Gastroesophageal Junction Cancer Research Articles

Cost-effectiveness of tislelizumab plus chemotherapy vs chemotherapy as first-line treatment of PD-L1 positive advanced gastric or gastroesophageal junction adenocarcinoma from a Chinese perspective

ABSTRACT Background This work was designed to assess the cost-effectiveness of front-line tislelizumab plus chemotherapy (TIS+Chemo) in advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) with positive expression of programmed cell death ligand 1 (PD-L1) from the perspective of Chinese healthcare system. Research design and methods A 10-year partitioned survival model was undertaken utilizing clinical data from RATIONALE 305. Costs and utilities were both discounted at an annual rate of 5%. The primary outcome was incremental cost-effectiveness ratios (ICERs) and calculated as the cost per quality-adjusted life years (QALYs). The willingness-to-pay (WTP) threshold was set as $18,625/QALY. Only direct medical costs were considered. Sensitivity analyses and subgroup analyses were performed to evaluate the robustness of the model. Results In the base-case analysis, the incremental cost and effectiveness associated with TIS+Chemo vs Chemo was 7,361 and 0.38 QALYs, respectively, leading to an ICER of 19,371/QALY. At the WTP threshold of $18,625/QALY, the TIS+Chemo was not a cost-effective first-line treatment option. The model outcomes were robust. Conclusions TIS+Chemo did not provide a cost-effective approach for PD-L1 positive advanced GC/GEJC in China setting. However, TIS+Chemo might be cost-effective in provinces with higher WTP threshold. Clinical trial registration RATIONALE 305, www.clinicaltrials.gov, identifier is NCT03777657.

Risk, Predictive Factors, and Nomogram of Liver Metastatic Gastroesophageal Junction Cancer: A New Study Based on the Surveillance, Epidemiology, and End Results Database.

Liver metastasesare associated with a poor prognosisin gastroesophageal junction (GEJ) cancer patients. The high rate of liver involvement is attributed to the unique anatomical location of the GEJ, which is close to the liver. Patients with liver metastasis typically have advanced, unresectable disease and limited treatment options. Therefore, early detection and predictionare crucial to guide appropriate treatment planning and improve the outcomes for patients with GEJ cancer at risk of liver metastases. Using data from the Surveillance, Epidemiology, and End Results (SEER) database, the present study aimed to elucidate the incidenceand risk factorsof liver metastases in GEJ cancer patients diagnosed between 2010 and 2019. This research employed univariable and multivariable logistic regression models to identify risk factors for the development of liver metastases. A predictive nomogram for liver metastases was developed and assessed. Patients' overall survival (OS) with liver metastases was analyzed using the Kaplan-Meier method. The study included 1,322 eligible patients with GEJ cancer, 181 (13.6%) of whom were diagnosed with liver metastases. The median overall survival (mOS)for patients with liver metastasis was approximately eight months, compared to a shorter mOS for patients without liver metastasis (P < 0.001). Factors significantly associated with the occurrence of liver metastasis includedN3 stage (OR: 1.84; 95% CI: (1.13-2.96); P < 0.001),surgery (OR: 0.09; 95% CI: (0.06-0.14); P < 0.001), lung metastasis (OR: 2.88; 95% CI: (1.78-4.63); P < 0.001), chemotherapy (OR: 0.54; 95% CI: (0.32-0.87); P < 0.001), and radiation therapy (OR: 0.33; 95% CI: (0.25-0.45); P < 0.001). The nomogram demonstrated good performance in predicting liver metastases in GEJ cancer patients (c-index: 0.820). The study identified lymph node status, surgical, lung metastasis, chemotherapy, and radiation as important predictors of outcomes for patients with GEJ cancer. The developed nomogram might be a valuable tool for predicting the risk of liver metastases in GEJ cancer patients, potentially enhancing clinical decision-making processes.By predictingthe risk of liver metastasis occurrence, clinicians mightintervene in patients with GEJ cancersas early as possible.

Immune checkpoint inhibitor plus chemotherapy versus chemotherapy alone in HER2-negative advanced gastric or gastroesophageal junction cancer: A systematic review and meta-analysis of randomized controlled trials.

e16052 Background: Synergistic effects of immune checkpoint inhibitors (ICI) and chemotherapy (CTX) have been documented, demonstrating promising efficacy across diverse cancer types. This report presents a meta-analysis aimed at assessing the effectiveness and safety profile of ICI plus CTX in patients diagnosed with Human Epidermal Growth Factor Receptor type 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) cancers. Methods: PubMed, EMBASE, Cochrane Central, and ASCO Abstracts databases were systematically searched for randomized controlled trials comparing PD-1 or PD-L1 inhibitors plus CTX with CTX alone in patients diagnosed with HER2-negative gastric or GEJ cancers. The assessed outcomes included Progression-Free Survival (PFS) and Overall Survival (OS), stratified by PD-L1 Combinated Positive Score (CPS) in tumors, as well as any Adverse Events (AE) and Treatment-Related Adverse Events (TRAE) graded as ≥ 3. Statistical analysis employed a random effects model in R version 4.3.2, with heterogeneity assessed using the I2 statistic. Results: We conducted a meta-analysis comprising 6 RCTs involving 5,520 patients, among whom 2,766 received PD-1 or PD-L1 inhibitors in combination with chemotherapy. This combined regimen demonstrated significant improvements in both general PFS (HR 0.73; 95% CI [0.68; 0.78]; p &lt; 0.01) and OS (HR 0.77; 95% CI [0.71; 0.84]; p &lt; 0.01). Specifically, the combination of ICI with CTX exhibited enhanced PFS across various subgroups, including CPS ≥ 5 (HR 0.66; 95% CI [0.59; 0.75]; p &lt; 0.01), CPS ≥ 10 (HR 0.75; 95% CI [0.65; 0.87]; p &lt; 0.01), and CPS ≤ 1 (HR 0.75; 95% CI [0.69; 0.82]; p &lt; 0.01). Median OS similarly reflected this improvement in CPS ≥ 5 (HR 0.71; 95% CI [0.63; 0.81]; p &lt; 0.01) and CPS ≥ 10 (HR 0.66; 95% CI [0.57; 0.75]; p &lt; 0.01) subgroups, albeit not in the CPS ≤ 1 subgroup (HR 0.91; 95% CI [0.77; 1.08]; p = 0.29). Furthermore, no significant differences were observed in the incidence of adverse events (AE) (RR 1.01; 95% CI [0.99; 1.04]; p = 0.221), while grade 3 or more treatment-related adverse events (TRAE) were slightly higher in the ICI plus CTX group (RR 1.15; 95% CI [1.01; 1.32]; p = 0.038). Conclusions: These findings indicate that the combination of ICI with CTX demonstrates superior efficacy compared to CTX alone in HER2-negative gastric or GEJ cancer. However, this efficacy trend is not maintained in patients with PD-L1 CPS ≤ 1 tumors. Moreover, the absence of differences in AE and the slight increase in TRAE in the ICI plus CTX group still further supports the safety profile of this combination therapy.

Influence of neoadjuvant regimen on the prognosis of locally advanced gastric and gastroesophageal junction cancer with HER2 overexpression.

e16082 Background: The relative high recurrence rate in locally advanced gastric or gastroesophageal junction (G/GEJ) cancer with Her2 overexpression after surgery, along with the absence of a standard neoadjuvant treatment protocol, necessitates exploration of novel approaches for this patient population. Methods: In this study, we conducted a retrospective analysis of clinical characteristics, postoperative pathological results, and survival data for patients who underwent neoadjuvant treatment and subsequent surgery at our center from September 2020 to December 31, 2022. The inclusion criteria were as follows: 1) pathologically confirmed adenocarcinoma of the G/GEJ; 2) diagnosed as cT3-4 or N+ by enhanced CT and endoscopic ultrasound; 3) Her2 immunohistochemistry 3+ or 2+ with Fish positive in biopsy specimens; 4) discussed in a multidisciplinary team for the need for neoadjuvant treatment; 5) received 2-4 cycles of neoadjuvant therapy; 6) underwent radical D2 surgery; 7) had complete follow-up data. Results: Seventy-three patients met the inclusion criteria, with 19 receiving chemotherapy + anti-PD-1, 10 receiving chemotherapy + anti-Her2, and 44 receiving chemotherapy alone. Their pCR rates were 31.6%, 10%, and 2.3%, respectively (P = 0.003); MPR rates were 42.1%, 30%, and 11.4% (P = 0.022). As of the last follow-up on December 31, 2023, the median DFS for the chemotherapy group was 18.1 months (95% confidence interval 14.9-21.3); median DFS for the other two groups had not been reached. DFS analysis revealed differences in median DFS among different neoadjuvant treatment regimens (P = 0.025); further pairwise comparisons indicated that this difference mainly stemmed from the chemotherapy + anti-Her2 group compared to the chemotherapy group. Conclusions: In locally advanced gastric and gastroesophageal junction cancer with Her2 overexpression, neoadjuvant chemotherapy combined with anti-Her2 treatment improves the pCR rate and prolongs DFS compared to neoadjuvant chemotherapy alone.

Neoadjuvant therapy using PD-1 inhibitor plus chemotherapy with different intervals between chemotherapy cycles for locally advanced gastric or gastroesophageal junction cancer: A randomized phase 2 study.

4064 Background: To explore the influence of reducing dose-intensity of chemotherapeutic agents by prolonging the interval of chemotherapeutic cycles on clinical efficacy, especially when combined with immune checkpoint inhibitors, we conducted a single-center, prospective, randomized, phase II exploratory study in patients with locally advanced gastric or gastroesophageal junction (G/GEJ) cancer. Methods: Patients were randomly assigned to receive either toripalimab plus FLOT regimen for four biweekly cycles or three triweekly cycles before the operation. The primary endpoint was pathological complete response (pCR) rate, the secondary endpoints were major pathological response (MPR) rate, event-free survival (EFS), and safety. Results: 70 patients were enrolled; of these, 69 were eligible for inclusion. The overall pCR rate was 26.1% and the MPR rate was 55.1%. There were no statistical differences in pCR rates and MPR rates between the two groups. Although no statistical differences were found among the subgroups, the pCR rate for patients with PD-L1 CPS ≥1 was 42.1% (8/19) while 6.7% (1/15) for PD-L1 CPS&lt;1 in the triweekly group ( P=0.047). Analysis of lymphocyte subsets in peripheral blood showed that CD3+CD8+PD-1+Ki-67+ T lymphocyte absolute counts were elevated in triweekly group and reduced in biweekly group before the second and third cycle of therapy. The incidence rates of pyrexia and myelosuppression in the biweekly group were higher than those in the triweekly group. Conclusions: These data support the idea that the efficacy of toripalimab plus FLOT, given triweekly for three cycles, was not inferior to its administration biweekly for four cycles in locally advanced G/GEJ cancer. The finding is particularly significant for those with PD-L1 CPS ≥1 and warrants further validation. Clinical trial information: NCT04891016 .

Impact of pathogenic germline variants in HRR genes on gastroesophageal cancer in a large real-world Chinese population: A comprehensive study.

10588 Background: Genetic testing in gastroesophageal cancer has been limited to those with hereditary cancer syndromes, restricting understanding of the impact of germline variants in sporadic cancers. Our study expands this by exploring germline and somatic characteristics in a broad Chinese cohort, enhancing risk assessment and guiding treatment strategies in a wider population. Methods: From October 2017 to April 2023, we retrospectively analyzed 2596 Chinese gastroesophageal cancer (GEC) patients, including 2003 with gastric cancer (GC), 196 with gastroesophageal junction cancer (GEJC), and 397 with esophageal cancer (EC). A 520-gene panel including 62 genes associated with cancer predisposition, was employed for genomic profiling of paired tumor and white blood cell samples. The pathogenicity of germline variants was determined according to ACMG guidelines. Results: In this retrospective cohort, the proportion of patients carrying pathogenic/likely pathogenic (P/LP) germline variants was 5.3% in GC, 5.6% in GEJC, and 5.0% in EC, respectively. Notably, genes associated with HRR exhibited the highest rates of P/LP germline mutations in GEC (94, 3.7%), with the majority occurring in non-BRCA HRR genes (77, 3.0%). The top five genes with the highest mutation rates were ATM, PALB2, FANCA, CHEK2, and RAD54L. Compared to the East Asian population without cancer in the genomAD database, a higher proportion of P/LP germline mutations were found in the CDH1(Inf [6.46-Inf], p &lt; 0.001), PALB2 (5.60 [1.61-13.09], p = 0.002), SDHA (8.99 [1.29-99.42], p = 0.012), ATM (2.15 [1.08-4.09], p = 0.02), and CHEK2 (3.83 [1.06-13.32], p = 0.02) genes in GC. Similarly, significant increases in PALB2 (10.36 [2.32-37.28], p = 0.002) and ATM (4.42 [0.86-14.33], p = 0.036) were also observed in EC and GEJC. The HRR P/LP variant group exhibited a higher incidence of biallelic inactivation (loss of wildtype allele) compared to the B/LB variant group (24.7% vs 6.6%, p&lt;0.001). Moreover, the similar trend was observed for the moderately/uncertainly penetrant gene ATM and FANCA (38.5% vs 0.6%, p &lt; 0.001; 42.9% vs 9.8%, p = 0.025), which suggests that ATM and FANCA may be associated with a high risk. The HRR genes ATM(56 vs 61, p = 0.052), CDH1(33 vs 61, p = 0.003), and FANCI(48 vs 61, p = 0.041) with P/LP variants were associated with a younger age of onset. Carriers of HRR P/LP variants had less prevalent somatic TP53 variants in GC and GEC and higher HRD score compared to non-carriers (p=0.005). Conclusions: Our research delineates the germline P/LP variant landscape in Chinese GEC, revealing the significant role of HRR P/LP variants. The presence of P/LP variants in HRR genes in GEC is linked to distinct disease characteristics and progression, underscoring their importance in guiding personalized treatment approaches and risk evaluation.

Preoperative nivolumab plus SOX in patients with locally advanced gastric or gastro-esophageal junction cancer: A phase 2, single-arm trial.

4074 Background: Preoperative chemotherapy has been widely recommended in patients with locally advanced gastric or gastro-esophageal junction cancer (GC/GEJC), and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. We conducted a single-arm phase II trial (Stimulate-01) to evaluate the efficacy and safe of the anti-PD-1 antibody nivolumab plus SOX regimen in patients with locally advanced GC/GEJC and to explore the biomarker associated with therapy response. Methods: Patients with locally advanced GC/GEJC (cT3-4N+M0) were enrolled and received either 3 preoperative and 3 postoperative cycles of nivolumab (360 mg, IV, d1, Q21d) plus SOX regimen (oxaliplatin 130 mg/m2, IV, d1 with oral S-1 40-60mg, bid, d1-d14, Q21d) therapy, followed by 11 cycles of nivolumab monotherapy. The primary endpoint was the pathological complete response (pCR) rate, while the major pathological response rate (mPR), 3-year-DFS and 3-year-OS as the second endpoint. This clinical trial was registered at Clinicaltrial.gov (NCT05739045). In addition, tissue sample before and after treatment from patients were performed scRNA-seq. Results: Forty-six patients were enrolled from November 2022 to March 2023, with a median age of 66 years (range, 34-74), and 38 were male. The pCR rate was 28.26% [95% confidence interval (CI), 15.2%-41.3%], and the major pathologic response (mPR) [tumor regression grade (TRG)0/1] rate was 41.3% (95% CI, 27.1%-55.5%). All the patients underwent R0 resection. The mPR rate in patients with PD-L1 CPS ≥5 and patients with PD-L1 CPS&lt;5 was 42.86% vs 38.89% ( P= 0.790). In addition, This clinical study period spans from epidemic control to full liberalization in China. The mPR rate in patients infected with COVID-19 was 44.44% (12/27), while the mPR rate in patients who have not been infected with COVID-19 was 36.84% (7/19) ( P=0.146). There were no severe complications or death related to the surgery. The scRNA-seq data revealed that the composition of MHC-II (HLA-DRA, HLA-DPA1, HLA-DRB1, HLA-DPB1 and HLA-DQB1) were significantly over-expressed in cancer cell of treatment-sensitive patients (TRG0/1) compared to that of treatment-insensitive patients (TRG2/3). Then the MHC-II expression in pre-treatment biopsy samples from 240 GC patients who received preoperative immunotherapy plus chemotherapy were performed by immunohistochemistry. The results showed that the mPR rate in patients with MHC-II IHC ≥2 and patients with MHC-II IHC&lt;2 was 58.87% (83/141) vs 21.21% (21/99) ( P&lt;0.001). Conclusions: Nivolumab plus SOX as neoadjuvant therapy showed an encouraging pCR rate, mPR rate, and manageable safety. The long-term efficacy of this combination of regimens will be continued to follow up. In addition, the MHC-II expression may be a potential biomarker for predicting the effectiveness of immunotherapy combined with chemotherapy for GC/GEJC. Clinical trial information: NCT05739045 .

Exploration of neoadjuvant chemotherapy and post-tumor microenvironment for advanced gastric cancer (GC) or gastroesophageal junction cancer (EGJ).

e16099 Background: Neoadjuvant chemotherapy (NAC) is still the main strategy for operable local advanced gastric cancer (GC) or gastroesophageal junction cancer (EGJ). Keynote585 and Matterhorn studies had demonstrated the improvement of pathologic complete response rate (PCR), however, the overall survival benefit remains unclear. Little is known why patients’ response differently to NAC in terms of chemotherapy regiment and post neoadjuvant tumor microenvironment (TME). Methods: We retrospectively analyzed the resectable GC or EGJ patients who had been treated with neoadjuvant chemotherapy followed by surgery during 2019.11.26-2023.8.18 in the Chinese PLA general hospital. Patients with complete survival data were enrolled in the final evaluation. The association between clinical features or chemotherapy regiment and outcomes including TGR grade (NCCN criteria) and survival data were explored. Furthermore, tumor-microenvironment by means of multiplex fluorescence staining(mIHC) (CD8, CD68, CD56, PD1, PDL1, PANCK) after SOX neoadjuvant chemotherapy was analyzed. Results: 184 patients were offered neoadjuvant chemotherapy and underwent surgery. Due to follow-up lost, 141 patients with complete survival data were included in this analysis finally. Average age was 61, majority of patients were male. 85 patients received Sox and 33 received Xelox and 12 patients with docetaxel and S1(DS) and 11 patients were administered with triplets (FOLT and DOS). The median cycle of neoadjuvant treatment was 4(range from 1-7). Large proportion of patients were performed Laparoscopic. 31 patients suffered from post surgery complication. Above all, 1-year DFS and 2-year DFS, 3-year DFS rate were 72.6%, 54.8%, 49.0% respectively. 2-year OS and 3-year OS rate were 76.9%, 64.5%. PCR rate was 6.38% (n=9), which is consistent with other previous studies. 9 patients achieved TRG 0 and 26 had TRG 1. There is no statistical difference between triplets and double regiment of NEC for TRG0-1 group (45.5% vs 23.1%, p=0.099). The addition of docetaxel to oxaliplatin based therapy had not improved the TRG0-1 population compared with docetaxel-free regiment (30.4% VS 23.7%, p=0.496). YN0 is a predictor of longer survival in contrast YN+( 1-year DFS, 89.4% vs 62.8%, p=0.000).In the mIHC analyses, the density of CD8 positive and CD8+PD1- in the TGR0-1 group is higher than those cells in the TGR 2-3 group(P&lt;0.05). TGR0-1 group had lower density of PDL1+,CD68+PDL1+ and CD68+PDL1- cells in contrast to TGR 2-3 group(P&lt;0.05).Other multi-dimensional analyses were ongoing to be further disclosure. Conclusions: Neoadjuvant chemotherapy led to nearly 7% PCR rate for patients with local advanced GC. YN0 after NAC is a predictor of longer survival. CD8 positive and CD8+PD1- might be the determinant immune cells for better anticancer-response when exposed to chemotherapy.

434P First-line oxaliplatin-based chemoimmunotherapy for advanced HER2/neu-negative gastric and gastroesophageal junction cancer: A systematic review and network meta-analysis

434P First-line oxaliplatin-based chemoimmunotherapy for advanced HER2/neu-negative gastric and gastroesophageal junction cancer: A systematic review and network meta-analysis

438P Adjuvant nivolumab after neoadjuvant chemoradiotherapy and surgery for patients with esophageal or gastroesophageal junction cancer: A nationwide real-world matched comparison of overall survival

438P Adjuvant nivolumab after neoadjuvant chemoradiotherapy and surgery for patients with esophageal or gastroesophageal junction cancer: A nationwide real-world matched comparison of overall survival

420P Q-TWiST analysis of nivolumab + chemotherapy versus chemotherapy as first-line (1L) treatment for advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma (GC/GEJC/EAC) in patients with PD-L1 CPS≥1 and CPS≥5: 4-year follow-up from CheckMate 649 (CM 649)

420P Q-TWiST analysis of nivolumab + chemotherapy versus chemotherapy as first-line (1L) treatment for advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma (GC/GEJC/EAC) in patients with PD-L1 CPS≥1 and CPS≥5: 4-year follow-up from CheckMate 649 (CM 649)

A phase 1/1b study of the IL-2 prodrug WTX-124 in patients with locally advanced or metastatic solid tumors after checkpoint inhibitor therapy: Initial results of the combination dose escalation with pembrolizumab.

2623 Background: High dose IL-2 can produce durable remissions in patients who have progressed on checkpoint inhibitors but is infrequently used due to its life-threatening toxicities such as vascular leak syndrome (VLS). WTX-124 is a half-life extended, masked cytokine (INDUKINE molecule) rationally engineered to release wild type IL-2 in tumors. We previously reported that WTX-124 is clinically active as a monotherapy at doses safely administered in the outpatient setting. Here we update the data and present initial results from the combination dose escalation with pembrolizumab (anti-PD-1; NCT05479812). Methods: In this first-in-human trial, WTX-124 is administered IV Q2W alone or with pembrolizumab 400 mg IV Q6W. Eligible patients are adults with relapsed/refractory solid tumors who have previously received standard of care checkpoint inhibitor regimens. Primary endpoints are safety and ORR; secondary endpoints are PK, PD, immunogenicity, and PFS/OS. The dose escalation is guided by a mTPI-2 study design. Results: As of January 29, 2024, 32 patients have been treated with WTX-124 in five monotherapy dose escalation cohorts (1-18 mg; N=24) and two combination cohorts (3-6 mg; N=8). The most common AEs related to WTX-124 monotherapy were arthralgias, myalgias, fatigue and pruritis. Of ten evaluable patients treated with 12 or 18 mg WTX-124 monotherapy, three had objective responses, including a confirmed CR in a patient with cutaneous squamous cell cancer and unconfirmed PRs in patients with melanoma and gastroesophageal junction cancer. On-treatment tumor biopsies showed evidence of increased lymphocyte activation and PD-L1 expression. Addition of pembrolizumab to 3-6mg WTX-124 did not change the character of AEs observed with WTX-124 monotherapy. Related AEs occurred more frequently for the combination than for 3-6mg WTX-124 monotherapy, but all were mild to moderate in severity (Gr1: 74.2%, Gr2: 25.8%) and there was no increase in the percentage of Gr2 events. No DLTs, related serious AEs, treatment discontinuations due to related toxicities, or occurrences of VLS have been observed in any patient treated to date with either WTX-124 or WTX-124/pembrolizumab. Pembrolizumab did not affect WTX-124 or IL-2 PK. WTX-124 has been escalated to 12 mg IV Q2W, the initial monotherapy dose that produced objective responses, in combination with pembrolizumab. Conclusions: WTX-124 administered as a monotherapy IV Q2W in the outpatient setting is well tolerated and clinically active in patients with relapsed/refractory solid tumors after checkpoint inhibitor therapy. Preliminary results from the ongoing combination dose escalation with pembrolizumab show no new safety signals. Updated data on safety, biomarkers, and preliminary clinical activity for the combination will be presented. Clinical trial information: NCT05479812 .

Impact of regulatory t cells in peripheral blood on pathological complete response in patients with locally advanced gastric or gastroesophageal junction cancer undergoing neoadjuvant chemoimmunotherapy.

e16081 Background: Neoadjuvant chemotherapy has become the standard treatment for locally advanced gastric or gastroesophageal junction (G/GEJ) cancer. With the widely clinical application of immune checkpoint inhibitors, represented by anti-PD-1 antibodies, an increasing number of patients with locally advanced G/GEJ cancer are undergoing neoadjuvant chemoimmunotherapy. However, there is currently no effective predictive marker for neoadjuvant chemoimmunotherapy in locally advanced G/GEJ cancer. We explored the role of peripheral blood regulatory T (Treg) cells in patients with locally advanced G/GEJ cancer. Methods: We retrospectively analyzed lymphocyte subpopulations before and after treatment in patients with locally advanced G/GEJ cancer who received neoadjuvant chemotherapy combined with anti-PD-1 antibodies and curative surgery. Inclusion criteria were: 1) Pathologically confirmed adenocarcinoma of the G/GEJ; 2) Clinically staged as gastric cT3-4 or N+ without distant metastasis by enhanced CT and endoscopic ultrasound examination; 3) Patients requiring neoadjuvant treatment according to gastric cancer multidisciplinary team decisions; 4) Receipt of neoadjuvant treatment with chemotherapy combined with PD-1 antibodies; 5) Completion of 3-4 cycles of treatment; 6) Underwent curative resection; 7) Lymphocyte subpopulation testing performed before the first and second cycles. Results: From July 1, 2020, to May 31, 2023, 85 patients were included. All 85 patients underwent D2 radical surgery and achieved R0 resection, with 21 patients achieving pathological complete response (pCR), resulting in a pCR rate of 24.7% (95% confidence interval (CI) 15.3-34.1%). There were no statistically significant differences in baseline characteristics between the pCR and non-pCR groups. There were no statistically significant differences in lymphocyte subpopulations between the baseline pCR and non-pCR patient groups. After one cycle of treatment (before the second cycle), there were statistically significant differences in lymphocytes, T lymphocytes, and Treg cells between the two groups. Further analysis of the absolute changes in lymphocyte subpopulations before and after one cycle of treatment revealed a greater decrease in Treg cells in the pCR group. Based on the increase or decrease in Treg cells after one cycle of treatment, the 85 patients were divided into Treg cell increase and decrease groups. The pCR rate was 11.4% (4/35, 95% CI 0.3-22.5%) in the Treg cell increase group and 34% (17/50, 95% CI 20.4-47.6%) in the Treg cell decrease group, with a statistically significant difference between the two groups ( P= 0.022). Conclusions: In locally advanced G/GEJ cancer, changes in Treg cells after one cycle of neoadjuvant treatment may serve as a predictive marker for achieving pCR.

First-line immunochemotherapy modulates peripheral immune landscape in advanced gastric cancer and gastroesophageal junction cancer (GC/GEJC): Prediction of response to combination therapy.

e14540 Background: The use of immunochemotherapy has brought about a change in the treatment of advanced or metastatic GC/GEJC, but only a subset of patients could benefit substantially. Therefore, seeking efficacious biomarkers to identify favorable populations for the regimen is imperative. This study aims to explore predictive markers and potential mechanism of combination therapy for GC/GEJC in real-world settings based on blood proteomic biopsy. Methods: This is a prospective, single-center trial in which all patients are adults with advanced or metastatic GC/GEJC confirmed by pathology or imaging. 30 eligible patients will receive PD-1 mab (sintilimab/nivolumab (NIVO) Q3W) and chemotherapy (SOX/XELOX Q3W) regardless of programmed death ligand-1 status. Blood samples were collected before treatment and after every two treatment cycles for Olink Target 96 IO analysis. CT scans were performed after every two cycles and will be categorized as responding (complete response plus primary response) or non-responding (progress disease plus stable disease) according to RECIST 1.1. Results: As of January 17, 2024, a total of 21 patients were enrolled. Eight of these patients received 16 samples before and after treatment, with 4 each of the 8 patients responding and non-responding. By analyzing the baseline samples comparing the responding and non-responding groups, it was found that patients in the responding group had lower expression of serum PD-L1 (sPD-L1) ( p=0.015). In the post-treatment samples, angiopoietin 1 was found to be poorly expressed in the responding patients ( p&lt;0.001). In contrast, high expression of angiopoietin 2 in post-treatment blood samples was more pronounced in non-responders compared to pre-treatment ( p=0.020). Additionally, we observed that immunotherapy can modify the immune microenvironment by up-regulating the T cell receptor signaling and NK cell-mediated toxic effects pathways. These pathways may be potential targets for treatment. Conclusions: In summary, low sPD-L1 level before treatment may be a predictive biomarker for better efficacy of immuno-combination chemotherapy in advanced GC/GEJC; whereas elevation of angiopoietin after treatment predicts poor efficacy and suggests that antiangiogenic therapy may subsequently be added in non-responding patients. We are further recruiting more patients to obtain more accurate conclusions. Clinical trial information: ChiCTR2300078000 .

FS-1502 in patients with HER2 high expression, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: An open-label, multicenter, phase II study.

e15000 Background: FS-1502 is an antibody-drug conjugate composed of an anti-HER2 antibody, linker, and Monomethylauristatin F. In this study, we conducted an open-label, multicenter, two-cohort phase II trial to evaluate the efficacy and safety of FS-1502 in HER2- positive locally advanced or metastatic gastric or gastroesophageal junction cancer. Methods: Pts with HER2-positive (IHC 3+ or 2+/FISH+) who had received ≥1 prior treatment regimens were eligible and received FS-1502 2.3 mg/kg alone every 3 weeks. The study consists of Cohort 1 for pts received ≥2 lines of previous therapy and Cohort 2 for pts only received first-line of previous therapy, respectively. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), duration of response, disease control rate, and safety. Results: At data cutoff (Dec 24,2023), 46 pts were enrolled (intent-to-treat [ITT]), 35 pts were confirmed HER2-positive (IHC 3+ or IHC 2+/ISH+, Efficacy Evaluable Set [ES]) by central laboratory. In the ES, the median age was 58.3 years, 48.6% were IHC3+ and primary tumor location in 77.1% of pts was GC. 45.7% (16/35) pts had assigned to cohort 1 and 54.3% (19/35) pts had assigned to cohort 2. In cohort 1, median study follow-up time was 10.1 months, the investigator-assessed ORR was 37.5% (95% CI, 15.2-64.6), median PFS and OS were 4.3 months (95% CI, 1.5-5.8 months) and 10.0 months (95% CI,5.1-NA months), respectively. In cohort 2, median study follow-up time was 12.5 months, the investigator-assessed ORR was 52.6% (95% CI, 28.9-75.6). PFS and OS were 4.4 months (95% CI, 3.0-7.3 months) and 14.6 months (95% CI, 8.7-NA months), respectively. Grade≥3 treatment-related TEAEs were reported in 12 (26.1%) pts, ≥5% were hypokalemia (6.5%) and fatigue(6.5%). No adverse events leading to drug discontinuation or death. Efficacy and safety data are shown in table. Conclusions: FS-1502 showed promising activity with tolerable and manageable safety profile, which warrants further development in HER2-postive, advanced gastric or gastroesophageal junction adenocarcinoma who had received ≥1 prior treatment regimens. [Table: see text]

428P Total neoadjuvant FOLFIRINOX in patients with resectable locally advanced gastric and gastroesophageal junction cancer: Updated survival results

428P Total neoadjuvant FOLFIRINOX in patients with resectable locally advanced gastric and gastroesophageal junction cancer: Updated survival results

Efficacy of disitamab vedotin (RC48) plus tislelizumab and S-1 as first-line therapy for HER2-overexpressing advanced stomach or gastroesophageal junction adenocarcinoma: A multicenter, single-arm, phase II trial (RCTS).

4009 Background: Integrating immunotherapy with trastuzumab and chemotherapy has shown a significant improvement in overall response rate (ORR) and progression-free survival (PFS) in HER2-overexpression gastric or gastroesophageal junction cancer (GC/GEJC). However, the overall survival (OS) did not achievestatistical significance, and there was no benefit in patients with a PD-L1 combined positive score (CPS) &lt;1. RC48, an antibody-drug conjugate drug, has proven its effect in advanced HER2-positive (HER2 3+ or 2+ by IHC, regardless of FISH positivity) GC/GEJC in later-line treatment setting. This trial was to assess the efficacy and safety of combining RC48, immunotherapy (Tislelizumab), and S-1 as a first-line treatment for HER2-overexpressing GC/GEJC. Methods: This was a single-arm, multi-center, phase II trial conducted in patients with HER2-overexpressing metastatic or unresectable GC/GEJC for first-line treatments. Participants received RC48 (2.5 mg/kg), Tislelizumab (200 mg), and S-1 (40-60 mg BID for 14 days) every 3 weeks until disease progression or intolerable toxicities. The primary endpoint was ORR, while the secondary endpoints included disease control rate (DCR), PFS, OS, and safety. Results: A total of 47 patients were enrolled from 8 centers, median 65 (39 ~ 81) years old, 37 male, 37 GC and 8 GEJC, and all adenocarcinoma. Of them, 30 (63.8%) were HER2 IHC 3+, 11 (23.4%) HER2 IHC 2+/FISH+, and 6 (12.8%) IHC 2+/FISH-. Patients with PD-L1 CPS≥5, ≥1 accounted for 14.9%, 36.2% respectively. With a median follow-up duration of 116.5 days, patients received a median of 5.0 treatment cycles. As of January 20, 2024, 40 patients were included for efficacy analysis, and 44 patients for safety. The ORR reached 95.0% (38/40, 95% CI: 83.1-99.4%), clinical Complete Response rate was 20.0% (5/40, 95% CI: 4.2-26.8%), and the DCR was 100.0% (95% CI: 91.2-100.0%). The median PFS and OS were not reached, while the 6-month and 9-month PFS rates were 100.0% and 80.8%, the 6-month and 9-month OS rates were 100.0% and 83.8%. ORR among the HER2 IHC 3+, IHC 2+/FISH+, and IHC 2+/FISH- groups showed no significant difference (93.3%, 100.0%, 100.0%). ORR for patients with CPS≥1 or &lt; 1 were 100.0%, 92.9%, respectively. One stage IVA GC patient (cT4bN3M0, HER2 3+, CPS 0) and another stage IVB GEJC one (cT3N2M1, HER2 2+/FISH+, CPS≥5) received radical surgery and both achieved pathological complete response. Grade 3/4 treatment-related adverse events occurred in 40.9% of patients, notably neutropenia, fatigue, and diarrhea. Conclusions: The combination of RC48, Tislelizumab, and S-1 showed notable efficacy with manageable safety in the first-line treatment of advanced HER2-overexpressing GC/GEJC patients. These findings support further exploration in this context. Clinical trial information: NCT05586061 .

425P Updated results of induction FOLFOX prior to CROSS chemoradiotherapy and surgery in patients with locally advanced esophageal and gastroesophageal junction cancer: A phase II study

425P Updated results of induction FOLFOX prior to CROSS chemoradiotherapy and surgery in patients with locally advanced esophageal and gastroesophageal junction cancer: A phase II study

495TiP CLARITY-Gastric 01: A randomised phase III study of AZD0901, a Claudin18.2 (CLDN18.2)-targeted antibody-drug conjugate, in second- or later-line (2L+) advanced gastric or gastroesophageal junction cancer (GC/GEJC)

495TiP CLARITY-Gastric 01: A randomised phase III study of AZD0901, a Claudin18.2 (CLDN18.2)-targeted antibody-drug conjugate, in second- or later-line (2L+) advanced gastric or gastroesophageal junction cancer (GC/GEJC)

First-in-human phase I/II safety and preliminary efficacy of PM1032, a bispecific antibody targeting CLDN18.2 and 4-1BB, in patients with advanced solid tumors.

2662 Background: PM1032 is an anti-CLDN18.2 x 4-1BB bispecific antibody that activates immune cells, such as T and NK cells, via CLDN18.2-mediated crosslinking of 4-1BB. Potent anti-tumor efficacy is facilitated with limited toxicity as immune activation is only stimulated in the context of CLDN18.2 expression on target cells. Here, we present the preliminary safety and efficacy results from an ongoing Phase I/II trial, which is a first-in-human (FIH), dose-escalation, and expansion study of PM1032 in patients (pts) with advanced solid tumors. Methods: This FIH study of PM1032 with adults with previously treated, advanced or metastatic solid tumors includes dose escalation (3+3 design; regardless of CLDN18.2 expression) and dose expansion stages (CLDN18.2+ gastrointestinal (GI) cancers). During the dose escalation stage, PM1032 was administered at doses of 0.3, 1, 3, 5, 8 and 12 mg/kg for the assessment of drug limiting toxicity (DLT) after 3 weeks, followed by administration Q2W until disease progression (PD) or observations of intolerable toxicity. Responses were evaluated according to RECIST 1.1. Adverse events (AEs) were graded using CTCAE v5.0. CLDN18.2 positivity was defined as ≥1% of tumor cells with ≥1+ signal intensity by immunohistochemistry. Results: As of January 12, 2024, a total of 30 pts received PM1032 (18 pts during dose escalation and 12 pts during dose expansion) with no DLTs observed (median age 54y; most pts had ≥2 metastatic sites). CLDN18.2 expression was evaluable in 80% of the pts and 66.7% were positive. The most common tumor types were GI cancers including 14 gastric and gastroesophageal junction cancers (GC/GEJ), 10 pancreatic adenocarcinoma (PDAC) and 5 other GI cancers. All pts had ≥1 line of prior therapy and 17 pts (56.7%) had prior immunotherapy. TRAEs occurred in 22 subjects (73.3%), and ≥ Grade 3 TRAEs occurred in 3 subjects (10%). The most common TRAEs were nausea (20%) and aspartate transaminase increase (16.7%). Among a total of 16 CLDN18.2+ pts enrolled at the 5, 8, and 12 mg/kg dose levels who completed at least one tumor evaluation, 2 pts achieved PR, 7 pts had SD and 3 pts were Non-CR/Non-PD. Additionally, the ORR was 20% in 10 measurable and evaluable CLDN18.2+ GC/GEJ pts. The longest treatment duration was 18 months and 5 pts had treatment durations ≥ 6 months. Pharmacokinetics (AUC0-336h &amp; Cmax) were dose-proportional across the dose ranges of 0.3 mg/kg – 12 mg/kg with a terminal half-life of 6.0~10.1 days. Conclusions: PM1032 was well-tolerated up to 12 mg/kg Q2W and demonstrated preliminary anti-tumor activity in CLDN18.2+ tumors. Further development of PM1032 as a monotherapy and/or combination therapy for CLDN18.2-positive cancers is planned. Clinical trial information: NCT05839106 .