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The decision to treat advanced gastroesophageal cancers (GECs) with targeted therapy and immunotherapy is based on key biomarker expression (human epidermal growth factor receptor 2 (HER2), programmed cell death-ligand 1 (PD-L1), microsatellite instability (MSI), and/or mismatch repair (MMR)). Real-world data on testing, results, and treatment patterns are limited. This retrospective observational study used a nationwide electronic health record-derived de-identified database of patients from the United States. The analysis included adult patients with advanced GECs who initiated systemic treatment between 2017 and 2020. Biomarker testing patterns, timing, assays, tissue collection site, results, and treatment sequences were assessed. Of 1142 eligible patients, adenocarcinoma was the most prevalent histology (83% of patients). Overall, 571 (50%) patients were tested for PD-L1, 582 (51%) were tested for MMR/MSI, and 857 (75%) were tested for HER2. Between 2017 and 2020, the PD-L1 testing rate increased from 39% to 58%, and the MMR/MSI testing rate increased from 41% to 58%; the median time from initial diagnosis to first test decreased for both biomarkers. Programmed cell death receptor-1 inhibitor use was observed among patients with positive PD-L1 or MMR-deficient/MSI-High results. These results supplement data reported in key clinical trials and may inform decision-making as treatment options for advanced GECs evolve.

PURPOSE To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer. METHODS The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS Eighteen randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS For human epidermal growth factor receptor 2 (HER2)–negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

BACKGROUND: MMR proficient (pMMR) colorectal cancer (CRC) is usually unresponsive to immunotherapy. Recent data suggest that ibrutinib may enhance the anti-tumour activity of anti-PD-1 immunotherapy. In this study, we evaluated the safety and efficacy of ibrutinib plus pembrolizumab in refractory metastatic CRC. METHODS: This was a phase 1/2 study in patients with refractory metastatic pMMR CRC. The primary endpoints for phases 1 and 2 were maximum tolerated dose (MTD) and disease control rate, respectively. The secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 40 patients were enrolled. No dose-limiting toxicity was observed, and MTD was not identified. The highest tested dose of ibrutinib, 560 mg once daily, was combined with a fixed dose of pembrolizumab 200 mg every 3 weeks for the phase 2 portion. The most common grade 3/4 treatment-related adverse events were anaemia (21%), fatigue (8%) and elevated alkaline phosphatase (8%). Among 31 evaluable patients, 8 (26%) achieved stable disease, and no objective response was observed. The median PFS and OS were 1.4 and 6.6 months, respectively. CONCLUSION: Ibrutinib 560 mg daily plus pembrolizumab 200 mg every 3 weeks appears to be well tolerated with limited anti-cancer activity in metastatic CRC. CLINICALTRIALS.GOV IDENTIFIER: NCT03332498.

Background Biliary tract cancer (BTC) has a poor prognosis despite treatment with first-line gemcitabine and cisplatin. In BTC, PI3K/AKT pathway activation has been shown to increase resistance to chemotherapy, which may be overcome with PI3K inhibition. This phase 2 study evaluated the safety and efficacy of copanlisib, a PI3K inhibitor, with gemcitabine and cisplatin in advanced BTCs. The role of PTEN expression in outcomes was also explored. Methods Patients with advanced/unresectable BTC received gemcitabine, cisplatin, and copanlisib as their first-line treatment. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were the response rate (RR), median overall survival (OS)/PFS, and safety profile. An assessment of PTEN expression by immunohistochemistry was also performed along with molecular profiling. Results Twenty-four patients received at least 1 dose of the study drug. The PFS rate at 6 months was 51%; the median OS was 13.7 months (95% CI, 6.8-18.0 months), and the median PFS was 6.2 months (95% CI, 2.9-10.1 months). Nineteen patients were evaluable for RR: 6 patients achieved a partial response (31.6%), and 11 (57.9%) had stable disease. The most common grade 3/4 adverse events were a decreased neutrophil count (45.83%), anemia (25%), increased lipase (25%), and hypertension (20.8%). Twenty patients had tissue evaluable for the PTEN status. The PFS for low (n = 9) and high PTEN expression (n = 11) was 8.5 and 4.6 months, respectively (P = .19). The median OS for low and high PTEN expression groups was 17.9 and 7.0 months, respectively (P = .19). Conclusions The addition of copanlisib to gemcitabine and cisplatin does not improve PFS at 6 months. However, future studies using PTEN as a potential biomarker should be considered. Lay summary The addition of copanlisib, a PI3K inhibitor, to standard chemotherapy for advanced biliary tract cancers was assessed for efficacy and safety. Twenty-four patients with advanced biliary tract cancer received treatment in this study. There was no difference in survival with the addition of copanlisib in comparison with standard chemotherapy. Copanlisib may be more effective and increase survival in patients with low PTEN expression levels. Further studies are needed to confirm this. No unexpected adverse events occurred.

Introduction To develop a radiomic-based model to predict pathological complete response (pCR) and outcome following neoadjuvant chemoradiotherapy (NACRT) in oesophageal cancer. Methods We analysed 68 patients with oesophageal cancer treated with NACRT followed by esophagectomy, who had staging 18F-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET) and computed tomography (CT) scans performed at our institution. An in-house data-characterization algorithm was used to extract 3D-radiomic features from the segmented primary disease. Prediction models were constructed and internally validated. Composite feature, Fc = α * FPET + (1 - α) * FCT , 0 ≤ α ≤ 1, was constructed for each corresponding CT and PET feature. Loco-regional control (LRC), recurrence-free survival (RFS), metastasis-free survival (MFS) and overall survival (OS) were estimated by Kaplan-Meier analysis, and compared using log-rank test. Results Median follow-up was 59 months. pCR was achieved in 34 (50%) patients. Five-year RFS, LRC, MFS and OS were 67.1%, 88.5%, 75.6% and 57.6%, respectively. Tumour Regression Grade (TRG) 0-1 indicative of complete response or minimal residual disease was significantly associated with improved 5-year LRC [93.7% vs 71.8%; P = 0.020; HR 0.19, 95% CI 0.04-0.85]. Four separate pCR predictive models were built for CT alone, PET alone, CT+PET and composite. CT, PET and CT+PET models had AUC 0.73 ± 0.08, 0.66 ± 0.08 and 0.77 ± 0.07, respectively. The composite model resulted in an improvement of pCR predicting power with AUC 0.87 ± 0.06. Stratifying patients with a low versus high radiomic score showed clinically relevant improvement in 5-year LRC favouring low-score group (91.1% vs. 80%, 95% CI 0.09-1.77, P = 0.2). Conclusion The composite CT/PET radiomics model was highly predictive of pCR following NACRT. Validation in larger data sets is warranted to determine whether the model can predict clinical outcomes.

The gold standard for locoregional esophageal cancer (LEC) treatment includes preoperative chemoradiation and surgical resection, with possible perioperative or adjuvant systemic therapy. With few data associating histologic grade and prognosis in LEC patients receiving neoadjuvant chemoradiation followed by resection, we seek to evaluate this association.Our institutional esophagectomy database between 1999 and 2019 was queried, selecting esophageal adenocarcinoma patients who completed neoadjuvant therapy (NAT), followed by esophagectomy. Propensity-score matching of low- and high-histologic grade groups was performed to assess survival metrics using initial clinical grade (cG) and final pathologic grade (pG). We performed a multivariable logistic regression to study predictors of pathologic complete response as a secondary objective.A total of 518 patients met the inclusion criteria. Kaplan-Meier analysis of the matched dataset showed no difference in initial or 5-year recurrence-free survival or overall survival (OS) between cG1 and cG2 versus cG3 based on original grade. When matched according to pG, cG1-2 had improved median survival parameters compared to cG3, with 5-year OS for cG1-2 of 45% versus 27% (p = 0.001). Higher pG, pathologic N stage, and poor response to NAT are predictors of poor survival.Patients with post-NAT pG1-2 demonstrated improved survival. Integrating histologic grade into postneoadjuvant staging may be warranted.

Robotic-assisted gastrectomy is increasingly utilized for the treatment of gastric malignancies. However, the benefits of robotic surgery have been questioned. This study describes short-term outcomes in the establishment of a comprehensive robotic program for gastric malignancies.Patients who underwent robotic-assisted gastric resections between 2013 and 2018 were studied. Preoperative measures and surgical outcomes were analyzed. Finally we studied and analyzed robotic and open gastrectomy for the management of gastric adenocarcinoma (GC) at the same institution between 2000 and 2018 for quality benchmarking.Forty six patients (pts.) underwent robotic-assisted gastric resections. 26 (56.5%) were male, with a median age of 62 y (range: 29-87). Pathology included GC, gastrointestinal stromal tumors, neuroendocrine tumors, metastatic lesions, and benign processes. 19 pts. underwent total gastrectomy, 16 distal gastrectomy, four subtotal gastrectomy, and seven wedge resection. Pts. undergoing distal gastrectomy and wedge resection experienced shorter operative times and length of stay than total gastrectomy (P 0.01; P 0.01). Four operations (8.8%) were converted to open and 13 pts (28.3%) had postoperative complications, including an 8.7% readmission rate. Median lymph nodes retrieved during total, subtotal, and distal gastrectomy were 20 (13-46), 12.5 (0-26), and 16.5 (0-34), respectively. All pts. underwent margin negative resection. Median follow-up for GC was 21 mo, and 60% of pts. received adjuvant therapy at a median of 59d (range: 23-106).Robotic gastrectomy is a feasible alternative to open gastrectomy. Our results will help establish benchmarks to improve perioperative outcomes, especially length of stay and time to initiation of therapy.

We are presenting a 63-year-old Caucasian male who complained of 2 months of progressive dysphagia. Upper endoscopy discovered a mass in the distal esophagus near the gastroesophageal junction. Biopsy was consistent with adenocarcinoma. Endoscopic ultrasound (EUS) showed extension beyond the muscularis propria, with an enlarged paraesophageal lymph node (T3N1). Initial positron emission tomography (PET)/computed tomography (CT) showed hypermetabolic portocaval lymphadenopathy presumed to be metastatic, but otherwise without distant disease extension. Neoadjuvant treatment included induction FOLFOX followed by 5,600 cGy over 28 fractions in combination with 5-FU and oxaliplatin. Approximately 3.5 weeks after completion, a repeat PET/CT revealed reduced uptake in both the primary esophageal mass and regional lymph nodes. Of note there were several new mass-like foci of hypermetabolism in the liver, specifically the left lobe, concerning for metastatic disease. Image-guided biopsy did not show any identifiable lesions, but sampling was performed based on anatomical landmarks. Pathology revealed benign parenchyma with minimal inflammation and mild reactive regeneration. In light of this, the patient proceeded to undergo definitive resection via robotic Ivor-Lewis esophagectomy with only 1 positive lymph node. Given pleural involvement by the tumor, staging was revised to pT4aN1 with final histology characterized as adenosquamous carcinoma. Postoperative course was fairly uneventful, with a mild exacerbation of his chronic heart failure. The patient was discharged on post-operative day 7, with his feeding tube removed at his 2-week post-operative clinic visit. This scenario is of particular educational value from the standpoint that when the post-treatment PET/CT images are registered to the radiotherapy treatment planning CT and dose, the areas of abnormal uptake in the liver fall within the higher dose regions. Given this and the liver biopsy findings, caution should be exercised before declaring progressive disease following radiotherapy without first reviewing the treatment plan.

BACKGROUND: The incidence of esophageal cancer (EC) is increasing in the USA. Neoadjuvant therapy for locally advanced cancers followed by surgical resection is the standard of care. The most common post-esophagectomy cardiac complication is atrial fibrillation (AF). New-onset postoperative AF can require a prolonged hospital stay and may confer an overall poorer prognosis. In this study, we seek to identify clinical factors associated with postoperative AF. METHODS: Query of an IRB approved database of 1,039 esophagectomies at our institution revealed 677 patients with EC from 1999 to 2017 who underwent esophagectomy after neoadjuvant treatment. Age, treatment location (primary vs. other), gender, neoadjuvant radiation type [2D vs. 3D vs. intensity modulated radiation therapy (IMRT)], radiation dose, surgery type (transthoracic vs. transhiatal vs. three field), smoking history, coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), operative time, blood transfusions, fluid management, and length of stay (LOS) were analyzed in relationship to the development of AF. Statistical analysis was performed with SPSS 24. RESULTS: The mean age of the entire cohort was 64.3 (range, 28–86 years), with a Caucasian and male preponderance (White: 94.5%; male: 83.6%). Of the 677 patients, 14.9% (n=101) developed postoperative AF. Increasing age (P

Gastric cancer is the sixth most common cancer and is known to be the fifth-leading cause of cancer-related deaths globally in 2018. Systemic therapy remains the only curative option in advanced gastric carcinoma with the primary goal of improving the Health-related Quality of Life (HRQoL) (including palliation of symptoms such as dysphagia) and prolonging overall survival. Recently, ramucirumab is approved by the United States Food and Drug Administration (US-FDA) as a second-line agent either as monotherapy or in combination with paclitaxel in advanced or metastatic gastric and gastro-esophageal junction adenocarcinoma patients who have progressed on prior treatment with fluoropyrimidine or platinum containing chemotherapy. HRQoL is a subjective term that typically constitutes four components - psychological, social, occupational and physical well being. This has been evaluated as secondary endpoint in the pivotal Phase III trials with ramucirumab. HRQoL measurement can potentially provide additional information for clinical decision making beyond that of traditional medical outcomes. The present work is primarily focused on discussing HRQoL in gastric cancer patients and the impact of ramucirumab on the HRQoL in the patients with advanced gastric cancer. We also summarized the studies that evaluated the benefits of systemic therapies on HRQoL in advanced gastric cancer.

In contrast to mismatch repair deficient (dMMR) colorectal cancer (CRC), mismatch repair proficient (pMMR) CRC is usually unresponsive to anti-PD-1 immunotherapy. Recent preclinical data suggest that regorafenib may enhance the antitumor activity of anti-PD-1 immunotherapy. However, the safety and efficacy of regorafenib plus nivolumab have not been established in patients with refractory metastatic pMMR CRC. This study aimed to evaluate the safety and efficacy of regorafenib plus nivolumab in metastatic pMMR metastatic CRC.This was a phase I/Ib study with standard 3 + 3 design plus dose expansion of the maximum tolerated dose (MTD) in patients with refractory metastatic pMMR CRC. Patients were treated with regorafenib combined with nivolumab. The primary end-points were dose-limiting toxicity (DLT) and MTD. The secondary end-points were objective response rate, safety and overall survival (OS).A total of 52 patients were enrolled, and 51 patients received at least one dose of treatment. Three patients experienced DLT (all grade 3 rash). MTD was regorafenib 80 mg and nivolumab 240 mg every 2 weeks. Most common grade 3/4 treatment-related adverse events were hypertension (16%), rash (10%) and anaemia (6%). Among 40 evaluable patients, four (10%) achieved partial response, including one unconfirmed response, 21 (53%) achieved stable disease, and disease control rate was 63%. The median progression-free survival and OS were 4.3 and 11.1 months, respectively.Regorafenib plus nivolumab appears to be well tolerated with limited anticancer activity in metastatic pMMR CRC.ClinicalTrials.gov identifier: NCT03712943.

188 Background: Our previous phase I/Ib study revealed modest clinical efficacy of rego/nivo in refractory MSS-CRC, implying benefits in selected populations. This has prompted us to investigate predictive biomarkers. Methods: Pre-treatment tumor samples from the previous phase Ib rego/nivo study were obtained and assessed for mRNA sequencing (RNAseq). Response-associated transcripts were identified using DESeq2 method and annotated using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Results: A total of 19 pretreatment tumor samples were analyzed including 14 patients (pts) with disease control (DC) (2 partial response and 12 stable disease) and 5 pts with progression disease (PD). We observed significant upregulation of 89 genes including SFTPB ( P

427 Background: Gastric and esophageal cancers (GECs) together account for a significant global burden in terms of new diagnoses and deaths. Over the last several years, the utility of ctDNA has ranged from estimating tumor burden and characterizing the genomic landscape of tumor biology and response to therapy in the metastatic setting to detection of minimal residual disease (MRD) and cancer surveillance in the locally advanced setting. We have previously studied the role of a commercial ctDNA assay for MRD detection and surveillance in locally advanced GECs. Herein, we present our experience with the same ctDNA assay in advanced stage settings for GECs. Methods: In this retrospective analysis of real-world data obtained from commercial circulating tumor DNA (ctDNA) testing, 53 patients with recurrent/ metastatic esophageal cancer were analyzed. A total of 216 plasma samples were collected between 10/29/2008 and 08/23/2022. The patients were divided into 3 cohorts: Cohort A (N=30) included patients with stage II/III disease who had confirmed clinical recurrence (R). Cohort B (N=25) included recurrent and Stage IV patients who achieved a state of no evidence of disease (NED) on imaging. Cohort C (N=5) included recurrent and Stage IV patients who transiently achieved NED on imaging. A personalized, tumor-informed multiplex PCR-based next-generation sequencing assay (Signatera) was used to quantify ctDNA either postoperatively, on adjuvant or palliative therapy, or during active surveillance. Results: Of 53 patients, 30 patients with recurrent stage II/III esophageal cancer had ctDNA status available postoperatively within 150 days of confirmed clinical recurrence. Cohort A: Among these cases, 25 patients were ctDNA-positive ahead of clinical recurrence (sensitivity 83.3%) with a median of 31 days (range: 1-147 days). Cohort B: Next, we explored the correlation between ctDNA status and imaging, wherein, 96% (24/25) of patients showed a significant correlation between ctDNA status (positive or negative) and disease status by imaging (Fisher exact test p=0.0001). Of the 23 patients, 17 patients were ctDNA-negative and showed NED on imaging (negative predictive value of 100%; 17/17). Cohort C: 100% of patients (N=6) who demonstrated recurrent disease on imaging after NED were ctDNA-positive prior to imaging (positive predictive value of 100%). Conclusions: Our data demonstrate the utility of ctDNA in accurately predicting disease progression and support the potential use of ctDNA to inform treatment decisions or prompt early radiographic imaging. ctDNA may ultimately supersede traditional radiographic surveillance with the advantage of being minimally invasive and cost-effective in monitoring patients during/post-treatment.

429 Background: Gastroesophageal cancers (GECs) are the 2nd highest cause of cancer mortality globally. Biomarkers such as MMR, PD-L1, and HER2 are critical for treatment strategies. Emerging biomarkers in late-stage clinical development include FGFR2b. Approximately 30% of GECs express FGFR2b, which is associated with a poor prognosis. FGFR2 amplification ( FGFR2amp) is seen in a subset of patients and may be particularly responsive to FGFR2-targeted approaches. We sought to elucidate the genomic landscape of FGFR2ampGECs using a ctDNA platform. Methods: We retrospectively queried the Guardant Health database from 2017-2022 for patients with advanced GECs who had ctDNA NGS (Guardant360, Redwood City, CA) performed as part of clinical care. Co-alterations were evaluated for patients who harbor FGFR2amp vs those without FGFR2amp detected via ctDNA. Fisher’s exact test was used for group comparisons. Results: Approximately 7100 patients met the diagnosis criteria. FGFR2amp was detected in 263 patients (3.7%). The majority were males (66 and median age in the cohort of FGFR2amp patients was 66 years (range 22-81 yrs). Most amps were high (+++) in gastric and GEJ (plasma CN≥4) and more frequently observed in patients who are tested at diagnosis (44%) vs progression (19%) (p=0.0147). The mean VAF across samples with high-level FGFR2amp is 22.42%. Patients with FGFR2amp were enriched for EGFR co-occuring amplifications and cell cycle pathway alterations. CDH1 was frequently mutated in pts under 50 who harbor FGFR2amp (p=0.0028). Thirty nine percent of patients with FGFR2amp were also found to harbor a gene fusion and 14% of patients with FGFR2amps harbored an activating fusion in FGFR1/2/3. Conclusions: FGFR2 is a validated target in GECs, and the contexture of FGFR2amp will be important to defining patient subgroups with responses to FGFR2-directed therapy. Here we define the FGFR2amp landscape which may help inform future combination strategies for this emerging biomarker.[Table: see text]

228 Background: We previously conducted a phase I/Ib study with regorafenib and nivolumab in patients with refractory metastatic mismatch repair proficient (pMMR) colorectal cancer (CRC). This study aimed to investigate the biomarkers that predict the treatment response. Methods: Out of the 51 patients who received regorafenib and nivolumab, 22 archival pretreatment tumor samples were subjected to the Xerna TME Panel, a machine learning-based RNA-sequencing biomarker assay and were classified into one of four TME biomarker subtypes: Angiogenesis (A), Immune Active (IA), Immune Desert (ID), or Immune Suppressed (IS). Potential predictive biomarkers including the TME subtypes, KRAS (wild type vs mutant), PD-L1 (negative vs. positive, samples with > 1% tumor cells for PD-L1 were considered positive), CD8 expression (low vs. high), and Treg cells (low vs. high) in tumor microenvironment were evaluated for correlation with overall survival (OS), progression free survival (PFS) and disease control rate (DCR, defined as complete response + partial response + stable disease). Results: Among the 22 patients, 16 (72.7%) had liver metastasis and 15 (68.2%) had lung metastasis. KRAS mutation was found in 16 (68.2%) patients. 11/21 (52.4%) were positive for PD-L1. 12 (54.5%) had high CD8 expression, whereas 9/21 (42.9%) had high Treg cells in tumor microenvironment. Ten (45.5%) patients were classified as biomarker-positive (IA + IS subtypes) and 12 (54.5%) were biomarker-negative (A + ID) based on Xerna TME panel. Two (9.1%) patients achieved partial response, 12 (54.5%) had stable disease, and five (22.7%) developed progressive disease. The median PFS was 5.6 months and median OS was 13.1 months. No significant correlation was observed between RAS mutation (p = 0.664, p = 0.609), PD-L1 expression (p = 0.287, p = 0.173), CD8 (p = 0.152, p = 0.456) and PFS or OS. Low Treg was found to be associated with prolonged PFS (median: 9.8 vs. 1.9 months, p = 0.011) but not OS (p = 0.280). Similarly, only low Treg level was related with DCR (83.3% vs. 33.3%, p = 0.032). While not reaching statistical significance, Xerna TME biomarker-positive patients showed trends for higher median PFS (7.9 months vs. 4.1 months, p = 0.254), median OS (15.75 months vs. 11.9 months, p = 0.378), and higher DCR (70% vs. 58%, p = 0.675) compared to biomarker-negative patients. Additionally, the two patients with partial responses were Xerna TME biomarker-positive. Conclusions: Our study demonstrated that low Treg in tumor microenvironment is correlated with better prognosis in patients with refractory metastatic pMMR CRC who were treated with regorafenib plus nivolumab. Xerna TME panel analysis of these patients also showed trends for predictive clinical benefit. Prospective and larger cohort studies are needed to better define predictive biomarkers for this combination in the future.

347 Background: Zanidatamab (zani) is an anti-HER2 bispecific antibody against ECD4 and ECD2 with demonstrated activity and tolerability in a range of HER2-expressing cancers. This Phase (Ph) 2 study (NCT03929666) evaluates zani in combination with chemotherapy (chemo) as first-line treatment for patients (pts) with advanced HER2-expressing mGEA. Methods: Eligible pts for this ongoing, open-label study had not received any prior systemic therapy for mGEA. Pts received zani + physician’s choice of multi-agent chemo (mFOLFOX6, CAPOX, or FP). Antidiarrheal prophylaxis for cycle 1 was added after the first 25 pts were treated. Following demonstration of tolerability of the regimens in an initial safety cohort, the primary study objective was to evaluate antitumor activity. Results: Pts were enrolled between Aug 29, 2019 and Feb 18, 2022 with a data cutoff of July 28, 2022 (N=46 pts; zani + mFOLFOX6 [24], zani + CAPOX [20], or zani + FP [2]). Median age was 58 yrs; 85% male; 42 pts (91%) had HER2+ tumors (IHC 3+ or 2+ with ISH-positivity) based on central testing. Median duration of follow-up among all 46 pts was 21.5 months (mo) and 20 pts (43%) remain on treatment. In 38 response-evaluable pts with HER2+ tumors, confirmed objective response rate (cORR) was 79% (95% CI: 63-90%) and disease control rate was 92% (95% CI: 79-98%); 3 pts achieved complete response. Median duration of response (DOR) was 20.4 mo (95% CI: 6.8-not estimable [NE]), with 57% (17/30) pts having an ongoing response at data cut-off (1 pt has ongoing response >29 months). In all 42 pts with HER2+ tumors, median progression-free survival (PFS) was 12.5 mo (95% CI: 7.1-NE) and median overall survival (OS) was not yet reached. Survival rate at 18 mo was estimated to be 87.3%. The most common (≥25% pts) treatment-related (zani and/or chemo) adverse events (TRAE) in all pts were diarrhea, nausea, peripheral sensory neuropathy, decreased appetite, fatigue, vomiting, and hypokalemia. Diarrhea was the most common Gr3+ TRAE, lasting a median (interquartile range) of 3 (2-5) days, with the majority of events occurring in cycle 1; incidence of all Gr3+ events was 56% in 25 pts who did not receive prophylaxis and 14% in 21 pts who did. There were no treatment-related deaths. Conclusions: In pts with HER2+ mGEA, zani + chemo is a highly active treatment regimen with a manageable safety profile. This maturing data set demonstrates durable disease control with encouraging cORR, DOR, PFS and OS results. A global Ph 3 study (HERIZON-GEA-01; NCT05152147) evaluating zani in combination with physician’s choice of standard chemo with or without the PD-1 inhibitor, tislelizumab, for first-line treatment of advanced HER2+ mGEA is currently enrolling. Clinical trial information: NCT03929666 .

Background Gastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ) are molecularly diverse. TP53 is the most frequently altered gene with approximately 50% of patients harboring mutations. This qualitative study describes the distinct genomic alterations in GCs and GEJs stratified by TP53 mutation status. Patients and Methods Tumor DNA sequencing results of 324 genes from 3741 patients with GC and GEJ were obtained from Foundation Medicine. Association between gene mutation frequency and TP53 mutation status was examined using Fisher’s exact test. Functional gene groupings representing molecular pathways suggested to be differentially mutated in TP53 wild-type (TP53WT) and TP53 mutant (TP53MUT) tumors were identified. The association of the frequency of tumors containing a gene mutation in the molecular pathways of interest and TP53 mutation status was assessed using Fisher’s exact test with a P-value of Results TP53 mutations were noted in 61.6% of 2946 GCs and 81.4% of 795 GEJs (P < .001). Forty-nine genes had statistically different mutation frequencies in TP53WT vs. TP53MUT patients. TP53WT tumors more likely had mutations related to DNA mismatch repair, homologous recombination repair, DNA and histone methylation, Wnt/B-catenin, PI3K/Akt/mTOR, and chromatin remodeling complexes. TP53MUT tumors more likely had mutations related to fibroblast growth factor, epidermal growth factor receptor, other receptor tyrosine kinases, and cyclin and cyclin-dependent kinases. Conclusion The mutational profiles of GCs and GEJs varied according to TP53 mutation status. These mutational differences can be used when designing future studies assessing the predictive ability of TP53 mutation status when targeting differentially affected molecular pathways.

OBJECTIVE We compare neoadjuvant chemotherapy (CT) to neoadjuvant chemotherapy plus chemoradiation (CRT) for patients with gastric adenocarcinoma (GA). SUMMARY OF BACKGROUND DATA The optimal neoadjuvant therapy regimen for resectable GA is not defined. METHODS Utilizing data from 2 high-volume cancer centers, we analyzed patients who underwent surgery for localized GA from 1/1/2000-12/31/2017. Standard CT regimens were used according to treatment period. We compared propensity matched cohorts based on age, sex, race, histology, and clinical stage. RESULTS Four-hundred five patients (age 62 ± 12 year, 58% male, 56% White) were analyzed. 231 (57%) received CRT and 174 (43%) received CT. Groups differed based on histopathologic characteristics including preoperative stage (p = 0.013). To control for these differences, propensity matched cohorts of 113 CT and 113 CRT patients were compared. CRT had similar frequencies of microscopically negative resections to CT (93% vs 91%, p = 0.81), but higher rates of complete pathologic response (15% vs 4%, p = 0.003) and lower pathologic stage (p = 0.002). Completion of intended perioperative therapy occurred in 63% of CT and 91% of CRT patients (p < 0.001). Median DFS was 45mo (95%CI: 20-70) in the CT group and 113mo (95%CI: 75-151) in the CRT group (p = 0.018). Median OS was 53mo (95%CI: 30-77) versus 120mo (95%CI: 101-138); p = 0.015. CONCLUSIONS In this multi-institutional comparison of neoadjuvant CT and CRT for resectable GA, CRT is associated with higher rates of completed perioperative therapy, higher rates of complete pathologic response, lower pathologic stage, and improved survival.Level of Evidence: Level III.

Objective: Gastrostomy tubes (g-tubes) have been used with caution prior to esophageal resection due to the risks of inoculation metastasis and of injury to the gastric conduit used for reconstruct...

3028 Background: OBT076, an Antibody Drug Conjugate (ADC) consisting of a fully human IgG1 antibody conjugated via a cleavable linker to the derivative microtubule inhibitor DM4. It has specificity for the CD205/Ly75 target antigen which is an endocytic receptor overexpressed on the cell surface and immunosuppressive dendritic cells. This phase 1 study evaluates safety, tolerability, PK/PD and preliminary efficacy of OBT076 in solid tumor patients with high expression of target protein CD205 (CAP-CLIA validated centralized IHC test). Methods: Open label, two parts trial in patients with metastatic CD205+ve solid tumors who progressed on standard therapy. Part 1 of the study consisted in dose escalation from 1.6 mg/kg to 3.5 mg/kg. An mTPI design is used to guide to determine the maximum tolerated dose (MTD) Treatment was given on day 1 every 3 weeks followed by GCSF on day 8. Blood samples and flow cytometry were used to assess PK/PD. Tumor response was assessed every three cycles. Part 2 of trial is an expansion basket trial enriched in indications where preliminary efficacy has been shown. Results: The study completed Part 1 dose escalation. Part 2 expansion phase is ongoing. Between Dec 2019 and January 2022, 20 patients were enrolled (18 patients in the dose escalation and 2 in the ongoing expansion). The median age 61, 9 patients were males and 9 had ECOG PS 0. All patients had at least one metastatic site and 90% received at least 2 lines of chemotherapy in the metastatic setting. Recommended dose for the expansion phase is 3.0 mg/kg. No other significant side effects have been observed. PK data showed that Cmax of 40.000-90.000 ng/ml was achieved between 2.5 and 3.5mg/kg dose and is comparable to the therapeutic dose in mouse models. In part 1 of the study, 7 patients derived clinical benefit despite being in disease progression at trial entry. One patient with gastric cancer with linitis plastica experienced major improvement with complete disappearance of ascites and metastatic adenopathy after cycle 3. The six other patients had lasting stable disease and received between 5-14+ cycles with median of 5 cycles. Two patients with low PD-L-1 expression received checkpoint inhibitor treatment with pembrolizumab after 2 and 5 cycles of OBT076, both patients experienced near complete response after only one to two cycles. Conclusions: OBT076 at 3.0mg/kg has shown favorable safety profile with manageable neutropenia. The preliminary efficacy has shown preliminary antitumoral single agent activity in gastric, ovarian and lung cancer. The two patients who received a sequential administration of pembrolizumab after OBT076 showed major tumor activity. Sequential administration of OBT076 followed by a PD-1 inhibitor was also supported by PD markers and warrants further evaluation. Clinical trial information: NCT04064359. [Table: see text]

Introduction: Alterations in DNA damage repair (DDR) genes are observed in up to 60% of biliary tract cancer (BTC) patients. Patients with advanced/metastatic BTC have few therapeutic options, so there is a demand for the development of new and innovative treatment approaches. The use of poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors (PARPis), either as a monotherapy or in combination, is being extensively studied in clinical trials.Areas Covered: This review examines the targeting of the DDR pathway with PARPis as a potential novel treatment option for the management of BTCs. The rationale behind the use of PARPis and current clinical experience is discussed. Moreover, further insights into potential future directions concerning the applicability of PARPis in the treatment of BTCs are proposed.Expert Opinion: Prospective clinical data with PARPis in the treatment of BTCs are limited. The potential combination of PARPis and IDH1 inhibitors or immune checkpoint inhibitors in clinical trials is interesting because of the potential synergistic preclinical data. There are other possible combinations including those drugs that target the angiogenesis or STAT3 pathways. An enhanced understanding of acquired resistance to PARPis is necessary to progress the use of these agents in clinical trials.

Background Neoadjuvant chemoradiation with fluoropyrimidine followed by surgery and adjuvant chemotherapy has been the standard treatment of locally advanced stages II and III rectal cancer for many years. There is a high risk for disease recurrence; therefore, optimizing chemoradiation strategies remains an unmet need. Based on a few studies, there is evidence of the synergistic effect of VEGF/PDGFR blockade with radiation. Methods In this phase I, dose-escalation and dose-expansion study, we studied 3 different dose levels of lenvatinib in combination with capecitabine-based chemoradiation for locally advanced rectal cancer. Results A total of 20 patients were enrolled, and 19 were eligible for assessment of efficacy. The combination was well tolerated, with an MTD of 24 mg lenvatinib. The downstaging rate for the cohort and the pCR was 84.2% and 37.8%, respectively. Blood-based protein biomarkers TSP-2, VEGF-R3, and VEGF correlated with NAR score and were also differentially expressed between response categories. The NAR, or neoadjuvant rectal score, encompasses cT clinical tumor stage, pT pathological tumor stage, and pN pathological nodal stage and provides a continuous variable for evaluating clinical trial outcomes. Conclusion The combination of lenvatinib with capecitabine and radiation in locally advanced rectal cancer was found to be safe and tolerable, and potential blood-based biomarkers were identified. Clinical Trial Registration NCT02935309

Objective To evaluate perioperative and oncologic outcomes in our RAMIE cohort and compare outcomes with contemporary OE controls. Summary of background data RAMIE has emerged as an alternative to traditional open or laparoscopic approaches. Described in all esophagectomy techniques, rapid adoption has been attributed to both enhanced visualization and technical dexterity. Methods We retrospectively reviewed patients who underwent RAMIE for malignancy. Patient characteristics, perioperative outcomes, and survival were evaluated. For perioperative and oncologic outcome comparison, contemporary OE controls were propensity-score matched from NSQIP and NCDB databases. Results We identified 350 patients who underwent RAMIE between 2010 and 2019. Median body mass index was 27.4, 32% demonstrated a Charlson Comorbidity Index ≥4. Nodal disease was identified in 50% of patients and 74% received neoadjuvant chemoradiotherapy. Mean operative time and blood loss were 425 minutes and 232 mL, respectively. Anastomotic leak occurred in 16% of patients, 2% required reoperation. Median LOS was 9 days, and 30-day mortality was 3%. A median of 21 nodes were dissected with 96% achieving an R0 resection. Median survival was 67.4 months. 222 RAMIE were matched 1:1 to the NSQIP OE control. RAMIE demonstrated decreased LOS (9 vs 10 days, P = 0.010) and reoperative rates (2.3 vs 12.2%, P = 0.001), longer operative time (427 vs 311 minutes, P = 0.001), and increased rate of pulmonary embolism (5.4% vs 0.9%, P = 0.007) in comparison to NSQIP cohort. There was no difference in leak rate or mortality. Three hundred forty-three RAMIE were matched to OE cohort from NCDB with no difference in median overall survival (63 vs 53 months; P = 0.130). Conclusion In this largest reported institutional series, we demonstrate that RAMIE can be performed safely with excellent oncologic outcomes and decreased hospital stay when compared to the open approach.

To develop a radiomic-based model to predict pathological complete response (pCR) and outcome following neoadjuvant chemoradiotherapy (NACRT) in oesophageal cancer.We analysed 68 patients with oesophageal cancer treated with NACRT followed by esophagectomy, who had staging 18F-fluorodeoxyglucose (Median follow-up was 59 months. pCR was achieved in 34 (50%) patients. Five-year RFS, LRC, MFS and OS were 67.1%, 88.5%, 75.6% and 57.6%, respectively. Tumour Regression Grade (TRG) 0-1 indicative of complete response or minimal residual disease was significantly associated with improved 5-year LRC [93.7% vs 71.8%; P = 0.020; HR 0.19, 95% CI 0.04-0.85]. Four sepjmirote pCR predictive models were built for CT alone, PET alone, CT+PET and composite. CT, PET and CT+PET models had AUC 0.73 ± 0.08, 0.66 ± 0.08 and 0.77 ± 0.07, respectively. The composite model resulted in an improvement of pCR predicting power with AUC 0.87 ± 0.06. Stratifying patients with a low versus high radiomic score showed clinically relevant improvement in 5-year LRC favouring low-score group (91.1% vs. 80%, 95% CI 0.09-1.77, P = 0.2).The composite CT/PET radiomics model was highly predictive of pCR following NACRT. Validation in larger data sets is warranted to determine whether the model can predict clinical outcomes.

In cancer care, tissue seeding after curative resections is a known potential complication, despite precautions taken during surgical treatment. We present an uncommon case of an abdominal wall metastasis along the tract of a surgical drain following gastrectomy for gastric adenocarcinoma. To our knowledge, this is the first case of such an occurrence in the setting of a negative staging peritoneal lavage. Aside from the rarity of such a recurrence, this instance highlights an opportunity to reevaluate best practices with regard to the extent of coverage of postoperative salvage radiotherapy. The oncologic patient provides many challenges and may require multiple catheters for drainage and at times infusion of nutrition or therapeutic agents. These foreign bodies should be scrutinized both clinically and radiographically, as they may create vulnerabilities in keeping malignant diseases contained and controlled. We provide a review of the literature with reasonable treatment options for the benefit of future patients.

255 Background: With the advent of immunotherapy as an option for gastric, gastroesophageal junction (GEJ), or esophageal cancer, guidelines recommend testing for mismatch repair (MMR) or microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) at time of advanced cancer diagnosis. However, little real-world information is available on testing patterns and results for MMR/MSI and PD-L1. Methods: This study used the nationwide Flatiron Health electronic health record-derived de-identified database. Starting with a subset of 1594 patients (pts) from the Advanced Gastric/ Esophageal Cancer database who had initiated first-line (1L) treatment 01Jan2017-31Aug2020 and for whom additional abstraction for details on MMR/MSI and PD-L1 testing was conducted, adult pts with ≥3 months (mos) of follow-up were selected. 1L initiation was index date. For each biomarker, pts were classified as tested vs not. Pt and disease characteristics and test results were summarized. Testing relative to line of therapy and PD-1 inhibitor use were evaluated (data will be presented later). Results: Of 1142 eligible pts, 88% were initially diagnosed with advanced disease and 92% treated in community practice. 582 (51%) were tested for MMR/MSI and 571 (50%) for PD-L1; 451 pts were tested for both. MMR/MSI testing rates were 59% for gastric, 51% for GEJ, and 46% for esophageal. PD-L1 testing rates were similar across primary tumor sites (48-54%), but lower in those with squamous histology (38% for esophageal/GEJ). For both, testing increased over time with ̃40% in 2017 and 60% in 2020. For both, median number of tests per pt was 1 (range 1-6 for MMR/MSI, 1-4 for PD-L1). For both, mean time from initial diagnosis to first test was approximately 4 mos (> 5 mos in pts in 2017 and < 2 mos for those in 2020). Majority (> 68%) of all tests used tissue from primary tumor site. 46% of all MMR/MSI tests were performed with immunohistochemistry and 43% with next-generation sequencing; 5% were dMMR/MSI-H. 71% of all PD-L1 tests were performed using the commercial 22C3 assay. Reported composite positive score (CPS) results are summarized below. Conclusions: Rates of MMR/MSI and PD-L1 biomarker testing are increasing and time relative to initial diagnosis is shortening. A high proportion of pts tested positive for PD-L1 with CPS > 1. PD-L1 CPS varies by primary tumor site, histology, and tissue collection site. In the new era of 1L immunotherapy, increased rates of testing and reduced time to testing are likely to make more meaningful impact on treatment decisions.[Table: see text]

341 Background: Brain metastases from esophageal cancer are extremely rare with an estimated incidence of 1.7% but limited survival. Some reports highlight the rich microvascular density of such tumors and their distinctive degree of HER2, HIF1-a and EGFR expression, further emphasizing the potential role of angiogenesis in their neurotropic behavior. With this in mind, we aimed to illustrate the transcriptomic landscape of brain metastases from esophageal cancers and better understand the disease biology. Methods: Following IRB approval, we collected retrospective data on patients with a diagnosis of esophageal cancer with histology-proven brain metastases treated at our institution between 2008 and 2020. We identified 10 adequate, paired samples with available tissue for RNA extraction. Expression data was generated using NanoString TS 360 panels to characterize gene signatures of interest and analyzed using GSEA_4.1.0. Results: All 10 patients were Caucasian, 90% were male. Median age was 63 years. All had adenocarcinoma with G2-G3 histology. Median follow-up was 39.4 mos (95%CI, 27.4 to 51.4). At data cutoff, 6 patients had died. Median OS was 24.6 mos. Median time from curative surgery to CNS recurrence was 8.3 mos. Ninety percent of patients developed brain metastases within 24 mos of surgery. Median time from brain metastases to death was 4.7 mos. Almost a third of patients had HER2 positive disease. 48 gene signatures were analyzed; 5 being significantly enriched between metastatic and primary site accounting for cell cycle, DNA damage repair, MYC, mTOR signaling and immortality and stemness. Out of a pool of 760, significant overlap was seen between 12 genes across the 5 signatures of interest: POLE, LIG1, FEN1 (involved in DNA repair and replication); AURKA and PLK1 (cell proliferation and triggers for G2/M transition), BUB1 (establishment of the mitotic spindle checkpoint and chromosome congression), MCM2 and MCM4 (initiation of genome replication); BRIP1 and RAD51 (critical in homologous recombinational repair); CCNE1 (cell cycle G1/S transition) and WRAP53 (dual role as p53 regulator and protein involved in telomere elongation and DNA repair). ERBB2 was similarly enriched in primary and metastatic sites. Conclusions: These preliminary data demonstrate that the genomic basis of brain metastases in esophageal cancer goes beyond EGFR/ERBB2 signaling. A complex genomic interaction is present in brain metastases as compared to primary site that offers these cells the advantage for neurotropism. To our knowledge this is the first study attempting to illustrate genomic differences between primary and matched brain metastasis sites in esophageal cancer.

355 Background: Perioperative chemotherapy is the standard of care for locoregional gastric cancers in western populations. However, the impact of response to therapy as a biomarker of cancer survival has not been fully defined. This study focuses on the pathological response to neoadjuvant chemotherapy, as measured by tumor regression grade (TRG), for gastric cancer and its impact on patient outcomes, primarily overall survival. Methods: Patients undergoing gastrectomy for nonmetastatic invasive gastric adenocarcinoma following perioperative chemotherapy (clinical T2+/N+cM0) were identified from an institutional database (2000-2021). Demographics, clinical staging including histologic grade, surgical factors and survival outcomes were included. The association between TRG and overall survival from time of surgery was assessed. OS was estimated using the Kaplan Meier method with adjustment for covariates using Cox regression. Results: One hundred seventeen patients were identified. Median age was 65 years (IQR 57–73). The majority of the patients were male (n = 64, 55%). Seventy-six patients underwent total gastrectomy, 22 subtotal gastrectomy, and 19 distal gastrectomy. Six patients (5.1%) had a TRG of 0, 18 patients (15.4%) had a TRG of 1, 25 patients (21.4%) had a TRG of 2, and 68 patients (58.1%) had a TRG of 3. Median survival overall was 40.9 months (95% CI 28.7–66.4). TRG status was not significantly different between chemotherapy regimens (doublet vs triplet, p = 0.96). Median survival was longest in the TRG 0 group (86.9 months), followed sequentially by TRG 1 (74.5 months), TRG 2 (51.5 months), and lastly, TRG 3 group with 27.0 months. Increased tumor regression (lower TRG) was significantly associated with prolonged survival (p < 0.01 by log-rank for trend). After adjustment for clinical patient factors and tumor factors, TRG remained significantly associated with overall survival (Table; TRG hazard ratio 1.62, p = 0.007). In addition to TRG status, clinical T4 tumors and diffuse histology were associated with poor survival (cT4 hazard ratio 2.09, p = 0.039, diffuse histology hazard ratio 1.82 (p = 0.071). Conclusions: In patients receiving perioperative chemotherapy for treatment of gastric cancer, response to therapy as defined by TRG is independently prognostic of survival.[Table: see text]

302 Background: The RAINBOW trial established the standard of care for treatment of metastatic GEAs with ramucirumab and paclitaxel after failure of fluoropyrimidine and platinum-based chemotherapy. While the combination achieved an objective response rate (ORR) of 28%, the incidence of any grade neuropathy was 46%. Therefore, there is an unmet need for novel treatment combinations that minimize the long-term toxicity of neuropathy. In a recently published Asian study, the combination of RAM+TAS-102 showed good disease control and acceptable toxicity profile. Methods: This was a single arm, single institution phase II trial using the combination of TAS-102 plus RAM in refractory GEAs. Patients (pts) received RAM 8mg/kg intravenously on day 1 and 15, and TAS-102 35mg/m2 orally twice daily on days 1-5 and days 8-12 every 28-day cycle. The primary endpoint was 6-months overall survival (OS) rate and secondary endpoints were progression free survival (PFS), ORR and safety profile. The trial was registered at www.clinicaltrials.gov (NCT03686488). Results: At data cut-off of August 15, 2021, 23 pts were enrolled. Baseline demographics are as follows: median age of 62 years (range: 23-74), median lines of prior therapy of 1 (1: 14 pts vs ≥2: 9 pts) and location of primary tumor (GEJ:19 vs GC: 4). 6-month OS rate was 56.2%. Median OS was 6.2 month (95% CI: 5.4-7.0) and median PFS was 4.9 months with median observation of 2.3 months. Of 17 evaluable pts defined as more than one baseline imaging, 1 (6%) had partial response (PR) and 15 (88%) had stable disease (RECIST v1.1). Eleven pts came off the study due to progression of disease, 8 for toxicities and 4 for consent withdrawal. Most common treatment-emergent adverse events (TEAEs) were diarrhea (39%), fatigue (39%) and hypertension (39%). Total 11 pts (48%) experienced grade 3 and 4 TEAEs, and most common Gr3 and 4 TEAEs were neutropenia (17%) and anemia (13%). Conclusions: The combination of RAM and TAS-102 showed very similar disease control rate as the study in Asia. The combination has now shown modest activity in advanced GEAs and should be investigated further now in the context of patients receiving immunotherapy-based treatment as first-line treatment. A randomized phase II study is currently enrolling patients with ramucirumab and TAS-102 or paclitaxel. Clinical trial information: NCT03686488.

284 Background: Ramucirumab, a humanized monoclonal antibody targeting VEGFR2, is used for treatment of metastatic gastroesophageal adenocarcinoma after disease progression on first-line chemotherapy. Superior survival outcome is expected when combined with paclitaxel. However, many patients suffer from chemotherapy-induced peripheral neuropathy after oxaliplatin-containing first-line treatment and are unable to tolerate paclitaxel. Irinotecan has shown survival benefit as a single agent or in combination with other agents for treating gastroesophageal cancer, but has not been evaluated with ramucirumab. We hypothesized that the combination regimen of irinotecan and ramucirumab administered as second-line treatment for advanced gastroesophageal adenocarcinoma will be better tolerated than ramucirumab and paclitaxel with similar clinical efficacy. Methods: The primary objective of this multi-institutional, single-arm phase 2 clinical trial is to determine the progression-free survival (PFS) after disease progression on up to one line of cytotoxic chemotherapy. Secondary objectives include objective response rate, overall survival, time to progression, and clinical benefit; and to evaluate toxicity and tolerability. Patient-derived xenograft and organoid models generated in a subgroup of patients. Investigation of blood-based angiome profiling and cell-free DNA are planned. Patients received 8 mg/kg ramucirumab with 180 mg/m2 irinotecan IV every 14 days. A sample of 40 achieves 85.7% power at a one-sided significance level of 5% to detect a median PFS of 4 months compared to historic control of 2.5 months assuming the accrual time of 12 months and additional follow-up of 12 months and using a one-sample log rank test. NCT03141034. Results: Forty patients were enrolled from four institutions from December 2017 through May 2021. All patients received platinum-based chemotherapy prior to enrollment, 8 patients had HER2 positive disease, and 6 patients had received an immune checkpoint inhibitor. As of September 2021, median follow up time was 7.7 months. Median PFS was 4.6 months (95% CI 2.7 – 5.4). Of 31 patients evaluable for response, 9 patients (29%) had objective responses (1 complete response, 8 partial responses) and 5 patients (16%) had stable disease greater than 6 months. Diarrhea, nausea, vomiting, and neutropenia were common adverse events; no G3/4 neuropathy was reported. Patient-derived organoid and xenograft models were generated from 9 patient samples, treated in vitro to correlate with each patient’s disease response. Conclusions: Ramucirumab and irinotecan appears to be effective and well-tolerated in patients with previously treated gastroesophageal adenocarcinoma. This regimen is now part of standard guidelines and could be a preferred option for patients after disease progression on first-line chemotherapy. Clinical trial information: NCT03141034.

About 1/3 of all metastatic colorectal cancer (mCRC) patients may harbor a mutation in the KRAS or NRAS gene suggesting inefficacy of EGFR inhibitors cetuximab and panitumumab. In spite of tailoring treatment in RAS wild-type patients to receive EGFR inhibitors, not all show response. Studies have shown that HER2-neu amplification/alteration in addition to alteration in BRAF and PI3KA may explain resistance to EGFR inhibitors. Several pre-clinical studies have identified that HER2-neu amplification can result in both de novo and acquired resistance to EGFR inhibitors. Recently, several clinical studies have highlighted the use of single or combination HER2-neu directed therapies in HER2-neu amplified/overexpressed mCRC. About 5% mCRC patients will demonstrate HER2-neu overexpression and response to HER2-neu-directed therapies can be in the range of 30–38%. Patients not responding to EGFR-inhibitors warrant testing for HER2-neu testing to explain resistance. In the near future, HER2-neu testing is likely to be integrated into our routine clinical practice for management of metastatic colorectal cancer patients.

Gastric and esopahgeal cancers account for the six most common causes of cancer death worldwide. Locally advanced resectable cancers have a 5-year life expectancy of 30%. Despite use of chemotherapy, median overall survival for stage IV cancer rarely exceeds 1 year. A subset of gastric cancers such as microsatellite-instable tumor and Epstein-Barr virus-positive tumors have a rich immune infiltrate that makes them more responsive to immune-directed therapies. Tumors can evade T-cell-mediated "immune surveillance" by activating the programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway. Targeting PD-1 and thus de-engaging them from its ligands can help restore immunogenicity. Pembrolizumab is the first immunotherapy to be approved by US FDA for PD-L1 expressing gastric and gastroesopahgeal junction (GEJ) cancers after they have progressed on at least two prior lines of treatment. While PD-L1 positivity does not define tumor's responsiveness to pembrolizumab, PD-L1-positive tumors have better overall response rates. The treatment is usually well tolerated and has a favorable adverse events profile. The exact setting for use of pembrolizumab remains to be determined. Pembrolizumab failed to improve overall survival when administered as second-line treatment for advanced, metastatic gastric and GEJ cancers. There are several ongoing studies with various combinations and different settings not only with pembrolizumab but also with other checkpoint inhibitors.

Current treatment options for patients with unresectable locally advanced pancreatic cancer (LAPC) include chemotherapy alone or followed by chemoradiation or stereotactic body radiotherapy. However, the prognosis for these patients remains poor, with a median overall survival

The incidence of esophageal cancer is increasing in the United States. Although neoadjuvant therapy (NAT) for locally advanced cancers followed by surgical resection is the standard of care, there are no clearly defined guidelines for patients aged ≥79 y.Query of an institutional review board-approved database of 1031 esophagectomies at our institution revealed 35 patients aged ≥79 y from 1999 to 2017 who underwent esophagectomy. Age, gender, tumor location, histology, clinical stage, Charlson Comorbidity Index (CCI), NAT administration, pathologic response rate to NAT, surgery type, negative margin resection status, postoperative complications, postoperative death, length of stay, 30- and 90-d mortality, and disease status parameters were analyzed in association with clinical outcome.The median age of the octogenarian cohort was 82.1 y with a male preponderance (91.4%). American Joint Committee on Cancer clinical staging was stage I for 20% of patients, stage II for 27% of patients, and stage III for 50% of patients, which was not statistically significant compared with the younger cohort (P = 0.576). Within the octogenarian group, 54% received NAT compared with 67% in the younger group (P = 0.098). There was no difference in postoperative complications (P = 0.424), postoperative death (P = 0.312), and recurrence rate (P = 0.434) between the groups. However, CCI was significantly different between the octogenarian and nonoctogenarian cohort (P = 0.008), and octogenarians had shorter overall survival (18 versus 62 mo, P0.001). None of the other parameters assessed were associated with clinical outcomes.Curative surgery is viable and safe for octogenarians with esophageal cancer. Long-term survival was significantly shorter in the octogenarian group, suggesting the need for better clinical selection criteria for esophagectomy after chemoradiation and that identification of complete responders for nonoperative management is warranted.

Immune checkpoint inhibitors (CPI) have become the standard of care in multiple lines of treatment in different settings in variety of cancers such as lung cancer, melanoma, renal cell carcinoma and some gastrointestinal cancers. In May 2017, Food and Drug Administration (FDA) provided the first tissue agnostic approval for pembrolizumab in mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) advanced solid tumors who have progressed on prior treatments or for which no other standard treatment exists (1).

Colitis is a frequent, clinically-significant immune-related adverse event caused by anti-programmed death-1 (PD-1). The clinical features, timing, and management of colitis with anti-PD-1-based regimens are not well-characterized. Patients with advanced melanoma that received either anti-PD-1 monotherapy (“monotherapy”) or combined with ipilimumab (“combination therapy”) were screened from 8 academic medical centers, to identify those with clinically-relevant colitis (colitis requiring systemic steroids). Of 1261 patients who received anti-PD-1-based therapy, 109 experienced colitis. The incidence was 3.2% (30/937) and 24.4% (79/324) in the monotherapy and combination therapy cohorts, respectively. Patients with colitis from combination therapy had significantly earlier symptom onset (7.2 weeks vs 25.4 weeks, p

The management of patients with advanced-stage hepatocellular carcinoma (HCC) has changed dramatically over the past year. Partial hepatectomy, liver transplantation, ablation, radiation therapy, and embolization procedures remain important interventions for localized HCC, whereas systemic therapy is the cornerstone of therapy for patients with extrahepatic disease. Since 2017, several agents, including regorafenib, lenvatinib, cabozantinib, ramucirumab, nivolumab, and pembrolizumab, have been approved or are likely approved as first- and second-line therapies by Food and Drug Administration (FDA) for systemic treatment of advanced-stage HCC. In this chapter, we overview the molecular mechanisms underlying HCC and how improved understanding of these pathways has helped the development of targeted therapies. We also discuss the value of these molecular-targeted therapeutic agents, safety profile, and their impact on personalization of HCC therapy.

TPS4157 Background: GEA remains incurable and novel therapies are needed. Studies have shown that cytotoxic chemotherapy can enhance antigenicity of tumors, leading to the recent practice changing studies that demonstrate checkpoint inhibition therapy combined with chemotherapy in PD-L1 overexpressing patients significantly improves patient survival (Keynote-590 and Checkmate-649). But long-term use can also subsequently dampen the immune response. Moreover, the stop-and-go strategy with chemotherapy can maintain patient survival while minimizing chemotherapy related side effects when compared to the traditional strategy of continuous chemotherapy. These observations prompted the inception of this trial with the hypothesis that a short course of FOFLOX therapy combined with immunotherapy will likely have similar activity to that of continuing FOFLOX until disease progression when combined with immunotherapy. We also will examine the hypothesis that low dose radiotherapy can further augment immunotherapy efficacy. Methods: This is a multicenter, randomized phase II study examining Nivo alone vs radiation therapy (RT) with Nivo in subjects who did not have disease progression with 3 months of FOLFOX + Nivo. Subjects with advanced unresectable or metastatic GEA cancer are eligible. All subjects will receive FOLFOX + Nivo therapy. Subjects who demonstrate at least stable disease, on their first imaging assessment at 2 months will receive 1 additional month of FOLFOX + Nivo, and then will be randomly assigned at a 1:1 ratio to receive either Nivo alone or Nivo + RT. After 4 mos of therapy, patients who remain on study will receive Nivo Q4WKly. The primary endpoint is to demonstrate that the addition of fractionated radiation to immunotherapy is associated with an improvement in the 12-month progression-free survival (PFS) proportion from 25% (i.e., historical control estimate; Nivo alone; Arm A) to approximately 50% (i.e., with the fractional radiation and Nivo; Arm B). A key secondary aim is to demonstrate that short course FOLFOX of 3 months + Nivo is similar in efficacy to continuing FOLFOX until disease progression. Another secondary aim of this study is to demonstrate safety of the combination of fractionated RT + Nivo. Target sample size is 74 patients. The study is now open at six sites across the United States. Clinical trial information: NCT04021108.

238 Background: Gastric (GC) and gastroesophageal adenocarcinomas (GEA) are molecularly diverse. Molecular biomarkers of clinical significance have been identified that impact treatment decision making. TP53 is the most frequently altered gene with approximately 50% of patients harboring mutations. However, TP53 mutations have not yet been confirmed as a target of therapeutic benefit. This study aimed to identify distinct genomic alterations that are dominant in TP53 mutated (MUT) versus wild-type (WT) GC and GEA in order to elucidate alternative therapeutic targets within these subsets. Methods: De-identified data for 3741 patients with GC and GEA was obtained from Foundation Medicine. The data obtained were age, gender, tumor mutational burden (TMB), and the distinct genomic alterations noted on DNA sequencing. The dataset was sorted by TP53 mutation status. Differences in mutation frequency were detected using the Fisher’s exact test of independence with a p-value of < 0.01 designated as the cutoff value for statistical significance. Results: The dataset consisted of 2946 GCs and 795 GEAs. TP53 mutations were present in 65.8% of specimens. 61.6% of GCs and 81.4% of GEAs were TP53 MUT positive (p = < .001). Median TMB score and the frequency of tumors with a TMB score > 10 was similar in both TP53 MUT and WT groups. 49 genes had statistically different mutation frequencies in TP53 MUT vs. WT patients. Top co-occurring genetic alterations in TP53 MUT patients included amplification and point mutations in MYC, CCNE1, MET, ERBB2, and EGFR. Amplification and point mutations in MDM2, CDK4, ARID1A, PIK3CA, and ERBB3 were the top co-occurring genetic alterations in TP53 WT patients. Conclusions: There was a high frequency of TP53 mutations in this group of GC and GEA patients, with a higher incidence of TP53 mutations identified in GEA samples. The mutational profiles of these tumors differed according to TP53 mutation status. These differences may be able to serve as the foundation for future clinical investigations.

170 Background: Few epidemiological studies address differences in outcomes by gender in locoregional esophageal cancer (LEC) for which the current standard of care is chemoradiation followed by surgical resection. Although male gender is associated with the majority of LEC cases, we sought to determine if gender could impact clinical presentation as well as surgical and oncologic outcomes in our single institution 20 year experience. Methods: A retrospective query of our institution’s IRB-approved database of patients that had surgical therapy between 2008 and 2019 for esophageal cancer (EC) was performed. Patients were stratified by gender and analyzed based on characteristics such as tumor histology, tumor location, clinical stage at presentation, age at diagnosis, receipt of neoadjuvant therapy, surgical intent, surgical complications, length of post-operative hospital stay, response to neoadjuvant therapy, final pathology, and recurrence. Chi-square, ANOVA and Kaplan Meier survival analysis were performed on the previously defined groups. Results: The cohort studied included 1180 patients with resection for EC. Of those, 1005 (85.2%) had adenocarcinoma, 145 (12.3%) had squamous cell cancer (SCC), 10 (0.8%) had adenosquamous carcinoma, and 20 (1.7%) had other histological variants. There were 985 (83.5%) male patients and 195 (16.5%) female patients. SCC was more common in females (29.2% in females vs. 8.9% in males, p = 0.000) and females tended to have tumor location in the upper thoracic esophagus more often (4.7% in females vs. 0.9% of males, p = 0.000). Additionally, females developed surgical complications more often than males (72.2% vs. 64.7%, p = 0.045). Staging at diagnosis (p = 0.508), receipt of neoadjuvant treatment (p = 0.676), and age at diagnosis (65.3 years in males vs. 66.3 years in females, p = 0.934) had no association with gender. Response to neoadjuvant therapy (p = 0.157) and cancer recurrence (p = 0.434) did not have significant associations with gender. The median overall survival was not statistically significantly different but trended to be longer for females (73.4 months in females [95% CI: 51.5-95.4] vs. 47.0 months in males [95% CI: 39.6-54.5], p = 0.160). Conclusions: Based on our high-volume cancer center study, female patients were more likely to have SCC, upper thoracic esophageal lesions, and surgical complications following resection. While univariate analysis did not demonstrate significant differences in overall survival between genders, there are plans to report additional data after controlling for other variables. Further studies are warranted to validate these findings, given the potential for higher prioritization of an organ preservation approach for this patient population.