Gastroesophageal Junction Cancer Research Articles

Effectiveness and tolerability of programmed cell death protein-1 inhibitor + chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers

BACKGROUND The combination of programmed cell death protein-1 (PD-1) inhibitor and chemotherapy is approved as a standard first- or second-line treatment in patients with advanced oesophageal or gastric cancer. However, it is unclear whether this combination is superior to chemotherapy alone. AIM To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or oesophageal carcinoma. METHODS We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer. We employed either random or fixed models to analyze the outcomes of each clinical trial, encompassing data on overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events (AEs). RESULTS Nine phase 3 clinical trials (7016 advanced oesophageal and gastric cancer patients) met the inclusion criteria. Our meta-analysis demonstrated that the pooled PD-1 inhibitor + chemotherapy group had a significantly longer OS than the chemotherapy-alone group [hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.71-0.81]; the pooled PFS result was consistent with that of OS (HR = 0.67, 95%CI: 0.61-0.74). The count of patients achieving an objective response in the PD-1 inhibitor + chemotherapy group surpassed that of the chemotherapy-alone group [odds ratio (OR) = 1.86, 95%CI: 1.59-2.18]. AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group, regardless of whether ≥ grade 3 only (OR = 1.30, 95%CI: 1.07-1.57) or all AE grades (OR = 1.88, 95%CI: 1.39-2.54) were examined. We performed a subgroup analysis based on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) and noted extended OS and PFS durations within the CPS ≥ 1, CPS ≥ 5, and CPS ≥ 10 subgroups of the PD-1 inhibitor + chemotherapy group. CONCLUSION In contrast to chemotherapy alone, the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer, GEJ tumor, or oesophageal cancer. This holds true particularly for individuals with PD-L1 CPS scores of ≥ 5 and ≥ 10.

Palliative care for patients with gastroesophageal cancer at all stages: a narrative review.

Gastroesophageal junction (GEJ) cancer is a highly morbid disease with a poor prognosis. While uncommon in the United States, globally it is ranked as the sixth or seventh most common cancer depending on survey tool. GEJ cancer presents a unique and challenging symptom profile for patients at all disease stages, regardless of histology. Even patients with early stage disease experience debilitating cancer-related symptoms and treatment side effects. The heavy symptom burden associated with this disease includes dysphagia, nausea and vomiting, pain, anxiety, depression and malnutrition. These symptoms require a multidisciplinary approach involving local therapies including radiation and stent placement, systemic cancer-directed therapy, nutritional support, and supportive medical management. This review aims to examine the unique symptom burden experienced by patients with GEJ cancer and provide an updated overview of symptom management techniques. A PubMed search was conducted using the terms "gastroesophageal junction cancer AND palliative care". Articles published from 2008 to 2022 with a primary focus on supportive care for patients with GEJ cancers were reviewed. A total of 119 articles were identified and screened in our database search. Of these, 22 full text articles met inclusion criteria and were reviewed. Seventeen articles addressed technical interventions for the alleviation of dysphagia, 1 article focused on nutrition, 1 article described the impact of multidisciplinary tumor boards, 1 article presented the effect of home nurse visits, 1 article described the use of antiemetics, and 1 article was a narrative review of supportive care. In this narrative review, we examine specific supportive care needs in the GEJ cancer population. While the predominant symptom addressed in the literature is dysphagia, patients with GEJ cancer carry a complex symptom burden from diagnosis, through cancer-directed therapy to end-of-life care. Early referral to specialty palliative care should be considered for all patients with GEJ cancer to foster symptom management and delivery of goal concordant care.

Abstract CT038: Preliminary efficacy and safety results of anti-TROP2 ADC SKB264 (MK-2870) in patients (pts) with previously treated advanced gastric (G) or gastroesophageal junction (GEJ) cancer from a Phase 2 study

Abstract Background: Overexpression of TROP2 (trophoblast cell surface antigen 2) in advanced gastric cancer is known as a poor prognostic factor. SKB264 (MK-2870) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. The linker is affected by both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage within tumor cells, which leads to efficiently release payload inside tumor cells as well as within tumor microenvironment to exert its anti-tumor effects. Here, we report the preliminary results from a Phase 2 expansion cohort in pts with advanced G/GEJ cancer. Methods: Pts with previously treated inoperable advanced G/GEJ adenocarcinoma were enrolled to receive SKB264 monotherapy at 5 mg/kg Q2W until disease progression or unacceptable toxicity in Phase 2 expansion cohort of KL264-01 study (NCT04152499). Pts with heavily pre-treated G/GEJ cancer were enrolled first, and then the cohort was amended to enroll pts with only one prior therapy of chemotherapy and anti-PD-1/L1 therapy. Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. Results: At data cutoff date (Nov 22, 2023), a total of 48 pts were enrolled and followed up for at least 9 weeks. 24 pts (50.0%) had received one prior line of therapy (2L), while 24 pts (50.0%) had received ≥ 2 prior lines of therapy (3L+). 40 pts (83.3%) had received prior anti-PD-1/L1 inhibitors. Treatment-related adverse events (TRAEs) of ≥ Grade 3 were reported in 52.1% of pts. The most common ≥ Grade 3 TRAEs (occurred in ≥5% of pts) were anemia (20.8%), neutrophil count decreased (18.8%), WBC decreased (12.5%) and neutropenia (6.3%). TRAEs leading to dose reduction and dose delay occurred in 18.8% and 33.3% of pts, respectively. No TRAEs leading to treatment discontinuation or deaths occurred. No neuropathy or drug-related ILD/pneumonitis was reported. Of 41 response-evaluable pts (defined as ≥ 1 on-study scans), the ORR was 22.0% (9 PRs, 2 pending confirmation) and disease control rate (DCR) was 80.5%. The ORRs in the 2L and 3L+ setting were 27.3% (including 2 pending confirmation) and 15.8%, respectively. Median duration of response (DoR) was 7.5 months (mos). In the subset of 3L+ pts (n=24 including 54.2% of pts with ≥ 4 prior lines of therapy) with more mature follow-up (median follow up of 14.6 mos), median progression free survival (mPFS) was 3.7 mos (95% Cl: 2.6, 5.4); median overall survival (mOS) was 7.6 mos (95% Cl: 5.3, 15.5) with 12-mo OS rate of 32.6%. Conclusions: The preliminary data suggests that pts with heavily pre-treated advanced G/GEJ cancer could achieve durable response and potentially prolonged OS from SKB264 monotherapy, with a manageable safety profile. A Phase 3 global study of SKB264 monotherapy vs SOC in 3L+ G/GEJ adenocarcinoma is being planned. Citation Format: Jordi Rodon, Zev A. Wainberg, Mingjun Zhang, Tianshu Liu, Bo Liu, Guohua Yu, Yongmei Yin, Shuang Zhang, Yanjun Mi, Xingya Li, Xian Wang, Yunpeng Liu, Xiang Wang, Ying Cheng, Xiaoqing Zhang, Yalan Yang, Junyou Ge, Omobolaji O. Akala, Elliot Chartash, Jin Li. Preliminary efficacy and safety results of anti-TROP2 ADC SKB264 (MK-2870) in patients (pts) with previously treated advanced gastric (G) or gastroesophageal junction (GEJ) cancer from a Phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT038.

Prognostic and predictive impact of sex in locally advanced microsatellite instability high gastric or gastroesophageal junction cancer: An individual patient data pooled analysis of randomized clinical trials

BackgroundSurgery plus peri-operative/adjuvant chemotherapy is the standard of care for locally advanced GC/GEJC, though with unsatisfactory results. dMMR/MSI-high tumors have better prognosis and scant benefit from chemotherapy as compared to pMMR/MSS ones. The differential outcome of therapies in terms of safety and efficacy according to sex is still debated in GC/GEJC patients. MethodsWe previously performed an individual patient data pooled analysis of MAGIC, CLASSIC, ITACA-S, and ARTIST trials including GC/GEJC patients treated with surgery alone or surgery plus peri-operative/adjuvant chemotherapy to assess the value of MSI status. We performed a secondary analysis investigating the prognostic and predictive role of sex (female versus male) in the pooled analysis dataset in the overall population and patients stratified for MSI status (MSI-high versus MSS/MSI-low). Disease-free (DFS) and overall survival (OS) were calculated. ResultsPatients with MSI-high tumors had improved survival as compared to MSS/MSI-low ones irrespective of sex, whereas in those with MSS/MSI-low tumors, females had numerically longer OS and DFS (5-year OS was 63.2% versus 57.6%, HR 0.842; p = 0.058, and 5-year DFS was 55.8% versus 50.8%, HR 0.850; p = 0.0504 in female versus male patients). The numerical difference for the detrimental effect of chemotherapy in MSI-high GC was higher in females than males, while the significant benefit of chemotherapy over surgery alone was confirmed in MSS/MSI-low GC irrespective of sex. ConclusionsThis pooled analysis including four randomized trials highlights a relevant impact of sex in the prognosis and treatment efficacy of MSI-high and MSS/MSI-low non-metastatic GC/GEJC.

Obesity and Upper Gastrointestinal Diseases.

Obesity increases gastroesophageal reflux disease through several factors. As a result, Barrett's esophagus, esophageal adenocarcinoma, and gastroesophageal junctional gastric cancer are increasing. Existing studies usually defined obesity by body mass index and analyzed the correlation. Recently, more studies have shown that central obesity is a more important variable in upper gastrointestinal diseases related to gastroesophageal reflux. Studies have reported that weight loss is effective in reducing gastroesophageal reflux symptoms. Obesity also affects functional gastrointestinal diseases. A significant correlation was shown in upper abdominal pain, reflux, vomiting, and diarrhea rather than lower abdominal diseases.

Abstract 2523: Predictive biomarkers for neoadjuvant FLOT4 chemotherapy response in gastroesophageal cancer: Results of multi-omics approach

Abstract Background: The FLOT4 chemotherapy regimen is a standard preoperative treatment for gastroesophageal junction (GEJ) and gastric cancer (GC), yet the response to this treatment is variable. Identification of predictive biomarkers is crucial for optimizing therapeutic strategies. This study aims to identify predictive biomarkers for FLOT4 treatment efficacy using a multi-omics approach. Methods: We conducted a preliminary differential gene expression analysis in diagnostic tissue pre-treatment and surgical resection post-treatment in six patients (two GEJ and four GC) who all exhibited a partial pathological response (G2) to neoadjuvant FLOT4 chemotherapy. Utilizing DESeq2 for differential gene expression and David pathway analysis for functional insights, we have begun to unravel the complex molecular response to treatment. Upcoming assays include blood gDNA and tumor tissue whole exome sequencing (WES), comprehensive methylation profiling, miRNA characterization, and proteomics via LC-MSMS. Results: Our preliminary data suggest alterations in gene expression associated with cell adhesion, extracellular matrix interaction, and immune response pathways. Three common genes (CXCL2, CXCL3, CXCL1) were identified among upregulated pathways in GEJ patients, while one common gene (IL1A) was observed in GC patients. These findings suggest a complex network of biological processes influenced by FLOT4. In-depth results, including whole-exome sequencing, methylation patterns, and miRNA profiles, will be completed and presented at the conference. Conclusion: These initial findings propose that changes in gene expression related to cellular architecture and immune response are indicative of a partial response to FLOT4 in both GEJ and GC patients. The identified genes and pathways may serve as potential biomarkers for predicting treatment outcomes. Future Directions: By the time of the conference, we anticipate including a more extensive patient cohort with complete response or no response to FLOT4, and comparative analyses with a FOLFOX treatment group. The integration of forthcoming WES, methylation, miRNA, and proteomics data will provide a more comprehensive molecular predictive model. Keywords: FLOT4 chemotherapy, gastroesophageal junction cancer, gastric cancer, predictive biomarkers, differential gene expression. Citation Format: Amira Al-Fahdi, Shoaib Al Zadjali, Ibrahim Al Haddabi, Anoopa Pullanhi, Muna Al Jabri, Aida Al Yayahee, Nada Al Shuaili, Nahad Al Mahrouqi, Mansour Al Moundhri. Predictive biomarkers for neoadjuvant FLOT4 chemotherapy response in gastroesophageal cancer: Results of multi-omics approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2523.

Tislelizumab plus chemotherapy is an optimal option for second-line treatment for advanced gastroesophageal junction adenocarcinoma.

The development of programmed cell death receptor-1 and its ligand (PD-L1) have offered new treatment options for several cancers, but the clinical benefit of tislelizumab in the gastroesophageal junction (GEJ) adenocarcinoma is still murky. Thus, we aim to investigate the efficacy and safety of tislelizumab combined with chemotherapy in patients with GEJ cancer. In this study, 90 GEJ patients were retrospectively enrolled including 45 patients who received chemotherapy plus tislelizumab while 45 underwent chemotherapy only. Overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) were estimated and safety was assessed by treatment-related adverse events between two arms. The ORR was significantly higher in the tislelizumab group than in patients with chemotherapy alone (71.1 vs. 44.4%). The PFS [54.7% (47.2-62.2) vs. 33.3% (26.3-40.3), P = 0.047] and OS [62.1% (54.5-69.7) vs. 40.0% (32.5-47.5), P = 0.031] were also significantly improved in patients with concomitant use of tislelizumab. When stratified by PD-L1 combined positive score (CPS), patients with PD-L1 CPS ≥ 1 also with significantly higher PFS and OS when taking tislelizumab (P = 0.015 and P = 0.038). The incidence of hematologic toxicity was similar in the combination arm compared to the chemotherapy alone arm and the number of adverse events was not significantly increased by adding tislelizumab (all P > 0.05). Concomitant use of tislelizumab and chemotherapy in GEJ patients may be with optimal therapeutic effect and similar incidence of adverse events than chemotherapy alone. Further studies with larger number of patients are warranted to confirm it.

Abstract 572: Identifying potential therapeutic targets through gene expression analysis of peritoneal cavity cells in gastric cancer with peritoneal dissemination

Abstract Background: Peritoneal dissemination (PD) is the primary mode of metastasis in gastric cancer (GC) and is strongly associated with a poor prognosis. However, the mechanisms underlying PD formation in GC remain largely unknown.Methods and Results: In this study, we collected peritoneal washings from three cytology-positive (CY1) and five cytology-negative (CY0) gastric cancer patients undergoing laparotomy. We performed RNA sequencing on cell components in the peritoneal washings and identified 13 genes that were differentially expressed and upregulated in the CY1 group. Among these genes, we focused on thrombospondin 1 (THBS1) and 2 (THBS2). We evaluated their expression levels in 317 patients with gastric or gastroesophageal junction cancer who underwent primary curative resection at the Kanagawa Cancer Center between January 2002 and December 2012. Patients were stratified into two groups based on the median expression values of these genes, and Kaplan-Meier analysis was conducted. THBS2 expression was found to be inversely associated with disease-free survival (DFS) (p = 0.041), peritoneal dissemination-specific DFS (p = 0.041), and overall survival (OS) (p = 0.041) in the study cohort. In contrast, THBS1 expression did not exhibit a significant association with any of the aforementioned outcomes.Conclusion: Our results suggest that THBS2 expression in gastric cancer tissues may serve as a useful independent prognostic factor for patients, potentially playing a crucial role in the formation of PD. Citation Format: Yukihiko Hiroshima, Wataru Kawase, Itaru Hashimoto, Shizune Onuma, Hayato Watanabe, Mitsuhiro Furuta, Takashi Oshima, Yohei Miyagi. Identifying potential therapeutic targets through gene expression analysis of peritoneal cavity cells in gastric cancer with peritoneal dissemination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 572.

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

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

Abstract 962: Monitoring on-treatment tumor molecular dynamics using plasma whole genome sequencing (pWGS) and whole exome sequencing (pWES) of circulating tumor DNA (ctDNA) in advanced esophageal cancer: An exploratory analysis of KEYNOTE-590

Abstract Background: We evaluated on-treatment tumor molecular dynamics using ctDNA-based pWGS and pWES in patients (pts) with locally advanced or metastatic esophageal cancer that responded to pembro + chemo or chemo alone and later experienced PD in KEYNOTE-590 (NCT03189719). Methods: Pts with locally advanced, unresectable, or metastatic esophageal or Siewert type 1 gastroesophageal junction cancer were randomized 1:1 to first-line pembro 200 mg or placebo + chemo (5-fluorouracil + cisplatin) Q3W for ≤35 cycles. Cell-free DNA (cfDNA) was isolated and sequenced from plasma samples collected at baseline (BL), during on-treatment response (cycle 5 [C5]), and at PD (discontinuation [D]) from pts with response and subsequent PD. ctDNA burden (tumor fraction [TF]) was estimated using low-pass pWGS by quantifying tumor aneuploidy in cfDNA. All samples with TF >1.5% underwent high-depth pWES. ctDNA burden from pWES was estimated as maximum somatic allele frequency (MSAF). Associations of TF with MSAF were assessed using Spearman correlation coefficient r. For each subject, Jaccard index (JI) was calculated to evaluate the overlap of variants between BL and D. Variant allele frequency (VAF) and normalized VAF (nVAF) were used to determine variant clonality. Results: 108 pts (pembro + chemo, 59; chemo, 49) with initial response and subsequent PD had plasma samples available from BL, C5, and D. Samples from 94 pts had TF >1.5% by pWGS and underwent pWES. MSAF correlated with TF at BL (r = 0.84), C5 (0.56), and D (0.86). ctDNA TF was lower at C5 than at BL and D, with a mean of 4.4% (C5) vs 20.9% (BL) and 14.0% (D) with pembro + chemo and 4.0% (C5) vs 15.8% (BL) and 15.5% (D) with chemo. In variant-level analyses of pWES data from samples with high TF (≥2.5%) at BL and D (n = 65), 39.2% and 44.2% of variants were shared between BL and D with pembro + chemo and chemo, respectively. Higher overlap was observed for variants between BL and D for the chemo arm (JI: median, 0.54; range, 0.04-0.91) vs pembro + chemo (0.37; 0.01-0.92). Shared variants between BL and D had higher clonality compared with variants at BL-only or D-only with pembro + chemo (BL and D mean nVAF = 0.50 vs BL-only = 0.39, and D-only = 0.38) and chemo (0.49 vs 0.38 and 0.38). In pooled variant analyses, TP53 was the most commonly observed mutation and was rarely lost or acquired at D. Conclusions: Comprehensive pWES was feasible with sufficient ctDNA burden (TF ≥2.5%). ctDNA burden dynamics followed high disease burden at BL and D, consistent with radiographic determination of response/PD. Tumor variants at BL and D generally had a common clonal trunk and a higher overlap of variants was observed at D in the chemo arm. These results provide preliminary molecular evidence of immune editing in pts receiving immunotherapy that warrants further study. Citation Format: Minita Shah, E.J. Dettman, Andrew Albright, Cai Chen, Julie Kobie, Sukrut Shah, Carol Peña, Razvan Cristescu, Z Alexander Cao. Monitoring on-treatment tumor molecular dynamics using plasma whole genome sequencing (pWGS) and whole exome sequencing (pWES) of circulating tumor DNA (ctDNA) in advanced esophageal cancer: An exploratory analysis of KEYNOTE-590 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 962.

HER2 and PD-L1 Expression in Gastric and Gastroesophageal Junction Cancer: Insights for Combinatorial Targeting Approaches.

Gastric and gastroesophageal junction adenocarcinomas (GA/GEJA) are associated with a poor prognosis, primarily due to late disease diagnosis. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression and programmed death-ligand 1 (PD-L1) expression are important biomarkers for treatment selection in locally advanced unresectable and metastatic GA/GEJA, and there is increasing interest in their role in earlier stages of disease. In this study, we aimed to evaluate HER2 and PD-L1 expression in a curative-intent GA/GEJA cohort to describe their expression patterns and analyze the association between HER2 expression and clinicopathological features. HER2 expression was evaluated in surgical and endoscopic submucosal dissection tumor samples, and PD-L1 was evaluated in HER2-positive cases. The clinical cohort included 107 patients, with 8.4% testing positive for HER2 (seven of whom also exhibited a PD-L1 combined positive score of ≥1. HER2 status was not significantly associated with survival outcomes. A pathologist-guided, region-specific analysis revealed that PD-L1 expression rarely overlaps with HER2-positive tumor areas. While the therapeutic implications of these observations remain unknown, these findings suggest that combination strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. The herein disclosed region-specific biomarker expression patterns may have important therapeutic and prognostic impacts, warranting further evaluation.

Whole-transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential.

Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies.

Proximal gastric cancer—time for organ-sparing approach?

IntroductionA steady increase in gastroesophageal junction and proximal gastric cancer (GC) incidence has been observed in the West. Given recent advances in neoadjuvant chemotherapy (NAC), we sought to characterize short- and long-term outcomes of patients with proximal GC who underwent total (TG) versus proximal gastrectomy (PG). MethodsPatients with stage II/III proximal GC who underwent curative intent treatment between 2009 and 2019 were identified using National Cancer Database (NCDB). Multivariable analysis was used to identify oncological outcomes following TG versus PG. ResultsAmong 7,616 patients with GC who underwent surgical resection, PG and TG were performed on 5,246 (68.8%) and 2,370 (31.2%) patients, respectively. Patients who underwent PG were more likely to receive NAC (TG: 52.3% vs. PG: 64.5%)(p<0.001). On pathologic analysis, patients who underwent TG were more likely to have pT4 tumors (TG: 11.7% vs. PG: 3.1%), metastatic lymph nodes (TG: 64.6% vs. PG: 60.4%), and >16 lymph nodes evaluated (TG: 64.1% vs. PG: 53.1%), yet a lower likelihood of negative resection margins (TG: 86.6% vs. PG: 90.0%)(all p<0.001). While gastrectomy procedure type did not impact long-term survival, receipt of NAC was associated with OS among patients who underwent TG (5-year OS, NAC: 43.5% vs. no NAC: 24.6%) and PG (5-year OS, NAC: 43.1% vs. no NAC: 26.7%)(both p<0.001). ConclusionsPG may be an alternative surgical approach to TG in well-selected patients with proximal GC after administration of preoperative systemic chemotherapy.

Effectiveness of prehabilitation during neoadjuvant therapy for patients with esophageal or gastroesophageal junction cancer: a systematic review.

Progression of the physical weakness during neoadjuvant therapy (NAT) in patients with esophageal or gastroesophageal junction cancer is a serious problem; however, prehabilitation during NAT has the potential to overcome the unmet need. Nevertheless, systematic reviews on this topic have not been summarized. Therefore, this systematic review aimed to determine prehabilitation's effectiveness, acceptability, and safety during NAT for patients with esophageal or gastroesophageal junction cancer. An electronic search was performed in the MEDLINE, Web of Science, CENTRAL, CINAHL, and PEDro databases. A meta-analysis was conducted to assess the effectiveness of prehabilitation during NAT, along with a descriptive analysis of acceptance and safety. This study analyzed data from three randomized controlled trials (RCTs) and nine non-RCTs involving 664 patients. The meta-analysis of two RCTs demonstrated that prehabilitation during NAT may be more effective than usual care in enhancing tolerance to NAT and grip strength; moreover, one RCT and three non-RCTs revealed that prehabilitation may reduce the risk of postoperative complications. The adherence rates for exercise programs in two RCTs and seven non-RCTs were 55-76%. Additionally, two studies reported a 76% adherence rate for multimodal prehabilitation programs, including exercise, dietary, and psychological care. Six studies reported no serious prehabilitation-related adverse events during NAT. Prehabilitation during NAT may be a safe and beneficial intervention strategy for patients with esophageal or gastroesophageal junction cancer. However, the investigation of strategies to enhance adherence is essential. Furthermore, additional high-quality RCTs are needed to examine the effect of prehabilitation during NAT.

A proactive financial navigation intervention in patients with newly diagnosed gastric and gastroesophageal junction adenocarcinoma

PurposeMany cancer patients and caregivers experience financial hardship, leading to poor outcomes. Gastric and gastroesophageal junction (GEJ) cancer patients are particularly at risk for financial hardship given the intensity of treatment. This pilot randomized study among gastric/GEJ cancer patients and caregivers tested a proactive financial navigation (FN) intervention to obtain a signal of efficacy to inform a larger, more rigorous randomized study.MethodsWe tested a 3-month proactive FN intervention among gastric/GEJ cancer patients and caregivers compared to usual care. Caregiver participation was optional. The primary endpoint was incidence of financial hardship, defined as follows: accrual of debt, income decline of ≥ 20%, or taking loans to pay for treatment. Data from participant surveys and documentation by partner organizations delivering the FN intervention was analyzed and outcomes were compared between study arms.ResultsNineteen patients and 12 caregivers consented. Primary FN resources provided included insurance navigation, budget planning, and help with out-of-pocket medical expenses. Usual care patients were more likely to experience financial hardship (50% vs 40%) and declines in quality of life (37.5% vs 0%) compared to intervention patients. Caregivers in both arms reported increased financial stress and poorer quality of life over the study period.ConclusionsProactive financial navigation has potentially positive impacts on financial hardship and quality of life for cancer patients and more large-scale randomized interventions should be conducted to rigorously explore the impact of similar interventions. Interventions that have the potential to lessen caregiver financial stress and burden need further exploration.Trial registrationTRN: NCT03986502, June 14, 2019.

Top Gastric Cancer Articles from 2022 and 2023 to Inform Your Cancer Practice.

The multimodality management of patients with gastroesophageal cancers is rapidly evolving, with the introduction of new therapies against potential molecular targets paving the way to personalized medicine for patients with both resectable and metastatic disease. Over the past 2years, several important studies evaluating these new targeted therapies, as well as minimally invasive surgical approaches to gastric cancer, have been published. This review article summarizes the top studies published in gastric cancer over the past 2years that are fundamentally changing our practice approach to gastric cancer patients. First, the long-term safety and efficacy of laparoscopic distal gastrectomy as compared with open gastrectomy for locally advanced gastric cancer was confirmed with the publication of the 5-year outcomes of the CLASS-01 and KLASS-02 randomized clinical trials. In addition, several important studies of perioperative immunotherapy for patients with resectable gastric or gastroesophageal junction cancers are ongoing, and in 2022, an interim analysis of the DANTE trial and the final results of the GERCOR NEONIPIGA study were reported. Lastly, the KEYNOTE-859 and SPOTLIGHT trials address an unmet need for additional targeted therapies for patients with previously untreated, human epidermal growth factor receptor-2 (HER2)-negative, unresectable or metastatic gastroesophageal cancers, incorporating immune checkpoint inhibitors and targeting Claudin-18 isoform 2 (CLDN18.2) with the monoclonal antibody zolbetuximab, respectively. This article summarizes the findings and implications of several important studies published over the past 2years that are fundamentally changing the way we treat patients with gastroesophageal cancer.

Role of Preoperative Radiation Therapy for Resectable Gastric Cancer.

While surgery is the primary curative treatment for resectable gastric and gastroesophagealjunction (GEJ) cancer, rates of locoregional and distant recurrence remain high with surgery alone,especially in more advanced disease. Multimodal approaches with perioperative therapy includingchemotherapy and/or radiation therapy (RT) have thus evolved as ways to reduce the rates of diseaserecurrence and improve survival outcomes. This review article provides a comprehensive literaturereview on the role of preoperative RT for resectable gastric and GEJ cancer. A literature review on the role of preoperative RT for resectable gastric and GEJ cancer wasconducted. Preoperative RT has the potential to facilitate tumor downstaging and improved R0 resection,allowing for better locoregional control and thereby survival. For resectable locally advanced GEJ cancer,preoperative chemoradiotherapy (CRT) is currently a standard of care option along with perioperativechemotherapy, based on evidence from randomized trials. In resectable gastric cancer, however, therole of preoperative CRT is less defined with no randomized data to date, although phase II single-armstudies have shown promising results. Current standard of care for gastric cancer remains perioperativechemotherapy, with consideration for preoperative CRT in select cases. Results from ongoing and future randomized controlled trials are expected to help definethe role of preoperative CRT compared to perioperative chemotherapy alone as well as postoperativeCRT for gastric and GEJ cancer.

Interleukin-6 as a Predictive Factor of Pathological Response to FLOT Regimen Systemic Treatment in Locally Advanced Gastroesophageal Junction or Gastric Cancer Patients.

Perioperative treatment is a gold standard in locally advanced gastric cancer or GEJ cancer in the Western population. Unfortunately, the response rate after neoadjuvant chemotherapy (NAC) remains limited. Moreover, there are currently no biomarkers enabling an individual prediction of therapeutic efficacy. The aim of this study was the identification of serum biomarkers of early response to NAC. We conducted this prospective study in the MSCNRIO in Warsaw, Poland. A total of 71 patients and 15 healthy volunteers gave informed consent. Complete blood count, carcinoembryonic antigen (CEA), carcinoma antigen 125 (CA125), carcinoma antigen 19.9 (CA19.9), and fibrinogen (F) were measured at baseline and before every cycle. Circulating tumour cells (CTCs) and interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) were measured in a pilot group of 40 patients at baseline and before cycle two (C2) and cycle three (C3). Of all the measured parameters, only the IL-6 serum level was statistically significant. The IL-6 level before C2 of chemotherapy was significantly decreased in the complete pathological response (pCR) vs. the non-pCR group (3.71 pg/mL vs. 7.63 pg/mL, p = 0.004). In all patients with an IL-6 level below 5.0 pg/mL in C2, tumour regression TRG1a/1b according to the Becker classification and ypN0 were detected in postoperative histopathological specimens. The IL-6 level before C1 of chemotherapy was significantly elevated in ypN+ vs. ypN0 (7.69 pg/mL vs. 2.89 pg/mL, p = 0.022). The trial showed that an elevated level of IL-6 prior to treatment and C2 might be a predictor of pathological response to NAC.

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enrolled in this phase II study. Patients received neoadjuvant sintilimab (200mg every 3 weeks) for three cycles plus FLOT (50mg/m2 docetaxel, 80mg/m2 oxaliplatin, 200mg/m2 calcium levofolinate, 2600mg/m2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by 4 cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. Thirty-two patients were enrolled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-one (96.9%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8%-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 16 (55.2%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2%-89.2%), 78.8% (95% CI, 65.1%-95.5%), and 70.9% (95% CI, 54.8%-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3%-93.1%) and 96.9% (95% CI, 84.3%-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: final analysis of the randomized phase 2 FIGHT trial.

We report the final results of the randomized phase 2 FIGHT trial that evaluated bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 in patients with FGFR2b-positive (2 + /3 + membranous staining by immunohistochemistry), HER-2-negative gastric or gastroesophageal junction cancer (GC). Patients received bemarituzumab (15mg/kg) or placebo once every 2weeks with an additional bemarituzumab (7.5mg/kg) or placebo dose on cycle 1day 8. All patients received mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24months. In the bemarituzumab-mFOLFOX6 (N = 77) and placebo-mFOLFOX6 (N = 78) arms, respectively, 59.7% and 66.7% of patients were FGFR2b-positive in ≥ 10% of tumor cells. The median PFS (95% confidence interval [CI]) was 9.5months (7.3-13.7) with bemarituzumab-mFOLFOX6 and 7.4months (5.7-8.4) with placebo-mFOLFOX6 (hazard ratio [HR], 0.72; 95% CI 0.49-1.08); median OS (95% CI) was 19.2 (13.6-24.2) and 13.5 (9.3-15.9) months, respectively (HR 0.77; 95% CI 0.52-1.14). Observed efficacy in FGFR2b-positive GC in ≥ 10% of tumor cells was: PFS: HR 0.43 (95% CI 0.26-0.73); OS: HR 0.52 (95% CI 0.31-0.85). No new safety findings were reported. In FGFR2b-positive advanced GC, the combination of bemarituzumab-mFOLFOX6 led to numerically longer median PFS and OS compared with mFOLFOX6 alone. Efficacy was more pronounced with FGFR2b overexpression in ≥ 10% of tumor cells. Confirmatory phase 3 trials are ongoing (NCT05052801, NCT05111626). NCT03694522.