GI Tumors Research Articles

Clinical results of a phase 1 trial evaluating a HER2 directed CAR-T product selective for the tumor microenvironment (TME) in patients with GI and other solid tumor malignancies.

449 Background: A major limitation of CAR-T in solid tumors has been the inability to safely target antigens shared between healthy and malignant tissue. One approach to improving selectivity is to regulate CAR affinity through the unique metabolism of the tumor microenvironment (TME). This first in human trial evaluated an autologous (41BB) CAR-T product encoding a tumor metabolism regulated HER2 CAR. Methods: This Phase 1, dose escalation, basket trial evaluated the safety, tolerability, pharmacokinetics and efficacy in 12 patients (pts) with HER2 IHC 3+ / FISH + Stage IV r/r solid tumor malignancies (gastric, esophageal, colorectal, breast). They had failed multiple lines of therapy (66.7% patients had failed 4~10 lines of therapies previously). Dose cohorts of 3E5 (n=3), 1E6 (n=3), or 1E7 (n=6) CAR-T cells/kg were evaluated with a 28-day in-patient DLT observation period. Cell product was manufactured from whole blood, with a 12-day closed process and release on day 17. Lymphodepletion regimen was 500 mg/m 2 Cy and 30 mg/kg 2 Flu X 3 prior to infusion of CAR-T. Results: Data cutoff 09/16/24. All 12 patients were evaluable for safety and efficacy. No DLTs, ICANS or SAEs were observed. For HER2 positive normal tissues of special concern (e.g. cardiomyocytes), longitudinal functional, biochemical and clinical cardiovascular tests showed no signs of OTOT. One patient experienced Grade 2 CRS and recovered. No AE’s lead to study discontinuation. In one patient, there were two Grade 3 AEs attributed to product (neutropenia and hypoxia); both which resolved. With a median follow-up of 302 days for cohort 3, 12-month survival rate in this cohort is 83.3%, compared to the 12-month survival rate of 33.3% for cohorts 1 and 2 combined. Encouraging signals of efficacy were observed with an ongoing (at 24 wks) deep PR (100% reduction SLD) in a GC patient. The median peak copy number of CAR-T cells in peripheral blood (n=12) was 1,818 copies/µg DNA (range 403 – 10,466). Conclusions: The tumor metabolism regulated HER2 CAR-T product was generally well tolerated, with no DLTs, and evidence of radiologic objective response in patients with gastroesophageal cancer. Combined, the safety and activity observed in this study suggests that a previously challenging solid tumor antigen may be safely targeted by a CAR with affinity regulated by the metabolism of the TME. Enrollment for the study was complete as of 28-Feb-2024 (NCT04511871). Clinical trial information: NCT04511871 .

Rate of gene fusion/rearrangement identification in GI cancers as sequencing evolved from limited panels to whole exome sequencing.

809 Background: Gene fusion/rearrangements occur at a frequency of 0-15% in GI system cancers. Detection and treatment of fusion genes such as NTRK, FGFR2, NRG1 and RET fusions are included in NCCN guidelines and are commonly detected using next generation sequencing (NGS). NGS panels have continued to expand over time, which should result in increases in the identification of gene fusions. The aims of this study were to describe the percent of patients with advanced GI tumors undergoing NGS with identified gene rearrangements across time as panels expanded. Methods: The study included 7237 patients in the Kaiser Permanente Northern California Integrated Health System receiving care for advanced GI cancers from 2017 to Aug 2024, whose tumors samples were evaluated using NGS (Stomach=926, Colorectal=2792, Gallbladder=569, Esophagus=761, liver=218, Pancreas=1971). Results: A total of 231 patients (3.2%) were identified with a gene rearrangement, including 4.6% in stomach(N=43), 2.8% in colorectal(N=78), 8.9% in gallbladder(N=24), 5.3% in esophagus(N=40), and 1.9% in pancreatic (N=38 ). Rearrangements included NTRK1/2/3, FGFR2/3, NRG, ALK, ROS, CLDN18-ARHGAP, RSPO2/3, DNAJB1-PRKACA, BRAF, MET and RET. The numbers per year were (see table). Conclusions: The use of more comprehensive NGS panels such as WES did not appear to increase the detection rate for fusion/rearrangements. In resource limited settings, limited panels may suffice. The number of GI cancer patients getting NGS testing has increased over time. Gene rearrangements/fusions identified per year. YEAR 2018 2019 2020 2021 2022 2023 2024 (Jan – Aug) Gene Rearrangement identified 29 37 43 55 54 62 38 TOTAL GI Cancer Samples Sequenced 610 858 900 1047 1249 1181 785 Percentage 4.75% 4.31% 4.78% 5.25% 4.32% 5.25% 4.84%

Esophageal cancer: new developments in prevention and therapy

Esophageal carcinomas comprise 2 entities, squamous cell carcinoma and adenocarcinoma, which differ in pathogenesis and treatment. Elimination of inflammatory influences and risk factors, such as obesity and gastroesophageal reflux that contribute to a rising incidence of adenocarcinoma, is crucial for tumor prevention. In Germany, general endoscopic screening for upper GI tumors is not recommended, whereas endoscopic surveillance is applied in the presence of Barrett's metaplasia. In the future, better prediction models will be needed to identify patients at risk who will benefit from endoscopic surveillance. Precancerous lesions and early tumor stages can be removed endoscopically using modern resection methods. In recent years, therapeutic strategies for advanced esophageal tumors have undergone significant changes. In the multimodal treatment of locally advanced stages, radiochemotherapy remains to play a key role for squamous cell carcinoma, whereas new evidence highlights the importance of perioperative chemotherapy for the optimal management of adenocarcinoma. Systemic treatment options for both tumor entities have been significantly expanded due to the successful use of immune checkpoint inhibitors in adjuvant and palliative treatment regimen. Determination of PD-L1 and MSI status has therefore become decisive for the choice of therapy. In metastatic stages of adenocarcinoma, chemotherapy can now be supplemented by multiple antibodies directed against Her2, PD1, or claudin 18.2, and the antibody-drug conjugate trastuzumab deruxtecan has become a Her2-targeted option in second line treatment.

The application of the combination between artificial intelligence and endoscopy in gastrointestinal tumors

AbstractGastrointestinal (GI) tumors have always been a major type of malignant tumor and a leading cause of tumor‐related deaths worldwide. The main principles of modern medicine for GI tumors are early prevention, early diagnosis, and early treatment, with early diagnosis being the most effective measure. Endoscopy, due to its ability to visualize lesions, has been one of the primary modalities for screening, diagnosing, and treating GI tumors. However, a qualified endoscopist often requires long training and extensive experience, which to some extent limits the wider use of endoscopy. With advances in data science, artificial intelligence (AI) has brought a new development direction for the endoscopy of GI tumors. AI can quickly process large quantities of data and images and improve diagnostic accuracy with some training, greatly reducing the workload of endoscopists and assisting them in early diagnosis. Therefore, this review focuses on the combined application of endoscopy and AI in GI tumors in recent years, describing the latest research progress on the main types of tumors and their performance in clinical trials, the application of multimodal AI in endoscopy, the development of endoscopy, and the potential applications of AI within it, with the aim of providing a reference for subsequent research.

Effects of High-Linear-Energy-Transfer Heavy Ion Radiation on Intestinal Stem Cells: Implications for Gut Health and Tumorigenesis.

Heavy ion radiation, prevalent in outer space and relevant for radiotherapy, is densely ionizing and poses a risk to intestinal stem cells (ISCs), which are vital for maintaining intestinal homeostasis. Earlier studies have shown that heavy-ion radiation can cause chronic oxidative stress, persistent DNA damage, cellular senescence, and the development of a senescence-associated secretory phenotype (SASP) in mouse intestinal mucosa. However, the specific impact on different cell types, particularly Lgr5+ intestinal stem cells (ISCs), which are crucial for maintaining cellular homeostasis, GI function, and tumor initiation under genomic stress, remains understudied. Using an ISCs-relevant mouse model (Lgr5+ mice) and its GI tumor surrogate (Lgr5+Apc1638N/+ mice), we investigated ISCs-specific molecular alterations after high-LET radiation exposure. Tissue sections were assessed for senescence and SASP signaling at 2, 5 and 12 months post-exposure. Lgr5+ cells exhibited significantly greater oxidative stress following 28Si irradiation compared to γ-ray or controls. Both Lgr5+ cells and Paneth cells showed signs of senescence and developed a senescence-associated secretory phenotype (SASP) after 28Si exposure. Moreover, gene expression of pro-inflammatory and pro-growth SASP factors remained persistently elevated for up to a year post-28Si irradiation. Additionally, p38 MAPK and NF-κB signaling pathways, which are critical for stress responses and inflammation, were also upregulated after 28Si radiation. Transcripts involved in nutrient absorption and barrier function were also altered following irradiation. In Lgr5+Apc1638N/+ mice, tumor incidence was significantly higher in those exposed to 28Si radiation compared to the spontaneous tumorigenesis observed in control mice. Our results indicate that high-LET 28Si exposure induces persistent DNA damage, oxidative stress, senescence, and SASP in Lgr5+ ISCs, potentially predisposing astronauts to altered nutrient absorption, barrier function, and GI carcinogenesis during and after a long-duration outer space mission.

MTAS-01 UPDATES ON BRAIN METASTASIS MANAGEMENT AND OUTCOMES IN LMICS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract BACKGROUND Brain Metastases (BM) occur in the natural course of malignant tumors and cause a high rate of morbidity and mortality. The approaches to their management have changed considerably over the past decade. We aimed to give an update regarding the current means of diagnosis, management, and the outcomes of brain metastases in LMIC. METHODS We searched PubMed, ScienceDirect, Medline, Embase, Global Index Medicus, African Journals Online, and Google Scholar for studies reporting data on Brain metastasis diagnosis, management, and outcomes in LMICs from inception to October 23rd, 2022. The systematic review was conducted using the PRISMA principles. RESULTS A total of 7916 unique studies were identified, of which, 48 were included. The most studied (21, 43.75%) and common cause of metastases was lung tumors (1602, 51.43%). A subtotal resection (STR) was archived in the majority of reported cases in the frequency of 56.2% (n = 1751), gross total resection (GTR) in 37.5% (n = 1169) of cases, while only biopsy was possible in 6.3% (n = 195). The reported adjuvant treatments were radiotherapy 39.9% (n = 1036), radiosurgery 22.5% (n = 585), and radiosurgery + radiotherapy 37.5% (N = 974). Management of the primary tumor was reported in 13 (27.08%) studies. Half (24, 50%) of the studies reported the overall survival time to be 4-52 months. CONCLUSION Lung, breast, and GI tumors were the most common primary tumors for the MB. Whole-brain radiotherapy is the most common management method in LMICs.

Blood Tumor Mutational Burden Alone Is Not a Good Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Patients With Gastrointestinal Tumors.

There has been a controversy about the predictive value of tissue-TMB-H for immune checkpoint inhibitors (ICIs) with limited data regarding blood-TMB (bTMB) in GI tumors. We aim to evaluate the predictive value of bTMB compared with MSI-H in GI tumors. Patients with unresectable/metastatic GI cancer, harboring either MSS with bTMB-H (≥10mut/Mb) or dMMR/MSI-H who received ICI were included. We compared ICIs' efficacy between MSS-bTMB-H (N=45) versus MSI-H (N=50) in GI tumors. Ninety-five patients were identified with the majority having colorectal (49.5%) or esophagogastric (34.7%) cancers. MSS-bTMB-H group had more esophagogastric cancer and later-line ICI recipients, with no significant differences in other known prognostic variables. At a median follow-up of 9.4 months, MSI-H group showed superior ORR (58.0% vs. 26.7%), DCR (84.0% vs. 42.2%), DoR (not-reached vs. 7.6mo), PFS (22.5 vs. 3.8mo), and OS (Not-reached vs. 10.1mo) compared with MSS-bTMB-H. Multivariable analysis showed that MSI-H was an independent favorable factor over MSS-bTMB-H for PFS (HR=0.31, CI 0.15-0.63, P =0.001) and OS (HR=0.33, CI 0.14-0.80, P =0.014). MSI-H group showed favorable outcomes compared with MSS-bTMB-16+ (ORR: 58.0% vs. 26.9%; DCR: 84.0% vs. 42.3%; PFS:22.5 vs. 4.0mo) and MSS-bTMB-20+ (ORR: 58.0% vs. 31.6%; DCR: 84.0% vs. 42.1%; PFS:22.5 vs. 3.2mo). There was no difference between MSS-bTMB10-15 compared with MSS-bTMB-16+ in ORR, DCR, and PFS, or between MSS-bTMB10-19 compared with MSS-bTMB20+. Regardless of bTMB cutoff at 10, 16, or 20, bTMB-H did not appear to be a predictive biomarker in MSS GI tumors in this retrospective analysis.

European Neuroendocrine Tumor Society (ENETS) 2024 guidance paper for the management of well-differentiated small intestine neuroendocrine tumours.

Both the incidence and prevalence of well-differentiated neuroendocrine tumours from the small intestine (Si-NET) are gradually increasing. Most patients have non-functioning tumours with subtle GI symptoms and tumours are often discovered incidentally by endoscopy or at advanced disease stages by imaging depicting mesenteric lymph node and /or liver metastases while around 30% of the patients present with symptoms of the carcinoid syndrome. Adequate biochemical assessment and staging including functional imaging is crucial for treatment-related decision-making that should take place in an expert multidisciplinary team setting. Preferably, patients should be referred to specialised ENETS Centres of Excellence or centres of high expertise in the field. This guidance paper provides the current evidence and best knowledge for the management of Si-NET grade (G) 1-3 following 10 key questions of practical relevance for the diagnostic and therapeutic decision making.

Real-world implementation of an EHR-integrated, SMS text remote patient monitoring platform at an academic cancer center.

e13669 Background: Remote monitoring studies in oncology have shown improved quality of life, decreased healthcare utilization, and even improved overall survival in an oncologic population, however applications in a real-world setting have been limited. Barriers to successful deployment include low patient engagement rates with smartphone apps, lack of integration with the EHR and burdensome clinical workflows for staff. Methods: We sought to assess the feasibility of an EHR-integrated, SMS text conversational AI agent to automate the collection of ePRO data as well as the assessment and triage of common patient symptoms for patients with GI and GU tumors receiving anti-cancer therapy. This program was developed collaboratively by a health system digital health team, nursing informatics, IT support resources, oncology nurses, medical oncologists, and representatives from Memora Health. Core components included 1) weekly ePRO collection based on the NIH’s CTCAE, 2) NLP activated symptom triage for 16 common symptoms and toxicities 3) weekly symptom check-in 4) weekly medication adherence assessment for patients on oral therapy. Patients received all messages through SMS on their phones, and all data collected were routed into the EHR. In-EHR visualizations allowed nurse coordinators to track ePRO symptoms over time and symptoms that met pre-specified criteria triggered EHR-based alerts. Results: Of 99 patients ordered into this SMS program, 83 enrolled (84% enrollment rate), with 55 Uro Onc patients; 44 GI Onc patients. A total of 2,583 surveys were sent to patients. 98% of patients completed at least 1 survey. Overall patient survey completion rate was 62%. Medication adherence surveys had the highest completion rate at 81%. ePRO completion rates were higher for GU (65%) vs GI (39%) patients (p<0.01). 71% of ePRO surveys generated a symptom alert to the nursing staff. Patient satisfaction was high with 93% rating this SMS program as “excellent” or “good” (n=78). Care team surveys found that 3 of the 6 Oncologists believe ePRO collection is valuable and 3 of 6 used ePRO data to adjust a care plan. Nurse coordinators had a mixed view of the program with a majority reporting that there were too many symptom alerts. Conclusions: We successfully deployed an EHR-integrated SMS program to collect ePRO data, track patient symptoms, and monitor adherence to oral therapy. We believe having a physician champion influenced patient engagement in the GU patient population. Patients had a favorable impression of this program and survey completion rates demonstrated ease of use for patients. Clinical staff, particularly nurses, felt that there were too many alerts. Additional workflow changes may reduce alert burden and better incorporate ePRO learnings into clinical practice.

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

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

Chemotherapy in the last 30 days of life, correlation with age and palliative care referral: A 1-year retrospective gastrointestinal program experience at SQCCCRC.

e24038 Background: Chemotherapy in the last days of life can carry unnecessary toxicities to the patient with no significant impact on survival and disease outcome. This is becoming of greater interest with the involvement of palliative care in patient’s management along with the advent of new therapeutic options with progressively increased cost of treatment. Methods: In our retrospective study, we aimed to analyze retrospectively the data of GI tumors treated at SQCCCRC over one year, by looking at the possible factors influencing the time from last treatment to death. We conducted chart review of all death that occurred between January 2023 and December 2023 in the GI cancer program at SQCCCRC. Information on demographics, type of GI cancer, type, intent and route of chemotherapy, line of chemotherapy and referral to palliative care were collected. Results: A total of 65 patients died within the GI cancer program between January 1st, 2023, to dec 31st, 2023. Most (72.7%) of the patients died of disease progression. Intent for chemotherapy was palliative in 90.9% of cases. Chemotherapy was parenteral (Intravenous) for the majority (60%, 38/63) of the patients. From all the recovered deaths, a total of 52 patients (82%) were referred to palliative team before death whereas palliative team was involved in the journey of all patients. 12 deaths out of 65 occurred in ICU. Only 11 out of 65 patients died within last 30 days of treatment: 81.8% of them were under palliative care at the time of death. For this group, the median age at diagnosis was 50 yo. Median age at death was 61 yo. 72.7% were male. Primary site of disease was colon followed by stomach. Median time from diagnosis to palliative referral was 13.5 months. 8 patients died within 3.5 days of referral to palliative care. In the logistic regression models, only age at diagnosis was a significant predictor for receiving chemotherapy in the last 30 days of life (p = 0.019). Older age was associated with lower odds of receiving chemotherapy in this period (OR = 0.94, 95% CI = 0.89-0.99). Referral to palliative chemotherapy was not associated with decreased rate of treatment administration within last 30 days of life. Conclusions: While some real-world data suggested correlation between shifting to palliative care and administration of chemotherapy in the last 30 days of life, this was not the case in our collected sample, and only the age of the patient played a role in the chemotherapy timing before death. Further studies are needed to study the reasons behind and the best way to improve patient’s centered approach.

Experience of personalizing cancer treatment in economically-constrained and resource-restricted community oncology practice in India through cost-effective broad spectrum NGS and survival outcomes: An observational study of 3 years.

e15173 Background: NGS based mutational findings are increasingly used in oncology practice to personalize treatment strategies. We elucidate the impact of comprehensive genomic profiling and the new avenues it opens for personalized precision medicine. Methods: This was a retrospective study evaluating patients who underwent a cost-effective (<US $1000), inhouse developed comprehensive NGS test. Descriptive data was tabulated & mutational distribution, therapeutic strategies and survival outcomes were evaluated. Results: A total of 336 patients were evaluated from a community oncology practice over the last 3 years in Western India. The mean age was 59.2 years; with F:M being 1.04:1 and stage distribution being 3.5%, 5.9%, 9.5% and 80.9% for Stage I, II, III and IV respectively. Comprehensive NGS was performed to evaluate SNVs, CNVs, and indels spanning across over 15000 loci for 1080 tumor specific genes wherein 71.7% were tissue-based, 24.4% were liquid biopsy-based and 3.8% were combined tissue-DNA and ctDNA-based analysis. Majority (69.9%) of the patients were pre-treated while 30% were therapy naïve. The most common cancers evaluated were Lung (18.1%), Pancreatobiliary (15.1%), Breast (11.3%), Gynaec (9.5%), and Lower GI (9.5%). Pathogenic mutations were reported in 83.6% of the cohort while in 16.3% no mutations were detected. Most common mutations observed in this retrospective study were TP53 (38.3%), KRAS (16.6%), PIK3CA (9.5%), EGFR (7.4%) and PTEN (5.6%); and the distribution was largely similar in untreated as well as pre-treated cohorts. Furthermore, genomic alterations for each cancer type are described in Table 1. MSI high and TMB high (>10) were reported in 0.5% and 7.4% respectively. PDL1 positive IHC was reported in 3.2% of tissue samples, whereas HRD high (>50) was reported in 2.3% of the cohort of which the majority (11.5%) were from Upper GI tumors. Targetable genomic alterations were detected in 53.8% (181/336) of which 38.1%(69/181) received the suggested targeted therapy. Clinical response was seen as PR in 14.4% and CR in 2.8% of patients. Of 336 patients 4.76% received modified therapeutic regimens which differed from the standard of care, wherein median PFS was 8 mo [CI 95% (5.3-10.7)] while median OS was 55.1 mo [CI 95% (25.8-NA)]. Conclusions: This observational study outlines the potential benefit of personalizing treatment regimens in the management of solid organ cancers, especially in scenarios where standard-of-care regimens may have failed and the need to incorporate broad-spectrum NGS. [Table: see text]

Personalized diagnostics for GI tumors: Which is useful?

Personalized diagnostics for GI tumors: Which is useful?

Abstract 996: Predicting early mortality in a large ethnically diverse phase I clinical trial program

Abstract Background: Various scoring systems are developed to optimize patient selection for phase I clinical trials. We evaluated the Royal Marsden Hospital (RMH), Princess Margaret Hospital Index (PMHI), and MD-Anderson Cancer Center (MDACC) prognostic scores and compared their power to predict 90-day mortality (90DM) in an ethnically diverse population enrolled in the USC Norris Comprehensive Cancer Center (NCCC) Phase I Program. Methods: We queried our database of patients enrolled in phase I clinical trials at the NCCC from 2015-2022 which includes demographics, treatment details and outcomes. The enrollment occurred at all NCCC sites including the Los Angeles General Medical Center, a safety net hospital. Prognostic scores were calculated: RMH (albumin < 35 g/L, LDH > ULN, > 2 metastatic sites), PMHI (albumin < 35 g/L, ECOG > 0, > 2 metastatic sites), MDACC (albumin < 35 g/L, LDH > ULN, ECOG > 0, > 2 metastatic sites, GI tumor type). Kaplan-Meier analysis was used to calculate median survival in each group. ROC analysis was performed to assess the 90DM prediction. Results: 611 patients (15 breast, 344 GI, 20 GU, 29 GYN, 110 Lung/H&N, 88 other) were accrued to 88 phase I trials. Patients had a median age of 61 (25-87) and a median of 3 prior lines of therapy (0-10). 31.9% of pts were Hispanic, 44.1% non-Hispanic white, 3.7% black, and 20.4% Asian. The 90DM rate was 24.9%. The objective response rate was 8.3%, and 41.5% had stable disease. For all systems, higher scores had shorter survival (p<0.001). The MDACC system had the largest AUC to predict 90DM (AUC: 0.678, p < 0.001). Score of 4-5 (high risk) per MDACC system corresponds to a specificity of 94.5% (91.1-97.2) and positive likelihood ratio of 3.6 (1.8-7.2). Conclusion: In our highly diverse phase I population, higher scores on the RMH, PMHI, and MDACC scoring systems were associated with worse prognosis and 90DM. Careful consideration should be given to potential patients with higher scores prior to enrollment in phase I trials. Characteristics and outcomes of the study participants (N = 611). Variable Median (IQR)/N (%) Scoring system N (%) Median survival days (95% CI) p-Value Age (yr) 61 [54-68] RMH score < 0.001 Female gender 288 (47.1%) 0 151 (36.7%) 505 (378-631) Safety net participant 120 (19.6%) 1 184 (44.8%) 509 (324-693) Non-English speaking 177 (29%) 2 64 (15.6%) 176 (107-244) Performance status ECOG 0 153 (33.3%) 3 12 (2.9%) 44 (12-76) ECOG 1 302 (65.7%) Area under ROC curve (95% CI) 0.650 (0.579-0.721) < 0.001 ECOG 2 5 (1.1%) Number of prior lines 0-2 298 (48.8%) PMHI score < 0.001 >= 3 313 (51.2%) 0 118 (25.7%) 603 (405-800) Tumor type Breast 15 (2.5%) 1 214 (46.5%) 462 (378-545) GI 344 (56.8%) 2 115 (25.0%) 254 (117-390) GU 20 (3.3%) 3 13 (2.8%) 87 (52-122) Gyn 29 (4.8%) Area under ROC curve (95% CI) 0.629 (0.560-0.697) < 0.001 Lung/H&N 110 (18.2%) Others 88 (14.5%) MDACC score < 0.001 Type of trial Chemotherapy 112 (18.3%) 0 (low risk) 26 (7.9%) Not estimated Immunotherapy 227 (37.2%) 1 (low-intermediate risk) 84 (25.5%) 597 (429-768) Targeted therapy 272 (44.5%) 2 (intermediate risk) 116 (35.2%) 471 (115-827) >2 metastatic sites 146 (23.9%) 3 (high-intermediate risk) 75 (22.7%) 297 (142-452) 90-day mortality 152 (24.9%) 4 (high risk) 25 (7.6%) 119 (108-130) Best response by RECIST Stable disease 225 (41.5%) 5 (high risk) 4 (1.2%) Not estimated Partial response 39 (7.2%) Area under ROC curve (95% CI) 0.678 (0.611-0.745) < 0.001 Complete response 6 (1.1%) Progressive disease 272 (50.2%) Citation Format: Hadi Erfani, Sabrina Woll, Austin Luong, Gage Guerra, Anthony Kharrat, Rebecca Umayam, Anastasia Martynova, Laurie Brunette, Lynda Roman, Negeen Izadian, Teshia Bustos, Diana Hanna, Anthony El-Khoueiry, Jacob Thomas. Predicting early mortality in a large ethnically diverse phase I clinical trial program [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 996.

Abstract 6357: Establishing a reverse translational platform to dissect mode of action and mechanisms of resistance to GUCY2C-CD3 T cell engager

Abstract PF-07062119 (GUCY2C x CD3), a bispecific T cell engager (TCE) targeting Guanylyl Cyclase C (GUCY2C), a GI tumor associated antigen, is currently being evaluated in a Phase 1 clinical trial in colorectal cancer (CRC) and other GI malignancies. Improved pre-clinical understanding of the correlates of PF-07062119 resistance mechanisms and PD in a human disease relevant context is critical to better inform drug combination and patient selection strategy. Due to limited translatability of mouse syngeneic tumor models, establishing a more human disease-relevant platform leveraging tumor patient material to better inform PF-07062119 clinical strategy is needed. Here, we will discuss our efforts to perform immune profiling of T cell and myeloid tumor infiltrates, and to evaluate tumor cell depletion and cytokine production of colorectal carcinoma (CRC) samples treated ex vivo with PF-07062119. This platform may be leveraged to 1) provide clinically relevant disease insights to the effect of TCEs across a range of tumor indications; 2) determine impact of different combinatorial partners on tumor cell killing to inform clinical decisions; 3) address questions related to the minimal efficacy of TCEs in the solid tumor space; and 4) provide potential solutions for future combination partners to overcome immunosuppression in the tumor microenvironment. Citation Format: Joana Borlido, Jade Lolarga, Rachael Whaley, Michael A. Damore, Cen Guo, Keith Abayasiriwardana, Xiaojun Xu, Maggie Liu, Gosia Nocula-Lugowska, Sam Stoner, Christopher Kraser, Ioanna Cheronis, Maria Delioukina, Lee Clark, Raj Bhadra, Murali Gururajan. Establishing a reverse translational platform to dissect mode of action and mechanisms of resistance to GUCY2C-CD3 T cell engager [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 6357.

Efficacy and safety of LY3537982, a potent and highly selective KRAS G12C inhibitor in KRAS G12C-mutant GI cancers: Results from a phase 1 study.

94 Background: LY3537982 is an oral, potent, and highly selective inhibitor of GDP-bound KRAS G12C with unique pharmacologic properties that achieve high target occupancy at low absolute exposures. Here we present results of GI tumors treated on LOXO-RAS-20001, a phase 1 study of LY3537982 in patients (pts) with a KRAS G12C mutation. Methods: Dose escalation followed a mTPI-2 method. Dose expansion included a combination with cetuximab in colorectal cancer (CRC). All pts were KRAS G12C inhibitor naïve. Key objectives were to determine the RP2D, safety, PK, and antitumor activity per RECIST v1.1. Results: As of 24 July 2023, 73 pts with CRC (32), PANC (24), BTC (10), and other GI tumors (7) were treated with 50-200 mg BID LY3537982. Median age was 62 yrs (range, 36-85) and median number of prior lines of therapies was 3 (range, 0-11). No DLTs were observed. Grade 1 diarrhea was the highest frequency TEAE regardless of attribution (33%). At a median time on treatment of 4 months (range, 0.1-18), 20 pts are ongoing and 53 discontinued treatment. In the combination cohort, 46 pts with CRC were treated with 100 or 150 mg BID LY3537982 and cetuximab. Median age was 57 yrs (range, 35-77) and median number of lines of prior therapies was 3 (range, 1-8). 1 pt at 100 mg BID had a DLT (ALT/AST increased) and required a dose reduction. TEAEs ≥30% were dermatitis acneiform (59%), diarrhea (44%), dry skin (44%), hypomagnesemia (33%), and fatigue (30%). Vomiting, pruritus, skin fissures, headache, nausea, pyrexia, and rash were mostly grade 1 with 20-24% occurrence. At a median time on treatment of 6 months (range, 0.6-11), 37 pts are ongoing and 9 discontinued treatment (none due to AE). Table shows efficacy data. Conclusions: In pts with GI tumors, LY3537982 alone or in combination with cetuximab demonstrated preliminary efficacy and a favorable safety profile. Clinical trial information: NCT04956640 . [Table: see text]

Durable efficacy of selpercatinib in patients with RET fusion+ solid tumors, with a focus on GI tumors: LIBRETTO-001.

746 Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-activated cancers. This update includes more patients (pts, n=52) and 16 months (mo) longer follow-up (data cut-off: 13Jan2023) in RET fusion+ solid tumors other than lung/thyroid with a focus on GI histologies. Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET fusion+ solid tumors. 51/52 pts received the recommended dose of 160 mg orally. The efficacy analysis set consisted of pts enrolled ≥6 months prior to the cut-off date. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), and safety. Results: Of the 52 pts with RET-activated solid tumors other than lung or thyroid, 51.9% were female with a median age of 54.0 years. The majority (31/52) of patients had GI RET fusion+ tumor types, with pancreatic (N=13) and colorectal (N=13) as the most common (Table). 47 pts received prior systemic therapy (median prior lines: 2, range 0-9); 28.8% received ≥3 lines. In 52 efficacy-evaluable pts, confirmed ORR by IRC was 44.2% (23/52, 95% CI: 30.5, 58.7). ORR by IRC for pts with pancreatic tumors was 53.8% and for colorectal tumors was 30.8%. Clinical benefit (complete response + partial response + stable disease ≥16 weeks) was observed in 67.3% (35/52) of pts. Median DoR was 37.2 mo (95% CI: 13.3, NE) for overall pts (Table). No new safety signals were identified compared to previous reports. 4 grade 5 AEs were observed (unrelated to treatment by INV), and 2 pts discontinued due to treatment-related AEs per INV. Conclusions: Selpercatinib continued to demonstrate durable antitumor activity and tolerable safety in pts with RET fusion+ cancers across multiple tumor types and fusion partners, including difficult-to-treat GI cancers with poor results in standard-of-care options, such as pancreatic and colorectal. These results emphasize the importance of comprehensive genomic profiling across all tumor types in order to identify actionable oncogenic drivers, including RET fusions. Clinical trial information: NCT03157128 .[Table: see text]

Results from the phase 1b/2 SGNTUC-024 study: Assessment of tucatinib, trastuzumab, and FOLFOX for HER2+ GI cancers.

100 Background: HER2 is overexpressed in various GI tumors. Tucatinib (TUC), which is approved in combination with trastuzumab (Tras) in the US for previously treated RAS WT HER2+ metastatic colorectal cancer (mCRC), is a tyrosine kinase inhibitor highly selective for HER2. Preliminary safety and antitumor activity results of TUC + trastuzumab + FOLFOX in patients (pts) with HER2+ GI cancers are presented. Methods: The phase 1b/2 SGNTUC-024 (NCT04430738) study evaluated TUC + Tras + FOLFOX in pts with HER2+ metastatic GI cancers in Cohorts 1A, 1B, 1D (pts in Japan), and 2B. For Cohorts 1A, 1B, and 1D (enrolled sequentially), eligible pts had unresectable or metastatic HER2+ GI malignancies, including mCRC. Cohort 2B is still enrolling, and pts with HER2+ mCRC are eligible. Pts received a combination of TUC 150 mg orally twice a day (PO BID; Cohort 1A) or TUC 300 mg PO BID (Cohorts 1B, 1D, and 2B) + Tras + FOLFOX. Pts in Cohort 2B were enrolled to further assess the study regimen. Antidiarrheal prophylaxis was required for Cohort 1D. Results: As of July 10, 2023, 25 pts were treated (5, 11, 7, and 2 in Cohorts 1A, 1B, 1D, and 2B, respectively). In Cohort 1A (TUC 150 mg PO BID), the most common TEAEs were diarrhea, fatigue, nausea, and proteinuria (each in 60.0% [3/5]). For pts receiving TUC 300 mg PO BID, the most common TEAEs were diarrhea (90.0% [18/20]) and fatigue (65.0% [13/20]). Table 1 presents the overall summary of adverse events. In Cohort 1A, Treatment-emergent adverse events (TEAEs) leading to any treatment discontinuation were reported in 40.0% (2/5) pts, with 20.0% (1/5) discontinuing tucatinib. For pts treated with TUC 300 mg, TEAEs leading to treatment discontinuation were reported in 35.0% (7/20), with 15.0% (3/20) discontinuing tucatinib. One TEAE leading to death (aspiration) in Cohort 1A was unrelated to study treatment. Grade ≥3 diarrhea was observed in 45.5% (5/11) pts in Cohort 1B; most were observed in elderly pts or pts with gastric, gastroesophageal, or esophageal cancer or pts who were generally noncompliant with antidiarrheal treatment. No grade ≥3 diarrhea was observed in Cohort 1D. Among pts receiving TUC 300 mg, confirmed objective response rate was 83.3% (5/6) for mCRC, 40.0% (4/10) for gastroesophageal cancers, and 0% (0/4) for biliary tract cancer. Conclusions: TUC + Tras + FOLFOX showed manageable safety in the enrolled pt population and preliminary antitumor activity in pts with HER2+ mCRC and gastroesophageal cancer. This regimen will be compared with the standard of care (FOLFOX with or without bevacizumab/cetuximab) in the ongoing randomized, phase 3 study (MOUNTAINEER-03; NCT05253651) for pts with HER2+ RAS WT mCRC. Clinical trial information: NCT04430738 . [Table: see text]

Valuing innovative endoscopic techniques: hemostatic powder for the treatment of GI tumor bleeding

Access to new endoscopic treatment modalities often depends on price. To resolve this gap and therefore help to ensure that care delivery can occur on a clinical basis, we aimed to establish the value to insurers of novel hemostatic powder to treat GI tumor bleeding. A decision-analytic model developed to assess the impact of endoscopic intervention on the risk of 30-day readmission for GI bleeding from an insurer perspective was adapted to assess GI tumor bleeding with hemostatic powder or standard endoscopic therapy. Costs were derived from Medicare populations. Outcomes were derived from a recent multicenter randomized clinical trial. Costs ranged from $651 to $1613 to treat upper GI tumor bleeding and from $531 to $1014 to treat lower GI tumor bleeding based on risk reduction in 30-day hospital readmission for recurrent bleeding. These valuations should represent medical device and incremental facility costs in addition to incremental physician and staff time. Coverage for novel endoscopic hemostatic powder therapy seems cost-saving to insurers.

First-in-Human Phase I Study of Minnelide in Patients With Advanced Gastrointestinal Cancers: Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity.

Minnelide is a water-soluble prodrug of triptolide. Triptolide is an anticancer agent that targets cancer resistance through several mechanisms. Minnelide was evaluated in a phase I study in patients with advanced GI carcinomas to establish the safety, pharmacodynamic, antitumor activity, and recommended phase II dose (RP2D). Patients with refractory GI carcinoma and with measurable disease on CT scan were eligible. The study used a 3 + 3 dose-escalation scheme. Due to neutropenia toxicity, 2 dosing schedules were evaluated to determine the RP2D for future studies. Response was assessed using RECIST 1.1 and Choi criteria. Minnelide and triptolide PK were evaluated. Patients who completed the first 28-day treatment cycle without DLTs continued treatment until disease progression or unacceptable toxicity. Forty-five patients were enrolled (23 pancreatic cancer, 10 colorectal, and the remaining 9 had other GI tumors); 42 patients received at least one dose of Minnelide. Grade ≥ 3 toxicities occurred in 69% of patients, most common neutropenia (38%). 2 patients with severe cerebellar toxicity who had a 2-fold higher triptolide concentration than other participants. ORR was 4%; the disease control rate (DCR) was 54% (15/28). Choi criteria demonstrated a decrease in average tumor density in 57% (16/28) patients. This first-in-human, phase I clinical study identified a dose and schedule of Minnelide in patients with refractory GI cancers. The primary toxicity experienced was hematologic. Evidence of efficacy of Minnelide treatment in this group of patients was observed. The DCR ranged from ~2 to 6 months in 14/28 (50%) of evaluable patients. Studies in monotherapy and combination treatments are underway.