Targeting claudins in gastric cancer: A novel GLOWing strategy in the SPOTLIGHT.

4056 Background: Ramucirumab as monotherapy or in combination with paclitaxel is a second-line treatment option recommended for patients with locally advanced unresectable or metastatic gastroesophageal junction (GEJ) or gastric adenocarcinoma. However, real-world data of large samples focused on ramucirumab plus paclitaxel in gastric cancer are limited. We conducted a nationwide retrospective study to evaluate the efficacy, safety, and factors potentially associated with survival in patients with gastric or GEJ adenocarcinoma who received second-line ramucirumab plus paclitaxel in a real-world setting. Methods: The study population comprised all patients with gastric or GEJ cancer who received ramucirumab plus paclitaxel in South Korea between May 1, 2018, and December 31, 2018. We included patients with advanced gastric or GEJ adenocarcinoma and disease progression after first-line platinum and fluoropyrimidine-containing combination chemotherapy. Results: A total of 1,063 patients with advanced gastric or GEJ adenocarcinoma who received ramucirumab plus paclitaxel were included. The objective response rate and disease control rate were 15.1% and 57.7%, respectively; the median progression-free survival was 4.03 months (95% CI, 3.80–4.27), and the median overall survival was 10.3 months (95% CI, 9.33–10.73). The common treatment-related adverse events (TRAEs) at any grade were neutropenia (44.7%), anemia (41.8%), neuropathy (29.1%), fatigue (25.9%), and anorexia (25.0%). Grade 3 or higher TRAEs with incidences of ≥5% were neutropenia (35.1%) and anemia (10.5%). Adverse events of special interest were infrequent, including hypertension (2.1%) and proteinuria (3.0%). Based on multivariate analysis, overall survival was negatively associated with Eastern Cooperative Oncology Group performance status ≥2, weight loss in the previous 3 months ≥10%, GEJ of primary tumor, poor or unknown histology grade, number of metastatic sites ≥3, presence of peritoneal metastasis, no prior gastrectomy, and time to second-line since first-line treatment < 6 months. Conclusions: Our large-scale, nationwide, real-world data analysis of an unselected real-world population added evidence for the efficacy and safety of second-line ramucirumab plus paclitaxel in patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Clinical trial information: NCT04192734.

The classical cadherin (CDH), claudin (CLDN) and nectin families of transmembrane-type adhesion molecules are located at adherens or tight junctions in epithelial cells but diffuse to the nonjunctional cell surface in solid tumors with epithelial–mesenchymal plasticity. Human/humanized antibody-drug conjugates (ADCs) with chemical linkers and cytotoxic payloads have been developed for the treatment of malignancies. Here, the clinical development of ADCs that target CDH6, CDH17, CLDN6, CLDN18.2 and NECTIN4 is reviewed. Enfortumab vedotin is an NECTIN4-targeting antibody-drug conjugate that is approved for the treatment of urothelial cancer, whereas other ADCs or derivatives that target NECTIN4, such as bulumtatug fuvedotin, SHR-A2102 and zelenectide pevedotin, are being studied in randomized phase III clinical trials. In contrast, arcotatug tavatecan, garetatug rezetecan, sonesitatug vedotin and tecotabart vedotin are anti-CLDN18.2 ADCs in phase III clinical trials for the treatment of CLDN18.2-positive gastric or gastroesophageal junction adenocarcinomas, and raludotatug deruxtecan is an anti-CDH6 ADC in a phase II/III clinical trial for the treatment of platinum-resistant ovarian cancer. ADCs that target cell-cell adhesion molecules are a rapidly emerging class of cancer therapeutics, and bispecific ADCs and longitudinal companion diagnostics are emerging to further improve the clinical benefits of conventional ADCs.

$169.99DavidKerrRebeccaJohnsonImmunotherapy for Gastrointestinal Cancer2017SpringerNew York, New York252ISBN: 978-3-319-43061-4. Web address for ordering:www.springer.com

Trastuzumab with cisplatin and fluoropyrimidine is the standard treatment in metastatic HER2-positive gastric or gastroesophageal (GE) junction adenocarcinoma; however, there is limited data on the efficacy of trastuzumab in combination with a three-drug regimen in this setting. We examined the efficacy and safety of modified docetaxel, cisplatin and 5 fluorouracil (mDCF) plus trastuzumab in a single-arm multicenter phase II trial. Previously untreated patients with HER2-positive metastatic gastric or GE junction adenocarcinoma were treated with mDCF and trastuzumab every 2weeks. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included objective response rate, overall survival (OS), and toxicity. We enrolled 26 patients with metastatic HER2-positive gastric or GE junction adenocarcinoma between February 2011 and June 2015. The median age of patients was 62years; 96% had a Karnofsky performance status equal to or greater than 80%. With a median follow-up of 25.4months, the 6-month PFS was 73% (95% CI 51-86%). The objective response rate was 65%, the median PFS was 13months (95% CI 6.4-20.7) and the median OS was 24.9months (95% CI 14.4-42.5). Grade 3/4 toxicities included neutropenia (42%), fatigue (23%), and hypophosphatemia (15%). There were no episodes of febrile neutropenia. The combination of mDCF and trastuzumab is effective and safe in patients with metastatic HER2-positive gastric or GE junction adenocarcinoma and can be considered as an option for selected patients. This trial is registered at ClinicalTrials.gov, number NCT00515411.

TPS4182 Background: A large proportion of patients (pts) with gastric cancer present with locally advanced or metastatic disease, which is linked with poor survival. Platinum- and fluoropyrimidine-based doublet chemotherapy (CTx) remains the standard of care in advanced gastric cancers. Based on recent clinical data, immuno-oncology (IO) agents plus CTx can improve overall survival (OS) in pts with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who have human epidermal growth factor receptor 2 negative/low expression (HER2–) and have not been previously treated for advanced/metastatic disease. GEMINI-Gastric (NCT05702229) is a phase 2, open-label, multidrug, multicenter, master protocol study designed to assess the efficacy, safety, tolerability, pharmacokinetics (PK), and immunogenicity of multiple novel IO + CTx combination therapies in this setting. Methods: Adults (≥18 years) with previously untreated HER2– locally advanced unresectable, or metastatic gastric or GEJ adenocarcinoma are eligible. Pts should have measurable target disease per RECIST v1.1 and an ECOG performance status of 0–1. The GEMINI-Gastric design allows assessment of multiple novel agents plus CTx in different substudies (Table). Novel agents include: volrustomig, an anti-PD-1/CTLA-4 bispecific humanized IgG1 monoclonal antibody (mAb); rilvegostomig, an anti-PD-1/TIGIT bispecific humanized IgG1 mAb; AZD0901, a claudin18.2-targeted antibody-drug conjugate; and AZD7789, an anti-PD-1/TIM-3 bispecific mAb. Co-primary endpoints are objective response rate and progression-free survival (PFS) at 6 months by investigator assessment per RECIST v1.1. Secondary endpoints include safety, duration of response, PFS, OS, PK, and immunogenicity. Sample sizes have been selected to provide adequate precision for the primary endpoints. The study is currently recruiting at sites in the US, Europe, and Asia. Clinical trial information: NCT05702229 . [Table: see text]

Gastric cancer, including gastroesophageal junction cancer, is one of the most commonly diagnosed cancers worldwide, with high mortality. Sugemalimab is a fully human anti-programmed death-ligand 1 (PD-L1) antibody. The combination of sugemalimab and chemotherapy showed promising antitumor activity and safety in a phase 1b study among patients with treatment-naive, unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. This combination was further evaluated in the GEMSTONE-303 phase 3 trial. To evaluate the efficacy of sugemalimab in combination with capecitabine and oxaliplatin (CAPOX) compared with placebo plus CAPOX as first-line treatment for patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 combined positive score (CPS) of 5 or greater. GEMSTONE 303 is a phase 3, randomized, double-blind, placebo-controlled study conducted at 54 sites in China that enrolled patients from April 9, 2019, through December 29, 2021, with follow-up to July 9, 2023. A total of 479 eligible patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS of 5 or greater who did not receive any prior systemic therapy were randomized. Patients received sugemalimab (1200 mg intravenously) (n = 241) or placebo (n = 238) every 3 weeks for up to 24 months, plus CAPOX every 3 weeks for up to 6 cycles. Primary outcomes were overall survival and investigator-assessed progression-free survival. Baseline characteristics were well balanced between the 2 groups. Most patients were male (71.4% in sugemalimab group, 74.8% in placebo group). Median follow-up was 25.1 months in the sugemalimab group and 26.3 months in the placebo group. The sugemalimab group demonstrated significant improvements in overall survival (median, 15.6 months [95% CI, 13.3-17.8] vs 12.6 months [95% CI, 10.6-14.1]; hazard ratio, 0.75 [95% CI, 0.61-0.92]; P = .006) and progression-free survival (median, 7.6 months [95% CI, 6.4-7.9] vs 6.1 months [95% CI, 5.1-6.4]; hazard ratio, 0.66 [95% CI, 0.54-0.81]; P < .001). Grade 3 or higher treatment-related adverse events occurred in 53.9% of patients in the sugemalimab group and 50.6% in the placebo group. Sugemalimab plus chemotherapy significantly prolonged overall survival and progression-free survival with a manageable safety profile in previously untreated patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. ClinicalTrials.gov Identifier: NCT03802591.

Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial

BackgroundCLDN18.2 is a tetraspanin family member, highly expressed in gastric, oesophageal and pancreatic cancer.1 2 CLDN18.2-targeted therapeutic approaches, including combination with chemotherapy, have demonstrated benefit in gastric cancer.3 4 AZD5863...

Biotin ligase tagging with ZO-1 was applied to identify a more complete tight junction proteome. Identical but also different proteins and functional networks were identified near the N and C ends of ZO-1. The ends of ZO-1 are embedded in different functional subcompartments of the tight junction. Biotin tagging with ZO-1 expands the tight junction proteome and defines subcompartments of the junction. The proteins and functional protein networks of the tight junction remain incompletely defined. Among the currently known proteins are barrier-forming proteins like occludin and the claudin family; scaffolding proteins like ZO-1; and some cytoskeletal, signaling, and cell polarity proteins. To define a more complete list of proteins and infer their functional implications, we identified the proteins that are within molecular dimensions of ZO-1 by fusing biotin ligase to either its N or C terminus, expressing these fusion proteins in Madin-Darby canine kidney epithelial cells, and purifying and identifying the resulting biotinylated proteins by mass spectrometry. Of a predicted proteome of ∼9000, we identified more than 400 proteins tagged by biotin ligase fused to ZO-1, with both identical and distinct proteins near the N- and C-terminal ends. Those proximal to the N terminus were enriched in transmembrane tight junction proteins, and those proximal to the C terminus were enriched in cytoskeletal proteins. We also identified many unexpected but easily rationalized proteins and verified partial colocalization of three of these proteins with ZO-1 as examples. In addition, functional networks of interacting proteins were tagged, such as the basolateral but not apical polarity network. These results provide a rich inventory of proteins and potential novel insights into functions and protein networks that should catalyze further understanding of tight junction biology. Unexpectedly, the technique demonstrates high spatial resolution, which could be generally applied to defining other subcellular protein compartmentalization.

Patients with locally advanced inoperable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma have a poor prognosis. The maximum benefit of systemic chemotherapy is usually achieved in the first-line setting. Even though systemic chemotherapy has been used for long time, in view of unsatisfactory results, no standard regimen has been emerged. Unfortunately, till date, there is no published prospective data from India, comparing the two most commonly used triplet regimens, epirubicin, cisplatin plus 5-fluorouracil (ECF) and docetaxel, cisplatin plus 5-fluorouracil (DCF), in this patient population. The present study aimed to compare the efficacy and safety of the first-line systemic chemotherapy with ECF and DCF regimens in locally advanced inoperable or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was overall survival (OS). The secondary endpoints were overall response rate, progression-free survival (PFS), and toxicity profile. Between January 2015 and December 2016, 58 patients were assigned and treated with ECF (n = 30) or DCF (n = 28) regimens. The median OS was 9.4 months with ECF and 12.5 months with DCF regimen (log-rank, P = 0.000), while median PFS was 5.8 and 7.5 months, respectively (log-rank, P = 0.002). Patients in the DCF arm had more frequent reductions in chemotherapy doses than those of the ECF arm (28.6% vs. 16.7%; P = 0.54). As compared with the ECF, the DCF regimen was associated with more frequent Grades 3-4 toxicities-neutropenia (16.7% vs. 39.3%, P = 0.17), febrile neutropenia (13.3% vs. 25%, P = 0.52), mucositis (6.7% vs. 17.8%, P = 0.43), and diarrhea (6.7% vs. 14.3%, P = 0.67). In comparison to ECF, the DCF regimen was associated with a statistically significant 3.1 months longer median OS without any significant increase in Grades 3-4 toxicities. DCF can be considered as one of the reference regimens, in properly selected patients with advanced/metastatic gastric or GEJ adenocarcinoma.

e16013 Background: Gastric cancer is the fifth most common cancer and third leading cause of cancer-related death in China, with about 90% classified as adenocarcinoma. Many patients (pts) also have gastroesophageal junction adenocarcinoma (GEJa). For most pts, diagnosis often occurs at an advanced stage. The aim of this observational, descriptive study was to understand the epidemiology, biomarker test results, clinical characteristics, and treatment patterns of unresectable locally advanced or metastatic (la/m) gastric adenocarcinoma (Ga) and GEJa in China. Methods: Electronic medical records dated January 2015–December 2022 from the China National Cancer Center Oncology Information Database were used. Eligible adults were diagnosed with la/m Ga and GEJa between January 2016 and June 2022. Demographic or clinical characteristics were assessed at index date (first diagnosis of la/m Ga or GEJa) or during the baseline (BL) period (1 year prior to and inclusive of index date). Biomarker test results were collected at BL and during the follow-up (f/u) period (until last hospital visit, occurrence of other primary cancer, participation in a clinical trial, or study termination, whichever came first). Treatments at f/u were also described. Results: From 2016–2022, 189,725 and 60,878 pts were diagnosed with Ga and GEJa, respectively, including 64,807 (34.2%) and 18,412 (30.2%) with late-stage (la/m) disease. A total of 22,156 la/m Ga pts and 6183 la/m GEJa pts met study criteria and are described henceforth; 67.0% and 82.9%, respectively, were male, and mean (SD) age at diagnosis of la/m disease was 59.0 (12.3) and 64.5 (10.1) years. Of pts with HER2 biomarker test results at BL, 309/3348 (9.2%) la/m Ga pts and 142/1087 (13.1%) la/m GEJa pts were HER2-positive (per IHC 2+/3+ or FISH); of pts with ≥1 HER2 test result at f/u, 895/7388 (12.1%) la/m Ga pts and 373/2162 (17.3%) la/m GEJa pts were HER2-positive. Of pts with PD-L1 combined positive score (CPS) test results at BL, 176/385 (45.7%) la/m Ga pts and 64/149 (43.0%) la/m GEJa pts had CPS ≥5; of pts with ≥1 PD-L1 CPS test result at f/u, 727/1539 (47.2%) la/m Ga pts and 229/513 (44.6%) la/m GEJa pts had CPS ≥5. First- (1L) and second-line (2L) treatments were recorded for a subset of pts. Oxaliplatin + tegafur was the most common 1L treatment, received by 3431/14,386 (23.8%) la/m Ga pts (median treatment duration: 2.9 mo [IQR: 1.4–5.6]) and 921/4335 (21.2%) la/m GEJa pts (2.8 mo [IQR: 1.4–5.4]). Chemotherapy with an anti-VEGF drug (apatinib) was the most common 2L treatment, received by 795/5495 (14.5%) la/m Ga pts (median treatment duration: 1.8 mo [IQR: 1.0–3.5]) and 276/1827 (15.1%) la/m GEJa pts (2.2 mo [IQR: 1.2–3.9]). Conclusions: Treatment patterns suggest an ongoing need to improve the care of la/m Ga and GEJa in China.

Immune checkpoint inhibitors are new targeted treatments that harness the body's immune system to attack cancers. Drugs that are most extensively used among checkpoint inhibitors inhibit the PD-L1 or PD-1 (programmed death 1) ligand or receptor pair and are currently approved for many cancer indications. In gastric or gastroesophageal junction adenocarcinomas one inhibitor, pembrolizumab has regulatory approval for PD-L1 positive carcinomas. This meta-analysis investigates available data on the efficacy of PD-L1 or PD-1 inhibitors as a class in gastric or gastroesophageal junction adenocarcinomas. The literature was reviewed to identify clinical studies that included arms with PD-L1 or PD-1 inhibitors as monotherapy in gastric or gastroesophageal junction adenocarcinomas. Relevant patient characteristics, outcomes, and adverse effects were recorded. Summary estimates of response rates (RR) and survival were calculated using a random or fixed effect model, depending on heterogeneity. Six studies with a total of 1068 patients were included in the analysis. The summary RR was 10.63% (95% confidence interval (CI) 5.36–15.89%). The summary disease control rate (DCR) was 28.11% (95% CI 24.60–31.63%). Summary progression-free survival (PFS) was 1.59 months (95% CI 1.24–1.94 months). Summary overall survival (OS) was 5.72 months (95% CI 0–12.19 months). A subset of patients derived long-term benefits as seen in other cancer locations. The adverse effect rate was low and consistent with that in other disease locations. Low efficacy of immune checkpoint inhibitors as a class in gastric or gastroesophageal junction adenocarcinomas is observed in this analysis and stresses the need for effective biomarker use for the identification of most probable responders.How to cite this article: Voutsadakis IA. A Systematic Review and Meta-analysis of PD-1 and PD-L1 Inhibitors Monotherapy in Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma. Euroasian J Hepato-Gastroenterol 2020;10(2):56–63.

Canada’s Drug Agency (CDA-AMC) recommends that Enhertu be reimbursed by public drug plans for second-line treatment of adult patients with unresectable locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior anti-HER2–based regimen, if certain conditions are met. CDA-AMC previously reviewed Enhertu for the second-line treatment of adult patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2–based regimen and issued a recommendation of time-limited reimbursement. This is a reassessment based on additional evidence to address the uncertainties in the original data. This recommendation supersedes the previous recommendation for this drug and indication dated April 23, 2025. The pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommended that Enhertu continue to be reimbursed by the participating drug programs in accordance with the initiation, discontinuation, and prescribing criteria that were previously recommended. The sponsor has satisfied the reassessment requirements, and the time-limited condition has been removed from the recommendation. Evidence from a clinical trial showed that Enhertu likely results in added clinical benefit in overall survival (OS) and may delay disease progression, compared with ramucirumab plus paclitaxel, in patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2–based regimen. Evidence from an indirect treatment comparison suggested that Enhertu may offer survival and disease control benefits compared to leucovorin (folinic acid), fluorouracil, and irinotecan (FOLFIRI), paclitaxel, irinotecan, and docetaxel. However, the clinical value was uncertain due to the methodological limitations of the indirect comparisons. Enhertu meets some patient needs, given that it is an alternative treatment option that may offer benefits in disease control and life prolongation. Enhertu should only be covered to treat adult patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have previously received anti-HER2–based treatment for locally advanced or metastatic disease, are in relatively good health, and do not have symptomatic spinal cord compression, clinically active central nervous system metastases, or current interstitial lung disease (ILD) or pneumonitis. Enhertu should only be reimbursed if it is prescribed by clinicians with experience and expertise in treating gastric or GEJ adenocarcinoma and if the cost of Enhertu is reduced.

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial

334 Background: For initially unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, the prognosis is poor and chemotherapy is the main treatment option. The AIO-FLOT3 Trial suggested that conversion therapy might improve outcome in pts with limited metastatic gastric cancer (GC). We conducted this prospective, single-arm, phase II trial to improve conversion efficacy of PD-1 inhibitor Cam combined with Nab-POF regimen (nab-paclitaxel , oxaliplatin, fluorouracil) in pts with initially unresectable locally advanced or limited metastatic gastric or gastroesophageal junction adenocarcinoma. Methods: Eligible pts received Cam 200mg, nab-PTX 125 mg/m 2 , oxaliplatin 85 mg/m 2 or with trastuzumab if Her2 positive, each was an IV followed by fluorouracil 2400 mg/m 2 as a 48-h continuous IV on day 1, every 2 weeks. Patients were assessed for tumor response and surgical feasibility every 3 cycles, and if confirmed feasible for surgical resection by both surgical and medical experts after 6 cycles, they would undergo surgery within 3-6 weeks. The primary endpoint was R0 resection rate. Results: In total, 53 pts were enrolled up to 01/2024. 52 pts were evaluable. 50% are younger than 65 years of age. Male was 73.1%. The metastatic sites included liver 46.2% (24), retroperitoneal lymph nodes 40.4% (21), Krukenberg 5.8% (3), and locally advanced unresectable tumors 21.2% (11). 4 pts (7.7%) were dMMR/MSI-H and 10 (19.2%) were Her2 positive. ORR was 88.5% (46/52) and DCR was 98.1% (51/52). 45(86.5%) pts were assessed as resectable. 3 pts (6.8%) refused surgery and 3 (6.8%) were cCR under observation. The R0 resection rate was 75.0% (39/52). CR rate was 23.1% (cCR, 5.8%; pCR,17.3%). The mPFS was not reached (95% CI = 17.0-NE), and the mOS was not reached (95% CI = 25.4-NE), either. The 3-year PFS and OS rate were 56.9% (95% CI = 45.7%-86.3%) and 62.8% (95% CI = 41.6%-78.0%), respectively. The 3 cCR pts have survived utill the last follow-up date of 07/2025 without tumors for 17, 29, and 34 months, respectively. Pts tolerated treatment well, although all pts experienced treatment-related adverse events (AE). Grade 3/4 AEs were 42.3% (22/52) and neutrophil decrease was the most common at 36.5%. 10 patients (19.2%) experienced immune related AEs (irAEs), and 2 of them experienced grade 3 irAEs. Conclusions: The PD-1 inhibitor Cam combined with the Nab-POF regimen safely induced a high conversion rate with very high R0 resection and high 3-year PFS and OS rates, preliminarily demonstrating promising effects, providing a new conversion drug treatment option for pts with initially unresectable locally advanced or limited metastatic advanced GC. These findings warrant further prospective, randomized controlled investigations. Clinical trial information: NCT04510064 .