Esophagogastric Adenocarcinoma Research Articles

Immunotherapy as a new perspective for the therapy of esophageal cancer

Abstract The therapeutic landscape in nearly every therapeutic line in advanced/metastatic patients with squamous cell carcinoma (SCC) and esophagogastric adenocarcinoma (EGC) is enriched by recent approvals of immune checkpoint inhibitors (ICIs). In curative intended therapy, patients without pathological residual disease of SCC or GEJ (esophagogastric junction) cancer after preoperative chemoradiation and complete resection have access to adjuvant immunotherapy (independent of PD-L1 (programmed cell death protein 1) status, nivolumab, CHECKMATE 577). For metastatic SCC in the first-line, nivolumab combined with chemotherapy or with ipilimumab (TPS (tumor proportion score) ≥1 %, SCC, CHECKMATE 648) are approved, as well as second-line nivolumab alone regardless of PD-L1 status (ATTRACTION 03). For both, locally advanced or metastatic SCC and EGC, chemotherapy with pembrolizumab is available for patients with CPS (combined positive score) ≥10 (KEYNOTE 590) and for adenocarcinoma with nivolumab (CPS ≥5, CHECKMATE 649). Recent added approvals are chemotherapy with pembrolizumab in CPS ≥1 patients (KEYNOTE 859) and the addition of trastuzumab for personalized therapy in HER-2 positive/CPS ≥1 gastric and GEJ patients (KEYNOTE 811).

Prevalence and Risk Factors for Malignant Nodal Involvement in Early esophago-gastric Adenocarcinoma: Results from the Multicenter Retrospective Congress Study (endosCopic resectiON, esophaGectomy or Gastrectomy For Early Esophagogastric Cancers).

The aim of this study was to quantify LNM risk and outcomes following treatment of early esophago-gastric (EG) adenocarcinoma. The standard of care for early T1N0 EG cancer is endoscopic resection (ER). Radical surgical resection is recommended for patients perceived to be at risk of lymph node metastasis (LNM). Current models to select organ-preserving vs. surgical treatment are inconsistent. CONGRESS is a UK-based multicentre retrospective cohort study. Patients diagnosed with clinical or pathological T1N0 EG adenocarcinoma from 2015-2022 were included. Outcomes and rates of LNM were assessed. Cox regression was performed to assess the impact of prognostic and treatment factors on overall survival. 1,601 patients from 26 centres were included, with median follow-up 32 months(IQR 14-53). 1285/1612(80.3%) underwent ER, 497/1601(31.0%) underwent surgery. Overall rate of LNM was 13.5%. On ER staging, tumour depth (T1bsm2-3 17.6% vs. T1a 7.1%), lymphovascular invasion (17.2% vs. 12.6%), or signet cells (28.6% vs. 13.0%) were associated with LNM. In multivariable regression analysis, these were not significantly associated with LNM rates or survival. Adjusting for demographic and tumour variables, surgery after ER was associated with significant survival benefit, HR 0.33(0.15-0.77),P=0.010. This large multicentre dataset suggests that early EG adenocarcinoma is associated with significant risk of LNM. This data is representative of current real clinical practice with ER-based staging, and suggests previously held beliefs regarding reliability of predictive factors for LNM may need to be reconsidered. Further research to identify patients who may benefit from organ-preserving vs. surgical treatment is urgently required.

Predictors of early recurrence of oesophagogastric adenocarcinoma after neoadjuvant FLOT

BackgroundAlthough survival of patients with oesophagogastric adenocarcinomas has improved over the years, rates of cancer recurrence remain high. There is limited research on predictors of 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 for ER. MethodsPatients receiving neoadjuvant chemotherapy with FLOT for oesophagogastric adenocarcinoma at single high-volume centre between August 2018 and January 2023 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. Results196 patients were included. 93.3 % and 40.3 % of patients completed all four neoadjuvant and adjuvant cycles of FLOT respectively. 54 patients (27.6 %) developed recurrence in the follow up period with 27 patients (13.8 %) having ER. Recurrence free survival and overall survival at one year were 83.7 % and 90.8 % respectively. The estimated median survival after recurrence was 4.1 months. Extracapsular spread was found to be independent risk factor for ER (OR 4.565, 95 % CI 1.450–14.369, p = 0.009) in multivariable analyses together with ypN3 stage (OR 7.978, 95 % CI 1.339–47.534, p = 0.023). ConclusionsThe 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.

1424P Maintenance capecitabine plus ramucirumab after first-line platinum-based chemotherapy in advanced oesophagogastric adenocarcinoma (OGA): Final analysis from the PLATFORM trial

1424P Maintenance capecitabine plus ramucirumab after first-line platinum-based chemotherapy in advanced oesophagogastric adenocarcinoma (OGA): Final analysis from the PLATFORM trial

556. PREDICTORS OF EARLY RECURRENCE AFTER OESOPHAGECTOMY AND NEOADJUVANT FLOT

Abstract Background FLOT, a novel type of perioperative chemotherapy, has led to improved survival after surgery for oesophageal adenocarcinoma. Yet, rates of cancer recurrence remain high. There is limited research on predictors for early recurrence (ER) in patients receiving FLOT. The aim of this study was to investigate ER and survival rates and identify risk factors of ER. Methods Patients who underwent neoadjuvant FLOT and oesophagectomy for oesophageal and oesophagogastric junction adenocarcinomas at a single high-volume centre between August 2018 and January 2023 were evaluated for ER, defined as disease present within one year of surgery. Multivariable logistic regression 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 145 patients were included. 139 (95.9%) and 63 (43.4%) patients fully completed neoadjuvant and adjuvant FLOT. 44 patients (30.3%) developed recurrence and 22 patients (15.2%) had ER in the follow up period. Distant, local or mixed type of recurrence was found in 32, 6 and 6 patients respectively. The estimated recurrence free survival and overall survival at one, two and three years were 81.4%, 66.9%, 52.0% and 89.0%, 73.7%, 65.5% respectively. The estimated median survival after recurrence was 4.9 months. In multivariable analysis ypN3 status was identified to be an independent predictor of ER (OR 13.769, 95%CI 1.358-139.573, p=0.026). Conclusions This study confirms that ER after neoadjuvant FLOT is common. Patients with a high pathological nodal stage are particularly at risk. It is possible that some patients with ER might have undetected metastases prior to surgery and some do not respond well to neoadjuvant treatment. Identifying chemotherapy non-responders is an important area for future research. These results might be beneficial for prognostication and tailoring follow up care, such as regular surveillance imaging, treatment, and frequency of reviews.

A randomized, open-label phase II/III efficacy and safety study of atezolizumab in combination with FLOT versus FLOT alone in patients with gastric cancer and adenocarcinoma of the oesophagogastric junction and high immune responsiveness: The IKF633/DANTE trial, a trial of AIO in collaboration with SAKK.

TPS4184 Background: Despite recent advances, long-term survival of patients with locally advanced, operable esophagogastric adenocarcinoma (EGA) is below 50%. Immune checkpoint inhibitors in the neoadjuvant setting of this tumor type have lately been shown to increase pathological responses in all comers (IKF633/DANTE pII, KEYNOTE-585, Matterhorn), but the effect on survival is still unknown. The IKF633/DANTE pIII trial evaluates the efficacy and clinical activity of atezolizumab (ATZ) with perioperative FLOT in patients (pts) with locally advanced, resectable EGA considered having an immune-responsive profile. Methods: IKF633/DANTE is conducted as a randomized, multinational, multicenter, prospective, investigator-initiated, open label phase II/III trial. For the phase III portion, pts with histologically confirmed EGA of a clinical stage ≥cT2 and/or cN+ without evidence of distant metastases and with at least one immune response criterium (MSI, PD-L1 CPS≥1, TMB ≥10/MB or EBV+) are eligible. Pts are stratified acc. to nodal stage (cN- vs. cN+), tumor site (GEJ type I vs. GEJ type II/III vs. gastric) and PD-L1 expression levels (CPS≥5 vs. CPS<5). Pts are randomized 1:1 to receive 4 pre- and post-operative cycles FLOT/ATZ, followed by 8 cycles ATZ maintenance (Arm A) or 2x4 perioperative cycles FLOT alone (Arm B). In total, 556 pts will be enrolled, thereof 379 pts in phase III. This estimates to a recruitment time of 30 months plus 18 months follow-up for 80% statistical power and a significance level of p<0.05 (two-sided log rank test). The primary endpoint is event-free survival (EFS) with a target hazard ratio of 0.72, reflecting a clinically relevant improvement to 41.65 months in arm A. Main secondary endpoints are pCR, overall survival (OS) also in high immune-responsive subgroups (CPS ≥5/ CPS≥ 10/ MSI), R0 resection rate and safety/tolerability. In addition, a prospective biomarker study with serial circulating tumor DNA (ctDNA) analysis accompanying therapy is performed to explore the prognostic impact of ctDNA on efficacy and survival parameters, as well as on relapse incidence. Recruitment of phase III started in Aug 2023 and is still ongoing. Clinical trial information: NCT03421288 .

Association of ERBB2 extrachromosomal DNA (ecDNA) with first-line HER2-targeted treatment outcomes in advanced esophagogastric adenocarcinoma (EGC).

Association of ERBB2 extrachromosomal DNA (ecDNA) with first-line HER2-targeted treatment outcomes in advanced esophagogastric adenocarcinoma (EGC).

Implementation of perioperative FLOT compared to ECX/EOX chemotherapy regimens in resectable esophagogastric adenocarcinomas: an analysis of real-world data.

Perioperative 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) is recommended in resectable esophagogastric adenocarcinoma based on randomised trials. However, the effectiveness of FLOT in routine clinical practice remains unknown as randomised trials are subject to selection bias limiting their generalisability. The aim of this study was to evaluate the implementation of FLOT in real-world patients. Retrospectively collected data were analysed in consecutive patients treated before or after the implementation of FLOT. The primary endpoint was complete pathological response (pCR) and secondary endpoints were margin-free resection (R0), overall survival (OS), relapse-free survival (RFS) tolerability of chemotherapy and surgical complications. Mean follow-up time for patients treated with FLOT (n = 205) was 37.7 versus 47.0 months for epirubicin, cis- or oxaliplatin, and capecitabine (ECX/EOX, n = 186). Surgical resection was performed in 88.0% versus 92.0%; pCR were observed in 3.8% versus 2.4%; and R0 resections were achieved in 78.0% versus 86.0% (p = 0.03) in the ECX/EOX and FLOT cohorts, respectively. Survival analysis indicated no significant difference in RFS (p = 0.17) or OS (p = 0.37) between the cohorts with a trend towards increased OS in performance status 0 (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.50-1.04). More patients treated with ECX/EOX completed chemotherapy (39% vs. 28%, p = 0.02). Febrile neutropenia was more common in the FLOT cohort (3.8% vs. 11%, p = 0.0086). 90-days mortality (1.2% vs. 0%) and frequency of anastomotic leakage (8% vs. 6%) were equal and low. Patients receiving FLOT did not demonstrate improved pCR, RFS or OS. However, R0 rate was improved and patients in good PS trended towards improved OS.

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.

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)...

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).

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.

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.

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.

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

BackgroundThe 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.MethodsWe 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.ResultsAmong 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%).ConclusionsFOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

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 .