Advanced Oesophagogastric Adenocarcinoma Research Articles

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).

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 < 1, showcased survival beyond four years without liver metastases. Immune dN/dS > 1 and no evidence of liver metastases displayed the best prognosis after treatment in contrast with those that have immune dN/dS < 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 .

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<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

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.

The AGAMENON-SEOM model for prediction of survival in patients with advanced HER2-positive oesophagogastric adenocarcinoma receiving first-line trastuzumab-based therapy.

Trastuzumab and chemotherapy is the standard first-line treatment in human epidermal growth factor receptor 2 (HER2)-positive advanced gastro-oesophageal cancer. The objective was to develop a predictive model for overall survival (OS) and progression-free survival (PFS) in patients treated with trastuzumab. Patients with HER2-positive advanced gastro-oesophageal adenocarcinoma (AGA) from the Spanish Society of Medical Oncology (SEOM)-AGAMENON registry and treated first line with trastuzumab and chemotherapy between 2008 and 2021 were included. The model was externally validated in an independent series (The Christie NHS Foundation Trust, Manchester, UK). In all, 737 patients were recruited (AGAMENON-SEOM, n = 654; Manchester, n = 83). Median PFS and OS in the training cohort were 7.76 [95% confidence interval (CI), 7.13-8.25] and 14.0 months (95% CI, 13.0-14.9), respectively. Six covariates were significantly associated with OS: neutrophil-to-lymphocyte ratio, Eastern Cooperative Oncology Group performance status, Lauren subtype, HER2 expression, histological grade and tumour burden. The AGAMENON-HER2 model demonstrated adequate calibration and fair discriminatory ability with a c-index for corrected PFS/OS of 0.606 (95% CI, 0.578-0.636) and 0.623 (95% CI, 0.594-0.655), respectively. In the validation cohort, the model is well calibrated, with a c-index of 0.650 and 0.683 for PFS and OS, respectively. The AGAMENON-HER2 prognostic tool stratifies HER2-positive AGA patients receiving trastuzumab and chemotherapy according to their estimated survival endpoints.

OGC P20 Metabolic tumour and nodal response to neoadjuvant chemotherapy on FDG PET-CT as a predictor of pathological response and survival in patients undergoing surgical resection for locally advanced oesophageal adenocarcinoma

Abstract Background 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) is routinely used for staging of oesophageal cancer and has an emerging role in assessing response to neoadjuvant therapy. Several studies have demonstrated that a reduction in FDG avidity of the primary tumour and loco-regional lymph nodes following neoadjuvant chemotherapy predicts pathological response and survival in this patient group. However, no studies have evaluated the prognostic significance of metabolic parameters with respect to pathological response in lymph nodes. Change in primary tumour maximum standardised uptake value (SUVmax) is the most widely used FDG PET-CT parameter to define metabolic response, with various thresholds described. The most commonly utilised are a 35% reduction in SUVmax (MUNICON), and a 30% reduction in SUVmax (PERCIST). However, there is no consensus regarding the optimal classification; the MUNICON threshold was derived from only 40 patients and PERCIST is not tumour specific. The primary aim of this study was to evaluate the ability of FDG PET-CT to predict pathological response in the primary tumour (pTR) and lymph nodes (pNR) in patients with oesophageal adenocarcinoma undergoing neoadjuvant chemotherapy before surgery. Secondary aims were to assess the prognostic effect of metabolic and pathological response and evaluate the predictive ability of response classifications. Methods Cohort study of 75 patients with locally advanced oesophageal or oesophago-gastric junctional adenocarcinoma who underwent FDG-PET-CT before and after neoadjuvant chemotherapy, prior to surgical resection at Guy's and St Thomas’ NHS Foundation Trust, London, UK, between 2017–2020. SUV metrics related to the primary tumour and loco-regional lymph nodes were derived on pre- and post- treatment FDG PET-CT. pTR and pNR were evaluated using the Mandard classification. Patients with Mandard scores of 1–3 were classified as pathological responders and those with Mandard scores of 4–5 as non-responders. Clinicopathological characteristics were compared using the Chi-squared test. Receiver operator characteristic (ROC) analysis was performed and area under the curve (AUC) calculated to determine optimum SUVmax thresholds for metabolic response in the primary tumour (mTR) and lymph nodes (mNR). Survival curves were created using the Kaplan-Meier method, with subgroups compared using the log-rank test. Survival analysis was performed using Cox proportional hazards regression providing hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age (continuous), sex (male or female), chemotherapy regimen (ECX or FLOT), cT stage (cT1–2 or cT3–4), cN stage (cN0 or cN+), tumour grade (well / moderately differentiated or poorly differentiated) and presence of signet ring cells (yes or no). Results Mean age was 63 years with the majority male (86.7%). Almost two thirds received FLOT (48/75, 64.0%) with the remainder receiving ECX chemotherapy. There was discordance between pathological response in the primary tumour and lymph nodes in several patients, including 23.1% (6/26) who demonstrated a lymph node response in the absence of a response in the primary tumour. ROC analysis demonstrated an optimum tumour SUVmax decrease of 51.2% for predicting pTR. Using a pragmatic cut-off of 50% this provided better prediction of pTR (AUC 0.714, sensitivity 73.5%, specificity 69.2%, p<0.001) than PERCIST (AUC 0.631, sensitivity 87.8%, specificity 38.5%, p=0.008) and MUNICON (AUC 0.659, sensitivity 85.7%, specificity 46.2%, p=0.003) criteria. ROC analysis demonstrated an optimum nodal SUVmax decrease of 32.6% for predicting pNR or pathological node negativity. Using a pragmatic 30% SUVmax cut-off and excluding metabolically negative nodes, mNR demonstrated high sensitivity but low specificity (AUC 0.749, sensitivity 92.6%, specificity 57.1%, p=0.010) for predicting pNR. pTR, mTR, pNR and mNR were independent predictive factors for overall survival on adjusted analysis (pTR responder HR 0.10 95% CI 0.03–0.34; mTR responder HR 0.17 95% CI 0.06–0.48; pNR responder HR 0.17 95% CI 0.06–0.54; mNR responder HR 0.13 95% CI 0.02–0.66). Conclusions In this study metabolic response on FDG PET-CT after neoadjuvant chemotherapy was predictive of pathological response in both the primary tumour and lymph node metastases of patients with oesophageal adenocarcinoma. Patients who had a favourable metabolic or pathological response in the primary tumour or lymph nodes had improved survival compared to non-responders. It has been suggested that commonly utilised thresholds of SUVmax are not optimal for response assessment in this patient group. This is supported by the results of the present study which suggest a reduction in SUVmax of 50% in the primary tumour was not only a better predictor of pathologic response, but also tumour recurrence and survival compared with PERCIST and MUNICON criteria. No previous studies have evaluated the ability of FDG PET-CT to predict pathologic nodal response despite recent findings suggesting it is an independent predictor of survival and evidence of a discrepancy, in some patients, who demostrate a nodal response in the absence of a response in the primary tumour. The use of FDG PET-CT in assessing response to neoadjuvant chemotherapy remains an under researched area and further evaluation is needed to establish whether it could be used to tailor individualised treatment strategies.

OGC P02 A comparison of body composition changes between the FLOT and MAGIC regimes in patients with locally advanced oesophageal cancer

Abstract Background Recently, peri-operative FLOT (fluorouracil plus leucovorin, oxaliplatin, and docetaxel) chemotherapy has superseded the ‘MAGIC’ regimen (epirubicin, cisplatin plus fluorouracil or capecitabine) as standard of care for locally advanced oesophago-gastric adenocarcinoma. However, concerns have been raised regarding the toxicity profile of FLOT. This study aims to compare the changes in body composition between both regimens. Methods 115 patients treated with FLOT (n = 61) or MAGIC (n = 54) who underwent an oesophagectomy for oesophageal or gastro-oesophageal junction (GOJ) adenocarcinoma between 2014 and 2020 at Queen Elizabeth Hospital, Birmingham, UK were analysed. Changes in body composition between pre- and post-neo-adjuvant chemotherapy were determined by analysis of computed tomography imaging. Results In both regimes, a large proportion of patients were sarcopenic prior to starting chemotherapy (FLOT 44.2%, MAGIC 44.4%; p=0.984). The percentage of patients who were sarcopenic increased post chemotherapy (FLOT 63.9%, MAGIC 57.4%; p=0.474). There was no significant pre vs post chemotherapy change in L3 skeletal muscle index in both regimes (FLOT 2.96 ± 4.03 vs MAGIC 2.76 ± 4.21; p=0.792). There was also no significant pre vs post chemotherapy change in L3 fat index in both regimes (FLOT 2.49 ± 22.6 vs MAGIC 5.78 ± 24.2; p = 0.453). Myosteatosis was observed in 44.3% of patients pre-FLOT and 42.6% of patients pre-MAGIC (p=0.857). This increased to 62.2% post-FLOT and 46.3% post-MAGIC (p=0.085). FLOT chemotherapy was associated with better tumour regression grade compared to MAGIC (p<0.001). Conclusions A large proportion of patients with locally advanced oesophageal/GOJ adenocarcinoma were sarcopenic and had myosteatosis prior to starting chemotherapy. A further loss of muscle and fat occurs during chemotherapy but there was no significant difference in loss of fat or muscle across both FLOT and MAGIC regimes. However, patients treated with the FLOT regime had better pathological response as compared with MAGIC.

577. FDG PT-CT METABOLIC TUMOUR AND NODAL RESPONSE AS A PREDICTOR OF PATHOLOGICAL RESPONSE AND SURVIVAL IN PATIENTS WITH OESOPHAGEAL ADENOCARCINOMA

Abstract 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography-computed tomography (FDG-PET-CT) is routinely used for staging of oesophageal cancer and has an emerging role in assessing response to neoadjuvant therapy. The primary aim of this study was to evaluate the ability of FDG-PET-CT to predict pathological response in the primary tumour (pTR) and lymph nodes (pNR) in patients with oesophageal adenocarcinoma undergoing neoadjuvant chemotherapy before surgery. The secondary aim was to assess the prognostic effect of metabolic and pathological response. Cohort study of 75 patients with locally advanced oesophageal or oesophago-gastric junctional adenocarcinoma who underwent FDG-PET-CT before and after neo-adjuvant chemotherapy, prior to surgical resection at a tertiary referral centre in the United Kingdom, between 2017-2020. Standardised uptake value (SUV) metrics related to the primary tumour and loco-regional lymph nodes were derived. pTR and pNR were evaluated using the Mandard classification. Receiver operator characteristic (ROC) analysis was performed and area under the curve (AUC) calculated to determine optimum SUVmax thresholds for metabolic response in the primary tumour (mTR) and lymph nodes (mNR). Survival was assessed using multivariable Cox regression. ROC analysis demonstrated an optimum tumour SUVmax decrease of 51.2% for predicting pTR. A pragmatic 50% cut-off provided better prediction of pTR (AUC 0.714, sensitivity 73.5%, specificity 69.2%, p<0.001) than PERCIST (30% reduction) and MUNICON (35% reduction) criteria. Using a 30% SUVmax threshold and excluding metabolically negative nodes, mNR demonstrated high sensitivity but low specificity (sensitivity 92.6%, specificity 57.1%, p=0.010) for predicting pNR. pTR, mTR, pNR and mNR were independent prognostic factors (pTR responder HR 0.10 95% CI 0.03-0.34; mTR responder HR 0.17 95% CI 0.06-0.48; pNR responder HR 0.17 95% CI 0.06-0.54; mNR responder HR 0.13 95% CI 0.02-0.66). Metabolic response predicted pathological response in both the primary tumour and lymph nodes in this cohort of patients with locally advanced oesophageal adenocarcinoma treated with neo-adjuvant chemotherapy. Metabolic tumour response, pathological tumour response, metabolic nodal response and pathological nodal response were all independent prognostic factors for survival. Currently utilised metabolic response criteria may not be optimal for this tumour group.

1253P Safety and efficacy of Wnt inhibition with a DKK1 inhibitor, DKN-01, in combination with atezolizumab in patients with advanced oesophagogastric adenocarcinoma: Phase IIa results of the WAKING trial

Immune checkpoint inhibitor (ICI) monotherapy has limited efficacy in patients (pts) with mismatch repair proficient (MMRp) oesophagogastric adenocarcinoma (OGA). Dickkopf-1 (DKK1) modulates Wnt/β-Catenin signaling and promotes a T-cell excluded or ‘immune desert’ tumour microenvironment (TME). DKN-01, a DKK1 neutralising antibody, can favourably reprogram the TME by reducing levels of myeloid-derived suppressor cells (MDSCs) and increasing entry of effector T-cells and may improve responses when added to ICI monotherapy. This phase IIa study (3+3 design) evaluated the safety and efficacy of DKN-01 (300mg/600mg) and atezolizumab (840mg) given intravenously q2W in pts with pre-treated, anti PD1/PDL1 naïve, MMRp advanced OGA. The primary endpoint was to establish the safety, tolerability, and recommended phase II dose (RP2D) for the efficacy phase. Safety, efficacy, and translational analyses (including intratumoural DKK1/PD-L1, peripheral MDSC and NK cell populations, TCR diversity analysis, tumour genomics and stool microbiome) are ongoing. Eleven pts were treated on study (5 pts at DKN-01 300mg, 6 at 600mg). Eight pts completed the DLT period (3 at 300mg, 5 at 600mg) and were therefore evaluated for the safety endpoint. No dose limiting toxicities were observed. Of the 11 treated pts, 10 (90.9%) experienced at least one treatment-related AE (TRAE). The most common TRAEs (experienced by ≥ 2 pts) were fatigue (36%), anaemia (18%), hypothyroidism (18%), diarrhoea (18%) and pain (18%). One pt experienced G3 urticaria and 1 experienced an SAE of G2 pneumonitis, both were treatment related. Of the 8 pts evaluated for the safety endpoint, 1 pt (12.5%) had PR and 4 pts (50%) had SD as their best response. No clear trend between peripheral MDSC levels at baseline and during treatment have yet been observed. Additional biomarker work is ongoing. DKN-01 plus atezolizumab has a manageable safety profile with no new safety signals in pts with advanced OGA. DKN-01 600mg plus atezolizumab 840mg q2W was the RP2D taken through to the ongoing expansion phase to confirm efficacy.

ELEVATE – evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial

BackgroundFor patients with oesophagogastric adenocarcinoma, surgery is the only curative option and despite the use of multimodality therapy, which combines it with chemotherapy and/or radiotherapy, more than 50% of patients will relapse and die. Many UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab, a checkpoint blockade inhibitor, has been found to work in some advanced cancers. It is proposed, for those where immunotherapy hasn’t worked, that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act.MethodsELEVATE is a single arm phase II trial testing the overall response to nivolumab following temozolomide treatment in patients with advanced unresectable previously treated adenocarcinoma which is O6-methylguanine-DNA-methyltransferase (MGMT) methylated. 18 patients are being recruited from UK secondary care sites. To be eligible, participants must have been treated with at least 3 months of platinum and fluoropyrimidine chemotherapy. Participants will receive 50 mg/m2 temozolomide continuously for 3 months. If their disease progresses during the 3 months, they will stop temozolomide and start nivolumab at a dose of 240mg every 2 weeks. If there is no progression after 3 months the participant will continue taking temozolomide in combination with nivolumab. All treatment will stop once the participant progresses on nivolumab. The primary endpoint is the best overall response to nivolumab, using both Response Evaluation Criteria in Solid Tumours version 1.1 and immunotherapy modified Response Evaluation Criteria in Solid Tumours. Secondary endpoints include progression-free survival, overall survival, and quality of life.DiscussionELEVATE will provide evidence for whether giving nivolumab after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma is safe and biologically effective prior to future randomised trials.Trial registrationsEudraCT Number: 2020-004771-41(issued 01 October 2020); ISCRTN11398887(registered 14 July 2021).

A feasibility trial of prehabilitation before oesophagogastric cancer surgery using a multi-component home-based exercise programme: the ChemoFit study

BackgroundTreatment for locally advanced oesophagogastric adenocarcinoma involves neoadjuvant chemotherapy which has a negative impact on patient fitness. Using ‘prehabilitation’ to increase activity levels and fitness may affect physiology, postoperative outcomes and improve patient wellbeing and quality of life. The aims of the trial were to address the feasibility and acceptability of recruiting participants to a home-based prehabilitation programme and provide data to allow design of future studies.MethodsWe recruited patients to a single-arm feasibility trial of home-based exercise prehabilitation. Eligible patients were aged ≥18years, had operable oesophageal or gastric adenocarcinoma and were receiving neoadjuvant chemotherapy at our tertiary referral hospital. All participants commenced a home-based exercise programme utilising pedometers and step counting to target daily aerobic exercise sessions alongside daily strengthening exercises. A weekly telephone consultation directed the exercise programme and facilitated weekly data collection. The primary (feasibility) outcomes for the trial were (a) recruitment rate, (b) completion rate, (c) engagement with the programme (use of pedometers, recording step counts, telephone consultations) and (d) compliance with exercise sessions, exercise intensity and strengthening exercises.ResultsThere were 42 patients recruited, and the recruitment rate was 72.4% (42/58). 92.3% (36/39) of patients completed the exercise programme. There was 98.7% (IQR 93.2–100.0%) compliance with wearing a pedometer and recording data, and 100.0% (IQR 93.1–100.0%) compliance with a weekly telephone consultation. Exercise sessions and strengthening exercises were completed 70.2% (IQR 53.1–88.9%) and 69.4% (IQR 52.1–84.3%) of the time, respectively. Appropriate exercise intensity was recorded 96% (IQR 85.4–99.4%) of the time. There were no adverse events. Participants were enrolled in the exercise programme for a median of 91 days (IQR 84 to 105 days).ConclusionsThe results of this trial support the feasibility and acceptability of recruiting participants to an appropriately powered randomised controlled trial of prehabilitation.Trial registrationClinicaltrials.gov NCT04194463. Registered on 11th December 2019—retrospectively registered.

187: EFFECT OF PERI-OPERATIVE CHEMOTHERAPY REGIMEN ON SURVIVAL IN THE TREATMENT OF LOCALLY ADVANCED GASTRO-OESOPHAGEAL ADENOCARCINOMA—FLOT VS ‘MAGIC’

Abstract Background and aim Peri-operative chemotherapy has been shown to improve survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two commonly used regimens are epirubicin, cisplatin plus capecitabine or fluorouracil (MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). The primary aim of this study was to evaluate the effect of chemotherapy regimen (FLOT vs MAGIC) on survival. We also aimed to assess pathological response, surgical complications, chemotherapy associated adverse events and chemotherapy completion rates. Methods Cohort study including 946 patients treated with peri-operative FLOT or MAGIC chemotherapy who underwent oesophagectomy or gastrectomy for oesophageal or gastric adenocarcinoma between 2002–2021 at St Thomas’ Hospital, London, UK or The Royal Marsden Hospital, London, UK. Survival analysis was performed using Kaplan–Meier and Cox regression. Results Patients treated with MAGIC had worse overall and disease-free survival compared with FLOT on multivariable analysis (overall survival HR 1.353 95% CI 1.039–1.763, disease-free survival HR 1.335 95% CI 1.025–1.739). Stratified analysis by tumour location revealed similar results for both oesophageal and gastric tumours. Patients treated with FLOT were more likely to have a favourable pathological response (Mandard 1–2) (11.1% MAGIC vs 21.8% FLOT, P < 0.001). Patients treated with FLOT were less likely to have a positive resection margin (19.1% FLOT vs 32.2% MAGIC, P < 0.001). Surgical complications, chemotherapy associated adverse events and chemotherapy completion rates were comparable between groups. Conclusion Patients with oesophageal and gastric adenocarcinoma treated with peri-operative FLOT had improved survival compared with those treated with peri-operative MAGIC. Surgical complications, chemotherapy associated adverse events and chemotherapy completion rates were comparable between groups. Table https://secure.sem-2000.it/semUpload/OLC/file/9203828791100911681076702/94509_Table.jpg.

Effect of peri-operative chemotherapy regimen on survival in the treatment of locally advanced oesophago-gastric adenocarcinoma – A comparison of the FLOT and ‘MAGIC’ regimens

BackgroundPeri-operative chemotherapy improves survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two regimens with proven survival benefits are epirubicin, cisplatin plus capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). This study aimed to compare the effect of these regimens on survival (primary aim) and pathological response, surgical complications, adverse events and chemotherapy completion rates. MethodsCohort study including 946 patients treated with FLOT (n = 257) or MAGIC (n = 689) who underwent surgical resection for oesophageal (n = 743) or gastric (n = 203) adenocarcinoma between 2002 and 2021 at St Thomas’ Hospital or The Royal Marsden Hospital, London, UK. Survival analysis was performed using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, clinical T-stage, clinical N-stage, tumour grade and presence of signet ring cells. ResultsPatients treated with FLOT had better overall survival (HR = 0.69, 95% CI 0.50–0.94) and disease-free survival (HR = 0.75, 95% CI 0.58–0.98) than MAGIC. Patients treated with FLOT were more likely to have a complete pathological response (9.5% FLOT versus 5.5% MAGIC, p = 0.027) and were less likely to have a positive resection margin (19.1% FLOT versus 32.2% MAGIC, p < 0.001). The stratified analysis revealed similar results for oesophageal and gastric tumours. Rates of surgical complications, chemotherapy-associated adverse events and completion were similarly distributed between treatment groups. ConclusionsPatients with oesophageal or gastric adenocarcinoma treated with peri-operative FLOT had better survival and pathological response than those treated with peri-operative MAGIC. Rates of surgical complications, adverse events and chemotherapy completion were comparable.

P-OGC17 Feasibility and impact of a home-based prehabilitation programme on patients receiving neoadjuvant treatment for oesophagogastric cancer (the chemofit study)

Abstract Background Treatment for locally advanced oesophagogastric adenocarcinoma (OGA) involves neoadjuvant chemotherapy (NAC) which has a negative impact on patient fitness. Using ‘prehabilitation’ to increase activity levels and fitness may affect physiology, postoperative outcomes and improve patient wellbeing and quality of life. The aim of this study was to evaluate feasibility, acceptability and the impact of a home-based structured prehabilitation programme in OGA. Methods This feasibility study recruited consecutive patients to a pragmatic home-based prehabilitation during NAC. Participants completed daily walking sessions to a targeted step-count and daily strengthening exercises, under the weekly supervision of the research team. The primary outcomes assessed feasibility through recruitment rate, completion rate and individual compliance with each component of the intervention. Secondary outcomes included fitness derived from cardiopulmonary exercise testing (CPET). Results A total of 42/58(72%) patients approached were recruited, 36/39(92%) patients completed the programme. Median compliance with wearing a pedometer and recording step count was 97.8%(IQR 93.2-100%) and median engagement with telephone contacts was 100%(IQR 93.1-100%). Median compliance with 30-minutes aerobic exercise was 70.2%(IQR 53.1-88.9%) and for strength exercises 69.4%(IQR 52.1-84.3%). Nineteen patients had pre and post intervention CPET with no significant difference in anaerobic threshold (mean difference -0.5 ml.kg-1.min-1, 95% CI -1.6 to + 0.6, p = 0.387) or VO2peak (mean difference -0.1 ml.kg-1.min-1, 95% CI -1.6 to + 1.4, p = 0.883). Conclusions This study shows that ChemoFit is feasible, safe and achieved excellent patient compliance and engagement. Future utilisation of this home-based prehabilitation programme may improve preoperative fitness during NAC and impact post-operative outcomes.

443P EMERGE: A phase II trial assessing the efficacy of domatinostat plus avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal cancers – phase IIA dose finding

Tumours that display a non-T-cell inflamed phenotype such as mismatch repair proficient (MMRp) oesophagogastric and colorectal cancers are less responsive to checkpoint inhibitors. Epigenetic modulation of tumours to enhance immunogenicity may improve responsiveness to immunotherapy. EMERGE is a phase IIA/B study evaluating domatinostat (selective class I histone deacetylase inhibitor) in combination with avelumab (PD-L1 antibody) in patients with advanced oesophagogastric adenocarcinoma (OGA) and colorectal cancer (CRC).

Maintenance durvalumab after first-line platinum-based chemotherapy in advanced oesophago-gastric (OG) adenocarcinoma: Results from the PLATFORM trial.

4015 Background: PLATFORM is a prospective, open-label, multicentre, adaptive phase II trial assessing maintenance therapy in patients (pts) with OG adenocarcinoma after platinum-based first-line induction chemotherapy. HER2 negative pts were initially randomised 1:1:1:1:1 to surveillance (A1), capecitabine (A2), durvalumab (A3), with rucaparib (A4) and capecitabine + ramucirumab (A5) added later as per adaptive design. Here we report the primary analysis of durvalumab maintenance vs. surveillance. Methods: Pts were randomised upon achieving response or stable disease following 18 weeks of platinum-based chemotherapy and were stratified by region, disease extent and performance status. A1 pts had 4 weekly surveillance visits and A3 pts received 10mg/kg durvalumab iv Q2W. Target accrual was 154 pts/arm; however, A3 was closed prematurely after cessation of industry support. The primary endpoint was progression-free survival (PFS) from randomisation post induction chemotherapy to disease progression according to RECIST 1.1 criteria, or death. Secondary endpoints were time to treatment failure (TTF), objective response rate (ORR), overall survival (OS) and toxicity. Survival analyses according to PD-L1 using the combined positive score (CPS, Ventana SP263 assay) was conducted. Results: A total of 205 pts were concurrently randomised into A1 (n = 100) and A3 (n = 105). At data cut-off (02 Feb 2021), median follow up was 24.2 months [95% confidence interval (CI) 21.6-36.8]. There was no significant difference in PFS between A1 and A3 [median PFS: 3.2 vs. 4.7 months (hazard ratio (HR) 0.79 (95% CI 0.59-1.06, p = 0.122) respectively]. Median OS was 11.4 vs. 11.3 months (HR 0.92, 95% CI 0.66-1.27, p = 0.60) in A1 and A3 respectively and no significant difference in TTF was detected between both arms (median TTF: 3.2 vs. 3.5 months (HR 0.92, 95% CI 0.69-1.23, p = 0.558)]. ORR was 6% in A3 (n = 2 complete and n = 4 partial responses) whereas no radiological responses were seen in A1. PD-L1 results were available for 76 pts in A1 and 77 pts in A3. PFS was comparable between subgroups using the PD-L1 CPS thresholds of ≥1, ≥5 and ≥10. The safety population consisted of 199 pts (A1: 98 pts and A3: 101 pts). Grade ≥3 treatment-related adverse events were reported in 18% of A3 pts and no new safety signals were identified. Conclusions: Although a survival advantage was not seen with maintenance durvalumab compared to surveillance, a subset of patients who received durvalumab demonstrated incremental radiological responses. Exploratory analysis of PD-L1 expression was not associated with improved survival outcomes. Clinical trial information: NCT02678182.

PET/CT-tailored treatment of locally advanced oesophago-gastric junction adenocarcinoma: a report on the feasibility of the multicenter GastroPET study.

Background:Perioperative chemotherapy is a recommended treatment approach for localised oesophago-gastric junction adenocarcinoma, but not all patients respond to neoadjuvant chemotherapy. Early identification of non-responders and treatment adaptation in the preoperative period could improve outcomes. GastroPET is a national, multicentre phase II trial evaluating a 18FDG-PET/CT-guided preoperative treatment strategy with the R0 resection rate as a primary endpoint. Here, we report on the accuracy of the methodology, the feasibility of the study design and patient safety data after enrolment of the first 63 patients.Methods:Patients with locally advanced oesophago-gastric junction adenocarcinoma (Siewert I – III) stage Ib–IIIc underwent baseline 18FDG-PET/CT scanning and re-evaluation after 14 days of oxaliplatinum-5FU-(docetaxel) chemotherapy. Responders were defined by a ⩾ 35% decrease in tumour FDG standardised uptake value (SUV)average from baseline. Responders continued with the same chemotherapy for 2 to 3 months prior to surgery. PET-non-responders switched to preoperative chemoradiotherapy [weekly carboplatin and paclitaxel with concurrent radiotherapy (45 Gy in 25 fractions)]. Here, we aim to confirm the feasibility of FDG-PET-based response assessment in a multicenter setting and to compare local versus central reading. In addition, we report on the feasibility of the study conduct and patient safety data.Results:A total of 64 patients received baseline and sequential 14-day 18FDG-PET/CT scanning. And, 63 were allocated to the respective treatment arm according to PET-response [35 (56%) responders and 28 (44%) non-responders]. The concordance of local versus central reading of SUV changes was 100%. Until the date of this analysis, 47 patients (28 responders and 19 non-responders) completed surgery. Postoperative complications of grade ⩾ 3 (Common Terminology Criteria for Adverse Events, CTCAE Version 5.0) were reported in five responders (18%; 95% CI: 7.9–36%) and two non-responders (11%; 95% CI: 2.9–31%), with no statistical difference (p = 0.685). One patient in each arm died after surgery, leading to a postoperative in-hospital mortality rate of 4.3% (2/47 patients; 95% CI: 1.2–14%).Conclusion:Local and central FDG-SUV quantification and PET-response assessment showed high concordance. This confirms the accuracy of a PET-response-guided treatment algorithm for locally advanced oesophago-gastric junction cancer in a multicenter setting. Preoperative treatment adaptation revealed feasible and safe for patients.

Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma

ObjectivePrognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop...

Salvage systemic therapy for advanced gastric and oesophago-gastric junction adenocarcinoma.

Salvage systemic therapy for advanced gastric and oesophago-gastric junction adenocarcinoma.