Therapy For Advanced Gastric Cancer Research Articles

A single-arm, multicenter, phase II study of utidelone in advanced solid tumors: Efficacy data from screening and the expansion cohort assessing utidelone plus sintilimab and oxaliplatin for advanced gastric cancer.

e16055 Background: Treatment regimens for many advanced solid tumors are limited and alternative options are needed.Utidelone is approved for the treatment of advanced breast cancer in China. NCT04911907 is a single-arm, multicenter, phase II study to assess the efficacy and safety of utidelone in advanced cancer. Stage I of the trial, completed in October 2023, included patients (pts) with pretreated advanced solid tumors. Based on the stage I data, a stage II expansion cohort (USO-G) investigated utidelone plus sintilimab and oxaliplatin as first-line therapy for advanced gastric cancer (GC). Here, we report efficacy and safety data from stage I and stage II for interim analysis. Methods: Eligible pts aged 18–70 years with pretreated advanced solid tumors were enrolled in stage I and received utidelone monotherapy (35 mg/m2/day iv on days 1–5 every 21 days). In stage II, eligible pts with metastatic and/or unresectable HER2 negative GC received utidelone (30mg/m2/day iv on days 1–5 every 21 days) plus sintilimab (200 mg iv Q3W) and oxaliplatin (130 mg/m2/day Q3W for up to 6 cycles), until disease progression or unacceptable toxicity. Results: From March 18th 2021 to October 13th 2022, 79 pts were enrolled into 7 tumor cohorts and 54 pts were evaluable for efficacy. The best overall responses were 1 CR, 3 PRs and 3 SDs in 10 esophageal cancer pts, 3 PRs and 5 SDs in 15 GC pts, 1 PR and 3 SDs in 10 ovarian cancer pts, SD for all 4 cholangiocarcinoma pts, 3 SDs in 4 cervical cancer pts, 2 SDs in 3 pancreatic cancer pts and a PR in 1 neuroectodermal tumor patient. Grade 3/4 TRAEs occurred in 27.8% of pts in stage I, and included anemia (13.9%), peripheral neuropathy (11.4%) and neutropenia (7.6%). No treatment-related deaths occurred. Gastric cancer was chosen as the expansion cohort indication. As of February 1st 2024, 14 eligible pts with GC with a median age of 57 years (range, 41–69) were enrolled. The median follow-up was 5.5 months (range, 1.0–9.7) and the longest duration of response was 8.0 months. A total of 8 PRs and 3 SDs were achieved in the 11 pts evaluable for efficacy, and 6 pts including the 3 with SD were still receiving treatment. Grade 3/4 TRAEs occurred in 28.6% of pts including diarrhea (14.3%), fatigue (14.3%), neutropenia (14.3%), and vomiting (7.1%). Other AEs were all Grade 1 or 2, with no treatment-related deaths. Conclusions: Utidelone monotherapy showed antitumor activity and manageable toxicity in pts with advanced solid tumors. Utidelone plus sintilimab and oxaliplatin demonstrated promising efficacy and an acceptable safety profile as first-line treatment for pts with GC. Stage II of the USO-G study is still actively enrolling; further data will be provided at the time of presentation. Clinical trial information: NCT04911907 .

Integrated clinical and genomic models using machine-learning methods to predict the efficacy of paclitaxel-based chemotherapy in patients with advanced gastric cancer

BackgroundPaclitaxel is commonly used as a second-line therapy for advanced gastric cancer (AGC). The decision to proceed with second-line chemotherapy and select an appropriate regimen is critical for vulnerable patients with AGC progressing after first-line chemotherapy. However, no predictive biomarkers exist to identify patients with AGC who would benefit from paclitaxel-based chemotherapy.MethodsThis study included 288 patients with AGC receiving second-line paclitaxel-based chemotherapy between 2017 and 2022 as part of the K-MASTER project, a nationwide government-funded precision medicine initiative. The data included clinical (age [young-onset vs. others], sex, histology [intestinal vs. diffuse type], prior trastuzumab use, duration of first-line chemotherapy), and genomic factors (pathogenic or likely pathogenic variants). Data were randomly divided into training and validation sets (0.8:0.2). Four machine learning (ML) methods, namely random forest (RF), logistic regression (LR), artificial neural network (ANN), and ANN with genetic embedding (ANN with GE), were used to develop the prediction model and validated in the validation sets.ResultsThe median patient age was 64 years (range 25–91), and 65.6% of those were male. A total of 288 patients were divided into the training (n = 230) and validation (n = 58) sets. No significant differences existed in baseline characteristics between the training and validation sets. In the training set, the areas under the ROC curves (AUROC) for predicting better progression-free survival (PFS) with paclitaxel-based chemotherapy were 0.499, 0.679, 0.618, and 0.732 in the RF, LR, ANN, and ANN with GE models, respectively. The ANN with the GE model that achieved the highest AUROC recorded accuracy, sensitivity, specificity, and F1-score performance of 0.458, 0.912, 0.724, and 0.579, respectively. In the validation set, the ANN with GE model predicted that paclitaxel-sensitive patients had significantly longer PFS (median PFS 7.59 vs. 2.07 months, P = 0.020) and overall survival (OS) (median OS 14.70 vs. 7.50 months, P = 0.008). The LR model predicted that paclitaxel-sensitive patients showed a trend for longer PFS (median PFS 6.48 vs. 2.33 months, P = 0.078) and OS (median OS 12.20 vs. 8.61 months, P = 0.099).ConclusionsThese ML models, integrated with clinical and genomic factors, offer the possibility to help identify patients with AGC who may benefit from paclitaxel chemotherapy.

Evaluation of the efficacy and safety of ramucirumab combined with nab-paclitaxel, lobaplatin, and S-1 in neoadjuvant and conversion therapy for advanced gastric cancer: A study protocol of prospective single-center, randomized controlled and open label clinical trial (RNPLS-01)

ObjectiveRamucirumab is a VEGFR2 antagonist. The aim of this trial is to evaluate the efficacy and safety of ramucirumab combined with nab-paclitaxel, lobaplatin and S-1 in neoadjuvant and conversion therapy for advanced gastric cancer. Methodsand analysis: This study is a prospective single-center, randomized controlled and open label clinical study, enrolling a total of 140 patients with advanced gastric cancer distributed across two distinct cohorts (Cohort A n = 70; Cohort B n = 70). The central focus of the study lies in evaluating the pathological complete response (pCR) of the cancer post-neoadjuvant or conversion therapy. Secondary endpoints encompass the assessment of the R0 resection rate subsequent to the aforementioned therapies, the occurrence of adverse events (AE), progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the total response rate and its duration, the disease control rate (DCR), and the duration of overall response (DOR). EthicsEthics approval has been obtained from the Ethics Committee at the First Affiliated Hospital (Xijing Hospital) of Air force Military Medical University (KY20232220–F-1). Trial registrationThis trial has been registered at the ClinicalTrials.gov: NCT06169410 (registration date: December 5, 2023).

Association of lymphocyte subsets with the efficacy and prognosis of PD‑1 inhibitor therapy in advanced gastric cancer: results from a monocentric retrospective study

PurposeThis retrospective study aimed to investigate the changes in peripheral blood lymphocyte subsets before and after immunotherapy in patients with advanced gastric cancer and their relationship n with the therapeutic efficacy and clinical prognosis.MethodsPeripheral blood lymphocyte subsets, including CD4 + T cells, CD8 + T cells, CD4+/CD8 + ratio, NK cells, Treg cells, and B cells, were collected from 195 patients with advanced gastric cancer who were admitted to the First Hospital of Shanxi Medical University with immunotherapy from January 2020 to October 2021, at the time of diagnosis of advanced gastric cancer, before immunotherapy and after 3 cycles of immunotherapy. T-tests were used to examine the factors influencing the patients’ peripheral blood lymphocyte subsets and the changes after immunotherapy. To examine the relationship between lymphocyte subsets and treatment outcomes, ROC curves were plotted using a logistic regression. Kaplan–Meier curve was drawn, and the Log Rank test was carried out to compare the differences in PFS between the different groups. Cox proportional hazards regression model was used to analyze the factors affecting PFS after calibration of other variables.ResultsThe proportion of peripheral blood lymphocyte subsets in patients with advanced gastric cancer was affected by age and PD-L1 level. Compared to the baseline, the treatment effective group had higher proportions of CD4 + T cells, a higher CD4+/CD8 + ratio, NK cells and Treg cells, and lower proportions of CD8 + T cells and B cells in the peripheral blood after three cycles of immunotherapy. In the treatment-naive group, there were no significant differences in the lymphocyte subsets. With cut-off values of 30.60% and 18.00%, baseline CD4 + T cell and NK cell ratios were independent predictors of immunotherapy efficacy and PFS. Treg cell ratio, gender, PD-L1 levels, and MMR status all predicted PFS independently.ConclusionThe proportion of peripheral blood lymphocyte subsets was modified in patients who responded to PD-1 inhibitors. Different lymphocyte subpopulation levels can be used as biomarkers to predict immunotherapy efficacy and clinical prognosis in patients with advanced gastric cancer.

A phase II study of perioperative capecitabine plus oxaliplatin (CapeOx) therapy for advanced gastric cancer with multiple lymph node metastases (OGSG 1701).

304 Background: Gastric cancer with paraaortic lymph node metastasis or bulky lymph node metastasis is difficult to undergo curative resection without preoperative chemotherapy. Even if curative resection can be performed, the prognosis is extremely poor. The purpose of this study was to evaluate the efficacy and safety of perioperative capecitabine plus oxaliplatin combined chemotherapy (CapeOx) for such advanced gastric cancer with multiple lymph node metastases. Methods: In this phase II trial, eligibility criteria were as follows; histologically proven gastric carcinoma; HER2 negative or unknown; with paraaortic lymph node metastases (#16a2/16b1) > 10 mm and/or bulky lymph node metastases located at celiac axis, common hepatic artery, splenic artery and/or upper mesenteric vein which make a huge bulk > 3.0 cm and/or multiple large bulks > 1.5 cm; without any other metastatic lesions; not a large (≥ 8 cm) type 3 or type 4 gastric cancer; and age between 20 and 80 years old. Treatment included three cycles of preoperative CapeOx (capecitabine; 2,000 mg/m2 for 14 days, oxaliplatin; 130 mg/m2 day 1) every 3 weeks, followed by five cycles of postoperative CapeOx after radical gastrectomy. The primary endpoint was response rate according to the RECIST v1.0. The planned sample size was 30 patients calculated on the hypothesis that the expected response rate was 65% and the threshold was 50%, with one-sided alpha of 0.05 and the power of 90%. Results: Thirty patients from 14 institutions were enrolled from September 2017 to June 2022. The number of patients with compete response, partial response, stable disease, progressive disease, and inevaluable were, 0, 20, 8, 1, and 1, respectively. The response rate was 66.7%, with the 90% confidence interval of 50.1 - 80.7% ( p = 0.049). The curative resection rate was 93.3%. The protocol treatment completion rate was 53.3%. The preoperative chemotherapy completion rate was 93.3%. The operation completion rate was 90.0%. The postoperative chemotherapy completion rate was 70.0%. The relative dose intensities were 94.8% for capecitabine and 95.2% for oxaliplatin on preoperative CapeOx, and 80.8% for capecitabine and 64.2% for oxaliplatin on postoperative CapeOx. The histological response rate (Grade ≥ 1b) was 66.7%. The adverse events of Grade ≥ 3 included neutropenia in 3.3%, anemia in 6.7%, and anorexia in 10% on preoperative CapeOx, and neutropenia in 23.8% and diarrhea in 9.5% on postoperative CapeOx. The final results of the survival analysis are yet to come. Conclusions: Perioperative CapeOx therapy for advanced gastric cancer with multiple lymph node metastasis showed favorable response rate, curative resection rate and acceptable adverse events, and was considered a promising treatment regimen. Clinical trial information: UMIN000028749 .

Nivolumab Rechallenge After Prior Nivolumab Therapy in Advanced Gastric Cancer: A Single-Center Case Series and Literature Review.

Pivotal phase III trials indicated that the anti-PD-1 inhibitor nivolumab prolongs overall survival in patients with advanced gastric cancer. Nivolumab is currently used in the first- or later-line treatment of patients with advanced gastric cancer in Japan. The efficacy of immune check inhibitor rechallenge after progression has been reported in other cancers. Therefore, this study investigated the clinical outcome of nivolumab rechallenge in patients with advanced gastric cancer who received nivolumab in a previous systemic line. We retrospectively reviewed the medical records of six patients with advanced or recurrent gastric cancer who received nivolumab rechallenge. During initial nivolumab therapy, three patients experienced partial responses, and one patient achieved stable disease. The reasons for discontinuing initial nivolumab therapy were progressive disease in five patients and immune-related adverse events in one patient. The median interval duration of treatment for patients receiving both nivolumab regimens was 13.7 (range: 5.1-17.8) months. During nivolumab rechallenge, no patients achieved partial responses, whereas two patients had stable disease. Median progression-free survival was 2.5 (95% confidence interval [CI] = 1.6-not available [NA]) months, and median overall survival was 7.4 (95% CI = 2.3-NA) months. Although one patient had discontinued prior nivolumab therapy because of immune-related adverse events, there were no immune-related adverse events associated with nivolumab rechallenge. The benefit of nivolumab rechallenge in patients with advanced gastric cancer was limited. Rechallenge with the same immune check inhibitor might be ineffective in patients with advanced gastric cancer.

Gastric cancer secreted miR-214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells.

Different from necrosis, apoptosis, autophagy and other forms of cell death, ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated fatty acids under the action of iron divalent or lipoxygenase, leading to cell death. Apatinib is currently used in the third-line standard treatment of advanced gastric cancer, targeting the anti-angiogenesis pathway. However, Apatinib-mediated ferroptosis in vascular endothelial cells has not been reported yet. Tumor-secreted exosomes can be taken up into target cells to regulate tumor development, but the mechanism related to vascular endothelial cell ferroptosis has not yet been discovered. Here, we show that exosomes secreted by gastric cancer cells carry miR-214-3p into vascular endothelial cells and directly target zinc finger protein A20 to negatively regulate ACSL4, a key enzyme of lipid peroxidation during ferroptosis, thereby inhibiting ferroptosis in vascular endothelial cells and reducing the efficiency of Apatinib. In conclusion, inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib, thereby promoting the antiangiogenic effect of Apatinib, suggesting a potential combination therapy for advanced gastric cancer.

Research progress and future directions of immune checkpoint inhibitor combination therapy in advanced gastric cancer.

In recent years, with the continuous development of molecular immunology, immune checkpoint inhibitors (ICIs) have also been widely used in the treatment of gastric cancer, but they still face some challenges: The first is that only some people can benefit, the second is the treatment-related adverse events (TRAEs) that occur during treatment, and the third is the emergence of varying degrees of drug resistance with long-term use. How to overcome these challenges, combined therapy based on ICIs has become one of the important strategies. This article summarizes the clinical application of ICIs combined with chemotherapy, targeted therapy, radiotherapy, photodynamic therapy, thermotherapy, immune adjuvant, and dual immunotherapy and discusses the mechanism, and also summarizes the advantages and disadvantages of the current combination modalities and the potential research value. The aim of this study is to provide more and more optimized combination regimen for ICI combined therapy in patients with advanced gastric cancer and to provide reference for clinical and scientific research.

Efficacy of Camrelizumab with Raltitrexed in the Therapy of Advanced Gastric Cancer on Postoperative Recurrence and Metastasis

Efficacy of Camrelizumab with Raltitrexed in the Therapy of Advanced Gastric Cancer on Postoperative Recurrence and Metastasis

Chemotherapy after nivolumab for advanced gastric cancer (REVIVE): a prospective observational study

Nivolumab therapy is a standard-of-care treatment for heavily pretreated patients with advanced gastric cancer (AGC). Previous studies have reported improvement in the objective response rate to chemotherapy after nivolumab therapy for other types of cancer. This study evaluated the efficacy and safety of chemotherapy after nivolumab therapy in AGC. We conducted a prospective, multicenter, observational study in pretreated patients with nivolumab-refractory or -intolerant AGC. Patients received irinotecan, oxaliplatin-containing regimens, or trifluridine/tipiracil. The primary endpoint was overall survival. A total of 199 patients were included (median age: 69 years; male: 70%; female: 30%). Median overall survival and progression-free survival were 7.5 months [95% confidence interval (CI): 6.7-9.7 months] and 2.9 months (95% CI: 2.2-3.5 months), respectively. Objective response and disease control rates were 16.8% (95% CI: 11.6% to 23.6%) and 18.9% (95% CI: 38.9% to 54.6%), respectively. A prognostic index using alkaline phosphatase and the Glasgow Prognostic Score was generated to classify patients into three risk groups (good, moderate, and poor). The hazard ratios of the moderate and poor groups to the good group were 1.88 (95% CI: 1.22-2.92) and 3.29 (95% CI: 1.92-5.63), respectively. At the initiation of chemotherapy, 42 patients had experienced immune-related adverse events due to prior nivolumab therapy. The most common grade 3-4 adverse events were neutropenia (7.5%), anemia (8.0%), and anorexia (7.5%). The administration of cytotoxic chemotherapy after nivolumab therapy may give rise to a synergistic antitumor effect in AGC. Further investigation is warranted to confirm these findings.

A Clinical Viewpoint on the Use of Targeted Therapy in Advanced Gastric Cancer.

The development of therapies for advanced gastric cancer (GC) has made significant progress over the past few years. The identification of new molecules and molecular targets is expanding our understanding of the disease's intricate nature. The end of the classical oncology era, which relied on well-studied chemotherapeutic agents, is giving rise to novel and unexplored challenges, which will cause a significant transformation of the current oncological knowledge in the next few years. The integration of established clinically effective regimens in additional studies will be crucial in managing these innovative aspects of GC. This study aims to present an in-depth and comprehensive review of the clinical advancements in targeted therapy and immunotherapy for advanced GC.

S-1 maintenance therapy in advanced gastric cancer without disease progression after first-line chemotherapy: A retrospective analysis.

For patients with advanced gastric cancer after chemotherapy, the optimal mode of maintenance therapy is not yet clear. This research aimed to compare the efficacy and adverse effects of S-1 maintenance therapy and follow-up observation in patients with advanced gastric cancer without disease progression after first-line combined chemotherapy. This study retrospectively analyzed 106 patients from January 2018 to December 2021. The primary endpoints were overall survival and progression-free survival, the secondary endpoint was chemotherapy-related toxicity, and the curative effects and baseline characteristics of the patients were analyzed. Longer progression-free survival and overall survival were observed in the S-1 maintenance treatment group than in the follow-up observation group (p < 0.001). No obvious differences existed in the subgroup results regarding progression-free survival or overall survival (p > 0.05). In the maintenance treatment group, the occurrence of thrombocytopenia and hand-foot syndrome was significantly increased (p < 0.001). No toxicity-related deaths occurred. The included patients without disease progression after first-line combined chemotherapy can achieve significant survival benefits by receiving S-1 maintenance therapy. The patient's tolerance to S-1 maintenance therapy was good.

Clinical analysis of immunotherapy rechallenge in advanced gastric cancer

Objective: To evaluate the efficacy and influencing factors of programmed death protein 1 (PD-1) monoclonal antibody rechallenge therapy in advanced gastric cancer (GC). Methods: The clinical data of patients with advanced GC who were treated with anti-PD-1 rechallenge in Henan Cancer Hospital from January 2020 to December 2021 were collected retrospectively. The progression-free survival (PFS) was defined as the time from the first or second used of anti-PD-1 treatment to the date of disease progression or the last follow-up, named PFS(1) and PFS(2), respectively. Kaplan-Meier method and Log rank test were used for survival analysis, Cox proportional hazard model was used to analyze the influencing factors. Results: A total of 60 patients with anti-PD-1 rechallenge therapy were collected, the median follow-up time was 12.2 months. The median progression-free survival (PFS(2)) of anti-PD-1 rechallenge therapy was 2.9 months, the objective response rate (ORR) was 16.7%, and the disease control rate (DCR) was 55.0%. The median PFS(2) of the first and second anti-PD-1 identical and different rechallenge treatment was 3.5 months and 1.9 months (P=0.007) respectively. The median PFS(2) of positive PD-L1 expression in rechallenge therapy was 3.4 months, ORR was 22.7%, and DCR was 63.6%; the median PFS(2) was 4.5 months, ORR was 27.3%, and DCR was 54.5% in patients with median PFS(1)≥6 months. Multivariate analysis showed that peritoneal metastasis was independently associated with anti-PD-1 rechallenge therapy with PFS(2) (HR=2.327, 95% CI, 1.066-5.082, P=0.034). The incidence of adverse reactions in grade 1-2 and grade 3-4 of anti-PD-1 rechallenge therapy was 83.3%, and 35.0%, respectively, and the safety was controllable. Conclusion: Rechallenge therapy with anti-PD-1 is a feasible treatment in advanced GC, but the screening of suitable population for rechallenge therapy still needs prospective data analysis and verification.

Clinical analysis of immunotherapy rechallenge in advanced gastric cancer.

e16049 Background: To evaluate the efficacy and influencing factors of programmed cell death protein 1 (PD-1) monoclonal antibody rechallenge therapy in advanced gastric cancer (GC). Methods: The clinical data of patients with advanced GC who were treated with PD-1 monoclonal antibody rechallenge in the Department of Gastroenterology, Henan Cancer Hospital from January 2020 to December 2021 were retrospectively collected. Results: A total of 60 patients with PD-1 monoclonal antibody rechallenge therapy were collected; the median follow-up time was 12.2 months. The median progression-free survival (PFS2) of PD-1 monoclonal antibody rechallenge therapy was 2.9 months, and the objective response rate (ORR) was 16.7%, and the disease control rate (DCR) was 55.0%. The median PFS2 of the same PD-1 monoclonal antibody for the first and second versus different PD-1 monoclonal antibody rechallenge treatment was (3.5 months vs. 1.9 months, P=0.006). The median PFS2 of positive PD-L1 expression in rechallenge therapy was 3.4 months, ORR was 22.7%, and DCR was 63.6%; the median PFS2 was 4.5 months, ORR was 27.3%, and DCR was 54.5% in patients with median PFS1≥6 months. Multivariate analysis showed that peritoneal metastasis was independently associated with PD-1 monoclonal antibody rechallenge with median PFS2 ( P=0.034, HR=2.327, 95%CI 1.066-5.082). The incidence of adverse reactions in grade 1-2 and grade 3-4 of PD-1 monoclonal antibody rechallenge therapy was 83.3%, and 35.0%, respectively. and the safety was controllable. Conclusions: Rechallenge therapy with PD-1 monoclonal antibody is a feasible treatment in advanced GC, but the screening of suitable population for rechallenge therapy still needs prospective data analysis and verification.

History and Future of HER2-Targeted Therapy for Advanced Gastric Cancer.

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that belongs to the human epidermal growth factor receptor family. It is overexpressed/amplified in approximately 20% of gastric or gastroesophageal junction cancers. HER2 is being developed as a therapeutic target in a variety of cancers, and several agents have been shown to be effective in breast cancer. The development of HER2-targeted therapy for gastric cancer successfully began with trastuzumab. However, while effective in breast cancer, the successive anti-HER2 agents lapatinib, T-DM1, and pertuzumab failed to demonstrate benefits regarding survival in gastric cancer compared with the existing standard therapies. Intrinsic differences lie between gastric and breast cancer in terms of HER2-positive tumor biology, which may make development difficult. Recently, a novel anti-HER2 agent, trastuzumab deruxtecan, was introduced, and the development of HER2-positive gastric cancer agents has been moving to the next stage. This review summarizes the current HER2-targeted therapy for gastric or gastroesophageal cancer in chronological order and describes the promising future of HER2-targeted therapy.

BEX2 is poor prognostic factor and required for cancer stemness in gastric cancer

Gastric cancer is the fifth most common malignancy worldwide. However, targeted therapy for advanced gastric cancer is still limited. Here, we report BEX2 (Brain expressed X-linked 2) as a poor prognostic factor in two gastric cancer cohorts. BEX2 expression was increased in spheroid cells, and its knockdown decreased aldefluor activity and cisplatin resistance. BEX2 was found to upregulate CHRNB2 (Cholinergic Receptor Nicotinic Beta 2 Subunit) expression, a cancer stemness-related gene, in a transcriptional manner, and the knockdown of which also decreases aldefluor activity. Collectively, these data are suggestive of the role of BEX2 in the malignant process of gastric cancer, and as a promising therapeutic target.

Retrospective analysis of drug intake affecting the intestinal microbiota and the therapeutic effects of chemotherapy on gastric cancer.

379 Background: Administration of some medications, such as antibiotics, antacids, and probiotic supplementation, may affects the treatment outcomes of immune checkpoint inhibitors (ICIs), through the change of gut microbiota in cancer patients. Even when ICIs are combined with cytotoxic chemotherapy (Chemo), a use of such medications is expected to be a potential biomarker. However, the impacts of medications that affect gut microbiota on the efficacy of Chemo alone is unclear. Methods: We retrospectively analyzed patients who received fluoropyrimidines and platinum-based therapy for advanced gastric cancer in our institutions between January 2010 and December 2019. Progression-free survival (PFS) and overall survival (OS) by history of antibiotic/antacid/probiotic supplementation, were analysed. Results: A total of 101 pts were analyzed. Median age was 66 years (range, 30-81), female/male; 36/65, 1st-line regimen SP/XP/SOX/XELOX/FOLFOX; 52/2/39/1/7. In all patients, The median PFS for first-line treatment was 5.8 months (95% CI: 5.0-7.3) and the median OS was 15.5 months (95% CI: 12.5-18.6).Univariate analysis for PFS of first-line treatment did not show a significant difference in antibiotic use (median 7.6 vs 5.5 months, HR: 0.79 [95%CI: 0.50-1.24], p=0.31), oral antacids (median 6.6 vs 5.8 months, HR: 0.96 [95%CI: 0.61-1.54], p=0.89) and probiotic supplementation (median 9.1 vs 5.5 months, HR: 0.7 [95%CI: 0.38-1.26], p=0.24). Similarly in OS, the use of antibiotics (median 18.4 versus 13.4 months, HR: 0.85 [95%CI: 0.53-1.37], p=0.49), oral antacids (median 16.3 vs 13.8 months, HR: 1.15 [95%CI: 0.70-1.88], p=0.58), and oral probiotic supplementation (median 20.2 vs 13.8 months, HR: 0.77 [95%CI: 0.42-1.40], p=0.40), with no statistically significant differences. Conclusions: In this study, there were no significant differences in PFS and OS between patients administered with or without antibiotics, antacids, or probiotic supplementation. Future studies are expected to investigate the impacts of these medications on the treatment outcomes of ICIs+Chemo combination.

Clinicopathological features of HER2-low expressed advanced gastric cancers.

459 Background: The DESTINY-Breast04 data demonstrated the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) was also effective for metastatic breast patients (pts) with HER2-low expression. Now that the HER2-low expressed cancer is categorized as an independent subset in breast cancer patients. It is unknown whether patients with the HER2-low expression are distinguishable from the HER2 negative or positive and are potential candidates for the anti-HER2 therapy in advanced gastric cancer (AGC) patients. Methods: We retrospectively reviewed the medical records of AGC pts who received standard chemotherapy with platinum containing regimens as the first-line treatment between Jan, 2011 and Dec, 2018 at the Cancer Institute Hospital of the JFCR. AGC pts were classified according to the HER2 status using immunohistochemistry (IHC) and in situ hybridization (ISH) as follows; HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-) and HER2 positive (IHC2+/ISH+ or 3+). This study was conducted to investigate the clinicopathological features and prognosis of HER2-low AGC pts compared with HER2 negative and positive. Results: A total of 734 AGC pts were received HER2 testing and classified into three groups according to HER2 status (HER2 negative; n=410, HER2-low; n=154, HER2 positive; n=170). The proportion of male (negative; 61.5%, low; 63.6% and positive; 69.4%), intestinal histology (negative; 21.0%, low; 44.2% and positive; 59.8%), liver metastases (negative; 18.3%, low; 24.8% and positive; 46.5%), higher serum CEA level (&gt;ULN) (negative; 32.2%, low; 41.6% and positive; 56.5%) and higher serum CA19-9 level (&gt;ULN) (negative; 34.1%, low; 36.7% and positive; 56.5%) were gradually increased along with HER2 expression level. The proportion of peritoneum metastasis (negative; 56.3%, low; 44.8% and positive; 21.8%) was decreased along with the HER2 expression level. One hundred and fifty-two pts (89.4%) received combination chemotherapy with trastuzumab in the first-line treatment. Sixteen pts received trastuzumab in the HER2-low (n=3) and HER2 negative (n=13) in the clinical trial. The median survival time (MST) of pts with HER-low was the same with that of HER2 negative (15.7ms). The statistically significant difference was observed in OS between the HER2-low and HER2 positive (HR 1.43 95% CI: 1.12-1.83, P=0.003). Conclusions: AGC Pts with HER2-low have intermediate clinicopathological features between HER2 negative and positive. A Novel effective anti-HER2 therapy for the HER2-low expressed tumor would be warranted in AGC treatment.

The transition and current pattern of drug therapy for advanced gastric cancer

The transition and current pattern of drug therapy for advanced gastric cancer

Safety and Efficacy of Trifluridine/Tipiracil Administered After Anti-PD-1 Therapies for Advanced Gastric Cancer.

The phase III TAGS trial of trifluridine/tipiracil showed a survival benefit compared with placebo as a third- or later-line treatment in patients with advanced gastric cancer (AGC), in which only a few patients had a history of previous treatment with immune checkpoint inhibitors. We retrospectively reviewed consecutive patients with AGC who received trifluridine/tipiracil monotherapy as third- or later-line chemotherapy at our institution. Clinical outcomes were assessed in both overall population and patients with previous anti-PD-1 therapies. A total of 60 patients were included in this study. Eastern Cooperative Oncology Group performance status was 0, 1, and 2 in 37%, 52%, and 12% of patients, respectively. Median number of previous treatment regimens was 4 (range=2-7). Forty-nine (82%) patients had previously received anti-PD-1 therapies. In the overall population, the most common grade 3 or higher treatment-related adverse events were neutropenia (37%), anemia (32%) leukopenia (20%), thrombocytopenia (8%), and anorexia (7%). The frequencies of grade 3 or higher events were not increased among patients with previous anti-PD-1 therapies, and no delayed onset immune-related adverse events occurred. In the overall population, objective response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS) were 4%, 42%, and 1.8 months, respectively. Efficacy results in patients with previous anti-PD-1 therapies (ORR 5%, DCR 47%, and median PFS 2.1 months) were almost comparable with those in the overall population. Trifluridine/tipiracil monotherapy after exposure to anti-PD-1 therapies showed manageable safety profile and anti-tumor activity in AGC patients.