Esophagogastric Adenocarcinoma Research Articles

Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides

BackgroundThe individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA)...

Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer: A systematic review and meta-analysis.

Heat shock proteins (HSPs) are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overexpressed in many cancers. The prognostic significance of HSPs and their regulatory factors, such as heat shock factor 1 (HSF1) and CHIP, are poorly understood. To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer. A systematic review was conducted in accordance with PRISMA recommendations (PROSPERO: CRD42022370653), on Embase, PubMed, Cochrane, and LILACS. Cohort, case-control, and cross-sectional studies of patients with esophagus or esophagogastric cancer were included. HSP-positive patients were compared with HSP-negative, and the endpoints analyzed were lymph node metastasis, tumor depth, distant metastasis, and overall survival (OS). HSPs were stratified according to the HSP family, and the summary risk difference (RD) was calculated using a random-effect model. The final selection comprised 27 studies, including esophageal squamous cell carcinoma (21), esophagogastric adenocarcinoma (5), and mixed neoplasms (1). The pooled sample size was 3465 patients. HSP40 and 60 were associated with a higher 3-year OS [HSP40: RD = 0.22; 95% confidence interval (CI): 0.09-0.35; HSP60: RD = 0.33; 95%CI: 0.17-0.50], while HSF1 was associated with a poor 3-year OS (RD = -0.22; 95%CI: -0.32 to -0.12). The other HSP families were not associated with long-term survival. HSF1 was associated with a higher probability of lymph node metastasis (RD = -0.16; 95%CI: -0.29 to -0.04). HSP40 was associated with a lower probability of lymph node dissemination (RD = 0.18; 95%CI: 0.03-0.33). The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis. The expression levels of certain families of HSP, such as HSP40 and 60 and HSF1, are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.

Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE

Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. Patients (n= 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n= 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage2. NCT03812796 (registered 23rd January 2019).

TRIFLURIDINE/TIPIRACIL (FTD/TPI) with or without bevacizumab in previously treated patients with esophago-gastric adenocarcinoma, a randomised phase III trial

Trifluridine-tipiracil has shown a survival benefit compared with placebo in patients with chemorefractory metastatic esophago-gastric adenocarcinoma. We aimed to compare the efficacy of trifluridine-tipiracil plus bevacizumab vs trifluridine-tipiracil monotherapy in pre-treated patients with metastatic esophago-gastric adenocarcinoma. This investigator-initiated, open-label, randomized trial enrolled patients with metastatic esophago-gastric adenocarcinoma. The main inclusion criteria were patients with pre-treated metastatic esophago-gastric adenocarcinoma, and WHO performance status 0 or 1. Participants were randomly assigned (1:1) to receive oral trifluridine-tipiracil (35mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with bevacizumab (5mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Randomisation was stratified by sex and treatment line. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2018-004845-18. From Oct 1, 2019, to Sept 30, 2021, 103 patients were enrolled and randomly assigned to trifluridine-tipiracil (n=53) or trifluridine-tipiracil plus bevacizumab (n=50). The clinical cut-off date was March 1st, 2023, after a median follow-up of 36.6 months. Median progression-free survival was 3.1 months (95% CI 2.0-4.3) in the trifluridine-tipiracil group vs 3.9 months (3.0-6.3) in the trifluridine-tipiracil plus bevacizumab group (hazard ratio 0.68, 95% CI 0.46-1.02; p=0.058). The most frequent grade 3 or worse adverse event was neutropenia, observed in 26 (49%) patients in the trifluridine-tipiracil group vs 23 patients (46%) in the trifluridine-tipiracil plus bevacizumab group. At least one hospitalization was observed in 21 patients (40%) in the trifluridine-tipiracil group and 22 patients (44%) in the trifluridine-tipiracil plus bevacizumab group. No deaths were deemed treatment related. In patients with pre-treated metastatic esophago-gastric cancer, trifluridine-tipiracil plus bevacizumab, compared to trifluridine-tipiracil monotherapy, did not significantly prolong progression-free survival. The combination of trifluridine-tipiracil with bevacizumab was well tolerated without increase in severe neutropenia and no new safety signals. Servier, Roche.

O138: Predictors of early recurrence of oesophagogastric adenocarcinoma after neoadjuvant FLOT

Abstract Background Although survival of patients with oesophagogastric adenocarcinomas has improved over the years, rates of cancer recurrence remain high. There is limited research on predictors for early recurrence (ER), especially in patients receiving FLOT chemotherapy. The aim of this study was to investigate ER and survival rates and identify risk factors of ER. Methods Patients receiving neoadjuvant chemotherapy with FLOT for oesophagogastric adenocarcinoma at single high-volume centre between August 2018 and October 2022 were evaluated for early recurrence defined as disease present within 1 year of surgery. Multivariable analysis was conducted to identify risk factors for ER. Patients who died in-hospital or within 90 days of surgery and those with positive longitudinal margin were excluded. Results 169 patients were included. 92.9% and 41.4% of patients completed all four neoadjuvant and adjuvant cycles of FLOT respectively. 51 patients (30.2%) developed recurrence in the follow up period with 24 patients (14.2%) having ER. Recurrence free survival and overall survival at one year were 84.1% and 91.7% respectively. The estimated median survival after recurrence was 4.8 months. Extracapsular spread was found to be independent risk factor for ER (OR 6.507, 95% CI 1.964-21.556, p=0.002) in multivariable analyses together with ypN3 stage (OR 7.204, 95% CI 1.118-46.403, p=0.038). Conclusions The variables identified in this study may be helpful in determining patients at a higher risk of ER following curative surgery. Understanding these predictors may help tailor the follow up care of these patients, such as regular surveillance imaging, treatment, and frequency of reviews.

Real-time ex vivo monitoring of NK cell migration toward obesity-associated oesophageal adenocarcinoma following modulation of CX3CR1

Oesophagogastric adenocarcinomas (OAC) are poor prognosis, obesity-associated cancers which may benefit from natural killer (NK) cell-based immunotherapies. Cellular immunotherapies encounter two key challenges to their success in OAC, namely recruitment to extratumoural tissues such as the omentum at the expense of the tumour and an immunosuppressive tumour microenvironment (TME) which can hamper NK cell function. Herein, we examined approaches to overcome the detrimental impact of obesity on NK cells and NK cell-based immunotherapies. We have demonstrated that NK cells migrate preferentially to the chemotactic signals of OAC patient-derived omentum over tumour in an ex vivo model of immune cell migration. We have identified CX3CR1 modulation and/or tumour chemokine profile remodelling as approaches to skew NK cell migration towards tumour. We also report targetable immunosuppressive facets of the obese OAC TME which dampen NK cell function, in particular cytotoxic capabilities. These data provide insights into approaches to therapeutically overcome key challenges presented by obesity and will inform superior design of NK cell-based immunotherapies for OAC.

Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON-SEOM registry.

The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

Prognostic factors in clinicopathology of oesophagogastric adenocarcinoma: a single-centre longitudinal study of 347 cases over a 20-year period

Oesophagogastric adenocarcinoma (EGA) includes oesophageal (EA), gastro-oesophageal junctional (GEJA), and gastric (GA) adenocarcinomas. The prognostic values of clinicopathological factors in these tumours remain obscure, especially for GEJA that has been inconsistently classified and staged. We studied the prognosis of EGA patients among the three geographic groups in 347 consecutive patients with a median age of 70 years (range 47-94). All patients were male, and 97.1% were white. Based on tumour epicentre location, EGAs were sub-grouped into EA (over 2 cm above the GEJ; n=3, 18.1%), GEJA (within 2 cm above and 3 cm below the GEJ; n=231, 66.6%), and GA (over 3 cm below the GEJ; n=53, 15.3%). We found that the median overall survival (OS) was the longest in EA (62.9 months), compared to GEJA (33.4), and GA (38.1) (p<0.001). Significant risk factors for OS included tumour location (p=0.018), size (p<0.001), differentiation (p<0.001), adenocarcinoma subtype (p<0.001), and TNM stage (p<0.001). Independent risk factors for OS comprised low-grade papillary adenocarcinoma [odds ratio (OR) 0.449, 95% confidence interval (CI) 0.214-0.944, p<0.05), mixed adenocarcinoma (OR 1.531, 95% CI 1.056-2.218, p<0.05), adenosquamous carcinoma (OR 2.206, 95% CI 1.087-4.475, p<0.05), N stage (OR 1.505, 95% CI 1.043-2.171, p<0.05), and M stage (OR 10.036, 95% CI 2.519-39.993, p=0.001)]. EGA was further divided into low-risk (common well-moderately differentiated tubular and low-grade papillary adenocarcinomas) and high-risk (uncommon adenocarcinoma subtypes, adenosquamous carcinoma) subgroups. In this grouping, the median OS was significantly longer in the low-risk (83 months) than in the high-risk (10 months) subgroups (p<0.001). In conclusion, the prognosis of EGA patients was significantly better in EA than in GEJA or GA and could be stratified into low and high-risk subgroups with significantly different outcomes.

Current and Future Biomarkers in Esophagogastric Adenocarcinoma.

Biomarker-based therapies have shown improved patient outcomes across various cancer types. The purpose of this review to summarize our knowledge of current and future biomarkers in esophagogastric adenocarcinoma (EGA). In this publication, we will review current standard biomarkers in patients with upper GI cancers. We will also discuss novel biomarkers that are under investigations and their associated therapies that are currently in clinical trials. EGAa are a group of heterogeneous diseases, both anatomically and molecularly. There are several established biomarkers (HER2, PD-L1, microsattelite instability or mismatch repair protein expression) that allow for individualized treatments for patients with these cancers. There are also several emerging biomarkers for EGA, some of which have clinically relevant associated therapies. Claudin 18.2 is the furthest along among these. Anti-claudin antibody, zolbetuximab, improved overall survival in biomarker select patients with advanced GEA in two phase 3 studies. Other novel biomarkers, such as FGFR2b and DKN01, are also in the process of validation, and treatments based on the presence of these biomarkers are currently in clinical studies. Ongoing efforts to identify novel biomarkers in EGA have led to enhanced subclassification of upper GI cancers. These advances, coupled with the strategic application of targeted therapies and immunotherapy when appropriate, hold promise to further improve patients outcomes.

Ramucirumab, Avelumab, and Paclitaxel as Second-Line Treatment in Esophagogastric Adenocarcinoma

Adding immune checkpoint inhibitors to chemotherapy has been associated with improved outcomes in metastatic esophagogastric adenocarcinoma, but treatment combinations and optimal patient selection need to be established. To investigate the efficacy and tolerability of the programmed cell death ligand 1 (PDL-1) inhibitor avelumab with paclitaxel plus ramucirumab. This multicenter, single-group, phase 2 nonrandomized controlled trial was conducted among patients with second-line metastatic esophagogastric adenocarcinoma. Patients pretreated with platinum plus fluoropyrimidine between April 2019 and November 2020 across 10 German centers (median follow-up, 27.4 months [95% CI 22.0-32.9 months]) were included. Data analysis was performed from January to December 2022. Patients received ramucirumab at 8 mg/kg on days 1 and 15, avelumab at 10 mg/kg on days 1 and 15, and paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 4 weeks. The prespecified primary end point was overall survival (OS) rate at 6 months, with the experimental therapy considered insufficiently active with an OS rate of 50% or less and a promising candidate with an OS rate of 65% or greater. Of 60 enrolled patients, 59 patients (median [range] age, 64 [18-81] years; 47 males [70.7%]) were evaluable, including 30 patients with metastatic adenocarcinoma of the stomach and 29 patients with gastroesophageal junction. All patients were pretreated with platinum plus fluoropyrimidine, and 40 patients (67.8%) had received prior taxanes; 24 of 56 evaluable patients (42.9%) had a PDL-1 combined positive score (CPS) of 5 or greater, centrally assessed. The OS rate at 6 months was 71.2% (95% CI, 61.5%-83.7%). The median OS in the intention-to-treat population (59 patients) was 10.6 months (95% CI, 8.4-12.8 months) overall. Among patients assessable by central pathology, median OS was 9.4 months (95% CI, 7.2-11.7 months) in 32 patients with a PDL-1 CPS less than 5 and 14.0 months (95% CI, 6.0-22.1 months) in 24 patients with a PDL-1 CPS of 5 or greater (P = .25). Treatment was generally well tolerated, without unexpected toxicities. Patients with higher vs lower than median T cell repertoire richness showed an increased median OS of 20.4 months (95% CI, 7.7-33.0 months) compared with 8.3 months (95% CI, 3.7-12.9 months; hazard ratio, 0.43; 95% CI, 0.23-0.81; P = .008). Patients with lower vs higher than median cell-free DNA burden had a median OS of 19.2 months (95% CI, 8.9-29.6 months) compared with 7.3 months (95% CI, 3.2-11.4 months; hazard ratio, 0.30; 95% CI, 0.16-0.59; P < .001). In this study, the combination of avelumab with paclitaxel plus ramucirumab showed favorable efficacy and tolerability in the second-line treatment for metastatic esophagogastric adenocarcinoma. A PDL-1 CPS score of 5 or greater, cell-free DNA level less than the median, and T cell repertoire richness greater than the median were associated with increased median OS. ClinicalTrials.gov Identifier: NCT03966118.

Pembrolizumab, radiotherapy, and chemotherapy in neoadjuvant treatment of malignant esophago-gastric diseases (PROCEED): Assessment of survival and patterns of recurrence in a prospective, phase II single-arm trial.

375 Background: Locally advanced esophagogastric adenocarcinoma (EGA) is commonly treated with neoadjuvant chemoradiation (CRT) prior to surgical resection. Adjuvant immunotherapy has been shown to improve outcomes for these patients. The primary objective of this trial was to investigate whether neoadjuvant pembrolizumab (P) + CRT improves pathologic complete response (pCR) compared to historical control of neoadjuvant CRT alone. Exploratory endpoints included time to local recurrence (TTLR), time to distant recurrence (TTDR), progression-free survival (PFS), and overall survival (OS). Methods: Single-institution, prospective phase II trial (NCT03064490) evaluating neoadjuvant P + CRT followed by adjuvant P in patients with locally advanced operable EGA. CRT (45 Gy in 25 fractions with concurrent, weekly carboplatin [AUC 2] and paclitaxel [50mg/m2 of BSA]) with three cycles of P were administered as neoadjuvant therapy. Patients also received three cycles of adjuvant P. Pathologic response was scored from 0-3 based on tumor regression grading (TRG): 0 indicating a complete response, 1 marked response (&lt;10% residual disease), 2 partial response, and 3 poor or no response. pCR was defined as the absence of viable tumor cells at the primary tumor site and all resected lymph nodes in the surgical specimens (ypT0N0, TRG 0). Major pathologic response (MPR) was defined as TRG 0-1. Treatment-responders (R) are those with MPR, while non-responders (NR) are those with TRG 2-3 TTLR was time from enrollment to local recurrence (LR); distant recurrences (DR) were ignored and deaths were censored. TTDR was defined analogously. PFS was time from enrollment to LR, DR, or death due to any cause. OS was time from enrollment to death due to any cause. The Kaplan-Meier method was used to estimate TTLR, TTDR, PFS, and OS. Two-sided statistical tests were performed with an α of &lt;0.05 considered significant. Results: 35 patients were enrolled from 2017-2022. 30 underwent neoadjuvant P + CRT followed by surgical resection. pCR and MPR rates were previously reported: 35.5% and 50%, respectively. Median follow-up of the whole cohort was 35.5 mo. PFS was significantly improved in R vs NR (p=0.046), and there was a trend towards improved OS (p=0.084), and TTDR (p=0.069). There was no significant difference in TTLR (p=0.128). At three years, in R vs NR, PFS was 72.7% vs 46.2%, OS was 80.0% vs 58.3%, TTLR was 100% vs 81.8%, and TTDR was 81.8% vs 53.8%. Conclusions: Patients undergoing neoadjuvant P + CRT for EGA experienced higher rates of pCR/MPR compared to historical controls treated with CRT alone. MPR correlated with improved PFS, with a trend towards improved OS, indicating the clinical significance of pathologic response. These correlations appear to be driven primarily by decreased risk of developing distant metastases. Clinical trial information: NCT03064490 .

Exploratory analysis of biomarkers of response to durvalumab in advanced HER2-negative oesophago-gastric adenocarcinoma within a phase 2 clinical trial.

384 Background: Advanced oesophago-gastric cancers have showcased varied responses to immunotherapy based on biomarkers such as tumour mutational burden, microsatellite instability, and PD-L1 expression. However, these markers may not fully capture tumour heterogeneity and evolutionary dynamics. Hence, understanding the intricate relationship between immune selection, specifically immune dN/dS,1 and tumour evolution is vital for devising personalized therapeutic strategies. Methods: In our phase 2 open label, multicentre, randomised PLATFORM trial (NCT02678182), patients received maintenance durvalumab post first-line chemotherapy. A survival advantage was not seen with maintenance durvalumab compared to surveillance and exploratory analysis of PD-L1 expression was not associated with improved survival outcomes.2 However, a subset of patients treated with durvalumab experienced durable responses and some experienced incremental radiological responses. A pilot substudy on a selected cohort (n=24) of these patients was designed to explore the potential of immunogenomics evolutionary-based metrics, notably dN/dS, as predictive biomarkers. DNA and RNA from FFPE baseline tumour samples underwent analysis, examining genomic factors including tumour mutational burden, indel signatures, PDL1 status, and immune evasion mechanisms. Furthermore, the evolutionary metric, immune dN/dS, which has implications in tumour immunoediting and its response to immunotherapies, was scrutinized. Results: A dominant indel mutational signature emerged from the analysis. The majority of patients displayed a significantly higher number of indel variants, compared to non-synonymous and synonymous single-nucleotide variants. A recurring observation was dN/dS values consistently above 1, indicating positive selection for non-synonymous somatic variants. Additionally, hypermutation in driver genes, notably TP53 and XIRP2, was detected. One patient, with a unique dN/dS &lt; 1, showcased survival beyond four years without liver metastases. Immune dN/dS &gt; 1 and no evidence of liver metastases displayed the best prognosis after treatment in contrast with those that have immune dN/dS &lt; 1 with or without liver metastases. Conclusions: Immune dN/dS emerges as a promising tool to decode tumour evolutionary mechanisms, providing profound insights into the dynamics of tumour evolution in advanced HER2 negative oesophago-gastric cancer patients receiving durvalumab immunotherapy. This pilot study underscores the potential of this novel immunogenomic approach in improving patient stratification and tailoring therapeutic strategies in cancer immunotherapy. 1. Zapata et al, Nature Genetics, 2023. 2. Fong et al, J Clin Oncol, 2021. Clinical trial information: NCT02678182 .

FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF, FLOT therapy for locally advanced esophageal carcinoma (JCOG1804E)—Primary safety and short-term efficacy results for cohort E.

326 Background: The standard neoadjuvant treatment in Japan for resectable locally advanced esophageal squamous cell carcinoma (ESCC) is DTX + CDDP + 5-FU (DCF). In addition, immune checkpoint inhibitors (ICIs) have shown a survival benefit for ESCC and are promising as neoadjuvant treatment for several cancers. We previously reported that neoadjuvant CDDP + 5-FU + nivolumab (Nivo) or DCF + Nivo therapy was tolerable and showed promising efficacy for ESCC. However, the efficacy of neoadjuvant treatment and safety of subsequent surgery remain unclear for 5-FU + l-LV + L-OHP + DTX (FLOT), the global standard of care for perioperative esophagogastric adenocarcinoma, plus ICI for ESCC. Methods: JCOG1804E (FRONTiER) is a multi-cohort phase I study designed to evaluate the safety and efficacy of Nivo combined with neoadjuvant chemotherapy in ESCC. The eligibility criteria were histologically proven ESCC staged as cT1N1-3M0 or cT2-3N0-3M0 (8th UICC TNM classification), age 20-75 years, performance status (PS) ≤1, and no prior cancer therapy. The primary endpoint was the incidence of dose-limiting toxicity (DLT) from the initial dose to postoperative day 30. The secondary endpoints included adverse events during the perioperative period and at 30 days and the objective response rate, R0 resection rate, histopathological complete response rate, and completion rate of the protocol treatment including planned chemotherapy as below followed by R0 resection. Among five study cohorts, patients in cohort E were planned to receive four courses of FLOT+Nivo–5-FU (2600 mg/m2), l-LV (200 mg/m2), L-OHP (85 mg/m2), DTX (50 mg/m2), and Nivo (240 mg)–on day 1 every 2 weeks. Results: Of the 12 patients enrolled in cohort E (median age [range]: 64.5 [53-71] years, PS 0/1: 12/0, clinical stage I/II/III/IVA: 4/5/3/0), 4 developed DLT (grade 3 mucositis, erythema multiforme, and pneumonitis, n=1 each; grade 5 pneumonitis, n=1), which was within the prespecified range of safety (n ≤ 4). Other grades≥3 adverse events were neutropenia (n=7), leukopenia (n=6), fever, fatigue, febrile neutropenia, rash, elevated amylase, elevated hepatic enzyme, hypotension, and thrombocytopenia (n=1 each) during FLOT + Nivo, and anastomotic leakage (n=1) during the postoperative period. One patient discontinued FLOT + Nivo due to DLT of erythema multiforme, eleven patients (91.7%) completed the protocol treatment and R0 resection rate achieved 91.7% (11/12). In cohort E, the objective response rate in patients with measurable lesion was 0% (0/4). However, 5 patients (41.7%) achieved a pathological complete response, and 6 (50.0%) achieved a pathological complete response in primary tumors among 12 patients. Conclusions: Neoadjuvant FLOT + Nivo followed by surgery for locally advanced ESCC was tolerated and showed promising efficacy. Clinical trial information: NCT03914443 .

OGC O02 CLDN18.2 expression in resectable gastroesophageal cancers: associated clinical and molecular signatures and impact of neoadjuvant chemotherapy on intra-tumour heterogeneity

Abstract Background Claudin 18.2 (CLDN18.2), a key component of tight junctions, is overexpressed in up to 40% of oesophagogastric adenocarcinoma (OGA) and is a clinically validated biomarker in the unresectable setting. However, data is required in the resectable stages, including chemotherapy effects, relationship with genomic and immune factors, and measures of heterogeneity. Methods CLDN18.2 (ab222512, Abcam) and PD-L1 (E1L3N, Cell Signaling) were assessed by immunohistochemistry on adjacent FFPE slides in 57 patients with resectable OGA. Positivity was defined as 2+/3+ staining in ≥40% of tumour cells for CLDN18.2 and combined positive score (CPS)≥1 for PD-L1. Twenty-four patients (43%) had additional tumour samples to assess CLDN18.2 intra-tumour heterogeneity. Tumour mutational burden (TMB) and copy number aberrations (CNAs) were estimated from WGS and tumour microenvironment (TME) composition from transcriptomic data. Mann Whitney/t-test was used to compare clinical and molecular characteristics, and log-rank test to compare survival curves. Statistical significance was set at p=0.05. Results Fifty-seven patients with resected OGA (79% after neoadjuvant chemotherapy (nCT)) were evaluated. CLDN18.2 was expressed in 18% and CLDN18.2 expression was not associated with clinicopathological features or survival. CLDN18.2 copy numbers (n=57, p=0.24) and RNA levels (n=20, p=0.48) were not associated with staining intensity. Compared to CLDN18.2-ve, CLDN18.2+ve cases did not differ in PD-L1 expression, TMB, CNAs, or TME composition (all p&amp;gt;0.05). However, exposure to chemotherapy was significantly associated with lack of CLDN18.2 (OR=0.2, 95% CI 0.04-0.79, p=0.03) and, among CLDN18.2+ve cases, CLDN18.2 status concordance between tumour samples was 100% in treatment-naïve but only 29% in cases exposed to chemotherapy.   Conclusions CLDN18.2+ve and CLDN18.2-ve tumours had similar clinical, genomic and immune features. However, exposure to chemotherapy substantially contributes to CLDN18.2 intra-tumour heterogeneity. Larger cohorts will need to clarify whether the evaluation of multiple tumour samples is required for an accurate assessment of CLDN18.2 expression.

OGC P01 Evaluating the use of FDG PET-CT for restaging patients with oesophageal adenocarcinoma treated with neoadjuvant chemotherapy

Abstract Background 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography-computed tomography (FDG-PET-CT) is routinely used for staging oesophageal cancer and has an emerging role in evaluating response to neoadjuvant chemotherapy (NACT). This study aimed to evaluate the clinical utility of FDG-PET-CT and contrast-enhanced CT (CECT) in restaging patients with oesophageal adenocarcinoma treated with NACT. The accuracy for evaluating depth of tumour invasion (ypT stage), pathological nodal disease (ypN stage) and identifying distant metastases compared with CECT was assessed. The ability of FDG-PET-CT to predict pathological response in the primary tumour (pTR) and LNs (pNR) was also evaluated. Methods Cohort study of 104 patients with locally advanced oesophageal or oesophago-gastric junctional adenocarcinoma who underwent FDG-PET-CT and CECT before and after NACT at Guy’s and St Thomas’ NHS Foundation Trust, London, UK, between 2017–2020. SUV metrics related to the primary tumour and loco-regional LNs were derived on pre- and post- treatment FDG-PET-CT. pTR and pNR were evaluated using the Mandard classification. Receiver operator characteristic analysis was performed and area under the curve (AUC) calculated to evaluate the discriminatory ability of FDG-PET-CT and CECT to predict ypT3-4 or pN positive disease. Clinicopathological characteristics were compared using the Chi-squared test. Results 91/104 patients underwent surgical resection following NACT. Four patients (3.8%) had metastatic disease identified on FDG-PET-CT only. None had metastatic disease identified on CECT only. The ability of FDG-PET-CT and CECT to predict ypT stage was comparable. However, FDG-PET-CT demonstrated better discriminatory ability (FDG-PET-CT; AUC 0.71, CECT; AUC 0.62, p=0.210). FDG-PET-CT was more accurate for ypT0-2 tumours (p=0.022), whilst CECT was superior for ypT3-4 tumours (p=0.002). The ability of both modalities to predict ypN1-3 disease was poor (FDG-PET-CT; AUC 0.55, CECT; AUC 0.53, p=1.00). Metabolic response on FDG-PET-CT was predictive of pTR (AUC 0.71, p&amp;lt;0.001) and pNR (AUC 0.75, p=0.010). Conclusions FDG-PET-CT after NACT identified occult metastatic disease undetected by CECT in a number of patients in this cohort, preventing futile surgery. The accuracy of FDG-PET-CT and CECT to predict ypT and ypN stage were comparable. However, CECT was more accurate for advanced tumours and FDG-PET-CT was superior for early tumours. Metabolic response on FDG-PET-CT after NACT was predictive of pathological response in both the primary tumour and LNs which may support pre-operative prognostication. These results suggest that concurrent CECT and FDG-PET-CT may be complementary for restaging and response assessment following completion of NACT prior to surgical resection.

ME04 Novel immunotherapy combinational approach in advanced oesophago-gastric adenocarcinoma

ME04 Novel immunotherapy combinational approach in advanced oesophago-gastric adenocarcinoma

1515P Maintenance rucaparib after first-line platinum-based chemotherapy in advanced esophagogastric (OG) adenocarcinoma: Interim results from the PLATFORM trial

1515P Maintenance rucaparib after first-line platinum-based chemotherapy in advanced esophagogastric (OG) adenocarcinoma: Interim results from the PLATFORM trial

First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial

The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma. This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m2 bolus followed by 2400 mg/m2 over 48 h], leucovorin [400 mg/m2], and oxaliplatin [85 mg/m2]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete. Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52-66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18·1 months (IQR 12·7-20·4). The primary endpoint was reached, with 25 (71%; 95% CI 54-85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths. Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned. Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute.

237. PRE-NEOADJUVANT CHEMOTHERAPY SARCOPENIA IS PREDICTIVE OF MORTALITY IN ESOPHAGOGASTRIC ADENOCARCINOMA PATIENTS

Abstract Background Sarcopenia is defined as a loss of skeletal muscle mass and function. Preoperative sarcopenia amongst patients with esophageal cancer has been linked to mortality, various postoperative complications and the severity of these complications. The majority of this evidence comes from populations with squamous cell carcinoma or where neoadjuvant chemoradiotherapy was used. Whether sarcopenia is associated with neoadjuvant chemotherapy (NAC) for esophagogastric adenocarcinoma (EGA) and any link to mortality is not fully understood. Methods Patients diagnosed with EGA between January 2017 and December 2021 and undergoing NAC followed by esophagectomy from a single high-volume center had their pre-NAC CT scans assessed for radiological sarcopenia. Skeletal muscle index (SMI) was calculated from muscle area measured on CT scans at the level of third lumbar vertebra. Previously published SMI cut off values for radiologically defined sarcopenia were used (52.4 cm2 for men and 38.5 cm2 for women). A cox-regression model was used to investigate mortality between those with sarcopenia and those without. Results There were 191 patients included in the analysis. Pre-NAC sarcopenia was associated with increased mortality (Hazard ratio 1.59, 1.00–2.54 p = 0.046). 5-year survival for sarcopenic and non-sarcopenic patients was 27.8% (17.1%, 45.2%) and 35.6% (21.3%, 59.5%), respectively. Median survival was 2.72 and 4.09 years, respectively. Conclusion EGA patients with sarcopenia pre-NAC have a significantly higher chance of mortality in the 5-years following their surgery. Strategies to treat sarcopenia and prevent its further development should be investigated with the aim to increase survival in this cohort.

238. ESOPHAGOGASTRIC ADENOCARCINOMA PATIENTS WITH SARCOPENIA BEFORE OR AFTER NEOADJUVANT CHEMOTHERAPY ARE MORE LIKELY TO HAVE LONGER POST-OPERATIVE INPATIENT STAYS

Abstract Background Sarcopenia is defined as a loss of skeletal muscle mass and function. It is prevalent amongst patients with esophagogastric adenocarcinoma (EGA) and associated with adverse treatment outcomes. The majority of this evidence comes from populations with squamous cell carcinoma or where neoadjuvant chemoradiotherapy was used. Protracted inpatient stays are directly associated with adverse events such as healthcare-associated infections and patient deconditioning and increase the economic burden on healthcare institutions. Methods Patients diagnosed with EGA between January 2017 and December 2021 and undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy from a single tertiary center in the UK had their pre- and post-NAC CT scans assessed for radiological sarcopenia. Skeletal muscle index (SMI) was calculated from muscle area measured on CT scans at the level of third lumbar vertebra. Previously published SMI cut off values for radiologically defined sarcopenia were used (52.4 cm2 for men and 38.5 cm2 for women). Wilcoxon signed-rank test for non-parametric data was used to determine significance. Results 191 patients were included in the analysis. The number of patients with sarcopenia increased from 96 to 123 following NAC. Sarcopenia before (p = 0.047) or after (p = 0.007) NAC was significantly associated with longer inpatient stays post-operatively. The median stay for patients with sarcopenia before or after NAC was 12 days compared to 9 for those without sarcopenia before or after NAC. Conclusion Radiological sarcopenia is highly prevalent in this cohort of patients and increases following NAC. This study demonstrates that sarcopenia before or after NAC in patients with EGA undergoing esophagectomy are likely to have longer inpatient stays following surgery. Peri-operative treatment to treat and reduce the incidence of sarcopenia should be trialed with the aim of improving post-operative outcomes in this cohort.