Esophageal Junction Research Articles

454. QUALITY OF LIFE AFTER ESOPHAGECTOMY WITH INTRATHORACIC VS CERVICAL ANASTOMOSIS: A NATIONWIDE COHORT STUDY

Abstract Background Transthoracic esophagectomy with either intrathoracic or cervical anastomosis is considered standard of care in patients with mid to distal esophageal or gastroesophageal junction (GEJ) cancer. Patients after esophagectomy will experience a deterioration in health-related quality of life (HR-QoL) after esophageal cancer surgery. Whilst some reports describe long-lasting deterioration, other reports show recovery of HR-QoL comparable with the general population after 2 years. The aim of this study was to investigate the difference in HR-QoL in patients after a transthoracic esophagectomy with either intrathoracic- or cervical anastomosis in a nationwide database. Methods A nationwide cohort study was performed combining data from two registries: Netherlands Cancer Registry (NCR) and Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP). All patients after esophagectomy for mid/distal esophageal or GEJ cancer between 2015 and 2022 were included. HR-QoL was measured at baseline, 3, 6, 9, 12, 18, and 24 months postoperatively using EORTC QLQ-C30 and OG-25 questionnaires. Linear mixed models were used to assess the mean score difference between patients with intrathoracic and cervical anastomosis. A difference of 10 points or more was considered clinically relevant. Adjustments were made for potential confounders (age, gender, ASA classification). Results Of the 4269 registered patients in the NCR, in 1274 patients at least one questionnaire was available. Of these patients 346 underwent an esophagectomy with cervical - and 928 with intrathoracic anastomosis. Patients after esophagectomy with cervical anastomosis reported statistically significant more problems in the following categories: dysphagia, couching, trouble eating with others and swallowing saliva during the first 3 months, choked when swallowing and trouble talking during the first 12 months postoperatively. In all other categories no significant difference was found. Only trouble talking at the 3-month time point was considered as a clinically relevant difference. Conclusion Although the intrathoracic anastomosis is associated with significantly better HR-QoL in several categories, only trouble talking at 3 months postoperatively was considered clinically relevant. Overall HR-QoL was comparable for esophageal cancer patients after an esophagectomy with either a cervical or intrathoracic anastomosis.

Does Radical Lymphadenectomy Improve Survival in Esophageal and Gastroesophageal Junction Cancer?

Background: Esophageal carcinoma is one of the deadliest cancer in gastrointestinal system with 5-years survival of only 24%. Lymphnode metastasis has been associated with worse outcome. But the extent of lymphnode dissection has been a debate among surgeons worldwide. This study aimed to compare the overall survival of patients undergoing radical and non-radical lymphadenectomy in a tertiary referral cancer hospital in Nepal. Methodology: This study included 634 patients of esophageal and gastroesophageal junction cancer who underwent surgical resection at our institution over a period of 2001- 2019. The patients were divided into 2 groups; radical lymphadenectomy (RLN) and non-radical lymphadenectomy (NRLN) groups. RLN group underwent two-field or three field lymphadenectomy for esophageal cancer and D2 or D2 + lower mediastinal lymphadenectomy for GEJ cancer. NRLN group underwent nodal sampling or D1 dissection. Results: RLN was performed in 85.9%. NRLN was done in 14.1%. Surgery alone was performed in 47.1% and multimodality approach in 52.9% cases. Median survival for RLN and NRLN groups was 34 and 15 months, respectively (p < .001). Conclusion: Improved median survival has been observed after radical lymphadenectomy for esophageal and GEJ cancer.

Indocyanine Green (ICG) fluorescence angiography of gastric conduit for reconstruction after esophagectomy: a single center prospective study

Introduction: Esophageal cancer ranks among the most aggressive neoplasms worldwide and is a significant contributor to cancer-related mortality. Surgical intervention through esophagectomy with radical lymph node dissection remains a cornerstone in the curative treatment of mid and lower esophageal and gastroesophageal junction tumors, often preceded by neoadjuvant therapy tailored to histological type. Anastomotic leak (AL) following gastroesophageal anastomosis is a major complication associated with substantial morbidity and mortality. Methods: A prospective study was conducted on 30 patients undergoing esophagectomy with gastric conduit reconstruction from May 2023 to April 2024. Gastroesophageal anastomosis was placed at neck. Intraoperatively, indocyanine green (ICG) fluorescence angiography was employed to assess gastric conduit perfusion. The anastomosis site was selected based on ICG fluorescence dynamics, aiming for anastomosis within 45 seconds of ICG enhancement. Results: The study cohort comprised predominantly male patients (60%) with a mean age of 60.67 years. Most patients presented with squamous cell carcinoma (66.67%), primarily located in the lower esophagus and minimally invasive surgery was predominantly performed. Mean ICG fluorescence angiography time was 32.1 seconds. Anastomotic leak occurred in 23.3% of patients, correlating with significantly longer hospital stays (p=0.005). Although ICG fluorescence angiography was used to guide anastomosis based on perfusion assessment, there was no statistically significant reduction in AL rates observed in this study (p=0.471). Conclusion: In conclusion, while ICG fluorescence angiography represents an innovative approach to evaluating gastric conduit perfusion during esophagectomy, its direct impact on reducing AL in our study was not statistically significant.

Model-based population pharmacokinetic and exposure response analyses for safety and efficacy of nivolumab as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer.

Nivolumab is approved as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer (EC/GEJC) based on results from the pivotal CheckMate 577 trial. We present a model-based clinical pharmacology profiling and benefit-risk assessment of nivolumab as adjuvant treatment in subjects with resected EC/GEJC supporting a less frequent dosing regimen. Population pharmacokinetic (popPK) analysis was conducted to characterize nivolumab pharmacokinetics (PK) using clinical data from 1493 subjects from seven monotherapy clinical studies across multiple solid tumours. The exposure-response (E-R) analyses included data from 756 patients from CheckMate 577. E-R relationships for efficacy and safety were characterized by evaluating the relationship between nivolumab exposure and disease-free survival (DFS) for efficacy; and time to first occurrence of Grade ≥2 immune-mediated adverse events (Gr2 + IMAEs) for safety. Nivolumab exposure was found to be associated with both DFS and risk of Gr2 + IMAEs. However, the hazard ratios (HRs) (95% confidence interval [CI]) at the 5th and 95th percentiles of nivolumab exposure were similar for DFS and Gr2 + IMAEs, indicating flat E-R relationships within the exposure range produced by the studied regimen. Model-predicted probability of DFS and Gr2 + IMAEs were similar between the two regimens of 240 mg every 2weeks or 480 mg every 4weeks for 16 weeks followed by 480 mg Q4W up to 1year. The analyses demonstrated a flat E-R relationship over the range of exposures produced by the studied regimen and supported the approval of an alternative dosing regimen with less frequent dosing in patients with adjuvant EC/GEJC.

A Cost-Effectiveness Analysis of Adjuvant Nivolumab for Patients with Resected Esophageal Cancer or Gastroesophageal Junction Cancer in France.

Esophageal and gastroesophageal junction cancer (EC/GEJC) is a poor prognosis disease with a high risk of recurrence even in patients curatively resected. Adjuvant nivolumab is currently used for patients with completely resected (R0) EC/GEJC who have residual pathologic disease following prior neoadjuvant chemoradiotherapy. This study aimed to determine the cost effectiveness of nivolumab in this indication in France according to the collective perspective excluding indirect costs. A simplified four-health-state semi-Markov model was developed to model EC/GEJC patients who have residual disease after neoadjuvant chemoradiotherapy followed by R0 over a 15-year time horizon, comparing adjuvant nivolumab versus surveillance, which was the recommended French clinical practice before immunotherapy arrival. Time-to-recurrence (TTR) from CheckMate 577 was used to inform transition from disease-free to post-recurrence health state; patients who recurred were split according to the distribution of type of recurrence observed during the trial. Post-recurrence survival (PRS) according to the type of recurrence was derived from a real-world registry. Adjuvant treatment with nivolumab led to an incremental survival gain of 1.19 years (+34%), mostly in the disease-free state, an incremental cost of €48,634 and QALY of 0.98 resulting in an incremental cost-utility ratio (ICUR) of €49,572/QALY with limited uncertainty. 'Cure assumption' at 5years had an important impact on the results (€41,115/QALY; -17%), as that tends to increase life-years and QALYs while costs remain the same. Probabilistic sensitivity analyses confirmed reference ICUR (€52,542/QALY) with 80% probability of nivolumab being cost effective at a willingness-to-pay threshold of €75,000/QALY. Our analysis suggests that adjuvant nivolumab is cost effective in the treatment of EC/GEJC patients who have residual disease after neoadjuvant CRT followed by R0 resection. Compared with previously evaluated cost-effectiveness analyses for other immune-checkpoint inhibitors indicated in metastatic settings, ICUR appears particularly low in this early setting thanks to the important impact on health outcomes and capped treatment duration.

Standardization and short-term outcomes of robot-assisted minimally invasive esophagectomy in the semi-prone position

Robot-assisted minimally invasive esophagectomy (RAMIE) has recently been developed and is increasingly performed for thoracic esophageal and esophagogastric junction (EGJ) cancers. At our institute, we performed RAMIE in the semi-prone position using the da Vinci Xi system with two- or three-field lymphadenectomy in 91 patients with resectable thoracic esophageal or EGJ cancers between October 2018 and March 2023. During this period, we improved and standardized the surgical procedures to perform precise and safe mediastinal lymphadenectomies and minimize postoperative complications. The rates of major operative morbidities (C-D grade, ≥ I) were acceptable (recurrent laryngeal nerve paralysis, 6.6%; pneumonia, 9.9%; atelectasis, 6.7%; anastomotic leak, 14.3%). Both operative and 30-day mortality rates were 0%. In this technical note, we present our standardized surgical techniques for RAMIE in the semi-prone position for esophageal and EGJ cancers.

A Prospective Pilot Study of Pencil Beam Scanning Proton Radiation Therapy as a Component of Trimodality Therapy for Esophageal Cancer

PurposeTo evaluate the safety and efficacy of pencil beam scanning (PBS) proton radiotherapy (RT) in trimodality therapy for esophageal cancer. MethodsThis prospective pilot study was planned to accrue 30 patients with locally advanced esophageal or gastroesophageal junction (GEJ) carcinoma, medically suitable for chemoRT (CRT) followed by esophagectomy. PBS proton RT consisted of 25 fractions, 50 Gy to tumor + 1 cm and 45 Gy to a 3.5 cm mucosal expansion and regional lymph nodes. Chemotherapy was weekly carboplatin (AUC = 2) and paclitaxel (50 mg/m2). At 4-8 weeks after CRT, patients underwent restaging and potential esophagectomy. The primary endpoint was acute grade 3+ adverse events (AEs) attributed to CRT. Overall (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier methodology; local-regional recurrence (LRR) and distant metastases (DM) rates were assessed by cumulative incidence methodology. The Functional Assessment of Cancer Therapy-Esophagus (FACT-E) assessed quality of life. ResultsThirty eligible patients enrolled June 2015-April 2017. Median age was 68 years. Histology was adenocarcinoma in 87% and location was distal esophagus/GEJ in 90%. Stage was T3-4 in 87% and N1-3 in 80%. All patients completed the planned RT dose. Acute grade 3+ AEs occurred in 30%, most commonly leukopenia and neutropenia. Acute grade 3+ non-hematologic AEs occurred in 3%. Esophagectomy was performed in 90% of patients (R0 in 93%). Pathologic complete response rate was 40%. Major post-operative complications (Clavien-Dindo score ≥ III) occurred in 34%. Postoperative mortality at 30 days was 3.7%. Median follow-up was 5.2 years. 5-year outcome estimates were OS 46%, PFS 39%, LRR 17%, and DM 40%. FACT-E scores (medians) were baseline (145), end of CRT (136, p=0.0002 vs. baseline), before esophagectomy (144), 12 months (146), and 24 months (157). ConclusionsPBS proton RT is feasible and safe as a component of trimodality therapy for esophageal cancer.

Triple combination treatment of trastuzumab, chemotherapy and immune checkpoint inhibitor in HER2 positive unresectable, locally advanced, metastatic gastric and esophageal adenocarcinoma: A systematic review and meta-analysis.

e16071 Background: The current standard of care for unresectable, locally advanced or metastatic HER2 positive gastric, esophageal and gastroesophageal junction adenocarcinomas is the combination of the anti HER 2 antibody trastuzumab and cytotoxic chemotherapy. In recent years, the addition of immune checkpoint inhibitors to this combination has been studied to determine if it can improve clinical outcomes for this disease. This systematic review and meta-analysis evaluated high-quality data from clinical trials to determine the role and efficacy of this triple combination treatment. Methods: A systematic search of English-language articles on PubMed, Cochrane and Google scholar was done to identify randomized trials (RCTs) investigating the use of triple combination treatment of anti-Her 2 antibody, chemotherapy and immune checkpoint inhibitor in the treatment of unresectable, locally advanced, or metastatic HER2 overexpression positive gastric, esophageal and gastroesophageal junction adenocarcinoma. Quality of the studies was assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Inverse variance was the statistical method used with random effects as the analysis model in the production of the Forest plot and calculation of risk ratio (RR) at 95% confidence intervals (CI). Results: Four (4) RCTs (N = 866) were included for quality assessment and data extraction. Two (2) of these RCTs (N = 80) were single arm studies which both showed favorable outcomes in terms of objective response rate and progression free survival. The two (2) other RCTS (N = 786), each had two arms (triple regimen versus comparator) and were used in the meta-analysis. Risk of bias was low and heterogeneity was low (I2 below 50%). Pooled results showed that in patients given triple combination regimen, there is statistically significant improvement in progression free survival (RR 1.55 95% CI 1.20-2.00, p 0.0007). There is also an increase in overall response rate in favor of the triple combination regimen, albeit not statistically significant (RR 1.31 95% CI 0.99-1.74, p = 0.06). Conclusions: The addition of an immune checkpoint inhibitor to the current standard of care of anti Her 2 antibody and chemotherapy provides meaningful results in terms of tumor response and progression free survival in Her 2 positive locally advanced or metastatic gastric and esophageal adenocarcinomas. More robust trials, and data on overall survival supporting the use of this triple regimen may help re-shape the current standard of care for this disease.

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

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

A phase II/III study of peri-operative nivolumab (nivo) and ipilimumab (ipi) in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: Results of the neoadjuvant pathologic complete response (pCR) rate (ECOG-ACRIN EA2174).

4000 Background: E/GEJ adenocarcinoma has a high mortality rate despite curative intent therapy. Although the use of immune checkpoint inhibition (ICI) in combination with chemotherapy in the metastatic setting and as adjuvant monotherapy both confer survival benefits, its role in combination with neoadjuvant chemoradiation or with other ICIs in the adjuvant setting remains unclear. Here we report the impact of nivo on pCR rate in pts with E/GEJ adenocarcinoma receiving neoadjuvant chemoradiation as part of the EA2174 clinical trial. Methods: Pts with a localized T1N1-3M0 or T2-3N0-2M0 E/GEJ adenocarcinoma with an ECOG PS of 0-1 and deemed surgical candidates for an esophagectomy were eligible. In step 1, pts were randomized to neoadjuvant therapy with carboplatin AUC 2 and paclitaxel 50 mg/m2 intravenously (IV) weekly x 5 along with 41.4-50.4 Gy radiation without (Arm A) or with (Arm B) nivo 240 mg IV during weeks 1 and 3 of treatment, followed by esophagectomy. Pts underwent a second randomization (step 2) to 6-12 months of adjuvant nivo with or without 6 months of ipi. Planned accrual for step 1 was 278 pts. The primary neoadjuvant endpoint was pCR rate with H0= 23% vs HA= 38%, 90% power, one-sided α = 0.10. The primary adjuvant endpoint comparing nivo to nivo/ipi is disease free survival and will be reported separately once data are mature. Results: Between May 2019 and Dec 2022, 275 pts were enrolled to step 1 of the study (Arm A, n = 138; Arm B, n = 137). Male = 89.5%; White = 92%, Asian = 2.2%, Black 1.5%; median age 65.5 years; E = 60.4%, GEJ = 39.3%. Only 78.5% of pts proceeded to surgery (Arm A = 76.1%, Arm B 81.0%). The pCR rate in Arm A was 21.0% (95% CI, 14.5-28.8) and in Arm B was 24.8% (95% CI, 17.8-32.9), showing no statistically significant difference (p = 0.27). Surgical complication rates between the two arms were similar (Arm A = 28.7%, Arm B = 25.4%). Grade (G) 3/4 events occurring in at least 5% of pts on Arm A—anemia (n = 7), dysphagia (n = 9), esophagitis (n = 7), decreased lymphocytes (n = 80), decreased neutrophils (n = 7); decreased white blood cells (n = 20). G3/4 events occurring in at least 5% of pts on Arm B—anemia (n = 10), dysphagia (n = 8), nausea (n = 8), decreased lymphocytes (n = 84), decreased neutrophils (n = 20), decreased white blood cells (n = 31). Three treatment related deaths occurred on Arm A and two on Arm B. There were no notable differences in chemotherapy or radiation exposure between the two arms. Conclusions: The addition of nivo to neoadjuvant carboplatin, paclitaxel and radiation does not improve the pCR rate in pts with resected E/GEJ adenocarcinoma. Given the known benefit of the addition of ICI to chemotherapy, a further understanding of the impact of radiation on ICI activity is needed. Clinical trial information: NCT03604991 .

Distinct tumor microbiome and metabolomic profiles to inform responses of patients with esophageal cancer to neoadjuvant chemoradiotherapy and immunotherapy.

4084 Background: Preclinical and clinical data indicate that neoadjuvant chemoradiotherapy (CRT) may prime an anti-tumor immunological response in esophageal cancer driven by intratumoral CD8+ T cells. However, responses to neoadjuvant therapy can vary widely across patients. The microbiome, a novel and potentially modifiable biomarker of immunotherapy response, may inform neoadjuvant response. Methods: Fecal and tumor samples were collected from patients with stage II-III resectable distal esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immunotherapy followed by chemoradiotherapy (CRT) and immunotherapy (IO). Patients on arm A (n=15) received 2 cycles of induction with nivolumab plus 3 additional cycles with CRT. Patients on arm B (n=10) received nivolumab and relatlimab on a similar induction schedule, but concurrent IO and CRT resulted in immune related adverse events and a protocol amendment to CRT (NCT03044613). We examined fecal (n=19) and tumor (n=12) patient samples across both arms using 16S rRNA amplicon sequencing and high-resolution taxonomic assignment. Additionally, fecal samples were analyzed using an untargeted panel (General Metabolics) and pathway analysis was performed using Metaboanalyst (v6.0). Results: The fecal microbiome of patients with pathological complete response (pCR) grouped in distinct clusters compared to patients without pathological complete response (non-pCR) using Bray-Curtis (p < 0.001). Patients with >10% and <10% residual tumor grouped similarly but were significantly different from patients with 0% residual tumor (p < 0.001). On a linear discriminant axis, the top 10 abundant bacteria were significantly increased in pCR compared to non-pCR (p < 0.001). After FDR correction, six bacteria had significantly differing abundances. Bacteroides finegoldii, Paraprevotella clara, Ruminococcus callidus, and Roseburis inulinivorans were significantly enriched in pCR patients. Clostridiales and Bacteroides were significantly enriched in non-pCR patients. Fecal metabolomic analysis demonstrated six significant metabolites: in non-pCR, ropinirole, valine, phenylalanine, and isoleucine were enriched; in pCR, C16cer and D-urobilinogen were enriched (p < 0.05). Patients with improved neoadjuvant response had significantly higher abundances of Bacteroides and corresponding C16cer levels. Pathway analysis revealed significant involvement in aminoacyl-tRNA biosynthesis and sphingolipid metabolism. Conclusions: Patients with complete responses to combined CRT and IO for operable esophageal cancer had distinct fecal microbiome profiles as well as metabolomic pathways. These results may be useful to further characterize and predict patients who have improved responses to neoadjuvant therapy and serve as a basis for therapeutic intervention.

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

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

Use of artificial intelligence–based digital pathology to predict outcomes for immune checkpoint inhibitor therapy in advanced gastro-esophageal cancer.

4013 Background: Accurate prediction of response and survival outcomes with anti-PD-1/PD-L1 immune checkpoint inhibition (ICI) remains a significant challenge in gastro-esophageal cancers. In this study, we use an artificial intelligence (AI)-based single-cell analysis of digitized whole-slide H&E images (WSIs) to predict objective response and survival benefit of ICI in two independent cohorts of gastro-esophageal cancer patients. Methods: WSIs were obtained from 82 ICI-treated advanced gastroesophageal cancer patients (gastric, esophageal, and gastro-esophageal junction adenocarcinoma and squamous cell carcinoma) at Stanford University for discovery, and 189 ICI-treated advanced gastric adenocarcinoma patients at Southern Medical University for external validation. Deep learning models were deployed for automated tumor area detection and segmentation of cell nuclei within WSIs. We developed a fully automated cell annotation approach by leveraging multiplex immunofluorescence and trained a deep learning model to classify nuclei into four cell types from H&E (tumor cells, lymphocytes, neutrophils, and macrophages). A total of 66 features were computed to quantify cell composition and cell-cell interactions within the tumor microenvironment. Treatment outcomes were assessed using progression-free survival (PFS) and best objective response per the Response Evaluation Criteria in Solid Tumors (v1.1), with statistical significance reported at the 95% confidence level. Results: In the training cohort, a spatial feature characterizing lymphocyte and neutrophil interaction had the strongest association with PFS (hazard ratio = 0.44, 95% CI 0.24-0.79, P = 0.0046). In the validation cohort, the spatial biomarker positive population had significantly improved PFS compared to the spatial biomarker negative population (hazard ratio = 0.41, 95% CI 0.27-0.61, P < 0.0001; median time to event: 19 months vs 9 months). For predicting objective response in the validation cohort, a multivariate model combining the spatial features achieved AUROC = 0.81 compared to AUROC = 0.65 for PD-L1 CPS (P = 0.0014), while combining the multivariate model with PD-L1 CPS achieved AUROC = 0.84. Conclusions: A single-cell computational pathology approachidentifies spatial biomarkers with predictive utility for determining ICI treatment outcomes in advanced gastro-esophageal cancer. Further validation of these findings is being pursued in additional cohorts.

456P Correlation between pathological complete response (pCR) and survival outcomes in patients with resectable esophageal (EC) or gastroesophageal junction cancer (GEJC): A large, real-world, single-center cohort analysis

456P Correlation between pathological complete response (pCR) and survival outcomes in patients with resectable esophageal (EC) or gastroesophageal junction cancer (GEJC): A large, real-world, single-center cohort analysis

Durable pembrolizumab response in metastatic MSS ARID1A-mutant undifferentiated carcinoma of the esophagus.

In 2021, the FDA approved the combination of pembrolizumab with platinum and fluoropyrimidine-based chemotherapy for advanced esophageal and gastroesophageal junction (GEJ) cancers, regardless of the PD-L1 score. Pembrolizumab alone may benefit MSI-H gastroesophageal adenocarcinomas, but most patients with pMMR/MSS types require it in combination with standard chemotherapy. The NCCN recognizes the predictive value of PD-L1 CPS and recommends pembrolizumab plus chemotherapy for PD-L1 CPS ≥10. Undifferentiated carcinoma of the esophagus, a rare esophageal cancer subtype with a poor prognosis, still lacks a well-defined optimal treatment. We report a case of an 87-year-old female with advanced, pMMR/MSS, HER2-negative, ARID1A-mutant, undifferentiated carcinoma of the esophagus with a PD-L1 CPS of 20, who has shown a durable ongoing response to pembrolizumab monotherapy for 2 years now. The case highlights a favorable response, possibly attributed to the high CPS score combined with the ARID1A mutation, as recent research suggests that ARID1A mutations may increase immunotherapy susceptibility.

Totally minimally invasive laparoscopic robot-assisted Ivor Lewis esophagectomy: improved technique and outcomes over 200 cases.

Surgical resection of esophageal and gastroesophageal junction cancers is a very complex procedure with step learning curve. New technologies have made minimally invasive surgery possible, but challenges still remain for wide spread adoption of these techniques. This article aims to describe the outcomes and salient technical points of a totally minimally invasive, laparoscopic, robot-assisted Ivor Lewis esophagectomy (LRAMIE). Retrospective observational cohort study performed at a specialty cancer center using a prospectively maintained institutional database. Patients undergoing LRAMIE (laparoscopic abdomen, robotic chest) from 2014-2023 were included. Patients undergoing transhiatal and three-field esophagectomy were excluded. Operative and postoperative outcomes were compared over the study period to identify potential associations between outcomes over time. Two-hundred patients were identified who underwent LRAMIE. Median age was 65 years and most were male (87.5%). The open conversion rate was 1% (n=2), which occurred within the first 30 cases. Operative time and blood loss were improved at the 60-case mark (P<0.001). Anastomotic stricture rate improved after 50 cases, and leak rate improved after 80 cases. Postoperative length of stay improved at both 50 and 100 cases with a median LOS of 6 days after 100 cases. Rate of postoperative pneumonia, 30- and 90-day mortality were reduced after 100 cases, although not statistically significant for mortality due to too few events. Totally minimally invasive Ivor Lewis esophagectomy at a high-volume center is a safe procedure. Operative outcomes improved significantly after 50-80 cases, followed by improvement in anastomotic results and postoperative outcomes, with corresponding excellent oncologic outcomes.

Chemotherapy Plus Atezolizumab Pre- and Post-Resection in Localized Esophageal or Gastroesophageal Junction Adenocarcinomas: A Phase I/II Single-Arm Study.

Efforts to improve the prognosis for patients with locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma have focused on neoadjuvant approaches to increase the pathological complete response (pathCR) rate, improve surgical resection, and prolong event-free and overall survival (OS). Building on the recent evidence that PD-1 inhibition plus chemotherapy improves the OS of patients with metastatic GEJ adenocarcinoma, we evaluated whether the application of this strategy in the neoadjuvant setting would improve the pathological response. This single-center phase I/II trial evaluated the safety, toxicity, and efficacy of neoadjuvant atezolizumab with oxaliplatin and 5-fluorouracil (modified FOLFOX) followed by esophagectomy followed by atezolizumab. The primary objective goal was to achieve 20% pathCR. From the twenty enrolled patients, eighteen underwent resection and two (10%, 95% CI: 1.24-31.7%) achieved pathCR. After a median follow-up duration of 40.7 months, 11 patients had disease recurrence and 10 had died. The median disease-free and OS were 28.8 (95% CI: 14.7, NA) and 38.6 months (95% CI: 30.5, NA), respectively. No treatment-related adverse events led to death. Although modified FOLFOX plus atezolizumab did not achieve the expected pathCR, an acceptable safety profile was observed. Our results support the continued development of a more refined strategy (neoadjuvant chemotherapy plus perioperative immunotherapy/targeted agents) with molecular/immune profiling in parallel.

Abstract 3317: KRASmulti inhibitor BI 3706674 shows efficacy in KRAS-driven preclinical models of cancer that supports clinical testing in patients with tumors harbouring KRASG12V mutations and KRAS wild-type amplifications

Abstract Alterations in KRAS are a main cancer driver. Amplifications of the KRAS wild-type (wt) allele account for ~7% of all KRAS-driven cancers and are frequent in gastric (~5%), esophageal (~13%) and gastroesophageal junction cancers (~12%). KRASG12V mutations account for ~28% of pancreatic cancers, 9% of colorectal cancers and 6% of lung adenocarcinoma. There is an urgent medical need to identify targeted therapies for these frequent KRAS alterations. Herein, we describe BI 3706674, a novel, potent and orally bioavailable small molecule inhibitor of the KRAS oncogene for clinical testing in patients with tumors harboring KRASG12V mutations and KRAS wild-type amplifications. BI 3706674 binds non-covalently to multiple KRAS mutant alleles, including the KRAS wt allele, in the GDP-bound state and thereby disrupts oncogenic signaling. Importantly, BI 3706674 is highly selective for KRAS vs HRAS or NRAS, and it is therefore expected to be well-tolerated in normal tissues. In two large cancer cell line panels (PRISM and Horizon), BI 3706674 shows sensitivity across a wide range of KRAS alleles (KRAS wt amplifications and KRAS mutations e.g., G12A/C/D/V, G13D and Q61H). The strongest sensitivity was observed for cell lines with KRAS wt amplifications (relative copy number (CN) of &amp;gt; 10) followed by cell lines with KRASG12V mutations along with significant pharmacodynamic (PD) biomarker modulation (e.g., down-regulation of DUSP6 mRNA). In vivo, BI 3706674 was well-tolerated and showed dose-dependent efficacy in cell line-derived and patient-derived xenograft models of human gastric cancer with KRAS wt CN &amp;gt; 10 and diverse tumor types with KRASG12V mutations. A twice daily oral dose of 30 mg/kg induced significant tumor regression and PD biomarker modulation. Combination of BI 3706674 with standard of care therapies and novel agents are being tested in preclinical models to guide clinical development. Results of the ongoing pre-clinical analysis will be shared. A Phase I clinical trial is in preparation in patients with advanced solid cancers harboring KRASG12V mutations and KRAS wt amplifications to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and efficacy of BI 3706674. Citation Format: Antonio Tedeschi, David H. Peng, Fiorella Schischlik, Lorenz Herdeis, Otmar Schaaf, Valeria Santoro, Daniel Gerlach, Fabio Savarese, Jesse Lipp, Christian Haslinger, Francesca Rocchetti, Johannes Popow, Heinrich J. Huber, Birgit Wilding, Matthias Treu, Julian Fuchs, Joachim Broeker, Tobias Wunber, Michael Gmachl, Klaus Rumpel, Matthew Rees, Melissa Ron, Jennifer Roth, Mariah Williams, Charles Deckard, Vandhana Ramamoorthy, Joseph R. Daniele, Jaffer A. Ajani, Funda Meric-Bernstam, Scott Kopetz, Michael Kim, Don L. Gibbons, Christopher P. Vellano, Joseph R. Marszalek, Timothy P. Heffernan, Darryl McConnell, Mark Pearson, Norbert Kraut, Dorothea Rudolph. KRASmulti inhibitor BI 3706674 shows efficacy in KRAS-driven preclinical models of cancer that supports clinical testing in patients with tumors harbouring KRASG12V mutations and KRAS wild-type amplifications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3317.

O220: The role of cardiopulmonary exercise testing in predicting sarcopenia after neoadjuvant chemotherapy and post-operative complications

Abstract Background Neoadjuvant chemotherapy (NAC) may contribute to sarcopenia development in patients with oesophageal and oesophagogastric junction (OGJ) adenocarcinoma. Preoperative cardiopulmonary fitness and sarcopenia are both variables which have been correlated with outcomes after major surgery. The aims of this study were to investigate if pre-operative cardiopulmonary exercise testing (CPET) variables were associated with radiological sarcopenia post NAC, and the effect of CPET variables on post-operative outcomes in sarcopenic patients. Methods Patients from a single high-volume tertiary centre diagnosed with oesophageal or OGJ adenocarcinoma between August 2015 and August 2022 were included. CPET variables and post-NAC CT scans to assess for radiological sarcopenia were evaluated. CPET variables included in statistical analyses were ventilatory equivalent for carbon dioxide (VE/VCO2), anaerobic threshold (AT) and peak oxygen consumption (VO2 peak). Results 208 patients were included. Median VE/VCO2 was 29 in patients with sarcopenia post-NAC and 28 in non-sarcopenic patients (p = 0.009). Other CPET variables were not associated with sarcopenia post NAC. Within the sarcopenic group, CPET variables were not associated with post-operative complications. Within the whole cohort, increased VE/VCO2 or decreased VO2 peak correlated with a longer hospital stay (p=0.043 and p=0.012 respectively), and an association was observed between VE/VCO2 and Clavien-Dindo grade of complications (p=0.019). Conclusions VE/VCO2 was associated with sarcopenia post NAC in patients with oesophageal and OGJ adenocarcinoma. Further analysis with a larger sample size might help establish this, which could be helpful in identifying and targeting patients at higher risk of sarcopenia and post-operative complications.

Multicenter analysis on the value of standard (chemo)radiotherapy in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction

BackgroundTo assess the tolerability and oncological results of chemoradiation in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction.MethodsThis multi-center retrospective analysis included 86 elderly patients (≥ 65 years) with esophageal or gastroesophageal junction adenocarcinoma (median age 73 years; range 65–92 years) treated with definitive or neoadjuvant (chemo)radiotherapy. The treatment was performed at 3 large comprehensive cancer centers in Germany from 2006 to 2020. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities according to CTCAE criteria v5.0 were analyzed, and parameters potentially relevant to patient outcomes were evaluated.ResultsThirty-three patients (38%) were treated with neoadjuvant chemoradiation followed by surgery, while the remaining patients received definitive (chemo)radiation. The delivery of radiotherapy without dose reduction was possible in 80 patients (93%). In 66 patients (77%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 48% of patients (n = 32) required chemotherapy de-escalation due to treatment-related toxicities and comorbidities. Twenty-nine patients (34%) experienced higher-grade acute toxicities and 14 patients (16%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS amounted to 72%, 49%, 46%, and 52%, respectively. In multivariate analysis, neoadjuvant chemoradiation followed by surgery was shown to be associated with significantly better PFS (p = 0.006), DMFS (p = 0.006), and OS (p = 0.004) compared with all non-surgical treatments (pooled definitive radiotherapy and chemoradiation). No such advantage was seen over definitive chemoradiation. The majority of patients with neoadjuvant therapy received standard chemoradiotherapy without dose reduction (n = 24/33, 73%). In contrast, concurrent chemotherapy was only possible in 62% of patients undergoing definitive radiotherapy (n = 33/53), and most of these patients required dose-reduction or modification of chemotherapy (n = 23/33, 70%).ConclusionsIn our analysis, omission of chemotherapy or adjustment of chemotherapy dose during definitive radiotherapy was necessary for the overwhelming majority of elderly esophageal cancer patients not eligible for surgery, and hence resulted in reduced PFS and OS. Therefore, optimization of non-surgical approaches and the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly patients with (gastro)esophageal adenocarcinoma is required.