts with KRASm/NRASm CRC or KRASm PDAC shows expected preliminary safety with reversible and manageable AEs. The highest dose evaluated and cleared by the safety review committee to date is ERAS-007 100 mg BID-QW in combination with the approved monotherapy dose of palbo 125 mg QD. Clinical trial information: NCT05039177 .

Preliminary results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with metastatic BRAF V600E mutated colorectal cancer (CRC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers).

3557 Background: The RAS/MAPK pathway (including BRAF) is dysregulated in a broad range of cancers including CRC, resulting in downstream activation of ERK1/2. Metastatic CRC with BRAF V600E mutation (BRAF V600E mCRC) has dramatically worse survival than non-BRAF V600E mutated CRCs, and novel therapies are needed. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK. The combination of a BRAF plus EGFR inhibitor (EC) is approved for the treatment of pts with BRAF V600E mCRC; however, only 20% of pts experience an objective response. ERAS-007 alone or in combination with EC showed promising in vitro and in vivo activity in BRAF V600E CRC models to support the combinatorial clinical benefit of ERAS-007+EC in BRAF V600E mCRC. Methods: HERKULES-3 is a Phase 1b/2 study to assess the safety, tolerability, PK, and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety and tolerability of escalating doses of ERAS-007 + EC in pts with BRAF V600E CRC. Prior BRAF inhibitor and EGFR inhibitor treatment is neither required nor excluded to be enrolled in this study. Results: As of 30 November 2022, 12 patients were dosed with ERAS-007 twice daily-once a week (BID-QW) (75 and 100 mg; n = 10) or once daily once a week (QW) (150 mg; n = 2) in combination with EC (300 mg oral daily + 500 mg/m2 intravenous infusion once every 2 weeks). The treatment-emergent AEs (TEAEs) occurring in ≥20% of pts were fatigue (50%), headache (42%), constipation, diarrhea, nausea, dermatitis acneiform (33% each), and vomiting (25%). No TEAEs led to ERAS-007 discontinuation or death. Grade ≥3 TEAEs were reported in 3 pts (25%). Grade ≥3 treatment-related AEs reported in ≥ 2 patients (17%) include hypertension, headache, confusional state, and skin toxicity. Three pts (25%) died due to disease progression. No DLTs were reported. Out of 4 efficacy evaluable EC naïve pts, one confirmed partial response (PR) and one unconfirmed PR were observed. Evaluation of PK is ongoing and preliminary data will be presented. Conclusions: ERAS-007+EC in pts with BRAF V600E CRC shows acceptable preliminary safety/tolerability and evidence of clinical activity. The highest dose of ERAS-007 evaluated and cleared by the safety review committee to date is 100 mg BID-QW when combined with EC. Observed PK, toxicity, and preliminary activity support continued evaluation of this combination in pts with BRAF V600E CRC. Clinical trial information: NCT05039177 .

A phase 2 basket trial of ulixertinib (BVD-523) in combination with hydroxychloroquine in patients with advanced gastrointestinal malignancies harboring MAPK pathway mutations (BVD-523-HCQ).

TPS4174 Background: RAS-induced signaling through the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway plays an important role in the pathogenesis of many solid tumors. Ulixertinib (BVD-523) is a first-in-class and best-in-class small molecule inhibitor of ERK 1/2 that is currently being investigated in multiple cancer clinical trials, both as a single agent and as part of combination therapy. Preclinical studies have demonstrated that inhibition of the RAS/MAPK/ERK signaling cascade leads to upregulation of autophagy, a catabolic pathway that includes the lysosomal degradation of proteins to support cellular metabolism during times of cellular stress. Given cancer cells’ increased reliance on autophagy to enhance their survival in this context, this study seeks to evaluate the combination of ulixertinib with hydroxychloroquine, an antimalarial drug known to suppress autophagy, in patients with advanced gastrointestinal malignancies harboring mutations in genes involved in MAPK signaling. Methods: This is an open-label, multicenter, phase II basket study of ulixertinib in combination with hydroxychloroquine in patients with advanced GI malignancies harboring mutations in one of the following MAPK signaling-associated genes: KRAS, NRAS, HRAS, BRAF (non-V600), MEK1/2, or ERK1/2. The completed Phase 1 dose-escalation trial (NCT04145297) established the recommended Phase 2 dose which will be the doses used in this study; ulixertinib 450mg PO BID combined with hydroxychloroquine 600mg PO BID, both drugs administered daily in 28-day cycles, with tumor assessments after every 2 cycles. The trial has five baskets based on primary disease: cholangiocarcinoma, pancreatic adenocarcinoma, colorectal adenocarcinoma, esophageal adenocarcinoma, and gastric adenocarcinoma. A Simon two-stage design will be employed within each of the 5 disease-specific baskets noted above, with the first stage of enrollment consisting of n=13 patients/ basket. To be considered evaluable, a patient must complete at least one cycle of therapy and receive at least 75% of the prescribed dose during that first cycle. If ≥ 4 patients in a specific basket achieve a response (complete or partial), that basket will then open to Stage 2 with enrollment of an additional 30 patients. Primary study endpoints will include safety/toxicity as well as ORR by RECIST 1.1. The secondary endpoint for efficacy is progression-free survival. Exploratory endpoints include pharmacokinetics of both ulixertinib and hydroxychloroquine, as well as predictive biomarkers from blood and tumor tissue-based samples. At the time of abstract submission, 26 of the planned 65 patients in Stage 1 had been enrolled. Clinical trial information: NCT05221320 .

Mapping the global research landscape on nutritional support for patients with gastrointestinal malignancy: visualization analysis.

Early nutritional treatment is crucial for the care of patients with operable and advanced gastrointestinal malignancies. Therefore, much research has focused on nutritional support for patients with gastrointestinal malignancies. Therefore, this study aimed to evaluate the global scientific output and activity with respect to nutritional support and gastrointestinal malignancy. We searched in Scopus for publications on gastrointestinal cancer and nutritional assistance published between January 2002 and December 2021. Then, using VOSviewer 1.6.18 and Microsoft Excel 2013, we conducted bibliometric analysis and visualization. A total of 906 documents were published between 2002 and 2021, including 740 original articles (81.68%) and 107 reviews (11.81%). China ranked first (298 publications, 32.89%), Japan ranked second (86 publications, 9.49%) and the USA ranked third (84 publications, 9.27%). The organisation with the highest number of publications was the Chinese Academy of Medical Sciences & Peking Union Medical College from China, with 14 articles, followed by the Peking Union Medical College Hospital from China and the Hospital Universitari Vall d'Hebron from Spain (13 publications for each). Before 2016, most studies focused on 'nutrition support for patients undergoing gastrointestinal surgery'. However, the latest trends showed that 'nutrition support and clinical outcomes in gastrointestinal malignancies' and 'malnutrition in patients with gastrointestinal cancer' would be more widespread in the future. This review is the first bibliometric study to provide a thorough and scientific analysis of gastrointestinal cancer and nutritional support trends worldwide over the last 20 years. This study can aid researchers in decision-making by helping them understand the frontiers and hotspots in nutrition support and gastrointestinal cancer research. Future institutional and international collaboration is expected to accelerate the advancement of gastrointestinal cancer and nutritional support research and investigate more efficient treatment methods.

Pain and palliative management in advanced gastrointestinal malignancies – How are we doing?

Pain and palliative management in advanced gastrointestinal malignancies – How are we doing?

Phase I trial of CA-4948, an IRAK4 inhibitor, in combination with FOLFOX/PD-1 inhibitor +/- trastuzumab for untreated unresectable gastric and esophageal cancer.

TPS4168 Background: Activated NFκB has been linked to aggressive phenotype, poor survival outcomes and resistance to chemotherapy in multiple gastrointestinal cancers including gastroesophageal cancer (GEC). Preclinical studies established that: 1) Genotoxic stress incurred by chemotherapy induces TLR9, which signals through IRAK4 to drive pro-survival NFκB signaling; 2) The survival mechanism through IRAK4 is independent of cancer types and mutational profiles based on colorectal and pancreatic cancer models; and 3) IRAK4 inhibition reduces tumor desmoplasia and revitalizes intratumoral T cells, setting the stage for successful combination with immune checkpoint inhibitors in a highly aggressive autochthonous pancreatic cancer mouse model. These data combined provide a strong rationale to add CA-4948 to systemic therapy for multiple advanced gastrointestinal malignancies, where resistance to chemotherapy is inevitable and benefit of PD-1 inhibitors is limited to small population. CA-4948 is a novel, first-in-class reversible inhibitor of IRAK4. In a phase I trial, patients with relapsed/refractory hematologic malignancies tolerated CA-4948 monotherapy well with mild fatigue, neutropenia, and nausea as most common adverse events. Recommended phase 2 dose (RP2D) was determined as 300 mg orally twice daily. CA-4948 has not been tested in combination with cytotoxic chemotherapy or immune checkpoint inhibitors for solid tumors in clinic. We hypothesize that inhibition of IRAK4 with CA-4948 will potentiate the effect of immune checkpoint inhibitor while deepening the efficacy of cytotoxic chemotherapy in GEC. Methods: This is a phase I trial of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab for unresectable GEC. During Dose Escalation, we will investigate CA-4948 in combination with FOLFOX/nivolumab by BOIN algorithm evaluating 4 different dose levels. Starting dose of CA-4948 for Part A will be 200 mg twice daily. Once RP2D is determined, the study will proceed to Dose Expansion, including Cohorts A and B. Cohort A will enroll up to 12 patients with HER2 negative disease at the RP2D of CA-4948 determined at the Dose Escalation phase. Cohort B will investigate CA-4948 in combination with FOLFOX/pembrolizumab and trastuzumab. The initial 6 patients in Cohort B will be considered safety lead-in to confirm the safety and tolerability at the RP2D, followed by additional patients, up to 12 patients treated at the RP2D. The primary objective is to determine the safety and RP2D of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab. Secondary objectives are to determine the preliminary efficacy of the combination. Correlative studies to evaluate pharmacodynamic effects and to identify biomarkers associated with disease response are planned. Clinical trial information: NCT05187182.

Poorly differentiated histology as a predictive biomarker in patients with advanced gastrointestinal (GI) cancers treated with immunotherapy.

664 Background: Checkpoint inhibitors (CPI) have significantly improved survival among patients with various cancer types. Prior studies have showed a correlation between immune cell infiltration and poorly differentiated cancers. We evaluated the impact of poorly differentiated histology on survival in patients with advanced GI malignancies treated with immunotherapy. Methods: We performed a retrospective, single institution analysis of patients with poorly differentiated GI tumors treated with CPI between 2016 and 2021. Univariate (UVA) and multivariable analyses (MVA) were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor/patient characteristics, progression free survival (PFS) and overall survival (OS). Results: A total of 123 patients were included. Median age was 66years. Majority had stage IV disease (88.2%), were White (65.5%) and male (64.5%). Most common diagnoses were HCC (28.5%), gastric (15.4%) and esophageal (14.6%) adenocarcinomas. About 32% were MSI-H, with 10% BRAF mutation rate. About 25% received CPI as initial treatment and 35.5% received 2 or more prior lines of therapy. Compared with well and moderately differentiated histology, poorly differentiated tumors had shorter mPFS (3.4 vs 2.5 vs. 2.2months; p = 0.29) and mOS (not reached [NR] vs. 20.9 vs. 14.2 months; p = 0.14) respectively. On UVA, the degree of tumor differentiation did not correlate with mPFS or mOS. Female patients (HR: 0.55, CI: 0.34-0.90, p = 0.018) and ECOG of 1 vs. ≥2 had significantly longer mPFS (HR: 0.58, CI: 0.35-0.97, p = 0.036). ECOG 1 correlated with better mOS (HR: 0.47, CI: 0.23-0.94, p = 0.034). Microsatellite stable (MSS) tumors had significantly shorter mPFS (HR: 5.74, CI: 2.41-13.63, p < 0.001) and mOS (HR: 5.45, CI: 1.64-18.12, p = 0.006). Number of prior systemic therapies was also associated with shorter mPFS (HR: 1.19, CI: 1.03-1.39, p = 0.022) and mOS (HR: 1.23, CI: 1.01-1.50, p = 0.045). On MVA, ECOG status of 0/1 vs. ≥2 and MSI-H vs. MSS remained significantly associated with longer mPFS and mOS. There was no correlation with race or mutations such as BRAF or KRAS. Conclusions: Poorly differentiated histology did not predict for PFS or OS. Treatment naïve patients, female gender, ECOG 1 and MSI-H were most likely to benefit from CPI.

Utility of tumor-informed circulating tumor DNA in the clinical management of gastrointestinal malignancies.

Gastrointestinal (GI) malignancies represent a heterogeneous group of diseases. Traditional tumor markers, though part of standard-of-care, lack sensitivity and specificity. Tumor-informed circulating tumor DNA (ctDNA) assay-based molecular residual disease assessment as well as recurrence and treatment response monitoring can serve as a robust tool in patients with wide range of GI malignancies and ethnicities. A personalized, tumor-informed multiplex PCR-NGS assay (SignateraTM) was used for the detection and quantification of ctDNA in 258 plasma samples from 198 patients with GI cancers at two institutions. Serial time- points were collected on a subset of patients (n=64) to monitor their ctDNA levels in response to treatment. Chi-square test was used to compare ctDNA-positivity rates in different cohorts. The study included stage I-IV patients with a median age of 62 years (61% females and 49% ethnic minorities); 92% had surgical resection, 83% received systemic treatment. ctDNA-positivity was significantly associated with advanced stage (P=0.004), and presence/extent of metastases (P<0.00003). Serial time-point analysis showed that 22% (14/64) patients cleared ctDNA following treatment. ctDNA was detected in all patients who recurred (4/4; 100% sensitivity). Serial monitoring of ctDNA using a tumor-informed ctDNA assay can be prognostic and predictive in advanced GI malignancies in adjuvant setting.

Tumor response as defined by iRECIST in gastrointestinal malignancies treated with PD-1 and PD-L1 inhibitors and correlation with survival

BackgroundAtypical tumor response patterns during immune checkpoint inhibitor therapy pose a challenge to clinicians and investigators in immuno-oncology practice. This study evaluated tumor burden dynamics to identify imaging biomarkers for treatment response and overall survival (OS) in advanced gastrointestinal malignancies treated with PD-1/PD-L1 inhibitors.MethodsThis retrospective study enrolled a total of 198 target lesions in 75 patients with advanced gastrointestinal malignancies treated with PD-1/PD-L1 inhibitors between January 2017 and March 2021. Tumor diameter changes as defined by immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST) were studied to determine treatment response and association with OS.ResultsBased on the best overall response, the tumor diameter ranged from − 100 to + 135.3% (median: − 9.6%). The overall response rate was 32.0% (24/75), and the rate of durable disease control for at least 6 months was 30.7% (23/75, one (iCR, immune complete response) or 20 iPR (immune partial response), or 2iSD (immune stable disease). Using univariate analysis, patients with a tumor diameter maintaining a < 20% increase (48/75, 64.0%) from baseline had longer OS than those with ≥20% increase (27/75, 36.0%) and, a reduced risk of death (median OS: 80 months vs. 48 months, HR = 0.22, P = 0.034). The differences in age (HR = 1.09, P = 0.01), combined surgery (HR = 0.15, P = 0.01) and cancer type (HR = 0.23, P = 0.001) were significant. In multivariable analysis, patients with a tumor diameter with a < 20% increase had notably reduced hazards of death (HR = 0.15, P = 0.01) after adjusting for age, combined surgery, KRAS status, cancer type, mismatch repair (MMR) status, treatment course and cancer differentiation. Two patients (2.7%) showed pseudoprogression.ConclusionsTumor diameter with a < 20% increase from baseline during therapy in gastrointestinal malignancies was associated with therapeutic benefit and longer OS and may serve as a practical imaging marker for treatment response, clinical outcome and treatment decision making.

1408P Efficacy of immunotherapy in the first line treatment of advanced upper gastrointestinal tract malignancies: A pooled analysis of randomized clinical trials

Upper gastrointestinal tract malignancies include cancers of the oesophagus, gastro-esophageal junction and stomach. For the management of advanced disease, chemotherapy remains the primary treatment option in the 1st line, but the use of immune checkpoint inhibitors is a rapidly evolving field of research.

1388P Efficacy of second line immunotherapy in advanced upper gastrointestinal tract malignancies: A pooled analysis of randomized clinical trials

The use of immune checkpoint inhibitors in upper track gastrointestinal malignancies is a major and rapidly evolving field of research. As a result in the last 5 years a lot of data have emerged from randomized clinical trials and even more are expected in the future.

Utilization of liquid biopsy for advanced gastrointesinal malignancies in a community oncology practice.

127 Background: Liquid biopsy (LB) offers a non-invasive alternative for obtaining genomic signature of malignancies to develop a tailor-made treatment plan. We evaluated the feasibility and impact on clinical management of liquid biopsies performed on patients with advanced gastrointestinal malignancies in a community setting. Methods: A retrospective chart review of adult patients with stage-IV gastrointestinal malignancies was conducted to gather all the pertinent information, including diagnoses, treatment regimens, results of liquid biopsies and any impact on further management. Results: Data on 42 liquid biopsies performed between Aug 2018 and Mar 2020 was collected. M:F ratio was 1.4: 1. Median age was 57yrs (range 31-86). The diagnoses were; Colo-rectal Ca 22(54.7%), pancreatic 9(21.9%), gastric 2(4.7%), biliary 2(4.7%), HCC 2(4.7%), Appendix 1 (2.3%), CUP 1(2.3%) and others 3(7.1%). One (2.3%) LBs was done before first line treatment and 41(97.7%) were done after the failure of first line treatment. There was insufficient sample in the bx to do tissue-NGS for the pt. who had LB before starting treatments. Majority of LBs, 37(88%) were done after the failure of second line/later treatments compared to 5(12%) done after failing the first line treatment. Patient preference and technical challenge to obtain adequate tissue were the commonest reasons for getting the LBs. Results were available in all (100%) the cases. Median turnaround time was 8 days (range:7-13). The commonest mutations were TP53,APC, KRAS, PIK3CA, BRAF, SMAD4. BRCA-2 was identified in 1 pancreatic ca pt. MSI-H was noted in 3 patients; 2 with Colon ca, and 1 with CUP. An actionable alteration was seen in, 40 (95.2%) of the patients. A FDA approved target-matched drug was available for 27/40(67.5%) pts., if we also consider off-label usage. For those who had an alteration, but no FDA approved target-matched drug was available, 13/40 (32.5%), a clinical trial was available for all 13/13 (100%) of the pts.. 43% of those who had a FDA approved target-matched treatment available, but not approved for their disease, were able to receive the drug off-protocol. Two out of 13(15.3%) of the pts. who had a clinical trial available, were enrolled on a study. Conclusions: Liquid biopsies can be efficiently utilized in a community oncology practice. It offers an attractive option to gather genomic information of malignant cells in patients with advanced GI malignancies to be able to deliver state of the art care to all patients, including those who may not have a convenient access to a tertiary center.

Feasibility of using a computerized food frequency questionnaire (FFQ) to assess dietary patterns in patients with advanced gastrointestinal (GI) malignancies.

465 Background: Identification of poor dietary patterns is important for the optimal management of patients with metastatic GI malignancies who suffer from high rates of malnutrition and sarcopenia which are associated with increased rates of treatment-related toxicity and worsened survival. Dietary records or recall methods and FFQs are available but have high patient burden and are seldom utilized in oncology settings outside of formal nutritional consultations. Thus, we evaluated the feasibility of conducting serial assessments of dietary patterns using a novel computerized FFQ technology. Methods: Assessments of diet using the computerized FFQ, nutritional status (NUTRISCORE), QOL and anorexia/cachexia burden (FAACT), anxiety/depression (HADS) and taste burden were done at the time of initiation of first-line chemotherapy (baseline) and 3 months later. The FFQ was done independently either at home on personal computer after visit or via iPad in infusion room. Dietary quality was defined by the Healthy Eating Index 2010 (HEI) score, which was automatically calculated by the computerized FFQ software. Feasibility was defined as at least 70% of patients completing baseline and 3-month assessments. Spearman’s correlations were used to determine associations between measures. Results: 29 patients with advanced (metastatic or unresectable) GI cancers were enrolled and 23 completed the baseline FFQ (8 colorectal, 5 pancreas, 5 gastroesophageal, 5 other). Median age was 58 (20-78) with M:F ratio of 10:13. The overall completion rate of baseline and 3-month assessments was 81.8%, meeting the pre-defined feasibility criteria. The mean baseline HEI score was 65 (range 38-88). Of patients who completed both baseline and 3-month assessments, the mean HEI score remained stable at 58 with changes in specific HEI components including a 20% decline in the seafood and plant protein score and a 13% decline in the whole grain score and small improvements in other areas (e.g. empty calories, dairy). There were no significant correlations between baseline HEI score and other assessments. Conclusions: It is feasible to use a computerized FFQ to assess for longitudinal changes in eating patterns and dietary quality in patients with advanced GI cancers, particularly when patients can complete the assessments during chemotherapy infusions. Preliminary findings also suggest that the FFQ can be helpful for highlighting areas in which diet quality could be improved. Additional analysis of other computerized FFQ data (e.g. macro/micronutrient consumption) is ongoing.

Targetable mutations in gastrointestinal malignancies: A comparison of RAS mutant and RAS wild type tumors.

129 Background: KRAS and NRAS (RAS) mutations are considered driver mutations in gastrointestinal malignancies such as colorectal and pancreatic cancer. Our institution obtains broad molecular testing (commercial panels with full exon coverage of at least 300 genes) for all stage IV gastrointestinal malignancies that are reviewed at an internal molecular tumor board (MTB). The MTB subjectively felt there was less benefit from comprehensive molecular testing in RAS mutant tumors and wished to quantify this using standardized analysis according to validated guidelines. Methods: We performed a retrospective cohort study of 209 consecutive genomic sequencing results of advanced gastrointestinal malignancies at our institution dating from March 2016 until December 2019. We compared the number of “targetable” mutations in the RAS mutant and wild type (WT) malignancies, as analyzed by an interpretation service according to the Association of Molecular Pathology (AMP) guidelines. A lower AMP score corresponds to a higher level of evidence as a predictive biomarker. We also compared molecular tumor board specific recommendations for each group (excluding recommendations regarding RAS such as EGFR mAbs). Results: There were 134 RAS mutant and 75 RAS WT cases. Alterations with AMP scores of 1A,1B, and 1C were more commonly seen in the RAS WT population 18/75 and 9/134 respectively (24.0% versus 6.7% p-value=0.0004). 39 of 75 cases in RAS WT and 27/134 in RAS mutant (52.0 versus 20.1%, p-value &lt;0.0001) cohort had at least one alteration that was deemed actionable by our institution’s current MTB criteria. Conclusions: Actionable mutations were significantly less common in the RAS mutant versus RAS WT population, and further studies assessing the value of comprehensive genomic testing in RAS mutant gastrointestinal malignancies may be warranted. [Table: see text]

Esophago-Pericardial Fistulae as a Sequela of Boerhaave Syndrome and Esophageal Stenting: A Case Report and Review of Literature

Esophago-pericardial fistulae is a rare and dreaded entity. Most reported cases in the literature were described in association with advanced upper gastrointestinal malignancies, prior surgical procedures, and radiofrequency atrial fibrillation ablation. It has been rarely reported in association with benign esophageal conditions. Surgery had been the mainstay of treatment, but there are increasingly reported cases treated successfully with esophageal stenting and pericardial drainage. In this article, we report a novel case of an esophago-pericardial fistulae occurring as a sequela of esophageal stent placed for the management of Boerhaave syndrome.