Metastatic Esophagogastric Cancer Research Articles

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.

A population-based comparison of patients with metastatic esophagogastric carcinoma between Japan and the Netherlands

PurposeDifferences exist between Asian and Western patients with esophagogastric cancer, for example in terms of histological subtype and treatment strategies. This study aimed to compare characteristics and treatment between patients with metastatic esophagogastric cancer from Japan and the Netherlands using nationwide cancer registry data.MethodsPatients diagnosed with metastatic esophageal or gastric cancer were included from the nationwide national cancer registry of Japan (2016–2019) and the Netherlands (2015–2020). Treatment strategies were analyzed using chi-squared tests.ResultsThe proportion of patients with metastatic esophageal (16.0% vs 34.2%) and gastric cancer (14.9% vs 45.2%) were lower in Japan compared to the Netherlands. Japanese patients with metastatic esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC) or gastric cancer (GC) were more often male and older compared to Dutch patients. Proportion of patients with metastatic disease who received surgical resection was higher in Japan compared to the Netherlands (EAC 9.3 vs 1.4%, p < 0.001; ESCC 10.7% vs 2.3%, p < 0.001; GC 12.0% vs 3.6% p < 0.001). Proportion of patients who received systemic therapy was also higher (EAC 44.8% vs 30.4%, p < 0.001; ESCC 26.6% vs 12.0%, p < 0.001; GC 50.7% vs 35.8% p < 0.001).ConclusionsJapanese patients less often presented with metastatic esophagogastric cancer and more often underwent surgical resection or received systemic therapy compared to Dutch patients. Further investigation should elucidate what the deliberations are in both Japan and the Netherlands and if more patients in the Netherlands could benefit from surgical resection or systemic therapy and whether this would translate in better survival and quality of life.

Ultra-sensitive, tumor-informed ctDNA profiling in patients with gastroesophageal cancer and treated with pembrolizumab and longitudinal ctDNA kinetics.

4040 Background: Metastatic esophagogastric cancer (mEGC) is a lethal disease with poor long-term survival. Recent studies have established anti-PD-1 therapy in combination with chemotherapy as the standard of care for first-line therapy for mEGC. KeyLargo (NCT03342937) was a single arm phase II study of pembrolizumab in combination with oxaliplatin and capecitabine in the first line treatment of patients (pts) with HER2 negative mEGC. While high response rates were noted, not all pts received benefit, emphasizing the need for better biomarkers. Paired tumor biopsies and plasma were collected for optimal biomarker testing. In this retrospective study, we employed a novel, tumor-informed ctDNA approach as a tool for longitudinal disease monitoring and dynamic tumor evolution. Methods: Thirty-six pts were enrolled between January 2018 and January 2020. Of 34 evaluable pts, 25 pts achieved a response (ORR = 74%), including 6 pts with a complete response (CR) and 19 pts with a partial response (PR). Our initial analysis includes baseline tumor samples collected from 16 pts with over 59 corresponding on-treatment (OT; up to cycle 35) plasma samples. NeXT Personal, a tumor-informed ctDNA assay, generated personalized liquid biopsy panels derived from somatic variants (SV) from tumor whole genome sequencing. Each personalized assay includes up to 1,800 SVs for sensitive minimal residual disease (MRD) detection and a constant set of 2,100 clinically actionable variants (CAV). Results: Of the 36 pts who enrolled on KeyLargo, 32 pts had baseline tumor and longitudinal plasma samples collected and stored for testing. In this initial cohort of 16 pts, MRD events dynamically varied from 5.3 to 302,000 parts per million (PPM). 16/16 (100%) pts were MRD-positive at baseline, with a limit of detection between 1.5 and 4.6 PPM. OT samples were collected every 3 cycles (9 weeks). The ratio of PPM (rPPM) between baseline and the first available OT sample (typically Cycle 4 to 7) correlated with progression free survival (PFS; p = 0.0004, logrank). rPPM was significantly reduced in pts having a best overall response of PR/CR (98% mean rPPM) versus progressive disease (25% mean rPPM, p &lt; 0.037, U-test). Two pts demonstrated CR, each with 11/11 (100%) MRD-negative plasma samples over approximately two years. CAVs were identified in longitudinal samples with TP53 repeatedly detected in 5 patients and a PIK3CA mutation emerging in the final 3 (of 9) timepoints from one patient. Conclusions: ctDNA was present in all pts at baseline; OT PPM reductions correlated with PFS and best overall response. CAV profiling suggested a de novo PIK3CA variant arising during therapy in one patient. These findings suggest that tumor-informed plasma-based ctDNA profiling in mEGC may detect known CAVs arising during therapy, and with subsequent investigations, may inform therapeutic decisions.

Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab

Trastuzumab plus chemotherapy is the standard of care for the first-line treatment of patients with HER2+ advanced esophagogastric (EG) cancer. Nevertheless, patients frequently develop resistance. In preclinical models, we identified the overexpression of Fibroblast Growth Factor Receptor (FGFR) 3 as a mechanism potentially involved in trastuzumab-acquired resistance. FGFR inhibition could be a potential mechanism as a second-line treatment. In this Simon's two-stage phase 2, single arm study, patients with advanced EG cancer refractory to trastuzumab-containing therapies received pemigatinib, an inhibitor of FGFR. The primary end point was the 12-week progression-free survival rate. Translational analyses were performed on tissue and plasma samples. Eight patients were enrolled in the first stage. Although the 6-week disease control rate was 25%, only one patient achieved a stable disease after 12 weeks of treatment. The trial was discontinued before the second stage. Two out of six evaluable tumor samples expressed FGFR3. No FGFRs amplification was detected. HER2 amplification was lost in three out of eight patients. Three patients had an high Tumor Mutational Burden, and two of them are significantly long-term survivors. These results do not support the therapeutic efficacy of targeting FGFR in unselected patients with advanced EG cancer, who are refractory to trastuzumab-containing therapies.

Chemotherapy-induced neuropathy in esophagogastric cancer.

309 Background: Treatment of locally advanced and metastatic esophagogastric cancer (EGC) largely depends on systemic treatment including taxanes or platinum compounds – agents which are known to cause chemotherapy induced peripheral neuropathy (CIPN). To date, the extend of CIPN in EGC has not been investigated in real-world data. Methods: We identified patients with EGC from the Netherlands Cancer Registry (NCR) and Prospective Observational Cohort study of Oesophageal-gastric cancer Patients (POCOP) who underwent systemic treatment between 2016 and 2018 and completed at least one EORTC QLQ-CIPN20 questionnaire. Total CIPN scores and scores for the motor, sensory and autonomic scales (ranged 0-100) were calculated, and analyzed over time for patients receiving chemoradiation (CRT), peri-operative chemotherapy (POC) and patients primarily treated with palliative chemotherapy (PC). To gain insight in the differences between CIPN score at baseline and after 3, 6, 9, 12, 18 and 24 months we constructed linear mixed effect models. Results: We included 1052 EGC patients. 769 patients received CRT (response: 76% at baseline, 30% after 24 months), 143 received POC (response: 79% at baseline, 33% after 24 months) and 140 received PC (response: 74% at baseline, 28% after 12 months). Over time, neuropathy scores increased in all scales for patients receiving POC and PC, with a maximum increase of 16.5 points in total CIPN score after 6 months in the PC group compared to baseline. For patients receiving CRT, increase in neuropathy scores was more subtle, with a maximum increase in total CIPN score of 4.3 points after 24 months compared to baseline. Results of mixed effect models showed a significant increase of CIPN scores over time in all three groups compared to baseline, persisting for as long as two years after start of initial treatment. Conclusions: CIPN frequently occurs in EGC patients treated with chemotherapy, especially with PC. Due to the possible irreversibility of CIPN, it is important that clinicians inquire patients about neurotoxicity often, adjust the dose of neurotoxic agents as needed and that more research is done into strategies possibly preventing the occurrence of CIPN. Results of mixed model analysis to assess changes in total CIPN score over time. Each model was adjusted for age, sex, performance status and number of comorbidities. The model for POC and PC was also adjusted for use of oxaliplatin.[Table: see text] *p-value &lt;0.001 aChemoradiotherapy bPeri-operative chemotherapy cPalliative chemotherapy, no estimates were calculated for 18 and 24 months due to the low number of responses.

Long-term quality of life in patients with metastatic esophagogastric cancer receiving first-line systemic therapy.

306 Background: Thus far, evidence that quality of life (QoL) remains stable during 1st line systemic therapy of patients with metastatic esophagogastric cancer (mEGC) originates from randomized clinical trials (RCTs). Outcomes from a population-based study provides inside into the effect of systemic therapy on HRQoL in daily clinical practice. The aim of this study was to assess QoL of patients with mEGC at baseline, during 1st line, at progression and after disease progression. Methods: Patients diagnosed with mEGC (2014-2020) receiving 1st line systemic therapy registered in the Prospective Observational Cohort study of Oesophageal-gastric cancer Patients (POCOP) were included. QoL was measured with the EORTC QLQ-C30 and -OG25 at baseline, during 1st line therapy, at progression and after disease progression. Results: Of the 263 included patients, 123, questionnaires were available at baseline, 161 during 1st line, 77 at progression and 89 after progression. Results of the mixed effect models showed that global health status and four functioning scales deteriorated after progression as compared to baseline. Largest improvements during 1st line treatment were observed for odynophagia (mean change -17.3), anxiety (-14.9), dysphagia (-11.7) and eating restrictions (-11.1). Trouble with taste deteriorated at all three time points. Conclusions: In accordance to RCTs, QoL outcomes remained relatively stable or improved during 1st line therapy in patients with esophagogastric cancer. Deterioration of functioning scales were mainly observed after progression. [Table: see text]

Noninvasive Assessment of Human Epidermal Growth Factor Receptor 2 (HER2) in Esophagogastric Cancer Using 89Zr-Trastuzumab PET: A Pilot Study.

Variations in human epidermal growth factor receptor 2 (HER2) expression between the primary tumor and metastases may contribute to drug resistance in HER2-positive (HER2+) metastatic esophagogastric cancer (mEGC). 89Zr-trastuzumab PET (HER2 PET) holds promise for noninvasive assessment of variations in HER2 expression and target engagement. The aim of this study was to describe HER2 PET findings in patients with mEGC. Methods: Patients with HER2+ mEGC were imaged with HER2 PET, 18F-FDG PET, and CT. Lesions were annotated using measurements (on CT) and maximum SUVs (on HER2 PET). Correlation of visualized disease burden among imaging modalities with clinical and pathologic characteristics was performed. Results: Thirty-three patients with HER2+ mEGC were imaged with HER2 PET and CT (12% esophageal, 64% gastroesophageal junction, and 24% gastric adenocarcinoma), 26 of whom were also imaged with 18F-FDG PET. More lesions were identified on 18F-FDG PET (median, 7 [range, 1-14]) than HER2 PET (median, 4 [range, 0-11]). Of the 8 lesions identified on HER2 but not on 18F-FDG PET, 3 (38%) were in bone and 1 was in the brain. Of the 68 lesions identified on 18F-FDG but not on HER2 PET, 4 (6%) were in bone and the remainder were in the lymph nodes (35, 51%) and liver (16, 24%). Of the 33 total patients, 23 (70%) were HER2 imaging-positive (≥50% of tumor load positive). Only 10 patients had 100% of the tumor load positive; 2 had 0% positive. When only patients receiving HER2-directed therapy as first-line treatment were considered (n = 13), median progression-free survival (PFS) therapy was not significantly different between HER2 imaging-positive and -negative patients. Median PFS for patients with at least 1 intense or very intense lesion (SUV ≥ 10) was 16 (95% CI: 11-not reached) mo (n = 7), compared with 12 (95% CI: 6.3-not reached) mo for patients without an intense or very intense lesion (n = 6) (P = 0.35). Conclusion: HER2 PET may identify heterogeneity of HER2 expression and allow assessment of lesions throughout the entire body. A potential application of HER2 PET is noninvasive evaluation of HER2 status including assessment of intrapatient disease heterogeneity not captured by standard imaging or single-site biopsies.

Incidence and survival of patients with oligometastatic esophagogastric cancer: A multicenter cohort study

Purpose/ObjectiveThis multicenter study assessed the incidence and survival of patients with esophagogastric cancer and oligometastatic disease (OMD) in two tertiary referral cancer centers in The Netherlands and Switzerland. Materials/MethodsBetween 2010 and 2021, patients with metastatic esophagogastric cancer were identified. Patients with de-novo OMD were included (first-time diagnosis of ≤5 distant metastases on 18F-FDG-PET/CT). Control of the primary tumor was considered in patients who underwent primary tumor resection or definitive chemoradiotherapy without locoregional recurrence. Treatment of OMD was categorized into (1) systemic therapy, (2) local treatment (stereotactic body radiotherapy or metastasectomy), (3) local plus systemic therapy, or (4) best supportive care. The primary outcomes were overall survival (OS) and independent prognostic factors for OS. Independent prognostic factors for OS were analyzed using multivariable Cox proportional hazard models. ResultsIn total, 830 patients with metastatic esophagogastric cancer were identified of whom 200 patients with de-novo OMD were included (24%). The majority of included patients had esophageal cancer (73%) with adenocarcinoma histology (79%) and metachronous OMD (52%). The primary tumor was controlled in 68%. Treatment of OMD was systemic therapy (25%), local treatment (43%), local plus systemic therapy (13%), or best supportive care (18%). Median follow-up was 14 months (interquartile range: 7–27). Median OS was 16 months (95% CI: 13–21). Improved OS was independently associated with local plus systemic therapy compared with systemic therapy alone (hazard ratio [HR] 0.47, 95% confidence interval [CI]: 0.25–0.87). Worse OS was independently associated with squamous cell carcinoma (HR 1.70, 95% CI: 1.07–2.74), bone oligometastases (HR 2.44, 95% CI: 1.28–4.68), brain oligometastases (HR 1.98, 95% CI: 1.05–4.69), and two metastatic locations (HR 2.07, 95% CI: 1.04–4.12). Median OS after local plus systemic therapy was 35 months (95% CI: 22-NA) as compared with 13 months (95% CI: 9–21, p < 0.001) after systemic therapy alone for OMD. ConclusionPatients with metastatic esophagogastric cancer present in 25% with de-novo OMD. Local treatment of OMD plus systemic therapy was independently associated with long-term OS and independently improved OS when compared with systemic therapy alone. Randomized controlled trials are warranted to confirm these results.

SOURCE beyond first-line: A survival prediction model for patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy.

4037 Background: Prediction models for survival may aid shared decision making between physicians and patients. Prior models have been developed that predict survival for patients with potentially curable esophagogastric cancer and patients with metastatic esophageal cancer who start first-line therapy (the SOURCE models). The aim of this study was to develop and internally validate a registry-based clinical prediction model, called SOURCE beyond first-line, for survival of patients with metastatic esophagogastric cancer after failure of first-line palliative systemic therapy. Methods: Patients with unresectable or metastatic (synchronous or metachronous) esophageal or gastric cancer who received first-line systemic therapy (N = 1067) between 2015-2017 were selected from the Netherlands Cancer Registry. Follow-up data were retrieved in 2019. Patient, tumor and treatment characteristics at primary diagnosis and at progression of disease, were used to develop the prediction model. A Cox proportional hazards regression prediction model was developed through forward and backward selection using Akaike’s Information Criterion. The model was internally validated through 10-fold cross-validations to assess performance on unseen data. Model discrimination (C-index) and calibration (slope and intercept) were used to evaluate performance of the complete and cross-validated models. Results: The final model consisted of 10 patient, tumor and treatment characteristics. The C-index was 0.75 (0.74-0.77), the calibration slope 0.99 (0.98-0.99) and the calibration intercept 0.02 (0.01-0.02). Internal cross-validation of the model showed that the model performed adequately on unseen data: C-index 0.79 (0.76-0.80), calibration slope 1.02 (1.00-1.04) and calibration intercept -0.01 (-0.01-0.02). Conclusions: The SOURCE beyond first-line model predicted survival with fair discriminatory ability and good calibration, and is a valuable addition to the existing SOURCE prediction models. In the future this model will be integrated in an online decision support tool that can be used in clinical practice to aid personalized treatment.

Anti-PD1, capecitabine, and oxaliplatin for the first-line treatment of dMMR esophagogastric cancer (AuspiCiOus-dMMR): A proof-of-principle study (AuspiCiOus).

TPS4163 Background: Doublet cytotoxic treatment demonstrates survival benefit over single drug therapies in patients with advanced esophagogastric cancer (EGC). Previous clinical data suggests an improved survival outcome in patients with microsatellite instability (MSI) treated with PD-1 inhibitor monotherapy or in combination with chemotherapy in first line palliative treatment. The positive effect of immunotherapy was only seen after a couple of months of treatment. This suggests that the patient might benefit from a short course of chemotherapy at the start of treatment. However, reports on the effects of cytotoxic treatment in MSI-high tumors range from beneficial to detrimental. Thus, the value of cytotoxic treatment, as well as the effect on the tumor immune microenvironment (TME) in MSI-high tumors is unclear. Therefore, in AuspiCious-dMMR we will study the effect of sequential treatment in patients with mismatch repair deficient (dMMR) EGC on the tumor immune microenvironment and, more specifically, the impact on the infiltration of cytotoxic T cells, before and after a short course of chemotherapy, and during treatment with PD-1 inhibition. Methods: AuspiCiOus is a multi-center, open-label, single arm (phase 2) study in patients with dMMR irresectable or metastatic EGC adenocarcinoma (NCT05177133). Patients are treated with Capecitabine and Oxaliplatin for two 3-weekly cycles, after which treatment is continued with retifanlimab (PD-1 inhibitor) for 4-weekly cycles up to progression or unacceptable toxicity, with a maximum of two years. Before treatment, after chemotherapy and after two cycles of immunotherapy fresh tumor biopsies are collected to study the primary outcome (T cell infiltration and the interferon-γ signature) as well as for translational research purposes (flow cytometry, nanostring profiling, (multicolor) immunohistochemistry and organoid culturing). Blood is collected at the same time points and on day 3 after the first course of immunotherapy for isolation of peripheral blood mononuclear cell, and determination of cytokine/chemokine profile, circulating stromal markers, and circulating tumor DNA. Also, fecal samples are collected to determine changes in the intestinal microbiome and patient reported outcome measures are used to determine quality of life. (s)AEs are assessed according to CTCAE v5 and tumor response is determined according to (i)RECIST 1.1. Key eligibility criteria are 1) histological confirmed diagnosis of untreated metastatic or irresectable HER2- adenocarcinoma of stomach or junction and 2) dMMR determination by IHC. Study is open for inclusion and three of planned 25 patients have been enrolled. Clinical trial information: NCT05177133.

Beyond median overall survival: Estimating multiple survival scenarios in patients with metastatic esophagogastric cancer.

261 Background: Recent clinical trials of novel systemic therapies showed improved survival of patients with metastatic esophageal cancer (EC) and gastric cancer (GC). Survival improvements observed in clinical trials might be unrepresentative for the total population as the percentage of patients whom participate in clinical trials is limited and more than half of all patients receive best supportive care (BSC). The aim of our study is to assess the best-case, typical and worst-case survival scenarios in patients with metastatic esophagogastric cancer. Methods: We selected patients with metastatic EC (including junction) or GC diagnosed in 2006-2019 from the Netherlands Cancer Registry. Survival scenarios were calculated based on percentiles of the survival curve stratified by tumor location and treatment (tumor-directed therapy or BSC). Survival scenarios were calculated for the 10th (best-case), 25th (upper-typical), 75th (lower-typical) and 90th (worst-case) percentiles. Linear trend analysis was performed to test if changes in survival over the diagnosis years were significant. Results: We identified 12739 patients with EC and 6833 patients with GC. Percentage of patients receiving tumor-directed therapy increased from 34% to 47% and 30% to 45% for patients with EC and GC, respectively. The median survival remained unchanged for patients with EC (5.0 months) and improved slightly for patients with GC (3.1 to 3.7 months; P=0.006). For patients with EC survival of the best-case scenario improved (17.4 to 22.8 months; P=0.001), whereas the other scenarios remained unchanged: upper-typical 11.2 to 11.7 (P=0.11), lower-typical 2.1 to 2.0 (P=0.10) and worst-case 0.9 to 0.8 months (P=0.22). For patients with GC survival improved for the best-case (13.1 to 19.5; P=0.005) and upper-typical scenario (6.7 to 10.6 months; P=0.002), whereas the lower-typical (1.2 to 1.4 months; P=0.87) and worst-case (0.6 to 0.6 months; P=0.60) remained unchanged. For patients with EC receiving tumor-directed therapy survival in all scenarios remained unchanged while for patients receiving BSC survival decreased: best-case 11.8 to 9.8 (P=0.005), upper-typical 6.0 to 5.0 (P=0.002), lower-typical 1.4 to 1.0 (P=0.003) and worst-case 0.7 to 0.5 months (P=0.03). For patients with GC receiving tumor-directed therapy survival improved for all scenarios: best-case 19.8 to 30.4 (P=0.005), upper-typical 6.4 to 10.3 (P=0.002), lower-typical 3.6 to 5.4 (P&lt;0.001) and worst-case 1.4 to 2.6 months (P&lt;0.001), and for patients receiving BSC survival for all scenarios remained unchanged. Conclusions: The proportion of patients with EC and GC receiving tumor-directed therapy increased over time. Despite the fact that survival improvements were not observed across all scenarios, at least an increase in survival was observed in certain subgroups of patients.

Advances in the treatment of gastric cancer: 2020-2021.

To review studies from 2020 to 2021 in esophagogastric cancer. After up front D2 gastrectomy for lymph node-positive gastric cancer, 6 months of adjuvant chemotherapy with S-1 and oxaliplatin achieved superior disease-free survival (DFS) compared with 1 year of S-1. The addition of adjuvant radiotherapy, however, added no benefit. After chemoradiotherapy and surgery in esophageal and gastroesophageal junction cancer, in patients with residual disease found at surgery, 1 year of adjuvant nivolumab substantially improved DFS compared with observation alone, leading to regulatory approval for adjuvant nivolumab. In metastatic esophagogastric cancer, the addition of either pembrolizumab or nivolumab to first-line chemotherapy improved response, disease free, and overall survival with the greatest survival benefit dependent on programmed death receptor ligand, programmed death receptor ligand -1 status, leading to regulatory approval for these agents. A preliminary report of a phase 3 trial adding pembrolizumab to first-line chemotherapy with trastuzumab in HER2-positive gastric cancer reported a significant improvement in response, leading to regulatory approval for pembrolizumab. The fibroblast growth factor receptor appears to be a promising new target in gastroesophageal cancer based on phase 2 data for bemarituzumab. Optimal adjuvant chemotherapy after D2 resection of node-positive gastric cancer is 6 months of a fluorinated pyrimidine and oxaliplatin, with no benefit for adjuvant radiotherapy. Adjuvant nivolumab after resection of esophageal cancer after chemoradiotherapy improves DFS and is a new care standard. Pembrolizumab added to first-line chemotherapy in both HER2-positive and negative esophagogastric cancer improves outcome and is a new standard of care. Nivolumab added to first-line chemotherapy in HER2-negative gastric cancer improves treatment outcome and is a new care standard.

Where to Start and What to Do Next: The Sequencing of Treatments in Metastatic Esophagogastric Cancer.

Esophagogastric cancer is associated with rising incidence and high mortality. Nearly 40% of patients have metastatic disease at the time of diagnosis with poor 5-year overall survival. The treatment of squamous cell carcinoma of the esophagus and gastroesophageal adenocarcinoma has started to bifurcate in recent years, owing to the evolving understanding of the biologic and genomic characteristics of these tumors. Incorporation of HER2-directed therapy in the form of monoclonal antibody and antibody-drug conjugate is now standard of care for patients with HER2-positive disease. The addition of immune checkpoint inhibitors to the therapeutic landscape of metastatic esophagogastric cancer is associated with modest improvement in overall survival, and definition of predictive biomarkers of response to checkpoint inhibition remains imprecise. A number of therapeutic targets including FGFR2b, Claudin 18.2, DKK-1, and DNA repair defects are being explored in clinical trials. Similarly, combination immunotherapy and novel HER2-targeting agents, such as bispecific antibody and small-molecule inhibitors, are at various stages of clinical development. Despite the progress made in the field of targeted therapies and checkpoint inhibition, chemotherapy remains an integral part of treatment of metastatic esophagogastric cancer but is associated with considerable toxicity. Clinical trials focusing on minimizing toxicity of currently available therapeutic agents, development of novel biomarker-driven treatment strategies, and overcoming resistance to immune checkpoint inhibition will define the future of this traditionally indelible disease.

Early predictors of benefit to dual anti-PD1/HER2 inhibition: Biomarker analysis from phase 2 trial of pembrolizumab/trastuzumab in HER2-positive metastatic esophagogastric (mEG) cancer.

4058 Background: Pembrolizumab and trastuzumab (P&amp;T) and chemotherapy demonstrated 27 month mOS, 13 month mPFS, and 91% response rate in first-line HER2-positive mEG cancer irrespective of PD-L1 status (Janjigian Lancet Oncology 2020). Biomarkers including 89Zr-trastuzumab PET, blood, and tumor analysis were correlated with progression-free survival. Methods: Twenty-five patients received P&amp;T once 3 weeks prior to addition of chemotherapy to P&amp;T. Pre-treatment tumor biopsies, 89Zr-trastuzumab PET scans, serial plasma ctDNA (Guardant360, Redwood City, CA) and CT scans were performed. Tumor-matched DNA alterations were identified by correlating ctDNA and tissue-NGS variant calls. Pre-, on-, and post-treatment biopsies were analyzed using WES and IHC (HER2, PD-L1). Biomarkers were correlated with mPFS and 6-month PFS, the primary endpoint. Results: Of patients with tumor-matched mutations ctDNA at baseline, 12 of 16 had a decline in their maxVAF by week 3, corresponding to a mPFS of 14.7 (11.0-NR) vs 5.9 (95% CI 4.1-NR) months (p=0.009) and a mOS of 29.7 (95% CI 27.2-NR) vs 7.71 (95% CI 6.6-NR) months (p=0.006). 9 of 12 (75%) patients with decline in ctDNA at 3 weeks post-P&amp;T achieved the 6-month PFS primary endpoint while the 4 patients with no decline in ctDNA all progressed in under 6-months. Similarly, 7 of 9 (78%) patients who had a decline in CT-measurements in all disease sites achieved the 6 month PFS primary endpoint, versus 10 of 16 (62.5%) of patients who did not respond in all sites (p=0.66), suggesting that ctDNA is superior to CT as an early predictive biomarker of response. Lack of ERBB2 amplification (amp) by NGS in ctDNA and/or tumor was associated with lack of response to P&amp;T alone prior to addition of chemotherapy. Interestingly, no lesions from patients lacking ERBB2 ctDNA amp (n=3) responded to induction P&amp;T by CT, while lesions from 3/9 patients lacking ERBB2 tissue amp responded to P&amp;T by 3-week CT, suggesting intrapatient HER2 heterogeneity. Eight patients also underwent 89Zr-Trastuzumab PET scans prior to P&amp;T and up to 5 lesions per disease site were measured on serial CT scans. All 15 lesions with intense uptake (SUVmax&gt;10) responded to P&amp;T, but only 9/24 lesions with SUVmax&lt;10. All 4 patients who had at least 1 intense lesion achieved a post-P&amp;T CT response and later 6+ month PFS. All 3 of 3 evaluable patients with intense uptake had baseline ctDNA ERBB2 amp. Conclusions: Patients with a decline in tumor-matched maxVAF after one dose of P&amp;T were more likely to achieve durable PFS. Pre-treatment ctDNA ERBB2 amp and/or intense 89Zr-trastuzumab PET avidity are non-invasive predictive biomarkers of response to HER2-directed therapy. Evaluation of tumor immune environment digital spatial profiling is underway. Clinical trial information: NCT02954536.

Survival and Patterns of Failure in Oligometastatic Esophagogastric Cancer

Metastatic esophagogastric cancer (EGC) has poor outcomes, with median overall survival (OS) of 9-11 months. Studies in other sites such as lung have shown improved survival with local treatment for oligometastasis (OM). However, there is very limited data on oligometastatic EGC. We investigated outcomes, prognostic factors, and patterns of first progression in patients with oligometastatic EGC. From 2008-2018, 1438 patients (pts) presented to our institution with stage IV EGC. Of these, 197 pts had OM (defined as ≤5 metastatic lesions, excluding primary) and were included for analysis. Median age was 67 years and most (77%) were male. 46 pts (23%) had gastric (GC) and 151 (77%) had esophageal/GE junction (GEJ) tumors. First progression was classified as limited to initial sites, new sites, or failure at both initial and new sites. OS was stratified by primary tumor site, number of OM, and sites of OM using Kaplan Meier and log rank tests. Cox proportional hazards model was used to investigate correlation between prognostic factors and outcomes. At a median follow up of 22.5 (1-117) months, median OS for the whole cohort was 25 months (95%CI: 22.6-27.4) with a statistically significant difference between GC and GEJ cancer (37 vs. 25 months, p = 0.03). Location of OM was as follows: non-regional nodes (44%), liver (17%), peritoneal nodules (7%), bone (6%), lungs (4%), brain (2%), liver plus non-regional nodes (5%), and other (15%). Peritoneal nodules were more common in GC whereas bone, lungs, and brain were more common in GEJ cancer. Most pts had a solitary OM (42.6%). The number or sites of OM did not correlate with OS. Of 152 pts who progressed, 91 (60%) had isolated initial site failure, 17% had isolated new site failure, and 23% had both initial and new site failure. 13% and 10% of pts underwent surgery for primary site and OM respectively. Radiation therapy (RT) to primary site (median 37.5 Gy in 15 fractions), was delivered to 37%, usually upon progression (57%). 11% received RT to OM. On univariate analysis, gastric primary, younger age, primary tumor or OM resection, RT to the primary, and isolated initial site failure were significantly associated with better OS. On multivariate analysis, age (HR: 1.031, p = 0.001) surgery to the primary (HR: 0.295, p = 0.002), and initial-site failure (HR: 1.4 p = 0.002) remained significantly correlated with OS. We observed a longer OS for oligometastatic EGC, compared to historical results for general metastatic disease reported in the literature. This suggests that EGC patients with OM are a prognostically distinct group and may benefit from tailored treatment strategies such as ablative local therapy. Most patients first progressed in their initial sites of disease, suggesting a role for local therapy earlier in the treatment course. Younger patients and those undergoing primary tumor resection had superior OS.

Advances in the treatment of gastric cancer.

To provide an up-to-date review on the management of cancers of the stomach and esophagogastric junction (EGJ). Microsatellite instable (MSI) high status in gastric cancer may portend a relatively good prognosis and indicate that adjuvant chemotherapy is of no added benefit to primary surgical management. In the preoperative treatment of HER2 (ErbB2)-positive EGJ adenocarcinoma with chemoradiotherapy, the addition of trastuzumab, a recombinant humanized mAb directed against the extracellular domain of Her2, failed to improve outcome over conventional chemoradiotherapy alone. Escalating the dose of radiation in combined chemoradiotherapy regimens did not improve survival over conventional dose radiotherapy in the nonoperative management of EGJ cancer. The use of proton vs. conventional external beam radiation therapy, although potentially less toxic, did not improve therapy outcome with preoperative or definitive chemoradiotherapy in EGJ cancer. In metastatic HER2-positive gastric cancer, after disease progression on trastuzumab, continuation of trastuzumab did not improve progression free or overall survival compared with second-line chemotherapy alone. However, in the setting or prior trastuzumab therapy in metastatic HER2-positive gastric cancer, the new agent trastuzumab deruxtecan achieved significant rates of response, progression free and overall survival compared with standard chemotherapy. After initial chemotherapy for metastatic esophagogastric cancer, maintenance therapy with the anti PDL-1 agent avelumab was no better than chemotherapy alone. MSI high gastric cancer has a better prognosis and may not require adjuvant chemotherapy. Trastuzumab, added to preoperative chemoradiotherapy in HER2-positive esophageal adenocarcinoma, does not improve outcome. Dose escalation of radiotherapy in the nonoperative management of EGJ cancer does not improve local control or survival, and proton therapy may not achieve superior outcomes compared with external beam radiotherapy. In metastatic HER2-positive gastric cancer, continuing trastuzumab into second-line chemotherapy does not add benefit; however, the novel agent trastuzumab deruxtecan has substantial activity after prior trastuzumab-based therapy.

1461P Sex differences in treatment and survival of patients with unresectable or metastatic esophagogastric cancer: A population-based study

1461P Sex differences in treatment and survival of patients with unresectable or metastatic esophagogastric cancer: A population-based study

Irinotecan with or without capecitabine as a beyond 2nd line regime for esophago-gastric adenocarcinomas.

e16545 Background: Purpose: The aim of this retrospective study was to assess the efficacy and toxicity of irinotecan +/- capecitabine for patients with metastatic esophago-gastric (EG) adenocarcinomas previously treated with at least two chemotherapy regimens including platinum-based, fluoropyramidines and taxanes. Introduction: Treatment for metastatic EG cancer beyond 2nd line remains controversial. Recently, the TAGS phase III trial (Shitara et al., 2018) showed overall survival benefit with Trifluridine/tipiracil of 2.1 months compared to placebo as a third line. Apatinib is also approved for use as third line in China (Li et al., 2013). Based on minimal evidence (Kang et al., 2013), irinotecan in combination with capecitabine is used in the UK. We performed a retrospective study to assess the efficacy and toxicity of irinotecan as a beyond 2nd line regime in metastatic EG adenocarcinomas in one of Europe’s largest cancer centres, The Christie. Methods: Data was collected retrospectively from all metastatic EG adenocarcinoma patients who were treated with irinotecan +/- capecitabine as a beyond 2nd line palliative treatment at the Christie Hospital from January 2014 to December 2019. Irinotecan was either given 2 or 3 weekly at dose of 180 mg/m² with or without capecitabine 800 mg/m². Response rate (RR) was calculated according to RECIST version 1.1, overall survival measured and toxicity data collected. Results: Fifty-six patients received irinotecan as beyond 2nd line palliative chemotherapy. Out of the thirty-seven patients with measurable disease on their scans, the overall response rate was 8.1% and the disease control rate was 51.4% as per RECIST 1.1. Median overall survival was 5 months (95% CI 4.2-5.8). The presence of grade 3-4 toxicities was 16% (9 patients) and included neutropenia, fatigue, nausea and diarrhea. On average, 3.7 cycles were administered, 32% (18 patients) required dose reductions, mainly secondary to grade 2 diarrhea and fatigue. Conclusions: Irinotecan in combination with capecitabine is efficacious as a beyond 2nd line regime in metastatic EG with an acceptable toxicity profile with a limited role in patients with resistant disease to first line platinum-based chemotherapies with fluoropyramidines.

Pembrolizumab with trastuzumab and chemotherapy (PTC) in HER2-positive metastatic esophagogastric cancer (mEG): Plasma and tumor-based biomarker analysis.

4559 Background: Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity with median OS 27 months and 91% objective response rate in HER2-positive mEG cancer irrespective of PD-L1 status (NCT02954536; Janjigian ESMO 2019). Tumor biopsies and blood samples were collected in this phase II trial to identify molecular and immune predictors of response and resistance to PTC. Methods: Pre-treatment and post-progression biopsies were analyzed using WES and IHC (HER2, PD-L1). Peripheral blood was collected pre-treatment, every 9 weeks on-treatment and at progression for plasma ctDNA (Guardant 360, Guardant Health, Redwood, CA). Tumor-matched DNA alterations were identified by correlating ctDNA and solid tumor WES results. Landmark PFS analysis was used to compare ctDNA clearance status at 9 weeks post-treatment. Results: Baseline ctDNA was analysed from 31 of 37 patients of whom 84% (26/31) had tumor-matched ctDNA detected at baseline. Patients who cleared ctDNA at 9 weeks (n = 17/23) achieved a longer median PFS than those who did not - mPFS 12.3 months (95% CI 7.44-NA vs 3.9 months (95% CI 2.01-NA) (log-rank p = 0.02). On serial blood monitoring of 16 patients with eventual radiographic progression, ctDNA re-appearance preceded CT detection in 8 (50%) patients. WES was completed in 31 patients with pre-treatment, and 12 patients post-progression, including matched samples from 10 patients. Loss of HER2 over-expression/amplification was noted in 44% (7/16) of post-progression samples by IHC/FISH (2 IHC 0/1, 5 FISH-). In paired post-progression samples on WES, we observed loss of ERBB2 in 2 patients, and new amplifications of CCND1/3, FGF3/4/19, CDK6/12, KRAS, MYC, and MET, as well as mutations in KRAS, PIK3CD and PIK3RA. Plasma analysis at progression demonstrated copy number increases and/or new amplifications in MET, CKD6, PIK3CA, KRAS, FGFR2, EGFR and CCDN1 as well as KRAS, RB1, PTEN, NF1, NOTCH1, BRAF, and FGFR1 mutations. Conclusions: The majority of patients with previously untreated HER2 positive mEG have detectable plasma ctDNA at baseline. The re-appearance of ctDNA during therapy may serve as an early predictor of progression and help identify genetic drivers of acquired resistance. Loss of ERBB2 over-expression/amplification and activating MAPK alterations occur at PTC progression. Evaluation of tumor immune environment by multiplex IHC and additional ctDNA analysis is underway.

811P - Second-line palliative systemic treatment for synchronous metastatic esophagogastric cancer: A population-based study

BackgroundMetastatic esophagogastric cancer patients can be treated with paclitaxel/ramucirumab, or another taxane, or an irinotecan-containing regimen in second line. The aim of this study was to explore the real-world use of second-line palliative systemic treatment in esophagogastric cancer and to compare treatment regimens in terms of overall survival (OS) and time to failure of second-line treatment (TTF). MethodsSynchronous metastatic esophagogastric cancer patients treated with systemic therapy (2010-2015) were selected from the nationwide Netherlands Cancer Registry. Systemic treatment was considered second line if a drug group was used that essentially differed from first-line treatment, irrespective of reason for switch of treatment. Thus, a switch from capecitabine/oxaliplatin (CapOx) to docetaxel was considered second line, while CapOx to i.v. 5-fluorouracil (5-FU)/oxaliplatin was not. OS and TTF were calculated from start of second-line treatment until date of death, or progression/failure of treatment, and analyzed using Kaplan Meier curves with logrank test. ResultsSecond-line systemic treatment was applied in 344 (20%) of the 1712 patients that received first-line systemic treatment in 2010-2015, of which 96% had adenocarcinoma and 4% squamous cell carcinoma. In the total cohort, 38 different second-line systemic treatment regimens were administered. Monotherapy with a taxane (31%), paclitaxel/ramucirumab (13%), carboplatin/paclitaxel (10%), trastuzumab-containing regimens (7%), fluoropyrimidine/platinum doublets (7%), irinotecan (6%), and 5-FU/irinotecan (6%) were most frequently used regimens. In patients that received second-line treatment, median OS was 5.2 (IQR 2.7, 8.6) and TTF 2.8 (IQR 1.5, 5.0) months. Median OS was 3.9 (IQR 2.3, 6.4) months in patients treated with second-line taxane monotherapy (n=108), and 5.4 (IQR 2.3, 9.7) months in patients treated with paclitaxel/ramucirumab (n=45, p=0.188). ConclusionsAccording to real-world evidence, 20% of synchronous metastatic esophagogastric cancer patients treated with first-line systemic therapy receive second-line systemic treatment, most frequently consisting of a taxane with or without ramucirumab. Legal entity responsible for the studyThe authors. FundingLilly. DisclosureR.H.A. Verhoeven: Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS. N. Haj Mohammad: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD. J. de Vos-Geelen: Non-remunerated activity/ies: BTG; Research grant / Funding (institution), Non-remunerated activity/ies: Servier; Advisory / Consultancy: Shire. T. Van Voorthuizen: Non-remunerated activity/ies: Astellas; Non-remunerated activity/ies: Ipsen; Non-remunerated activity/ies: Roche; Non-remunerated activity/ies: Bayer. M. van Oijen: Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Roche. H.W.M. van Laarhoven: Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Philips; Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.