Advanced Gastroesophageal Adenocarcinoma Research Articles

Concordance of PD-L1 combined positive score (CPS) analysis between primary gastric cancer and matched peritoneal metastasis.

e16068 Background: Peritoneum represents one of the most common metastatic sites of gastroesophageal adenocarcinoma (GEA) and is associated with poor prognosis. Programmed death-ligand 1 (PD-L1) expression is a recognized predictive biomarker of response to immune checkpoint inhibitors (ICIs) in the first-line setting. However, data from pivotal trials showed poorer clinical efficacy of ICIs in the sub-set of patients with peritoneal involvement, regardless of PD-L1 score magnitude. Here, we investigated the temporal and spatial heterogeneity of PD-L1 expression between primary tumor and matched peritoneal metastasis. Methods: PD-L1 expression according to CPS was determined by immunohistochemistry using VENTANA PD-L1 (SP263) assays on formalin-fixed paraffin-embedded (FFPE) tumor tissues derived from 22 patients treated at our institution for advanced GEA from September 2015 to August 2023. Concordance rate of PD-L1 expression between primary tumor and matched peritoneal metastasis using PD-L1 CPS cut-off of 1 and 5 was reported (spatial heterogeneity); additionally, concordance between PD-L1 value before and after the administration of systemic treatments was analyzed (temporal heterogeneity). Results: 12(54.5%)/5(22.7%) primary tumor samples and 12(54.5%)/1(4.5%) peritoneal metastases showed PD-L1 CPS ≥ 1/ ≥ 5, respectively. Concordance of PD-L1 CPS between primary and peritoneal specimens was 54.5% and 72.7% according to CPS cuts-off of 1 and 5, respectively, highlighting marked spatial heterogeneity. High concordance rate (94%) was reported between negative PD-L1 CPS primary tumor samples and matched peritoneal metastases, against the cut-off of CPS ≥ 5; in contrast, none of the positive primary tumor samples retained PD-L1 expression in the peritoneum. Evident temporal heterogeneity of PD-L1 expression was also observed, with 56% concordance against CPS ≥ 5 in the pre- versus post-treatment comparison. Conclusions: PD-L1 expression in GEA is characterized by spatial and temporal heterogeneity which is more prominent for lower CPS cut-offs values. This evidence could hamper its role as predictive biomarker for ICIs. The high intra-patient discordance rate of PD-L1 CPS expression between positive primary tumor samples and matched peritoneal metastases suggests that peritoneal specimens should not be recommended as the preferred source for PD-L1 assessment.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial

ObjectiveTo evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy.DesignRandomised, double blind,...

Outcomes of locally advanced gastric and gastroesophageal adenocarcinoma cancers treated with neoadjuvant FLOT in a tertiary care hospital in Pakistan.

Docetaxel, oxaliplatin, leucovorin and 5-fluorouracil (FLOT) may improve overall survival (OS) in patients with locally advanced gastric and gastroesophageal cancer. Our study aims to determine the pathological response in these patients with the FLOT chemotherapy in the Neoadjuvant setting. This is the first study conducted in our country. We conducted a retrospective cross-sectional study from March 2018 to December 2020. After ethical review committee approval, all patients who fulfilled the inclusion criteria and received treatment at our tertiary care center were included in the study. SPSS version 22 was used for data analysis. Frequencies and percentages were calculated for categorical. Values were presented as mean ± standard deviation (SD) for continuous variables. The chi-square test was used to determine the difference between categorical variables. A p-value of ≤0.05 was considered the level of significance. Kaplan-Meier curves were used to calculate survival analysis. Out of 41, 35 patients with locally advanced resectable gastric or gastroesophageal adenocarcinoma were included in our study analysis. The entire cohort had a male predominance, with a mean age of 59. All patients received neoadjuvant FLOT. Pathological treatment response achieved was 77%, of which 66% had partial and 11% had complete response. There is a significant association of pathological response with age, gender, stage, grade, co-morbid and number of chemotherapy cycles received (p-value =<0.05). The OS was 80% with the mean OS was 2.6 years (31 months). Our study shows comparable response rates to other studies conducted internationally. Our findings confirm that FLOT is an effective and well-tolerated perioperative regimen with reasonable response rates in the Pakistani population. A more extensive longitudinal study would ensure these preliminary results in the local patient population.

68Ga-FAPI-04 positron emission tomography/CT and laparoscopy for the diagnosis of occult peritoneal metastasis in newly diagnosed locally advanced gastric cancer: study protocol of a single-centre prospective cohort study

IntroductionAccurate baseline clinical staging is critical to inform treatment decision-making for patients with gastric cancers. Peritoneal metastasis (PM) is the most common form of metastasis in gastric cancer and mainly...

Neoadjuvant chemoimmunotherapy in locally advanced gastric or gastroesophageal junction adenocarcinoma.

Patients suffering from locally advanced gastric or gastroesophageal junction adenocarcinoma often face a high postoperative recurrence rate. Despite aggressive treatment, less than 50% survive beyond five years. Ongoing clinical studies are exploring ways to prolong patient survival, revealing that perioperative chemotherapy can extend both the period of recurrence-free survival and overall survival for this group of patients. Currently, combining chemotherapy and immune checkpoint inhibitors has become a critical treatment approach for advanced gastric or gastroesophageal junction adenocarcinoma. However, the effectiveness of this approach in locally advanced patients remains unverified. This article delves into the latest research concerning the use of perioperative chemotherapy coupled with immune checkpoint inhibitors in locally advanced gastric or gastroesophageal junction adenocarcinoma treatment, and highlights prospective challenges and discusses how to best identify patients who may benefit from combined chemotherapy and immune checkpoint inhibitor therapy.

Abstract LB417: Leveraging advanced human lung models to explore mechanisms underlying T-DXd-associated interstitial lung disease (ILD)

Abstract Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved for several indications, including HER2-positive unresectable or metastatic breast cancer that progressed on two or more prior therapies, HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen and HER2-mutant unresectable or metastatic non-small cell lung cancer (USPI-ENH-C9-1122-r006). While the safety profile of T-DXd is manageable, ILD is an important identified risk and considered as an Adverse Event (AE) of special interest (Powell et al ESMO Open 2022). The therapeutic options for patients that develop ILD are limited to steroid medications, including prednisone and methylprednisolone. Hence, a greater understanding of T-DXd-associated ILD pathophysiology has the potential to guide alternative interventions to prevent ILD progression and improve patient care. Here, we used advanced human lung models to explore if T-DXd can affect pulmonary epithelial cell homeostasis and function. Transcriptome and gene set enrichment analysis of bronchial epithelial cells cultured under air-liquid interface (ALI) conditions revealed that genes and pathways associated with senescence, inflammation, and barrier integrity were dysregulated upon treatment with T-DXd. These transcriptomic findings linked to senescence and inflammation were confirmed in follow-up ALI experiments where T-DXd was shown to activate the p53 pathway, and upregulate pro-senescence, -inflammatory and -fibrotic mediators. Similarly, T-DXd activated senescence- and inflammation-associated markers in a microphysiological alveolar lung-on-chip system, thus indicating that T-DXd has similar effects in alveoli epithelia. In addition, T-DXd induced epithelial injury of ALI cells, which was reflected by loss of barrier function and release of epithelial damage markers. These changes were also accompanied by upregulation of mesenchymal cell markers, suggesting cells transition to a partial epithelial-to-mesenchymal phenotype. Whereas the payload (deruxtecan; DXd) and IgG control antibody-DXd conjugate (IgG-DXd) could recapitulate effects measured with T-DXd on lung epithelial cells, trastuzumab did not have any effect, suggesting limited contribution of HER2 targeting to T-DXd-induced epithelial changes in the experimental models used. Altogether, these data demonstrate that DXd can drive epithelial mechanisms and pathways associated with pulmonary fibrosis, inflammation, and damage, which are dysregulated events observed in ILD. Ongoing studies aim to evaluate the translation of these discoveries to the clinic and to support the development of novel therapeutic strategies to manage or prevent ILD. Citation Format: Ingrid Lua, Lin Jia, Jeff Chen, Kevin Contrepois, Mary McFarlane, Anton I. Rosenbaum, Peter Newham, Sonia Terrillon. Leveraging advanced human lung models to explore mechanisms underlying T-DXd-associated interstitial lung disease (ILD) [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 LB417.

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 enroled in this phase II study. Patients received neoadjuvant sintilimab (200mg every 3 weeks) for three cycles plus FLOT (50mg/m 2 docetaxel, 80mg/m 2 oxaliplatin, 200mg/m 2 calcium levofolinate, 2600mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) 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, 21 (72.4%) 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.

Targeting HER2 in Gastroesophageal Adenocarcinoma: Molecular Features and Updates in Clinical Practice.

Gastroesophageal adenocarcinoma (GEA) is one of the principal causes of death related to cancer globally. Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor which is found to be overexpressed or amplified in approximately 20% of GEA cases. In GEA, the identification of HER2-positive status is crucial to activate a specific anti-HER2 targeted therapy. The landmark ToGA trial demonstrated the superiority of adding trastuzumab to platinum-based chemotherapy, becoming the first-line standard of treatment. However, unlike breast cancer, the efficacy of other anti-HER2 drugs, such as lapatinib, pertuzumab, and T-DM1, has failed to improve outcomes in advanced and locally advanced resectable GEA. Recently, the combination of trastuzumab with pembrolizumab, along with chemotherapy, and the development of trastuzumab deruxtecan, with its specific bystander activity, demonstrated improved outcomes, renewing attention in the treatment of this disease. This review will summarise historical and emerging therapies for the treatment of HER2-positive GEA, with a section dedicated to the HER2 molecular pathway and the use of novel blood biomarkers, such as circulating tumour DNA and circulating tumour cells, which may be helpful in the future to guide treatment decisions.

First-line camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and chemotherapy for advanced gastric cancer (SPACE): a phase 1 study

Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1–14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8–89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).

Abstract 6400: Tislelizumab combined with XELOX as a neoadjuvant therapy for locally advanced gastric and gastroesophageal junction adenocarcinomas: A prospective, phase II trial

Abstract Background: Combing anti-PD-(L)1 antibody with chemotherapy in neoadjuvant therapy of gastric/gastroesophageal junction (G/GEJ) adenocarcinomas is a promising strategy, but clinical data are remain insufficient. Whether immunotherapy biomarkers in previous studies (TMB, MSI, PD-L1, etc.) have equivalent predictive value for G/GEJ remains to be verified. In this phase II clinical trial of tislelizumab in combination with chemotherapy, potential therapy-related biomarkers in tumor samples, and changes in the tumor microenvironment during treatment were analyzed, and a predictive model for efficacy was developed. Methods: This was a prospective, single-center, single-arm, phase II trial. Patients with G/GEJ adenocarcinomas (stage cT3-4aN+M0) were treated with PD-1 inhibitor tislelizumab in combination with oxaliplatin plus capecitabine (XELOX) as neoadjuvant treatment for 2 or 3 cycles. The primary endpoint was the major pathological response (MPR). The secondary endpoints included pathological complete response (pCR) rate, R0 resection rate, and safety. Tumor samples underwent RNA-sequencing (Amoy Diagnostics Co Ltd, Xiamen, China), to identify potential biomarkers, and a predictive model was developed to explore factors influencing tumor response and survival. Results: 28 patients were enrolled; mean age was 59.5 years (SD = 8.2), 19 (67.9%) patients were male; 14 (50.0%) patients with primary tumor location in the stomach, and 14 (50.0%) patients with primary tumor location in the GEJ. All patients were EB virus negative. Except one patient with PMS2 loss, 27 patients were pMMR. Nine (32.1%) patients achieved MPR after treatment, with four (14.3%) of them achieved pCR. The R0 resection rate was 96.4%, with 14 (50.0%) patients achieved objective response. No serious adverse events were reported. The most common grade 2 TRAEs during neoadjuvant treatment were anemia (5 of 28, 17.86%) and nausea (3 of 28, 10.71%). Analysis of differentially expressed genes revealed enrichment of the antigen processing and presentation pathway in the MPR group, while the TGF-β signaling pathway was enriched in the non-MPR group. Notably, the differential immune microenvironment analysis also uncovered significant differences in the TGF-β signature between the MPR and non-MPR groups. Additionally, a therapeutic response prediction model (HT score) was developed with an AUC of 0.98 (0.932-1) in the training set, and its performance was validated in publicly available datasets. Conclusion: Tislelizumab combined with XELOX holds promise as a neoadjuvant therapy for resectable G/GEJ adenocarcinomas, especially for EBV- and pMMR population, offering a well-tolerated safety profile. Moreover, the HT score has the potential to predict treatment efficacy in this regimen. Trial registration numbers: NCT05507658 and NCT05508399. Citation Format: Haikun Zhou, Tao Han, Lei Tuo, Qingchuan Yang, Ruiqi Gao, Pengfei Yu, Jiangpeng Wei, Changbin Zhu, Jin Wang, Peng Cheng, Xiang Kang, Sihui Pi, Hui Liu, Xiaoxi Pan, Xiaohua Li, Gang Ji. Tislelizumab combined with XELOX as a neoadjuvant therapy for locally advanced gastric and gastroesophageal junction adenocarcinomas: A prospective, phase II trial [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 6400.

Abstract 6846: Tumor cell metaplastic programs and failure of T cell remodeling drive resistance and progression to frontline chemoimmunotherapy in advanced gastric cancer

Abstract Adding aPD1 to 5-FU/platinum in advanced gastroesophageal adenocarcinomas (GEA) has yielded modest and heterogeneous results. Understanding cooperativity between these two treatment modalities will inform novel combination treatments for GEA. Towards this end, we conducted a trial (n = 47) sequentially adding pembrolizumab to 5-FU/platinum in previously untreated advanced GEA. Using serial biopsy of the primary tumor at baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab we transcriptionally profiled 358,067 single cells and obtained TCR-sequences from single tumor-resident T cells. Stratifying patients into slow- (&amp;gt; 6 months) and fast-progressing (&amp;lt; 6 months) groups based on progression-free survival allowed us to quantify differences in immune, stromal and epithelial subpopulations across treatment time points. Using topic modeling with consensus non-negative matrix factorization (cNMF), we identified gene expression programs in each population at each time point and developed a methodology to verify the stability of those programs across the cohort using cross-validation. Faster clinical progression featured decreased M1-like macrophage repolarization and increased MUC5A and MSLN containing metaplasia programs in tumor cells. We next selected features from cell state gene programs and identified trajectories of tumor cells across a spectrum of treatment sensitive and resistant states. We identified several factors that correlated with these trajectories and regulons that may be influencing them. After pembrolizumab we observed slower progression was associated with further increased CD8 T cell infiltration with increased CXCL13+ T cells. We next calculated covarying programs between patient samples at each time point and performed permutation testing to identify which programs (and respective cell types they were expressed in) were significantly correlated to infer the presence of multicellular tumor communities. We found that the tumor cell interferon program co-varied with the CXCL13 T cell program, and the emergence of a covarying module with tumor-reactive CXCL13 program expression happens as early as after the first dose of chemotherapy. To better understand the behavior of tumor reactive T cells within the tumor microenvironment, we leveraged TCR-sequencing data to study T cell clonality and diversity across treatment time points and between fast and slow progressors. Our data provide an invaluable resource to dissect chemoimmunotherapy response in tumor cells, understand T cell behavior and propose strategies to drive anti-tumor immune hub formation to expand the portion of patients benefiting from immunotherapy approaches. Citation Format: Samuel J. Wright, Minae An, Byung Hoon Min, You Jeong Heo, Milan Parikh, Lynn Bi, Hyuk Lee, Taejun Kim, Song-Yi Lee, Jeonghyeon Moon, Ryan J. Park, Matthew R. Strickland, Woong Yang Park, Won Ki Kang, Kyoung-Mee Kim, Seung Tae Kim, Arnav Mehta, Samuel J. Klempner, Jeeyun Lee. Tumor cell metaplastic programs and failure of T cell remodeling drive resistance and progression to frontline chemoimmunotherapy in advanced gastric cancer [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 6846.

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.

Perioperative chemotherapy with docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) for the treatment of locally advanced gastric or gastro-esophageal junction adenocarcinoma (MATCH): an open-label, randomized, phase 2 clinical trial

BackgroundIt remains unclear whether addition of docetaxel to the combination of a platinum and fluoropyrimidine could provide more clinical benefits than doublet chemotherapies in the perioperative treatment for locally advanced gastric/gastro-esophageal junction (LAG/GEJ) cancer in Asia. In this randomized, phase 2 study, we assessed the efficacy and safety of perioperative docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) in LAG/GEJ adenocarcinoma patients.MethodsPatients with cT3–4 Nany M0 G/GEJ adenocarcinoma were randomized (1:1) to receive 4 cycles of preoperative DOS or SOX followed by D2 gastrectomy and another 4 cycles of postoperative chemotherapy. The primary endpoint was major pathological response (MPR).ResultsFrom Aug, 2015 to Dec, 2019,154 patients were enrolled and 147 patients included in final analysis, with a median age of 60 (26–73) years. DOS resulted in significantly higher MPR (25.4 vs. 11.8%, P = 0.04). R0 resection rate, the 3-year PFS and 3-year OS rates were 78.9 vs. 61.8% (P = 0.02), 52.3 vs. 35% (HR 0.667, 95% CI: 0.432–1.029, Log rank P = 0.07) and 57.5 vs. 49.2% (HR 0.685, 95% CI: 0.429–1.095, Log rank P = 0.11) in the DOS and SOX groups, respectively. Patients who acquired MPR experienced significantly better survival. DOS had similar tolerance to SOX.ConclusionsPerioperative DOS improved MPR significantly and tended to produce longer PFS compared to SOX in LAG/GEJ cancer in Asia, and might be considered as a preferred option for perioperative chemotherapy and worth further investigation.

First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 3-year efficacy and safety results from the phase III CheckMate 649 trial. Patients with previously untreated advanced or metastatic gastroesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy. Primary end points were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients whose tumors expressed PD-L1 combined positive score (CPS) ≥5. With 36.2-month minimum follow-up, for patients with PD-L1 CPS ≥5, the OS hazard ratio (HR) for nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI, 0.61 to 0.81); 21% versus 10% of patients were alive at 36 months, respectively; the PFS HR was 0.70 (95% CI, 0.60 to 0.81); 36-month PFS rates were 13% versus 8%, respectively. The objective response rate (ORR) per BICR was 60% (95% CI, 55 to 65) with nivolumab plus chemotherapy versus 45% (95% CI, 40 to 50) with chemotherapy; median duration of response was 9.6 months (95% CI, 8.2 to 12.4) versus 7.0 months (95% CI, 5.6 to 7.9), respectively. Nivolumab plus chemotherapy also continued to show improvement in OS, PFS, and ORR versus chemotherapy in the overall population. Adding nivolumab to chemotherapy maintained clinically meaningful long-term survival benefit versus chemotherapy alone, with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastroesophageal adenocarcinoma.

Fruquintinib plus paclitaxel versus paclitaxel as second-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma (FRUTIGA): A randomized, multicenter, double-blind, placebo-controlled, phase 3 study.

438780 Background: Fruquintinib (F), a highly selective and potent oral inhibitor of VEGFRs 1, 2, and 3, significantly improved the OS in metastatic colorectal cancer ( Li J, et al, JAMA 2018; Dasari A, et al, LANCET 2023). FRUTIGA was a randomized, double-blind, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of F plus paclitaxel (PTX) vs PTX alone in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma who experienced disease progression (PD) on fluoropyrimidine- or platinum-containing first-line chemotherapy. Methods: Eligible pts were randomized 1:1 to receive F (4 mg, once daily, 3 weeks on/1 week off) or matching PBO orally, plus PTX (80 mg/m2, intravenously, days 1/8/15 per cycle) in 4-week cycles until PD or intolerable toxicity; treatment of PTX was allowed for up to 6 cycles. PFS and OS were dual-primary endpoints with α split and recycle. The study was considered positive when at least one endpoint met statistical significance. Results: 703 pts were randomized (F+PTX 351 vs PBO+PTX 352), and 699 pts received at least 1 dose of study drug (350 vs 349). PFS was significantly improved with F+PTX vs PBO+PTX (median PFS [mPFS] 5.55m vs 2.73m; HR = 0.569; p &lt; 0.0001). The overall response rate was significantly higher in F+PTX group (42.5% vs 22.4%, p &lt; 0.0001). Median OS (mOS) was 9.63m with F+PTX and 8.41m with PBO+PTX (HR = 0.956; p = 0.6064). Given an imbalance of pts receiving subsequent antitumor therapies (F+PTX 52.7% vs PBO+PTX 72.2%), post-hoc analyses were performed using cox-proportional hazards model adjusting for subsequent antitumor therapies and baseline factors. Results showed a nominal statistically significant improvement in OS with F+PTX (HR range 0.793-0.828; p range 0.0105-0.0350 with different subsequent antitumor therapy factors). Furthermore, among pts with lymph node metastases and non-diffuse G/GEJ adenocarcinoma (190 vs 208), mPFS was even more prolonged (6.08m vs 2.69m; HR = 0.454; p &lt; 0.0001) and OS also showed a nominal statistically significant improvement (mOS 9.56m vs 7.85m; HR = 0.767; p = 0.0233). The most common TEAEs of Grade ≥ 3 were neutropenia (60.0% vs 36.4%), leukopenia (42.9% vs 23.5%), and anemia (11.7% vs 10.6%). The safety profile was consistent with F and PTX. No new safety signals were identified. Conclusions: FRUTIGA (NCT03223376) was a positive study by reaching statistical significance for one primary endpoint, PFS, and demonstrated improvement in the other primary endpoint, OS, that was not statistically significant, possibly due to the imbalance of subsequent antitumor therapies. These data support F+PTX as a potential new second-line treatment option for pts with advanced G/GEJ adenocarcinoma. Clinical trial information: NCT03223376 .

Fruquintinib plus oxaliplatin combined with S-1 (SOX) as neoadjuvant therapy for locally advanced gastric cancer (GC) or gastro-oesophageal junction adenocarcinoma (GEJ): a multicentre, phase II, single-arm, open-label clinical trial (FRUTINEOGA) protocol

IntroductionCuring locally advanced gastric cancer (GC) or gastro-oesophageal junction adenocarcinoma (GEJ) with surgery alone is challenging. Neoadjuvant chemotherapy (NCT) has become the standard treatment for patients with locally advanced GC/GEJ,...

Evidence to Date on the Therapeutic Potential of Zolbetuximab in Advanced Gastroesophageal Adenocarcinoma.

Gastric adenocarcinoma (GAC) continues to be a prevalent worldwide malignancy and a leading cause of cancer death, and it is frequently cited as incurable. Targeted therapy in GAC has lagged behind other solid tumors. The human epidermal growth factor receptor-2 (HER-2) represented the single target in GACs for many years, seen in approximately 20% of patients with advanced GAC. Recent advances in management now include the addition of immunotherapy checkpoint inhibition to select front-line advanced GACs. Unfortunately, outcomes remain poor for most patients. We anticipate finding a key to future discoveries in GACs in next-generation sequencing and more targeted approaches. Claudin 18.2 (CLDN18.2) has emerged as a therapeutic target in GACs. CLDN18.2 is reportedly expressed in 14-87% of GACs, and CLDN18.2 is available for monoclonal antibody (mAb) binding as it is expressed on the outer cell membrane. Here, we review the exploration of CLDN18.2 as a target in GACs via the use of zolbetuximab (IMAB362). Zolbetuximab is now under priority FDA review for GACs, and we eagerly await the review outcome.

Tislelizumab plus chemotherapy (chemo) versus placebo plus chemo as first-line treatment for locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: RATIONALE-305 European/North American patient subgroup.

330 Background: Tislelizumab (TIS), an anti-programmed cell death protein 1 monoclonal antibody, plus chemo, demonstrated significant overall survival (OS) benefit vs placebo (PBO) plus chemo (15.0 vs 12.9 months [mo], hazard ratio [HR]=0.80, 95% confidence interval [CI]: 0.70, 0.92, P=0.0011) as first-line therapy in patients (pts) with advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) in the randomized, double-blind, global, phase 3 RATIONALE-305 study (NCT03777657). Here we present results from the European/North American (Eu/NA) pts subgroup analysis. Methods: This double-blind, global, phase 3 study evaluated adult pts with previously untreated, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable, or metastatic GC/GEJC, regardless of programmed death-ligand 1 (PD-L1) expression status. Eligible pts were randomized (1:1) to receive TIS 200 mg or PBO intravenously once every 3 weeks plus investigator chosen chemo (5-fluorouracil + cisplatin or capecitabine + oxaliplatin). The primary endpoint was OS in the PD-L1+ (patients with tumor area positivity score ≥5%) and intent-to-treat (ITT) analysis sets. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results: Of 997 pts enrolled, 249 (25.0%) were from Eu/NA (TIS plus chemo arm, n=125; PBO plus chemo arm, n=124). In the Eu/NA pts subgroup, after a minimum follow-up of 26.6 mo at final analysis, TIS plus chemo resulted in OS improvements vs PBO plus chemo in the PD-L1+ (HR=0.75, [95% CI: 0.52, 1.07]; 24 mo rate 27.6% vs 12.5%) and ITT analysis sets (HR=0.71, [95% CI: 0.54, 0.94]; 24 mo rate 27.6% vs 13.6%). TIS plus chemo resulted in favorable PFS vs PBO plus chemo (HR=0.84, 95% CI: 0.63, 1.11), numerically higher ORR (36.0% vs 31.5%), and longer DoR (median 7.5 mo [95% CI: 4.4, 12.0] vs 5.0 mo [95% CI: 3.9, 6.7]). Sixty (48.8%) pts in the TIS plus chemo arm and 61 (49.2%) pts in the PBO plus chemo arm experienced grade ≥3 treatment-related treatment-emergent adverse events (TRAEs). Sixteen (13.0%) and seven (5.6%) pts discontinued treatment due to TRAEs in the TIS plus chemo and PBO plus chemo arms, respectively. Deaths due to TRAEs occurred in two (1.6%) pts in the TIS plus chemo arm and one (0.8%) pt in the PBO plus chemo arm. Conclusions: TIS plus chemo showed OS benefit compared with PBO plus chemo and a manageable safety profile in pts in the Eu/NA subgroup with previously untreated, HER2-negative, locally advanced unresectable, or metastatic GC/GEJC. These findings are consistent with the published results in the overall study population. Clinical trial information: NCT03777657 .

Fruquintinib combined with sintilimab as a second-line therapy for advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC): A phase II, single-arm, prospective study.

332 Background: The KEYNOTE-061 trial showed that anti-PD-1 monotherapy did not improve overall survival compared to chemotherapy in the second-line treatment of advanced GC/GEJC. Preclinical and clinical data have demonstrated the synergistic anti-tumor effect of fruquintinib, a highly selective oral VEGFR 1/2/3 inhibitor, in combination with immune checkpoint inhibitors (ICIs). Additionally, the phase III study (NCT03223376) of fruquintinib combined with paclitaxel in second-line GC/GEJC has yielded positive topline results. This study aims to assess the safety and efficacy of fruquintinib combined with sintilimab (an anti-PD-1 antibody) as a second-line therapy for GC/GEJC. Methods: In this phase II, open-label trial (NCT05625737), patients (pts) aged 18-75 years who were HER2-negative and had failed first-line standard therapy were enrolled. Eligible pts received fruquintinib at 4mg/day orally on days 1-14 and sintilimab at 200 mg intravenously on day 1, with treatment repeated every 3 weeks. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. An optimal Simon two-stage design was employed: if more than 1 pt achieved objective responses in the first stage (n = 7), the study would proceed to the second stage and enroll an additional 19 pts; otherwise, the study would be terminated. Results: At data cut-off (August 31, 2023), 7 pts were enrolled in the first stage and additional 7 pts in the second stage. Pts characteristics included: median age 50 (range 33–71); 29% male; 57% with ECOG PS 1; 57% with peritoneal metastasis, and 71% having previously received immunotherapy. Of the 12 pts evaluable for tumor response, 4 achieved partial responses, and 4 had stable disease, resulting in a confirmed ORR of 33.3% (95% CI: 9.9-65.1%) and a DCR of 66.7% (95% CI: 34.9-90.0%). The median PFS was 5.09 months (95% CI: 2.69–NA), while OS results were pending maturity. Grade 1-2 treatment-emergent adverse events (TEAEs) occurred in ≥20% of pts, including decreased white blood cell count (36%), hypertriglyceridemia (29%), abdominal pain (29%), decreased lymphocyte count (21%), and elevated aspartate transaminase and alanine transaminase (21%). Grade 3/4 TEAEs occurred in only one patient, consisting of increased blood bilirubin levels, aspartate transaminase elevation, and alanine transaminase elevation. No treatment-related deaths were reported. Conclusions: The combination of fruquintinib and sintilimab as a second-line therapy has demonstrated promising anti-tumor activity and an acceptable safety profile in pts with advanced GC/GEJC. The trial is ongoing, and further data analysis and reporting are anticipated. Clinical trial information: NCT05625737 .

Tislelizumab (TIS) plus chemotherapy (Chemo) vs placebo (PBO) plus chemo as first-line (1L) treatment of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC): Health-related quality of life (HRQoL) outcomes in the RATIONALE-305 study.

290 Background: RATIONALE-305 (NCT03777657), demonstrated statistically significant and clinically meaningful improvements in overall survival (OS) with TIS + chemo (n=501) over PBO + chemo (n=496) as 1L treatment in patients (pts) with advanced G/GEJC. This analysis examined HRQoL outcomes of the RATIONALE-305 study at final analysis. Methods: Adults with previously untreated, unresectable, or metastatic GC/GEJC, were randomized (1:1) to TIS 200 mg or PBO IV once every 3 weeks plus investigator-choice of chemo. HRQoL was assessed using EORTC QLQ-C30 and the QLQ-STO22. A mixed model for repeated measures using PRO endpoints at clinical Cycles 4 and 6 was performed. Time to deterioration was examined. Results: TIS + chemo had improved outcomes than PBO + chemo (Table) as indicated by least-squares mean change from baseline to Cycle 6 for QLQ-C30 GHS/QoL (2.52 [95% CI:0.29 to 4.74]), physical functioning (2.46 [95% CI: 0.49 to 4.43]), fatigue (-3.01 [95% CI: -5.78 to -0.24]), and the STO22 index score (-1.62 [95% CI: -3.12 to -0.12]), as well as maintaining upper gastrointestinal (GI) symptoms (-1.74 [95% CI: -3.55 to 0.06)] and pain (-1.88 [95% CI: -4.03 to 0.27]). Pts receiving TIS + chemo had a lower risk for deterioration of GHS/QoL (0.77 [95% CI: 0.60 to 0.98]), physical functioning (0.72 [0.57 to 0.92]), STO22 index score (0.64 [0.45 to 0.92]), pain/discomfort (HR: 0.74 [0.58-0.96]), and upper GI symptoms (0.73 [0.56 to 0.95]). Conclusions: Pts treated with TIS + chemo had better HRQoL outcomes vs pts treated with PBO + chemo, particularly for GHS/QoL, physical functioning, fatigue, GC/GEJC symptoms, pain/discomfort, and upper GI symptoms These results, along with prolonging of OS and other secondary efficacy endpoints, as well as a tolerable safety profile, support the benefit of TIS + chemo as a potential 1L treatment option for GC/GEJC. Clinical trial information: NCT03777657 . [Table: see text]