Advanced Gastrointestinal Tumors Research Articles

Clinical biomarkers for thyroid immune-related adverse events in patients with stage III and IV gastrointestinal tumors.

Thyroid immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) treatment appear to correlate with a better prognosis. We aimed to investigate clinical biomarkers associated with thyroid irAEs. We retrospectively analyzed data from 129 patients receiving programmed cell death protein 1 (PD-1) inhibitors for stage III and IV gastrointestinal tumors. Patients were divided into two groups: "thyroid irAEs" group and "no thyroid irAEs" group. We compared continuous variables using Mann-Whitney U and Kruskal-Wallis tests and categorical variables using Pearson's chi-square test. Survival curves were generated using the Kaplan-Meier method, and associations between clinical features and thyroid irAEs were assessed using univariate and multivariate logistic regression models. Associations for thyroid irAEs and outcomes [progression-free survival (PFS), overall survival (OS)] of the patients were performed with a Cox proportional hazard model. A total of 129 patients, including 66 gastric cancer, 30 esophageal squamous cell carcinoma, and 33 hepatocellular carcinoma (HCC), were involved in this analysis with 47 cases of thyroid irAEs occurrence. The Cox proportional hazard model analysis confirmed the extended PFS [hazard rate (HR) = 0.447, 95% confidence interval (CI): 0.215 to 0.931, p = 0.031] and OS (HR = 0.424, 95% CI: 0.201 to 0.893, p = 0.024) for thyroid irAEs group when compared with those of the no thyroid irAEs group. Association between thyroid irAEs and clinical characteristics at baseline was analyzed subsequently by univariate analysis. Higher body mass index (p = 0.005), increased eosinophil count (p = 0.014), increased lactate dehydrogenase (p = 0.008), higher baseline thyroid stimulating hormone (TSH) (p = 0.001), HCC (p = 0.001) and increased adenosine deaminase (ADA) (p = 0.001) were linked with thyroid irAEs occurrence. The multivariable logistic regression model indicated that ADA [odds rate (OR) = 4.756, 95% CI: 1.147 to 19.729, p = 0.032] was independently associated with thyroid irAEs occurrence. Increased baseline level of ADA was associated with thyroid irAEs occurrence in patients with advanced gastrointestinal tumors who received ICI treatment. In the case of abnormal ADA, attention should be paid to the risk of thyroid irAEs.

Abstract CT213: Anlotinib plus chemotherapy as first-line therapy for gastrointestinal tumor patients with unresectable liver metastasis: Updated results from a multi-cohort, multi-center phase II trial ALTER-G-001-cohort C

Abstract Background Advanced gastrointestinal (GI) tumors, such as colorectal, gastric and pancreatic cancers (CRC, GC, and PC), and esophageal squamous cell carcinoma (ESCC), 20%-50% with liver metastases (LMs) have a poor prognosis. Previous trials showed that anlotinib plus chemotherapy has promising clinical activity and a tolerable safety profile for advanced CRC and ESCC, especially with LMs. In this phase II trial, we assessed the efficacy and safety of anlotinib plus chemotherapy as first-line treatment for LMs GI tumors. Methods Patients with unresectable LMs GI tumors and without previous systemic treatment would be divided into cohort A (CRC), cohort B (ESCC), and cohort C (other GI tumors, such as PC, GC, biliary tract cancer (BTC), etc.). In cohort C, patients received induction therapy: anlotinib plus standard chemotherapy. Patients without progressive disease (PD) and radical resection received anlotinib and metronomic capecitabine (500 mg, PO, BID, days 1-21, q3w) maintenance until PD or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints were duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), time to response (TTR), depth of response (DpR), radical resection rate for LMs, and safety. Results As of November 13, 2023, 41 patients were enrolled in cohort C (29 PC, 6 GC, 5 BTC, and others), the median age was 64 years (34-74), 63.4% male, 92.7% ECOG-PS 1 and 56.1% had LMs only. The majority of the pancreatic cancer patients (26/29) received gemcitabine plus nab-paclitaxel chemotherapy combination with anlotinib as induction therapy. After induction therapy, 4 patients (1 PC, 2 GC, 1 BTC) received surgical resection. Of 38 evaluable patients in cohort C, 16 had partial response (PR), 17 had stable disease (SD) and 14 SD with reduced tumor size. The ORR was 42.1%, DCR was 86.8%. Of 26 evaluable pancreatic cancer patients, ORR and DCR were 42.3% (11/26) and 88.5%(23/26) respectively. 11 PRs and 10 SD- were observed with the median depth of response (DpR) of 37.6%. According to the Kaplan-Meier method, the median DoR was 4.1 (95%CI, 3.5-4.6) months and PFS was 5.8 (95%CI, 5.2-6.3) months. The median TTR was 1.7 (range, 0.8-3.5) months. 39 patients in cohort C had TEAEs and ≥ grade 3 TEAEs (53.7%) mainly included neutropenia (19.5%), white blood cell decreased (14.6%), and blood platelet decreased (9.8%). Conclusions Anlotinib plus chemotherapy as first-line treatment has shown promising efficacy and acceptable safety and maybe a favorable option for advanced LMs GI tumors, especially for pancreatic cancer. Clinical trial information: NCT05262335. Citation Format: Junwei Wu, Chenfei Zhou, Jun Yan, Zhengxiang Han, Chun Wang, Zhiquan Qin, Jinling Jiang, Chunbin Wang, Xinyu Tang, Lingjun Zhu, Jun Chen, Yong Mao, Xiaowei Wei, Chengfang Shangguan, Jun Zhang. Anlotinib plus chemotherapy as first-line therapy for gastrointestinal tumor patients with unresectable liver metastasis: Updated results from a multi-cohort, multi-center phase II trial ALTER-G-001-cohort C [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT213.

Malnutrition in advanced gastrointestinal cancer patients and nutritional support therapy

The advancement of comprehensive treatment has allowed an increasing number of patients with gastrointestinal tumor to achieve long-term survival. In current clinical practice, there is a growing population of patients with advanced gastrointestinal tumor. Due to various factors, such as tumor burden, treatments including chemotherapy and radiation therapy, as well as underlying diseases, patients with advanced gastrointestinal tumor often experience malnutrition, which negatively impacts their clinical outcomes. The mechanism of malnutrition in patients with advanced gastrointestinal tumor is complex, and conventional nutritional support therapy has shown limited effectiveness. With the continuous progress in the concept and technique of nutritional support therapy, the diversification of treatment strategies, and the strengthening of multidisciplinary collaboration, the nutritional management for patients with advanced gastrointestinal tumor tends to be standardized and rational, leading to effective improvement in patients' nutritional status and clinical outcomes. Based on the latest evidence-based medicine, combined with the author's practical experience and insights, this article aims to explore nutritional support therapy for patients with advanced gastrointestinal tumor.

Abstract 5180: Pharmacodynamic biomarker analysis of gastrointestinal cancer patients treated with metronomic chemotherapy in the Italian COMET Trial

Abstract Metronomic, or continuous low-dose, chemotherapy produces antitumor effects through multiple mechanisms. These include inhibition of angiogenesis and activation of the immune system. At AACR 2017 we presented a small, proof-of-concept, multiplex analysis of 14 cytokines specifically chosen by their association with activation of the immune system. The 14 cytokines were evaluated in 31 out of 38 patients with advanced refractory gastrointestinal tumors, enrolled in a phase II clinical trial of metronomic UFT (a 5-fluorouracil prodrug; 100 mg/twice per day p.o.) and cyclophosphamide (500 mg/mq2 i.v. bolus on day 1 and then 50 mg/day p.o.) plus celecoxib (200 mg/twice a day p.o.); the Italian COMET trial (Clinical Trial ID NCT02926911; Allegrini et al. Angiogenesis 2012: 15(2):275-86). We evaluated baseline (day 0) plasma levels with levels at days 28 and 56, and tested for correlations with observed Progression Free Survival, which we then reported (Valenzuela et al. Clin Exp Med. 2021: 21(1):149-159). We now present a comprehensive analysis of 75 cytokines in 34 of the 38 patients. Furthermore we extend the analysis to include baseline (day 0), days 28 and 56, and days 84 and 112 of the COMET trial, and we also correlated specific cytokines levels with Overall Survival. After an estimation of optimal cut-off points of plasma levels of the cytokines, survival analysis was performed, and log-rank tests and cox regression analyses were applied. We show that pre-treatment plasma level <435.46pg/ml of macrophage-derived chemokine (MDC), was a predictive marker for those patients with better progression-free survival at 3 and 6 months (log-rank test p=0.0046; Cox regression analysis p=0.016). Moreover, baseline plasma levels of three cytokines, including monocyte chemoattractant protein 2 (MCP-2), monocyte chemoattractant protein 4 (MCP-4) and TNF-related apoptosis-inducing ligand (TRAIL), were associated with an improved overall survival. MCP-2 values >26.21pg/ml (log-rank test p=0.0012; Cox regression analysis p=0.007), MCP-4 >72.97pg/ml (log-rank test p=0.012; Cox regression analysis p=0.019) and TRAIL >60.73pg/ml (log-rank test p=0.0059; Cox regression analysis p=0.011) were predictive markers for subjects with a better overall survival at 6 and 9 months. These results indicate that a methodology based on the detection of optimal cut-off points and survival analysis allowed the selection of potential biomarkers, such as MDC or MCPs. We propose that the systematic use of these statistical strategies, aimed at detecting potential biomarkers, could help to identify those patients that are likely to benefit from metronomic chemotherapy schedules. This would allow the stratification of such patients for future metronomic chemotherapy trials, and the potential identification of patients that should instead be offered alternative therapeutic strategies. Citation Format: Maria L. Manca, Diana Prospero, Saeedeh Darvishi, Arianna Bandini, Marta Banchi, Paola Orlandi, Hector Padilla, Alejandro Sanchez, Claire E. Perucho, Nydia de Avila, Hazel Padilla, Brianna E. Ortega, Ryley D. Stewart, Magdiel Santillan, Valeria Lopez, Robert Kirken, Giacomo Allegrini, Guido Bocci, Giulio Francia. Pharmacodynamic biomarker analysis of gastrointestinal cancer patients treated with metronomic chemotherapy in the Italian COMET Trial [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 5180.

Methylthioadenosine Phosphorylase Genomic Loss in Advanced Gastrointestinal Cancers.

One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker. We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI cancers. We compared the clinical outcomes of patients with GI cancer harboring MTAP-loss and MTAP-intact tumors in a retrospective study. The prevalence of MTAP-loss in GI cancers is 8.30%. MTAP-loss was most prevalent in pancreatic ductal adenocarcinoma (PDAC) at 21.7% and least in colorectal carcinoma (CRC) at 1.1%. MTAP-loss tumors were more prevalent in East Asian patients with PDAC (4.4% vs 3.2%, P = .005) or intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, P = .036). Significant differences in the prevalence of potentially targetable genomic alterations (ATM, BRAF, BRCA2, ERBB2, IDH1, PIK3CA, and PTEN) were observed in MTAP-loss tumors and varied according to tumor type. MTAP-loss PDAC, IHCC, and CRC had a lower prevalence of microsatellite instability or elevated tumor mutational burden. Positive PD-L1 tumor cell expression was less frequent among MTAP-loss versus MTAP-intact IHCC tumors (23.2% vs 31.2%, P = .017). In GI cancers, MTAP-loss occurs as part of 9p21 loss and has an overall prevalence of 8%. MTAP-loss occurs in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC and is not mutually exclusive with other targetable mutations.

Anlotinib plus chemotherapy as first-line therapy for patients with gastrointestinal tumor with unresectable liver metastasis: Updated results from a multi-cohort, multi-center phase II trial ALTER-G-001-cohort C.

653 Background: Advanced gastrointestinal (GI) tumors, such as colorectal, gastric and pancreatic cancers (CRC, GC, and PC), and esophageal squamous cell carcinoma (ESCC), 20%-50% with liver metastases (LMs) have a poor prognosis. Previous trials showed that anlotinib plus chemotherapy has promising clinical activity and a tolerable safety profile for advanced CRC and ESCC, especially with LMs. In this phase II trial, we assessed the efficacy and safety of anlotinib plus chemotherapy as first-line treatment for LMs GI tumors. Methods: Patients with unresectable LMs GI tumors and without previous systemic treatment would be divided into cohort A (CRC), cohort B (ESCC), and cohort C (other GI tumors, such as PC, GC, biliary tract cancer (BTC), etc.). In cohort C, patients received induction therapy: anlotinib plus standard chemotherapy. Patients without PD and radical resection received anlotinib and metronomic capecitabine (500 mg, PO, BID, days 1-21, q3w) maintenance until PD or unacceptable toxicity. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints were DoR, PFS, OS, DCR, radical resection rate for LMs, and safety. Results: As of September 14, 2023, 41 patients were enrolled in cohort C (29 PC, 6 GC, 5 BTC, and others), the median age was 64 years (34-74), 63.4% male, 92.7% ECOG-PS 1 and 56.1% had LMs only. The majority of the pancreatic cancer patients (26/29) received gemcitabine plus nab-paclitaxel chemotherapy combination with anlotinib as induction therapy. After induction therapy, 4 patients (1 PC, 2 GC, 1 BTC) received surgical resection. Of 37 evaluable patients in cohort C, ORR and DCR were 45.9% and 86.5% (PR, n=17; SD, n=15, 12 SD had reduced tumor size). Of 25 evaluable pancreatic cancer patients, 12 had PR, 10 had SD, ORR and DCR were 48% and 88%. According to the Kaplan-Meier method, the median DoR was 4.2 months (95%CI, 1.7-6.6) and the median PFS was 5.5 months (95%CI, 4.7-6.3). 37 patients in cohort C had TEAEs and ≥ grade 3 TEAEs (51.2%) mainly included neutropenia (19.5%), white blood cell decreased (12.2%), and blood platelet decreased (9.8%). Conclusions: Anlotinib plus chemotherapy as first-line treatment has shown promising efficacy and acceptable safety and maybe a favorable option for advanced LMs GI tumors, especially for pancreatic cancer. Clinical trial information: NCT05262335 .

Real-world data of anlotinib for gastrointestinal tumors with liver metastases in China.

738 Background: Patients with advanced gastrointestinal tumors, such as gastric cancer (GC), colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC), biliary tract cancer (BTC) and pancreatic cancer (PC), often develop liver metastases with poor prognosis. Recent clinical studies have implicated that anlotinib (a novel anti-angiogenesis agent) could improve survival outcomes in gastrointestinal tumors with liver metastases, albeit with limited real-world evidence. This study aimed to report the efficacy and safety of anlotinib for gastrointestinal tumors with liver metastases in real-world practice. Methods: Demographic and clinical data of patients treated with anlotinib in any line of treatment for solid tumors with liver metastases (excluding primary liver cancer) was collected retrospectively through 5 large hospitals in China, between Jan, 2016 and Feb, 2023. The primary endpoints were progression-free survival (PFS) and objective overall response (ORR). Secondary endpoints included overall survival (OS), hepatic PFS (hPFS), hepatic ORR (hORR) and safety. In this abstract, we present data from patients with gastrointestinal tumors. PFS, hPFS and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: A total of 475 patients were enrolled in the study and 238 patients with gastrointestinal tumors were analyzed, including 73 (30.7%) GC, 71 (29.8%) CRC, 46 (19.3%) ESCC, 24 (10.1%) PC, and 24 (10.1%) BTC. 75.2% were <75 years old, 82.4% were male, 63.9% had a normal body mass index (BMI) (18.5-24 kg/m2), 87.8% received third-line anlotinib, and 90.3% received anlotinib monotherapy. At data cut-off (Feb 28, 2023), the median PFS was 5.90 months (95% CI: 5.23-6.77), the median hPFS was 6.20 months (95% CI: 5.27-6.77), and the median OS was 9.37 months (95% CI: 8.40-NR). There was no statistically significant difference according to the tumor types in terms of PFS (p=0.66), hPFS (p=0.8) and OS (p=0.72). We also found patients with a BMI < 18.5 kg/m2 had significantly shorter PFS (p=0.005) and hPFS (p=0.01). Adverse events (AEs) were manageable and tolerable, 30 (12.6%) patients had treatment-emergent adverse events (TEAEs) and 3 patients (1.3%) had ≥3 TEAEs. The most common treatment-related adverse events (TRAEs) were leukopenia (5.9%). Conclusions: To our knowledge, this is the first real-world report about anlotinib for gastrointestinal tumors with liver metastases in China, showed the clinical benefit of anlotinib in any line of treatment for gastrointestinal tumors with liver metastases and indicated that anlotinib could be a feasible treatment option in this specific population.

Anlotinib plus chemotherapy as first-line therapy for patients with gastrointestinal tumor with unresectable liver metastasis: Updated results from multi-cohort, multi-center phase II trial ALTER-G-001-cohort A.

112 Background: Advanced gastrointestinal (GI) tumors, such as colorectal, gastric and pancreatic cancers (CRC, GC, and PC), and esophageal squamous cell carcinoma (ESCC), 20%-50% with liver metastases (LMs). The prognosis of CRC with unresectable LMs is poor, with a 5-year survival rate of less than 5%. Previous trials showed that anlotinib plus chemotherapy has promising clinical activity and a tolerable safety profile for advanced CRC and ESCC, especially with LMs. In this phase II trial, we assessed the efficacy and safety of anlotinib plus chemotherapy as first-line treatment for LMs GI tumors. Methods: Patients with unresectable LMs GI tumors and without previous systemic treatment would be divided into cohort A (CRC), cohort B (ESCC), and cohort C (other GI tumors, such as PC, GC, etc.). In cohort A, CRC patients received induction therapy (6 cycles, q3w): anlotinib (12 mg, PO, QD, days 1-14), oxaliplatin (130 mg/m2, IV, day 1), capecitabine (850 mg/m2, PO, BID, days 1-14). Patients without PD and radical resection received anlotinib and metronomic capecitabine (500 mg, PO, BID, days 1-21, q3w) maintenance until PD or unacceptable toxicity. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints were DoR, PFS, OS, DCR, radical resection rate for LMs, and safety. Results: As of September 14, 2023, 45 patients were enrolled in cohort A, the median age was 67 years (35-75), 66.7% male, 91.1% ECOG-PS 1 and 60% had LMs only. After induction therapy, 8 patients received surgical resection. Currently, 13 patients are receiving induction therapy and 10 are undergoing maintenance therapy, with a maximum duration of treatment (DOT) of 13.7 months. Of 39 evaluable patients in cohort A, ORR and DCR were 48.7% and 97.4% (PR, n=19; SD, n=19, 16 SD had reduced tumor size). The median PFS was not reached. 36 patients had TEAEs and ≥ grade 3 TEAEs (33.3%) mainly included neutropenia (11.1%), hypertension (6.7%), and white blood cell decreased (6.7%). Conclusions: Anlotinib plus chemotherapy as first-line treatment has shown promising efficacy and acceptable safety and maybe a favorable option for advanced LMs CRC tumors. Clinical trial information: NCT05262335 .

Ibrutinib combination therapy for advanced gastrointestinal and genitourinary tumours: results from a phase 1b/2 study

BackgroundIbrutinib, a first-in-class inhibitor of Bruton’s tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated.MethodsIbrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival [PFS] for CRC) in phase 2.ResultsA total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9–7.5) months in RCC, 4.0 (2.7–4.2) months in GC, and 5.4 (4.1–5.8) months in CRC.ConclusionsClinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours.Trial registrationClinicalTrials.gov, NCT02599324.

164P Clinical utility of comprehensive molecular profiling tests for advanced gastrointestinal tumors

164P Clinical utility of comprehensive molecular profiling tests for advanced gastrointestinal tumors

Efficacy of PD-1 inhibitors in the treatment of advanced gastrointestinal tumors and the effect on T-lymphocyte subsets and IL-6 levels in patients.

44 Background: Immune checkpoint inhibitors (ICIs) have improved the therapeutic prospects in advanced gastrointestinal tumors. The PD-L1 expression has become one of predictive biomarkers for immunotherapy and used in treatment, but there are still some drawbacks. The aim of this study was to investigate the changes in peripheral blood T-lymphocyte subsets, IL-6 levels before and after treatment with ICIs and clinical significance. Methods: 70 patients with advanced gastrointestinal tumors who were hospitalized in Shaanxi Provincial People's Hospital from January 2020 to December 2022 were selected. 30 healthy patients were selected as controls. PD-L1 was detected by immunohistochemistry. Patients were treated with ICIs (sintilimab or pembrolizumab). 1 day before treatment, 20 days after the end of the 4 cycles of treatment, peripheral venous blood was collected and CT or MRI was performed to evaluate the therapeutic effect. Complete response (CR), partial response (PR), and stable disease (SD) were classified as immune response group, and progressive disease (PD) was classified as immune non-response group. To evaluate the effects of ICIs on the levels of T-lymphocyte subsets (Percentage of CD3+T cells, percentage of CD4+T cells, percentage of CD8+T cells, CD4+/CD8+, CD3+T cells, CD4+T cells, CD8+T cells) and IL-6. Results: Compared to controls, CD3+T cells, CD4+T cells, CD8+T cells and CD4+/CD8+ were significantly lower ( P<0.05). After 4 cycles of immunotherapy, the CD3+T cells, CD4+T cells, CD8+T cells, and CD4+/CD8+ levels were significantly higher ( P<0.05), and IL-6 levels were lower ( P<0.05). After 4 cycles of treatment, 48 cases were divided in the immune response group and 22 cases in the immune non-response group, with a treatment efficiency of 68.6%. In the immune response group compared to the immune non-response group, the levels of percentage of CD4+T cells, CD4+/CD8+, CD3+T cells and CD4+T cells were significantly higher ( P<0.05), while the percentage of CD8+T cells level was lower ( P<0.05). The percentage of CD4+T cells, CD4+/CD8+, CD3+T cells, CD4+T cells and CD8+T cells were significantly higher ( P<0.05) in the immune response group after 4 cycles of immunotherapy, while the percentage of CD8+T cells level was lower ( P<0.05) compared to before immunotherapy. The percentage of CD4+T cells and CD4+/CD8+ were significantly lower ( P<0.05), the percentage of CD8+T cells and CD8+T cells were higher ( P<0.05) in the immune non-response group compared to before immunotherapy. In the immune response group, the percentage of CD4+T cells was higher in the PD-L1 high expression groups (≥ 50%) compared to the PD-L1 low expression groups (< 50%) ( P<0.05). Conclusions: PD-1 inhibitors can affect the distribution of immune cells such as T-lymphocyte subsets in patients with advanced gastrointestinal tumors and improve the immune status of patients.

Anlotinib plus chemotherapy as first-line therapy for patients with gastrointestinal tumor with unresectable liver metastasis: Results from a multi-cohort, multicenter phase II trial (ALTER-G-001).

e16268 Background: Patients (pts) with advanced gastrointestinal (GI) tumors, such as colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC), gastric cancer (GC) or pancreatic cancer (PC), often developed liver metastases (LMs) with poor prognosis. Currently, there was no formal option for those, thus, more effective regimens were needed. Previously clinical trials had demonstrated anlotinib plus chemotherapy as first-line regimen had encouraging efficacy and safety in advanced CRC and ESCC, especially in pts with LMs. Therefore, we conducted a phase II trial evaluate efficacy and safety of anlotinib plus chemotherapy as first-line treatment in pts with unresectable LMs GI tumors. Methods: A total of 116 eligible pts with unresectable LMs gastrointestinal tumors and without previous systemic treatment would be divided into cohort A (mCRC), cohort B (ESCC) and cohort C (others, such as PC, GC, etc.,). All enrolled patients received 6 cycles (3 weeks per cycle) of induction therapy, cohort A receiving anlotinib (12mg, po, qd, d1-d14), oxaliplatin (130 mg/m2, iv, d1) and capecitabine (850 mg/m2, po, bid, d1-d14), cohort B receiving anlotinib, cisplatin (60-750 mg/m2, i.v., d1/d1-3) and paclitaxel (135 mg/m2, i.v., d1) or docetaxel (75 mg/m2, i.v., d1) and cohort C receiving anlotinib plus standard chemotherapy. Then, pts in all cohorts without PD and radical resection received anlotinib and metronomic capecitabine (500mg, po. bid, d1-21, q3w) until PD or unacceptable toxicity. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, PFS, OS, DCR, radical resection rate for LMs and safety. Results: As of February 8th, 2023, 55 pts were enrolled, 23 in cohort A, 2 in cohort B and 30 in cohort C (including 18 PC, 6 GC, 5 biliary tract cancer (BTC) and others), with a median age of 62.5 years old (range 34-74), 67.3% of male, 89.1% of ECOG PS 1. 70.9% of pts had LMs only. After induction therapy, 7 pts (5 CRC, 1 PC, 1 BTC) received surgical resection. In 24 evaluable pts in cohort C, 12 had partial response (PR), 9 had stable disease (SD). ORR was 50.0% and DCR was 87.5%. Among 13 evaluable pts with PC, 7 had PR, 5 had SD, with an ORR of 53.8%. In 15 evaluable pts in cohort A, 11 reached PR and 4 had SD. The ORR of cohort A was 73.3% and DCR was 100.0%. For one evaluable ESCC pts in cohort B, the best response was PR. The median PFS was not reached. 50.9% of pts had treatment emergent adverse events (TEAEs). Incidence of grade 3/4 TEAEs was 16.4%, mainly included white blood cell decreased (7.3%), neutropenia and hypertension (5.5%). Conclusions: Anlotinib plus chemotherapy showed significant efficacy and manageable toxicities as first-line treatment in advanced gastrointestinal tumors with LMs, especially in pancreatic cancer, which might provide a new treatment strategy for those. Clinical trial information: NCT05262335 .

Tumor agnostic efficacy and safety of erdafitinib (erda) in patients (pts) with advanced solid tumors with prespecified FGFR alterations (FGFRalt): RAGNAR primary analysis.

3121 Background: FGFRalt are present across malignancies at various frequencies and may act as oncogenic drivers across tissue histology. Erda is an oral selective pan-FGFR tyrosine kinase inhibitor with activity and safety in pts with prespecified FGFR-altered locally advanced or metastatic urothelial carcinoma (UC) and cholangiocarcinoma . RAGNAR (NCT04083976) is an ongoing phase 2 open-label, single-arm tumor agnostic trial of erda in pretreated adult and pediatric pts with FGFRalt advanced solid tumors. Interim results showed erda clinical benefit, with an objective response rate (ORR) of 29.2%. Here we report results of the primary analysis. Methods: Pts aged ≥12 y with advanced or metastatic (non-UC) tumors of any histology with predefined FGFR1-4alt (mutations/fusions per local/central test), disease progression on ≥1 prior line of systemic therapy (tx), and no alternative standard tx received oral erda until disease progression or intolerable toxicity. The primary end point was ORR by independent review committee (IRC). Secondary end points included duration of response (DOR), disease control rate (DCR [CR + PR + SD]), clinical benefit rate (CBR [CR + PR + SD >4 mo]), progression-free survival (PFS), overall survival (OS), and treatment-emergent adverse events (TEAEs). Results: At data cutoff, 217 pts were treated, median age was 57.0 y (range, 12-79), median prior systemic tx was 2 (46%; ≥3 lines of tx) with an ORR to last line prior to study entry of 10.1%. ORR to erda tx by IRC was 29.5% (95% CI, 23.5-36.0) with 6 CRs (2.8%) and 58 PRs (26.7%) in 16 distinct tumor types, including advanced CNS, thoracic, gastrointestinal, gynecologic, and rare tumors. ORR was comparable across FGFR1-3 mutations (25.3% [95% CI, 16.0-36.7]) and fusions (32.6% [95% CI, 25.1-40.9]). Median DOR, PFS, and OS were 6.9 mo (95% CI, 4.4-7.1), 4.2 mo (95% CI, 4.1-5.5), and 10.7 mo (95% CI, 8.7-12.1), respectively; DCR was 73.7% and CBR was 45.6%. 99.5% of pts experienced TEAEs, including 70.0% with grade ≥3. Treatment-related serious AEs occurred in 8.3% of pts with no treatment-related deaths. Conclusions: Primary analysis results from RAGNAR, the largest tumor agnostic trial of targeted tx to date, confirm efficacy of erda in heavily pretreated pts with FGFRalt advanced solid tumors. Erda activity was observed in adults and adolescents across tumor types, and across FGFR1-3 gene mutations and fusions. Erda tolerability was consistent with its known safety profile. Clinical trial information: NCT04083976 . [Table: see text]

Efficacy and safety of anlotinib hydrochloride combined with nivolumab in the treatment of advanced upper gastrointestinal tumor as second-line or later-line therapy: The results of gastric cancer cohort.

e16015 Background: The upper gastrointestinal tumors, such as gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC), have high rates of incidence and poor prognosis in our country, lacking of efficient therapy after failure of first-line regimen. Despite available treatment, there are still huge unmet medical needs of second-line or later-line therapy for patients with GAC or ESCC. Therefore, we will investigate the efficacy and safety of Anlotinib Hydrochloride (a multi-target tyrosine kinase inhibitor) combined with Nivolumab (PD-1 antibody) in GAC and ESCC. Methods: Patients with unresectable or metastatic GAC or ESCC who have failed standard therapy were treated by Anlotinib Hydrochloride 12mg/day orally for two weeks and Nivolumab 360mg every 3 week until the disease progression or intolerable adverse effects occurring. The study protocol was registered on ClinicalTrial.gov (NCT04503967,07/08/2020). The primary endpoint of this study was ORR (Objective Response Rate). The secondary endpoints were PFS (Progression-Free Survival), OS (Overall Survival), DCR (Disease Control Rate), and safety. Results: Gastric adenocarcinoma cohort would be reported only. From December 2020 to September 2022, 45 patients were enrolled in gastric adenocarcinoma cohort. There were 34 male patients and 11 female patients. The median age was 59 years. The percentage of gastric cancer patients with second-line and later-line treatment were 62.2% and 37.8%, respectively. 2 patients (4.4%) achieved complete remission (CR), 11 patients (24.4%) got partial remission (PR), and 15 patients (33.3%) got stable disease (SD). The ORR (CR+PR) was 28.9%, and DCR (CR+PR+SD) was 62.2%. Among 28 patients (62.2%) treated as second-line therapy, ORR was 32.1%, and DCR was 57.0%. As for later-line therapy of 17 patients, ORR and DCR were 23.5% and 70.6%, respectively. The median follow-up duration was 15.0 months (95% CI 8.17~21.83), then median PFS was 3.80±0.94 months, and median OS was 11.10±3.04 months. When the patients were treated as second-line therapy, median PFS was 3.0±0.97 months, and median OS was 14.50±3.89 months. Median PFS and OS in later-line patients of gastric adenocarcinoma were 3.80±1.30 months and 8.0±0.68 months, respectively. 36 patients (80%) had treatment-related adverse events (TRAEs). More than 10% of incidence rate included hypothyroidism (n=8), liver dysfunction (n=6), and rash (n=6). G3-4 of TRAEs were hypothyroidism (n=1), liver dysfunction (n=1), palmar-plantar erythrodysesthesia (n=1), rash (n=1), and hypophysitis (n=1). Conclusions: Anlotinib hydrochloride combined with Nivolumab showed effective clinical response and tolerable safety in second-line or later-line treatment of advanced gastric adenocarcinoma. Clinical trial information: NCT04503967 .

Phase 1 study of WNT pathway Porcupine inhibitor CGX1321 and phase 1b study of CGX1321 + pembrolizumab (pembro) in patients (pts) with advanced gastrointestinal (GI) tumors.

3514 Background: Despite the fundamental role of WNT signaling in GI cancers, especially colorectal cancer (CRC), no drug targeting WNT signaling has been successfully developed. CGX1321, a highly-potent and selective inhibitor of O-acyltransferase Porcupine, blocks WNT ligand secretion. Preclinical studies show that CGX1321 inhibits WNT signaling and growth of tumors with RSPO fusions or inactivating RNF43 mutations. Activation of WNT signaling has been associated with cancer immune-suppression and resistance to immunotherapy. Methods: The first-in-human trials (NCT02675946 in U.S., NCT03507998 in China) include phase 1 CGX1321 dose escalation (3 – 18 mg, once daily) and dose expansion (18 mg), and phase 1b CGX1321 + pembro combination (Keynote 596). The primary objectives were safety, tolerability and identification of recommended doses and schedules for further evaluation. Secondary objectives were characterization of the PK profile and PD response and anti-tumor activity. CGX1321 was dosed once daily, orally, for 21 days out of 28-day cycles as single-agent, or for 14 days out of 21-day cycles in combination with pembro. Results: As of January 1, 2023, 77 pts were enrolled, including 38 pts with solid tumors in the CGX1321 dose escalation, 17 pts with CRC or small bowel cancer (SBC) carrying RSPO or RNF43 alterations in the CGX1321 expansion, 17 pts with microsatellite stable (MSS) CRC in the CGX1321 + pembro dose escalation and 5 pts with MSS CRC in the CGX1321 + pembro expansion. Six of the 17 pts with MSS CRC or SBC from the CGX1321 single-agent expansion were rolled over to CGX1321 + pembro upon disease progression. Across all cohorts, treatment was well tolerated with the majority of AEs being Grade 1/2 and not related to CGX1321, while Grade > 3 AEs related to CGX1321 were infrequent (~6%). Dysgeusia, a common AE observed with other WNT inhibitors, was mild (mostly Grade 1). Bone resorption, the main on-target AE, was manageable and preventable by prophylactic administration of denosumab or zoledronic acid. PK and PD analyses showed adequate drug exposure and significant inhibition of WNT signaling as measured by reduced hair follicle axin2 expression from 12 mg dose. Twelve of 17 pts (71%) with confirmed tumor genetic alterations in RSPO or RNF43 had SD with median time to progression of 112 days (range: 56 – 392). Of the 6 pts in the roll-over cohort, 3 pts with RSPO3 fusion tumors achieved PR during CGX1321 + pembro combination therapy. Conclusions: CGX1321 has demonstrated potent inhibition of the WNT pathway with manageable side effects. Promising efficacy signals have been observed in pts whose tumors harbor RSPO fusion, supporting further development of CGX1321 monotherapy and CGX1321 + anti-PD-1/L1 in a defined patient population that is historically known to be refractory to standard therapies and immune checkpoint inhibitors. Clinical trial information: NCT02675946 , NCT03507998 .

SEOM-GETNE clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2022).

Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise mainly due to an improvement on diagnostic techniques and awareness. Earlier detection, along with steadfast improvements in therapy, has led to better prognosis over time for advanced gastrointestinal and pancreatic neuroendocrine tumors. The aim of this guideline is to update evidence-based recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification, and therapeutic options, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, are reviewed and discussed, and treatment algorithms to guide therapeutic decisions are provided.

Acute inflammatory reaction during anti-angiogenesis therapy combined with immunotherapy as a possible indicator of the therapeutic effect: Three case reports and literature review.

The posterior line treatment of unresectable advanced or metastatic gastrointestinal (GI) tumors has always been a challenging point. In particular, for patients with microsatellite stable (MSS)/mismatch repair proficient (pMMR) 0GI tumors, the difficulty of treatment is exacerbated due to their insensitivity to immune drugs. Accordingly, finding a new comprehensive therapy to improve the treatment effect is urgent. In this study, we report the treatment histories of three patients with MSS/pMMR GI tumors who achieved satisfactory effects by using a comprehensive treatment regimen of apatinib combined with camrelizumab and TAS-102 after the failure of first- or second-line regimens. The specific contents of the treatment plan were as follows: apatinib (500 mg/d) was administered orally for 10 days, followed by camrelizumab (200 mg, ivgtt, day 1, 14 days/cycle) and TAS-102 (20 mg, oral, days 1-21, 28 days/cycle). Apatinib (500 mg/d) was maintained during treatment. Subsequently, we discuss the possible mechanism of this combination and review the relevant literature, and introduce clinical trials on anti-angiogenesis therapy combined with immunotherapy.

Claudin18.2 expression and clinicopathological features in cytology effusion specimens from gastric adenocarcinoma: Acomparative study with tissue specimens.

Zolbetuximab (IMAB362) is under investigation for treating advanced gastrointestinal tumors because it targets Claudin18.2 (CLDN18.2). CLDN18.2 is a promising molecule along with the presence of human epidermal growth factor receptor 2 in gastric cancer. This study evaluated cell block (CB) preparations of serous cavity effusions for the feasibility for CLDN18.2 protein expression and compared the results with those of biopsy or resection specimens. The association of CLDN18.2 expression in effusion samples and the clinicopathological features were also investigated. Cytological effusion specimens and matched surgical pathology biopsy or resection specimens of 43 gastric and gastroesophageal junctional cancer cases were stained for CLDN18.2 expression and quantified using immunohistochemistry based on the manufacturer's instructions. Positive staining was detected in 34 (79.1%) tissue and 27 (62.8%) effusion CB samples in this study. When "positivity" was defined as moderate-to-strong staining in ≥40% viable tumor cells, CLDN18.2 expression was observed in 24 (55.8%) tissue and 22 (51.2%) effusion CB samples. A cutoff of 40% for CLDN18.2 positivity was used to demonstrate high concordance (83.7%) between cytology CB and tissue specimens. The results showed that CLDN18.2 expression in effusion specimens correlated with tumor size (p=.021) but not with sex, age at diagnosis, primary tumor location, staging, Lauren phenotype, cytomorphologic features, or Epstein-Barr virus infection. Cytological effusions with or without CLDN18.2 expression did not significantly affect overall survival. This study's results show that serous body cavity effusions may be suitable for CLDN18.2 biomarker testing; however, discordant cases should be interpreted cautiously.

The genomic landscape of advanced gastrointestinal (GI) neuroendocrine tumors (NET) and carcinomas (NEC).

656 Background: The impact of specific genomic alterations in advanced GI neuroendocrine malignancies on prognosis and treatment decisions has not been fully characterized. In this study, we seek to evaluate next-generation sequencing (NGS) panels and corresponding clinical outcomes in patients with metastatic GI NET/NEC. Methods: Patients with GI-NET/NEC were identified from a database of NGS reports performed at the Cleveland Clinic, and clinical variables were extracted by chart review through an IRB-approved protocol. We provide an analysis of this cohort. Results: Of a total n=45 patients, 53% were male. Median age at diagnosis was 60 (range: 35-90 years) and 82% were non-Hispanic white, while 9% were black. There were n=25 GI-NETs, mostly intermediate or high grade (11 G3, 7 G2), and n=20 GI-NECs. There was a balanced distribution of primary sites, including colorectal (27%), pancreas (24%), small intestine (18%), unknown primary (24%) and a single case of biliary primary. High grade GI-NETs and GI-NECs were over-represented in the colorectal primary group vs other sites. (n=10 of 12; p=0.021). The majority of patients (73%) had at least one somatic variant, including 12 patients (27%) with one or more mutations deemed actionable, but only one patient (with MSH2 mutation) has received a mutation-matched drug (pembrolizumab). Some recurrent alterations appeared to co-segregate with aggressive histology (NEC vs NET), including 12 of 13 TP53 mutations (p<0.05 by Fisher Exact Test), 7 of 8 RB1 (p<0.05), and 5 of 6 APC (p=0.074). The most common mutations per person based on primary site is shown. Microsatellite instability high was rare (n=1) and median tumor mutational burden (TMB) was 3/mb, with TMB lower in NETs vs NECs. A number of patients (35%) underwent germline testing, with 6 of 16 having a pathogenic germline variant. Conclusions: As 42% of the 12 patients with actionable mutations were alive at time of analysis, it is possible that additional patients could be treated with mutation-matched therapies. More input will be needed from providers as to the role played by alternative effective treatments and barriers such as insurance coverage and prior authorization to implementing mutation-matched therapies. Given the overall low TMB of GI-NETs, with several tumors having zero or 1 reported mutation on targeted NGS, whole genome sequencing may prove useful. Finally, certain mutations such as RB1 and TP53 were associated with more aggressive histology (i.e. NEC). Lastly, only 9% of our cohort with NGS were black, a significant under-representation based on epidemiological data, which raises concerns about disparate accessibility and barriers to NGS testing. Further studies are needed to address any possible racial disparity.[Table: see text]

The evaluation of morbidity in gastrointestinal tumor patients underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC).

In this study, we aimed to determine the postoperative morbidity rate and identify demographic, clinical, and treatment-related variables that may be potential risk factors for morbidity in gastrointestinal tumor patients undergoing hyperthermic intraperitoneal chemotherapy (HIPEC) with or without cytoreductive surgery (CRS). In this retrospective study, 60 patients who had undergone HIPEC due to gastrointestinal tumor between October 2017 and December 2019 were included. Systemic toxicities were graded and evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria. Mean age of the patients was 60.43 ± 12.83. Primary tumor localization was the stomach in 33 patients (55%), colon in 21 (35%), rectum in five (8.3%), and appendix in one patient (1.7%). PCI mean value was 9.51 ± 10.92. CC-0 was applied in 37 (61.7%) patients, CC-1 in 11 (18.3%), CC-2 in 6 (10%), and CC-3 in six patients (10%). Morbidity was observed in 50 (83.33%) of the 60 patients participating in the study according to NCI-CTCAE v3.0 classification. Mild morbidity rate was 46.6%, severe morbidity rate was 36.6%, and mortality rate was 11.66%. Enteric diversion application, length of stay in the ICU, and length of hospital stay were shown to have a statistically significant effect on the NCI-CTCAE morbidity score (p= 0.046, p= 0.004, p <0.001). With proven beneficial effects on survival in patients with locally advanced gastrointestinal tumors, CRC and HIPEC are acceptable in these patients despite their increased morbidity and mortality rate. With new studies on this subject, morbidity and mortality rates may be reduced.