tbuckley/cabot-search huggingface dataset:
Genomic signature analysis and survival outcomes in cholangiocarcinoma (CCA) using oncology research information exchange network (ORIEN) database.
Authors: Riya Jayesh Patel, Spencer Rosario, Sahithi Sonti, Hua-Hsin Hsiao, Timothy M. Pawlik, Diamantis I Tsilimigras, Erin M. Siegel, Lyudmyla Derby Berim, Anita Ahmed Turk, Ashiq Masood, Bodour Salhia, Jill Kolesar, S. Lindsey Davis, Tri Minh Le, Christopher Duane Nevala-Plagemann, Carlos H.F. Chan, Michelle Churchman, Kannan Thanikachalam, Renuka V. Iyer
Journal: Journal of Clinical Oncology (2024)

4101 Background: Immunotherapy (IO) is standard of care for advanced CCA patients (pts) regardless of PD-L1 expression. Lack of biomarkers that predict prolonged benefit or resistance to therapies are unmet gaps in this field that we attempted to fill using transcriptional and survival data in the ORIEN dataset. Methods: Through an ORIEN intermember project, we accessed an avatar dataset for clinical characteristics and transcriptional data of the CCA cohort. We first identified clinical factors highly associated with transcriptional variability and conducted principal component analysis (PCA), focusing on factors linked to the first principal component (PC1). Both specimen site and type (p&lt;0.01) were found highly associated with PC1 and were included as co-variates in subsequent models. Then, immune deconvolution using XCell was performed on the ORIEN-CCA RNA-sequencing cohort to determine the transcriptome portion attributed to effector T cell (T eff ) and regulatory T cell (T reg ) for each patient. T eff :T reg ratios were calculated and used to divide patients into cold (low T eff :T reg ) and hot (high T eff :T reg ) cohorts based on their median (mT eff :T reg = 0.0004). Differential gene expression analysis comparing hot and cold tumors yielded 72 significantly differentially expressed genes (FC &lt;1.5, adjusted p&lt;0.05). Gene Set Enrichment Analysis (GSEA) of transcriptomic changes revealed enrichment for immune and metabolic pathway alterations. Results: The ORIEN avatar dataset comprised of 78 pts, with 39 designated as immune hot and 39 as immune cold (demographics in Table). Median overall survival (mOS) was 3.17 years in hot and 2.65 years in cold group . These groups exhibited significantly different T eff :T reg ratio (p&lt;0.0001). Differential gene expression identified 72 altered genes, including upregulated immune genes (e.g., IL2RA, CD80, GBP5) in the hot group and metabolic genes (e.g., AZGP1) in the cold group. GSEA of these genes revealed immune pathway enrichment in hot tumors, with increased antigen presentation, NK cell function, and B-cell activation. Surprisingly, cold tumors were enriched of pathways involved in lipogenesis, oxidation, and proliferation. Conclusions: ORIEN-CCA cohort analysis revealed immune hot and cold tumors with distinct transcriptional alterations and differences in mOS. Correlating these alterations with IO use, and further studies of enriched pathways in cold tumors are warranted. [Table: see text]
Molecular landscape and site of metastasis in PDAC.
Authors: Shafia Rahman, Yasmine Baca, Harshabad Singh, Joanne Xiu, Atrayee B Mallick, Mark P. Rubinstein, Andrew Aguirre, None George W. Jr., Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2024)

4159 Background: More than 50% of patients with Pancreatic ductal adenocarcinoma (PDAC) have metastatic disease at the time of diagnosis and liver is the most common site of metastatic spread. Liver metastasis (LM) is associated with poor prognosis. Herein we examine the difference in molecular landscape of PDACs with LM versus other metastatic sites (OM). Methods: Total of 7,979 PDAC tumors underwent next-generation sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). Tumors were then evaluated and divided into LM (N=4988) site vs OM (N=3073) sites based on tissue specimen sites. RNA expression data was used to analyze transcriptional signatures as well as tumor immune microenvironment (TME) using Quantiseq. Real-world overall survival (rwOS) information was obtained from insurance claims data and calculated from time of collection or first treatment to last contact. Hazard ratio (HR) was calculated using Cox proportional hazards model, and P values were calculated using log-rank test.Significance for molecular comparisons was calculated using either chi-square, Fisher’s exact, or Mann-Whitney U test, with p-values adjusted for multiple comparisons (q&lt;0.05). Results: Mutations in TP53 (81% vs 67%), KRAS (88% vs 83%), ARID1A (13% vs 11%), KDM6A (4% vs 3%), and BRCA1 (1.3% vs 0.7%) were all significantly higher in LM vs OM (all &lt;0.05). Conversely, TMB-H (3% vs 4%), MSI-H (0.7% vs 1.3%), GNAS (1% vs 3%), STK11 (1% vs 3%), ATM (3% vs 5%), PTPRD (2% vs 9%) and RNF43 (5% vs 6%) mutations were significantly lower in LM vs OM (all q&lt;0.05). In the TME, B cells, Tregs, M1, M2 macrophages, and NK cell infiltration was lower in LM vs OM (FC: 0.62-0.91, q&lt;0.05). However, LM had higher neutrophil infiltration vs OM (FC: 1.1, q&lt;0.05). Both interferon-gamma score (IFG) and T cell inflamed score (TIS) were significantly higher in OM vs LM (q&lt;0.05). OM had better OS than LM (11.4 m vs 6.8 m, HR=0.65 95% CI: 0.62-0.68, p&lt;0.001). This association held for tumors treated with Immune Checkpoint Inhibitors (ICI) (9.6 m vs 4.6 m, HR=0.71 95% CI: 0.52-0.97, p=0.031), Gemcitabine/Nab-paclitaxel treated (15.3 m vs 8.1 m, HR=0.57 95% CI: 0.52-0.61, p&lt;0.001) as well as mFOLFIRINOX treated tumors (20.3 m vs 12.0 m, HR=0.57 95% CI: 0.52-0.63, p&lt;0.001). Conclusions: When comparing pancreatic LM to OM sites, our data reinforces the observation that OS is better in OM vs LM and response to ICI was better in OM vs. LM. Significant differences were observed in molecular landscape, TME and signatures that are predictive of immunotherapy response (TIS and IFG scores). [Table: see text]
Deep immune profiling of intrahepatic cholangiocarcinoma with CODEX multiplexed imaging.
Authors: Soumya Shekhar, Vaibhav Sahai, Kathryn Howe, Qingfeng Zhu, Aya Kondo, Helen L. Fedor, Valerie Gunchick, Naziheh Assarzadegan, Nilofer Saba Azad, Mark Yarchoan, Marina Baretti
Journal: Journal of Clinical Oncology (2024)

4117 Background: Intrahepatic cholangiocarcinoma (iCCA) is subclassified by the presence or absence of potentially actionable molecular alterations, of which IDH1 mutations and FGFR2 fusions and rearrangements are most frequently observed. Little is known about the relationship between molecular features of iCCAs and the tumor immune microenvironment (TME). Methods: We performed a high-parameter immune phenotyping of the TME of FGFR2 fusion/rearrangement positive (FGFR2+), IDH1 mutation positive (IDH1+), and FGFR2/IDH1 wild type iCCA samples at the single-cell level using CO-Detection by indEXing (CODEX). Neighborhood analysis was based on a k-nearest-neighbors approach followed by k-means clustering to identify the spatial location of each cell type and their proximity to one another. Simplified spatial networks specific to molecular subtypes were generated based on the shortest Euclidean distances from any given cell to all other cell types. Results: A total of 24 tumors were examined (n=7 FGFR2+, n=9 IDH1+, n=8 other). Compared to other molecular subtypes, FGFR2+ tumors had an immune-desert phenotype characterized by a reduced abundance of CD8+ T cells (p &lt; 0.05), CD117+ mast cells (p &lt; 0.05), and CD68+/CD163+ macrophages (p &lt; 0.05) but with an increased number of CD11b+/CD15+ granulocytes (p &lt; 0.05). IDH1+ tumors were characterized by a decreased amount of CD11b+/CD15+ granulocytes (p &lt; 0.05) when compared to other subtypes. In terms of spatial analysis, CD4+ T cells were located further from tumor cells in FGFR2+ iCCA compared to IDH1+ iCCA (p &lt; 0.05) and other molecular subtypes (p=0.05). In contrast, CD11b+/CD15+ granulocytes were located closer to tumor cells in FGFR2+ tumors (p &lt; 0.05). Additionally, closer neighbor proximity between CD4+ T cells and CD11b+/CD15+ granulocytes was observed in FGFR2+ tumors compared to both IDH1+ tumors (p &lt; 0.05) and other tumor subtypes (p = 0.05), indicating a stronger lymphoid–myeloid neighboring relationship in the TME of FGFR2+ iCCA. Conclusions: FGFR2+ and IDH1+ iCCAs have distinct immunophenotypes, providing initial evidence that molecular alterations may inform the selection of patients for immunotherapy. Both the quantity of immune cells as well as the spatial relationships between immune cells may influence iCCA prognosis and response to therapy. Tailoring immunotherapeutic approaches to specific molecular subsets may improve outcomes across the divergent molecularly defined iCCA subtypes.
First-line osemitamab (TST001) plus nivolumab and capox for advanced g/GEJ cancer (TranStar102): Results of cohort G from a phase I/IIa study.
Authors: Xiaotian Zhang, Zengqing Guo, Jingdong Zhang, Weijian Guo, Meili Sun, Nong Xu, Charlie Qi, Xuelian Zhu, Lijuan Zhang, Xueming Qian, Caroline Germa, Lin Shen
Journal: Journal of Clinical Oncology (2024)

4048 Background: TST001 is a humanized monoclonal antibody with improved affinity to claudin 18.2 (CLDN18.2) and enhanced ADCC activity. In vivoanti-tumor activity of TST001 plus an anti-PD-1 antibody and chemotherapy is significantly stronger than chemotherapy plus anti-PD-1 antibody or chemotherapy plus anti-CLDN18.2 antibody, regardless of the CPS PDL1 levels. Promising efficacy of osemitamab plus CAPOX chemotherapy as 1 st line treatment of G/GEJ cancer has been observed in cohort C of TranStar102, making the triple combination of TST001, nivolumab and CAPOX an attractive combination to explore. Methods: Cohort G from TranStar102 (NCT04495296) is designed to evaluate the safety and preliminary efficacy of TST001 (at 2 doses: 3mg/kg or 6mg/kg Q3W) plus nivolumab and CAPOX as 1 st line treatment in patients with G/GEJ cancer, with a safety lead-in and expansion phase. 40 patients were planned to be enrolled in each dose cohort. Eligible patients include HER2 negative or unknown, unresectable locally advanced or metastatic G/GEJ cancer, regardless of CLDN18.2 or PD-L1 expression. CLDN18.2 and PD-L1 status are analyzed retrospectively using IHC 14G11 LDT assay and PD-L1 IHC 28-8 pharmDx. Results: As of Jan 19, 2024, 82 patients have been dosed with a median follow-up of 9.7 months, 40 patients at 3mg/kg, 42 patients at 6mg/kg. All patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were hypoalbuminemia (67.1%), nausea (63.4%), and vomiting (59.8%). The incidence of nausea (69% vs 57.5%) and hypoalbuminaemia (76.2% vs 57.5%) was higher at 6mg/kg than 3mg/kg. Most of the TRAEs are grade 1 or 2. The most common TRAE grade 3 or higher were neutrophil decreased (n=10), platelet count decreased (n=8), nausea (2 at 3mg/kg, 1 at 6mg/kg) and vomiting (2 at 3mg/kg). No new safety signal was detected when nivolumab was added to TST001 in combination with chemotherapy. 79 patients had measurable disease at baseline including 25 CLDN18.2 negative patients. 51/79 patients had partial response as of cut-off date, out of which 45 were confirmed (ORR 57%), with no significant difference between the 2 dose levels. 17 patients had stable disease. The disease control rate (DCR) was 91.9% in all patients across CLDN18.2 expression levels and CPS PD-L1 levels. The progression-free survival (PFS) and duration of response (DoR) are immature and need longer follow-up. Conclusions: Preliminary data indicate that the combination of TST001 6mg/kg Q3W plus nivolumab and CAPOX for the 1 st line treatment of patients with G/GEJ cancer is safe and well tolerated with encouraging preliminary anti-tumor activities. Updated clinical data, including PFS and DoR will be reported at the time of the conference. Clinical trial information: NCT04495296 .
Safety analysis by treatment periods from EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization with durvalumab with/without bevacizumab in participants with embolization-eligible unresectable hepatocellular carcinoma.
Authors: Stephen Lam Chan, Bruno Sangro, Masatoshi Kudo, Joseph P. Erinjeri, Shukui Qin, Zhenggang Ren, Yasuaki Arai, Valeriy Vladimirovich Breder, Shi-Ming Lin, Jean-Marie Peron, Tien Quang Nguyen, Lunan Yan, Chang-Fang Chiu, Florinda A. Santos, Anil Veluvolu, Satheesh Chiradoni Thungappa, Claire Morgan, Kerry Parsons, Ioannis Xynos, Riccardo Lencioni
Journal: Journal of Clinical Oncology (2024)

4122 Background: The global Phase 3 EMERALD-1 study (NCT03778957) primary endpoint was met: durvalumab (D) + bevacizumab (B) + transarterial chemoembolization (TACE) significantly improved progression-free survival vs placebos (pbos)+TACE (median 15.0 vs 8.2 mo; HR 0.77; 95% CI 0.61–0.98; p=0.032 [threshold 0.0435]) in participants (pts) with embolization-eligible unresectable hepatocellular carcinoma (uHCC) with a manageable safety profile. This post hoc, exploratory analysis assessed safety in the study’s 2 treatment (tx) periods (pds): D-TACE (D-T) and D-B. Methods: Pts were randomized 1:1:1 to D+TACE, D+B+TACE, or pbos+TACE. In the D-T pd, pts received 1–4 TACE (cTACE or DEB-TACE [investigator choice]) plus D (1500 mg Q4W) or pbo for D. In the D-B pd, post-last TACE, pts received D (1120 mg Q3W) plus pbo for B, D (1120 mg Q3W) plus B (15 mg/kg Q3W), or pbos for D and B. Adverse events (AEs), start/end date, maximum/change in CTCAE grade, and causality were assessed in the D-T and D-B pds in pts who received any study tx in the arm to which they were randomized, until end of follow-up. Results: The Table shows duration of exposure (DoE). In the D+TACE, D+B+TACE, and pbos+TACE arms, AEs were reported by 144 (74.6%), 139 (72.0%), and 148 (74.0%) pts in the D-T pd and 133 (68.9%), 147 (76.2%), and 132 (66.0%) pts in the D-B pd; were possibly related (pos rel) to study tx in 59 (30.6%), 56 (29.0%), and 41 (20.5%) pts in the D-T pd and 76 (39.4%), 114 (59.1%), and 69 (34.5%) pts in the D-B pd; and were provoked by TACE in 72 (37.3%), 90 (46.6%), and 85 (42.5%) pts in the D-T pd and 16 (8.3%), 18 (9.3%), and 21 (10.5%) pts in the D-B pd, respectively. Conclusions: D+B+TACE had a manageable safety profile across the D-T and D-B pds, consistent with the individual agents and underlying disease. These data further support D+B+TACE as a new potential standard of care in embolization-eligible uHCC. Clinical trial information: NCT03778957 . [Table: see text]
Genomic and transcriptomic biomarkers of nab-paclitaxel plus gemcitabine-cisplatin in patients with advanced biliary tract cancer.
Authors: Seonjeong Woo, Beodeul Kang, Sung Hwan Lee, Jung Sun Kim, Haeyoun Kang, Seok Jeong Yang, Chansik An, Gwangil Kim, Sohyun Hwang, Chan Kim, Hong Jae Chon
Journal: Journal of Clinical Oncology (2024)

4104 Background: Nab-paclitaxel plus gemcitabine-cisplatin (GemCis/nab-P) showed promising clinical outcomes in phase II trials for advanced biliary tract cancer (BTC) but did not demonstrate superiority over the control treatment in subsequent phase III clinical trials.In this study, we investigated predictive biomarkers of response to GemCis/nab-P in patients with advanced BTC using comprehensive genomic and transcriptomic analyses. Methods: This prospective cohort study (NCT04871321) enrolled 119 patients with advanced BTC who received GemCis/nab-P at CHA Bundang Medical Center, Korea from July 2021 to December 2022. Targeted genomic (Oncomine Comprehensive Assay) and whole-transcriptome sequencing data for tissue samples collected before the initiation of systemic chemotherapy were used for biomarker discovery (n = 108). To identify genomic and transcriptomic features related to overall survival (OS) and progression-free survival (PFS), the log-rank test, Cox proportional hazards model, and Lasso Cox regression model were used. Results: Among the 119 enrolled patients, 39.5% had intrahepatic cholangiocarcinoma, 37.0% had extrahepatic cholangiocarcinoma, and 23.5% had gallbladder cancer. Most patients had metastatic or recurrent disease (68.9%). The median follow-up duration was 23.7 months (range 0.8–30.2), median PFS was 8.3 months (95% Confidence interval (CI), 7.0–11.5), and median OS was 19.8 months (95% CI, 15.3–not reached). The most common genetic aberrations were TP53 (53.7%), KRAS (29.6%), and ARID1A (16.7%) alterations. TP53 mutations were associated with a poor OS (p = 0.001) and PFS (p = 0.005). In the transcriptome analysis, genes associated with immune responses, especially tumor-associated macrophages, were upregulated in patients with worse OS and PFS. We constructed a Lasso-Cox regression model and identified VSIG4 (hazard ratio (HR): 3.0, p = 2.0 × 10 -4 for OS; HR: 2.4, p = 4.0 × 10 -4 for PFS), ITGA3 (HR: 2.6, p = 0.001 for OS; HR: 1.7, p = 0.020 for PFS), and CCL8 (HR: 1.6, p = 0.110 for OS; HR: 1.6, p = 0.039 for PFS) as effective predictors of poor clinical outcomes during GemCis/nab-P treatment. Conclusions: GemCis/nab-P showed promising survival outcomes in advanced BTC. Further, patients with TP53 mutations or high tumoral levels of VSIG4, ITGA3, and CCL8 showed a poor prognosis after GemCis/nab-P treatment. Clinical trial information: NCT04871321 .
A phase III trial comparing 5-FU plus cisplatin (CF) versus CF plus docetaxel or radiotherapy as neoadjuvant treatment for locally advanced esophageal cancer: 5-year follow-up from JCOG1109.
Authors: Ken Kato, Yoshinori Ito, Hiroyuki Daiko, Soji Ozawa, Takashi Ogata, Hiroki Hara, Takashi Kojima, Tetsuya Abe, Takeo Bamba, Masaya Watanabe, Hirofumi Kawakubo, Yuichi Shibuya, Yasuhiro Tsubosa, Naoki Takegawa, Takeshi Kajiwara, Hideo Baba, Masaki Ueno, Ryunosuke Machida, Kenichi Nakamura, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2024)

4082 Background: Triplet chemotherapy with CF plus docetaxel (DCF) improved survival compared to CF as a neoadjuvant treatment for locally advanced esophageal squamous cell cancer (ESCC) based on the result from JCOG1109 (jRCTs031180202). Here we report results with 5 years minimum follow-up. Methods: Eligible patients (pts) with ESCC of clinical stage IB, II, III (excluding T4) (UICC 7th) from 44 institutions were randomized 1:1:1 to neoadjuvant CF (cisplatin 80 mg/m 2 on day1 plus 5-FU 800 mg/m 2 on days 1-5 Q3W/2 course), DCF (docetaxel 70 mg/m 2 on day 1, cisplatin 70 mg/m 2 on day1, plus 5-FU 750 mg/m 2 on days 1-5 Q3W/3 course), or CF-RT (cisplatin 75 mg/m 2 on day 1 plus 5-FU 1000 mg/m 2 on days 1-4 Q4W/2 course, radiation 41.4 Gy/23 fr). Primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), and safety. Differences in OS was assessed in the ITT using the stratified log-rank test. The data cutoff date for the analysis was July 20, 2023. Results: Of 601 pts 199 CF, 202 DCF, and 200 CF-RT were enrolled from December 5, 2012 to July 20, 2018. Among 601 pts, 88.2% were male, median (range) age was 65 (30-75), clinical stage III (nonT4) pts were 62.6%. Median follow-up time (range) was 5.5 years (y) (0-10.6). Median OS in CF, DCF, and CF-RT arm were 5.8 y, 10.2 y, and 8.2 y, and 5-year OS was 51.9%, 65.1%, and 60.2%, respectively (stratified log-rank test: one-sided p = 0.004 for CF vs. DCF and one-sided p = 0.15 for CF vs. CF-RT). By the stratified Cox regression analysis for OS, hazard ratios (HR) [95% CI] with DCF vs. CF was 0.68 [0.51–0.91] and that with CF-RT vs. CF was 0.86 [0.66–1.13]. The HR for OS in exploratory comparison between DCF vs. CF-RT was 0.78 [0.59-1.05]. Median PFS in CF, DCF, and CF-RT arm were 2.7 y, 9.5 y, and 5.8 y, and 5-year PFS was 42.6%, 55.7%, and 53.5%, respectively. In the CF arm, there were initially 4 treatment-related and 15 other deaths, with 1 additional treatment-related and 2 other deaths over two more years. The DCF arm reported 4 and 10 deaths respectively, with 3 additional deaths from other causes. In the CF-RT arm, there were 4 treatment-related and 27 other deaths, followed by 2 more treatment-related and 4 other deaths in the extended period. Conclusions: After 5 years follow-up, neoadjuvant DCF continued to demonstrate clinically meaningful improvements in OS and PFS compared to CF in patients with locally advanced ESCC. Clinical trial information: jRCTs031180202 .
Enfortumab vedotin (EV) in previously treated gastric/esophageal cancers cohorts of EV-202.
Authors: Kei Muro, Keisho Chin, Steven Brad Maron, Fadi S. Braiteh, Seiichiro Mitani, Hiroki Hara, Yasutoshi Kuboki, Mary F Mulcahy, Joaquina Celebre Baranda, Faithlore Patrice Gardner, Ning Jin, Satoshi Hamauchi, Jason Kaplan, Seema Rao Gorla, Shubin Liu, Michele Wozniak, Changting Meng, Shunsuke Kondo
Journal: Journal of Clinical Oncology (2024)

4046 Background: Gastric/esophageal cancers have moderate/high Nectin-4 expression. EV is a Nectin-4–directed antibody–drug conjugate approved for use in locally advanced or metastatic (la/m) urothelial carcinoma. We report antitumor activity and safety of EV monotherapy in esophageal and/or gastric cancer in EV-202 (NCT04225117). Methods: This open-label, multicohort, phase 2 study enrolled adults with la/m solid tumors and ECOG performance status 0–1. In the esophageal squamous cell carcinoma (ESCC) and gastric/esophageal adenocarcinoma (GEA; gastric cancer, gastroesophageal junction/esophageal adenocarcinoma) cohorts, patients (pts) had prior treatment with 1 platinum-based and ≤2 lines of cytotoxic therapy in the la/m setting and disease not amenable to curative intent. Inclusion required prior HER2-directed therapy if HER2-positive and prior PD-1/L1 inhibitor. Nectin-4 expression was assessed retrospectively. Pts received EV 1.25 mg/kg intravenously on days 1, 8, and 15 per 28-day cycle. Primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1; ≥7 out of 40 responders are needed to conclude promising antitumor activity. Secondary endpoints were investigator-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) per RECIST v1.1; overall survival (OS); and safety/tolerability. Results: Of the 44 (as of June 2, 2023) and 42 pts (as of Mar 3, 2023) in the ESCC and GEA cohorts, respectively, median age was 66 and 62 y, 82% and 71% of pts were male, and 68% and 69% had ≥2 prior lines of systemic therapy in the metastatic setting. Efficacy data are shown in the table. Efficacy was generally better in pts with &lt;3 (n=22) vs ≥3 (n=21) prior therapy lines in the ESCC cohort. Common treatment-related adverse events (TRAEs) were pruritus (n=12, 27%), maculopapular rash (n=12, 27%), and dysgeusia (n=11, 25%) for ESCC and pruritus (n=16, 38%), alopecia (n=15, 36%), and dysgeusia (n=13, 31%) for GEA. Grade ≥3 TRAEs (&gt;1 pt) were hypercalcemia, hyperglycemia, maculopapular rash, and decreased neutrophil count (each n=2, 5%) for ESCC and maculopapular rash (n=3, 7%), decreased neutrophil count (n=2, 5%), and hyperglycemia (n=2, 5%) for GEA. For ESCC and GEA, respectively, TRAEs of special interest included skin reactions (n=27, 61%; n=23, 55%), peripheral neuropathy (n=9, 20%; n=7, 17%), and hyperglycemia (n=3, 7%; n=3, 7%). Conclusions: In pts with pretreated gastric/esophageal cancers, EV demonstrated safety consistent with the known profile of EV. Promising antitumor activity was observed in pts with ESCC. Clinical trial information: NCT04225117 . [Table: see text]