Gastroesophageal Junction Cancer Research Articles

457. EVALUATING THE ACCURACY OF CLINICAL SIEWERT CLASSIFICATION, A RETROSPECTIVE REVIEW OF 807 PATIENTS

Abstract Background Adenocarcinoma of the gastro-esophageal junction (GEJ) is increasingly common in Western societies. GEJ tumours are typically categorized using the Siewert classification, which divides the tumours in to 3 types based on location relative to the GEJ. Studies have shown that there is improved survival with a proximal surgical resection such as esophagectomy for type 1 tumours while type 3 tumours have improved survival when managed as other gastric cancers with a total or extended total gastrectomy. This requires accurate clinical classification. This study aims to evaluate the accuracy of commonly used staging modalities in the clinical classification of GEJ tumours. Methods A review of 807 consecutive patients undergoing curative resection for GEJ cancer was performed. Patient data was obtained from a prospectively maintained database between February 2010 and April 2023. Siewert type was established clinically as part of the staging process. The standard staging modalities used for every patient included computerized tomography (CT) and endoscopy, with most patients also undergoing positron emission tomography (PET). Endoscopic ultra-sonography (EUS) and staging laparoscopy was also used selectively. Accuracy was determined by comparing clinical classification to pathological classification following surgery. Results 807 patients were included [319 type 1, 401 type 2, 87 type 3]. Clinical classification was the same as pathological classification in 59.5% of cases [69.6% for type 1, 48.6% for type 2, 71.3% for type 3 (p<0.001). The use of different staging modalities for each sub-type is presented in table 1. For patients that underwent EUS, Siewert type was accurate in 59.4% of cases overall. The failure rate for EUS was 2.9%. For patients undergoing staging laparoscopy Siewert type was accurate in 69.3% and for patients that underwent PET, EUS and staging lap the accuracy was 74.4%. Conclusion Accurately determining Siewert type clinically is challenging. This is particularly relevant for type 2 tumours which had the least accurate comparison of clinical to pathological type. The use of additional modalities including EUS, and staging laparoscopy improves accuracy but may not be feasible in all patients.

464. OUTCOMES AFTER CURATIVE RESECTION FOR GASTRO-ESOPHAGEAL JUNCTION ADENOCARCINOMA

Abstract Background Gastro-Esophageal Junction (GEJ) adenocarcinoma is becoming increasingly common in the west. Given the anatomical location of the junction there are several surgical approaches that can be used to treat these tumours, this is often guided by the sub-type of tumour, categorised using the Siewert classification. While overall survival for GEJ cancer tends to be poor compared with other solid organ cancers, changes in diagnosis and treatment have led to improvements in recent years. This study represents one of the largest retrospective reviews of its type to focus on the short- and long-term outcomes of patients undergoing curative resection for GEJ cancer. Methods Information was collected on 807 consecutive patients undergoing curative resection for gastro-esophageal junction adenocarcinoma between February 2010 and April 2023. The primary outcome was overall 5- and 10-year survival. Secondary outcomes included: disease free survival, survival based on surgical resection, 30- and 90-day mortality, post operative complications, oncology and pathology outcomes. For each outcome overall results and analysis comparing Siewert types was performed. Results 807 patients were included [319 type I cancers (39.5%), 401 type II (50%) and 87 type III (10.8%)]. Type I and II were predominantly managed with Esophagectomy (Type I = 100%, Type II = 97.5%). For Type III tumours 49% had esophagectomy and 51% had either a total or extended total gastrectomy. Siewert groups had comparable short-term outcomes, presented in table 1. Overall survival was 46% at 5 years and 37% at 10 years with no significant difference between Siewert types (p=0.24). Disease free survival was 55% at 5 years and 50% at 10 years with no significant difference between Siewert type (p=0.34). Conclusion The 3 Siewert classification subtypes of gastro-esophageal junction adenocarcinoma have similar short-term outcomes, overall and disease-free survival.

Perioperative FLOT + immunotherapy for resectable gastric and gastroesophageal junction cancer: A systematic review and meta-analysis.

66 Background: The current standard of care for resectable gastric and GEJ cancers is perioperative chemotherapy with FLOT.Although its benefits in improving rates of pathologic complete response, increasing prospects of R0 resection, and improving survival have been proven, efforts to find novel strategies which can improve on its gains continue.The addition of an immune checkpoint inhibitor to FLOT has been a focal point of research in this field. This meta-analysis evaluated high-quality data from clinical trials to determine the efficacy of this chemoimmunotherapy combination. Methods: A systematic search of English-language articles on PubMed, Cochrane and Google scholar was done to identify randomized trials investigating the use of perioperative FLOT and immune checkpoint inhibitors in the treatment of resectable gastric and GEJ cancer. Quality of studies was assessed using the Revised Cochrane risk-of-bias tool for randomized trials. Inverse variance was the statistical method used with random effects as the analysis model in the production of the Forest plot and calculation of odds ratio at 95% CI. Results: Three RCTs (N = 1446), each with two arms, were included in the meta-analysis. The Phase II Dante Trial (N= 295)compared perioperative FLOT alone with perioperative atezolizumab + FLOT. The Phase III Keynote 585 trial(N=203) and the phase III Matterhorn trial (N=948) compared perioperative placebo + FLOT with perioperative pembrolizumab + FLOT, and perioperative Durvalumab + FLOT, respectively. Risk of bias and heterogeneity were low. Pooled results showed that in patients given perioperative FLOT + immunotherapy, there is statistically significant improvement in the rate of pathologic complete response (OR 2.60 95% CI 1.88-3.61, p <0.0001). In terms of rate of R0 resection, there was no statistically significant difference between the two groups (OR 1.02 95% CI 0.75-1.38,p= 0.92). Conclusions: This analysis shows that adding immunotherapy to FLOT improves the rate of pathologic complete response, and maintains the high rate of R0 resection, in resectable gastric and GEJ cancers. Favorable results of pending survival outcomes from these trials may help re-shape the current standard of care in this field.

A single-arm, exploratory study of disitamab vedotin (DV) combined with camrelizumab and platinum-based chemotherapy as first-line treatment in patients with HER2 expressing locally advanced or metastatic esophageal squamous cell carcinoma (ESCC).

TPS217 Background: Esophageal cancer (EC) is one of the most common cancers worldwide with esophageal squamous cell carcinoma (ESCC) being the predominant histological subtype. PD-1 blockades combined with chemotherapy are now standard-of-care in first-line setting for patients with ESCC. HER2 expression, prevalent in an estimated 7.6% to 28.5% of ESCC cases, correlates with diminished overall survival, suggesting HER2-targeted therapy as a potential novel approach. To our knowledge, there is currently no clinical trial regarding anti-HER2 therapy in ESCC. Clinical evidence has suggested the potential synergistic anti-tumor effect of Disitamab Vedotin (DV) with PD-1 inhibitors in HER2-expressing gastric or gastroesophageal junction (G/GEJ) cancers. This single-arm, exploratory study aimed to evaluate the safety and preliminary anti-tumor activity of DV combined with camrelizumab and platinum-based chemotherapy in ESCC. Methods: This is a single-arm, exploratory study (NCT06055153). Approximately 20 patients will be enrolled in this study, phase 1 will initiate with a 3+3 dose-escalation scheme (2.5mg/kg to 2.0mg/kg) to identify dose-limiting toxicities (DLTs) and establish a safe dosage of DV. The expansion cohort will subsequently evaluate this dose for both efficacy and safety. The study population will included both male and female patients over the age of 18 with histologically confirmed ESCC, and locally advanced unresectable, recurrent unresectable or metastatic EC verified by imaging examination. This group also includes those patients who have experienced relapse or progression more than six months post the conclusion of last therapeutic regimen. Required HER2 expression levels in tumor specimens range from IHC 1+ to 3+. According to RECIST v1.1, participants must have at least one measurable lesion, an ECOG performance status of 0 or 1, and a minimum expected survival of 12 weeks with suitable organ function. Treatment protocol includes intravenous administration of DV (either 2.5 mg/kg or 2.0 mg/kg on day 1), Camrelizumab (200 mg on day 1), and Cisplatin (75mg/m2) or Nedaplatin (75mg/m2) on a 21-day cycle, continued until disease progression or the advent of unacceptable toxicity. The primary outcomes for evaluation are DLT for safety and the objective response rate (ORR) for efficacy. Adverse events will be monitored in accordance with the CTCAE 5.0 criteria. Secondary endpoints encompass progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), and time to response (TTR). Clinical trial information: NCT06055153 .

Cerebral arterial air embolism after esophageal stenting for recurrence of gastroesophageal junction cancer: a case report.

Cerebral arterial air embolism (CAE) is a rare complication after esophageal stenting, but it can be life-threatening. It is especially a concern for those with a history of previous gastrointestinal cancer therapies. We report a case of CAE after esophageal stenting in a patient with recurrent gastroesophageal junction cancer and a history of multiple cancer treatments. A 71year-old man with a history of a proximal gastrectomy, resection of the lower esophagus, chemotherapy, and radiation presented to our hospital 2weeks after stenting with epigastric and back pain. Mediastinitis was suspected and conservative treatment was begun. The patient suddenly developed altered mental status, left hemiplegia, and anisocoria after drinking water. A brain computed tomography (CT) revealed right-sided predominance of multifocal CAE. Chest and abdominal CT showed a hematoma in the gastric and duodenal wall and an intraluminal hematoma from the esophagus, around the stent, to the upper ileum. CAE was thought to be due to rupture of the recurrent tumor. Unfortunately, despite intensive care, the patient died about 5h after the onset of neurological symptoms. It has been reported that prior treatments, such as chemotherapy and radiotherapy, increase the risk of life-threatening adverse events, including CAE after esophageal stenting. Clinicians should keep in mind the possibility of CAE after esophageal stenting in patients with a history of multiple cancer treatments.

Oligometastatic disease – a renaissance for surgery?

Abstract Half of the patients with esophageal cancer, cancer of the gastro-esophageal junction and gastric cancer present metastasis at the time of diagnosis. In addition, even patients originally thought to be free of metastasis will present metachronous metastasis in the course of the disease. These patients are considered incurable and current standard of care for metastatic esophageal, gastro-esophageal junction and gastric cancers is a systemic therapy without curative intention. However, patients presenting only a low metastatic load are now defined as oligometastatic disease and should benefit from an aggressive, multimodal therapy. We present here a review of recent publications investigating multimodal therapies for oligometastatic disease and showing that a systemic therapy combined with a resection of the primary tumor together with metastasis is associated with a better prognosis than a systemic therapy alone. We also give a precise focus on esophageal squamous cell carcinomas and adenocarcinomas of the gastro-esophageal junction and of the stomach. Interestingly, patients with oligometastatic cancer of the esophago-gastric junction can even be treated in curative intention with such a multimodal therapy as we present here in a short case report. In conclusion, new therapeutic strategies including multimodal approaches for oligometastatic disease have shown promising results in the last years and ongoing randomized prospective trials will provide us the evidence to include them in future European guidelines.

Pembrolizumab in combination with trastuzumab for treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer.

Gastric cancer remains a challenging malignancy with a high global mortality rate. Recent advances in targeted therapy and immunotherapy have shown promise in improving patient outcomes. This paper reviews the impact of incorporating targeted agents such as trastuzumab and immunotherapeutic agents like pembrolizumab into standard chemotherapy regimens for gastric cancer treatment. A comprehensive analysis was conducted on pivotal clinical trials, including KEYNOTE-590, KEYNOTE-811, and ToGA, focusing on their methodologies, patient populations, treatment regimens, and outcome measures. The review also explored emerging research avenues in precision medicine, particularly genomic sequencing and biomarker identification. To assess the efficacy and survival benefits of adding trastuzumab and pembrolizumab to standard chemotherapy in the treatment of gastric cancer and to outline future directions in gastric cancer research. Including trastuzumab and pembrolizumab in treatment regimens for human epidermal growth factor receptor 2 (HER2)-positive and PD-L1-expressing gastric cancers significantly improved progression-free and overall survival rates compared to chemotherapy alone. These findings highlight the potential of personalized therapy in enhancing treatment outcomes. Furthermore, ongoing research into the gastric cancer microenvironment and the role of the microbiome suggests novel targets for future therapeutic interventions. The integration of targeted and immunotherapeutic agents with traditional chemotherapy represents a pivotal shift in gastric cancer treatment, moving towards more personalized and effective regimens.

The Impact of D2 Versus D1 Lymphadenectomy in Siewert II Gastroesophageal Junction (GEJ) Cancer

BackgroundAlthough multiple treatment options exist for gastroesophageal junction (GEJ) cancer, surgery remains the mainstay for potential cure. Extended nodal dissection with a D2 lymphadenectomy (LAD) remains controversial for Siewert II GEJ cancer. Although D2 LAD may lead to a greater lymph node harvest, its effect on survival remains elusive. The authors hypothesized that additional D2 dissection in Siewert II GEJ cancer does not lead to increased survival.MethodsThis study reviewed Siewert II patients who received a D1 or D2 LAD in addition to minimally invasive esophagectomy (MIE) after receiving neoadjuvant chemoradiation or perioperative chemotherapy (2012–2022). The patients were followed for up to 5 years. The outcomes measured were survival, number of nodes sampled, and operative time. The association between D1 or D2 LAD and overall survival was analyzed with Kaplan-Meier methods and a multivariable Cox regression model.ResultsAmong 155 patients, 74 % underwent D1 and 26 % underwent D2 LAD. The patients with D2 had more than 15 lymph nodes harvested more frequently than those who had D1 (83 % vs 48 %; p < 0.001), with no difference in positive nodes (2.8 ± 5.2 vs 2.1 ± 4.2; p = 0.4). The patients with D2 LAD had a longer median operative time than those who with D1 LAD (362 vs 244 min; p < 0.001). In Kaplan-Meier and multivariable Cox regression models, overall survival did not differ significantly between the patients undergoing D2 and those who had D1 (adjusted hazard ratio [aHR], 0.52; 95 % confidence interval [CI], 0.25–1.00; p = 0.067).ConclusionsLittle consensus exists regarding the optimal lymph node harvest for GEJ cancers. In Siewert II cancer, D2 LAD may not be mandatory and may lead to increased operative morbidity with no significant difference in survival.

Does Radical Lymphadenectomy Improve Survival in Esophageal and Gastroesophageal Junction Cancer?

Background: Esophageal carcinoma is one of the deadliest cancer in gastrointestinal system with 5-years survival of only 24%. Lymphnode metastasis has been associated with worse outcome. But the extent of lymphnode dissection has been a debate among surgeons worldwide. This study aimed to compare the overall survival of patients undergoing radical and non-radical lymphadenectomy in a tertiary referral cancer hospital in Nepal. Methodology: This study included 634 patients of esophageal and gastroesophageal junction cancer who underwent surgical resection at our institution over a period of 2001- 2019. The patients were divided into 2 groups; radical lymphadenectomy (RLN) and non-radical lymphadenectomy (NRLN) groups. RLN group underwent two-field or three field lymphadenectomy for esophageal cancer and D2 or D2 + lower mediastinal lymphadenectomy for GEJ cancer. NRLN group underwent nodal sampling or D1 dissection. Results: RLN was performed in 85.9%. NRLN was done in 14.1%. Surgery alone was performed in 47.1% and multimodality approach in 52.9% cases. Median survival for RLN and NRLN groups was 34 and 15 months, respectively (p &lt; .001). Conclusion: Improved median survival has been observed after radical lymphadenectomy for esophageal and GEJ cancer.

Radiomics in Oesogastric Cancer: Staging and Prediction of Preoperative Treatment Response: A Narrative Review and the Results of Personal Experience.

Oesophageal, gastroesophageal, and gastric malignancies are often diagnosed at locally advanced stage and multimodal therapy is recommended to increase the chances of survival. However, given the significant variation in treatment response, there is a clear imperative to refine patient stratification. The aim of this narrative review was to explore the existing evidence and the potential of radiomics to improve staging and prediction of treatment response of oesogastric cancers. The references for this review article were identified via MEDLINE (PubMed) and Scopus searches with the terms "radiomics", "texture analysis", "oesophageal cancer", "gastroesophageal junction cancer", "oesophagogastric junction cancer", "gastric cancer", "stomach cancer", "staging", and "treatment response" until May 2024. Radiomics proved to be effective in improving disease staging and prediction of treatment response for both oesophageal and gastric cancer with all imaging modalities (TC, MRI, and 18F-FDG PET/CT). The literature data on the application of radiomics to gastroesophageal junction cancer are very scarce. Radiomics models perform better when integrating different imaging modalities compared to a single radiology method and when combining clinical to radiomics features compared to only a radiomics signature. Radiomics shows potential in noninvasive staging and predicting response to preoperative therapy among patients with locally advanced oesogastric cancer. As a future perspective, the incorporation of molecular subgroup analysis to clinical and radiomic features may even increase the effectiveness of these predictive and prognostic models.

Model-based population pharmacokinetic and exposure response analyses for safety and efficacy of nivolumab as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer.

Nivolumab is approved as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer (EC/GEJC) based on results from the pivotal CheckMate 577 trial. We present a model-based clinical pharmacology profiling and benefit-risk assessment of nivolumab as adjuvant treatment in subjects with resected EC/GEJC supporting a less frequent dosing regimen. Population pharmacokinetic (popPK) analysis was conducted to characterize nivolumab pharmacokinetics (PK) using clinical data from 1493 subjects from seven monotherapy clinical studies across multiple solid tumours. The exposure-response (E-R) analyses included data from 756 patients from CheckMate 577. E-R relationships for efficacy and safety were characterized by evaluating the relationship between nivolumab exposure and disease-free survival (DFS) for efficacy; and time to first occurrence of Grade ≥2 immune-mediated adverse events (Gr2 + IMAEs) for safety. Nivolumab exposure was found to be associated with both DFS and risk of Gr2 + IMAEs. However, the hazard ratios (HRs) (95% confidence interval [CI]) at the 5th and 95th percentiles of nivolumab exposure were similar for DFS and Gr2 + IMAEs, indicating flat E-R relationships within the exposure range produced by the studied regimen. Model-predicted probability of DFS and Gr2 + IMAEs were similar between the two regimens of 240 mg every 2weeks or 480 mg every 4weeks for 16 weeks followed by 480 mg Q4W up to 1year. The analyses demonstrated a flat E-R relationship over the range of exposures produced by the studied regimen and supported the approval of an alternative dosing regimen with less frequent dosing in patients with adjuvant EC/GEJC.

Clinical significance of combined therapy with immune checkpoint inhibitor in perioperative treatment for locally advanced gastric cancer or adenocarcinoma of gastroesophageal junction

The clinical application of immune checkpoint inhibitor (ICI) offers novel treatment modality for locally advanced gastric cancer (LAGC) and adenocarcinoma of the gastroesophageal junction (AGEJ), with the crucial benefit of providing higher cure rates. These agents have become part of standard treatments in the perioperative setting for selected cases, such as tumor with MSI-H/dMMR, high expression of CPS (≥5) or EBV (+), MSI-H and MSS/TP53+ according to tumor immunohistochemical, genetic testing or molecular characterization. An in-depth understanding of the immune response mechanisms in "cold" and "hot" tumors enables us to better identify ICI beneficiary and further provide a rationale for converting nonresponsive "cold" tumors into responsive "hot" tumors, subsequently allowing nonresponders to benefit from ICI immunotherapy. Several recent clinical trials clearly demonstrated a synergistic and complementary effect of combining ICI with chemotherapy or chemoradiotherapy, as well as combining ICI with anti-HER2 or anti-VEGF/VEGFR and chemotherapy. Compared with chemotherapy alone, the combination treatment can significantly improve pCR, MRR or ypT0N0, and is expected to improve the prognosis. This article reviews the results of a series of clinical trials in recent years in the field of perioperative application of ICI with other modalities in LAGC/AGEJ, aiming at expanding upon the discussion of current standard neoadjuvant and adjuvant therapies for LAGC/AGEJ and exploring the feasibility of new perioperative combined immunotherapy in the future.

Meta-analysis of the Efficacy and Safety of Pembrolizumab in the Treatment of Advanced Gastric Cancer and Gastroesophageal Junction Cancer.

●Introduction: Pembrolizumab have been approved for the first-line treatment of patients with advanced gastric cancer (GC) and gastroesophageal junction (GEJ) cancer. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced GC/GEJ still needs to be precisely determined. ●Purpose: The aim of this meta-analysis was to assess the efficacy and safety of pembrolizumab in the treatment of advanced GC/GEJ. ●Methods: We conducted computerized searches across multiple databases, including PubMed, Cochrane Library, Web of Science, and Embase. We established the inclusion criteria to comprise randomized clinical trials examining the efficacy of pembrolizumab in late-stage GC/GCJ cancer. We conducted a meta-analysis of outcome measures using STATA 14.0 software. ●Results: A total of six studies involving 1,448 cases were included in this analysis. The results of the meta-analysis indicate that, when compared to chemotherapy, patients in the pembrolizumab group experienced a significant reduction in the risk of mortality in terms of overall survival (OS) (HR=0.72, 95% CI: 0.65-0.79, p&lt;0.01). In terms of progression-free survival (PFS), pembrolizumab was associated with a similar PFS as compared to chemotherapy (HR=0.88, 95% CI: 0.73-1.07, p=0.206). Subgroup analyses based on PD-L1 expression levels indicated a significantly longer PFS with pembrolizumab in subgroups of patients with PD-L1 CPS≥10, but not in these with PD-L1 CPS≥1 and PD-L1 CPS≥5. Subgroup analyses based on distinct geographical regions revealed a comparable effect of PFS in patients residing in Asia or the USA. Subgroup analysis based on tumor sites consistently demonstrated a similar effect of PFS in patients with EC/GEJ tumors and GC patients. ●Conclusion: Our findings demonstrated that pembrolizumab led to a significant extension in OS and ORR, along with a favorable tolerability profile compared to chemotherapy. Furthermore, the observed survival benefits were particularly pronounced in subgroup patients with a CPS of ≥10. Given the potential limitations inherent in our study, it is imperative to underscore the necessity for further large-scale RCTs to corroborate our results. ●Keywords: gastro-esophageal junction cancer, meta-analysis, chemotherapy, pembrolizumab.

Pembrolizumab (Keytruda)

CADTH recommends that Keytruda should be reimbursed by public drug plans for the treatment of locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumours express programmed cell death-ligand 1 (PD-L1) if certain conditions are met. Keytruda should only be covered to treat adult patients who have not received previous treatment for advanced or metastatic esophageal or GEJ cancer and have good performance status. Keytruda should only be reimbursed if prescribed in combination with trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy by a clinician with expertise and experience in treating gastric and GEJ cancer.

Cost-effectiveness analysis of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric/gastroesophageal junction cancer in the Chinese healthcare system

ABSTRACT Background This study compares first-line pembrolizumab plus chemotherapy with chemotherapy alone for patients with HER2-negative advanced gastric cancer (GC) and gastroesophageal junction cancer (GEJC) in China. Methods A Markov state-transition model was developed based on the phase 3 randomized KEYNOTE-859 clinical trial data. The health state utility values and direct medical costs were derived from the KEYNOTE-859 clinical trial, the relevant literature, and local charges. The measured outcomes included quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). Probabilistic and one-way sensitivity analyses (OWSA) were performed to assess the uncertainty of the model. Results In the base analysis, the incremental effectiveness and cost of pembrolizumab plus chemotherapy versus chemotherapy alone were 0.22 QALYs and $16,627.31, respectively, resulting in an ICER of $76,936.60/QALY, which is higher than the willingness-to-pay threshold in China ($35,864.61/QALY). Subgroup analyses revealed that the ICERs of pembrolizumab plus chemotherapy versus chemotherapy alone were $72,762.68 and $34,813.70 in the populations with PD-L1 CPS of 1 or higher (CPS ≥ 1) and PD-L1 CPS ≥ 10 (CPS ≥ 10), respectively. Conclusions As first-line therapy for patients with locally advanced or metastatic HER2-negative GC/GEJC in China, pembrolizumab plus chemotherapy is less cost-effective than chemotherapy alone, however, in the CPS ≥ 10 subgroup is more.

Zolbetuximab: First Approval.

Zolbetuximab (VYLOY™), a recombinant, chimeric, anti-claudin 18.2 (CLDN18.2) monoclonal antibody (mAb), is being developed by Astellas Pharma Inc. for the treatment of patients with HER2-negative (HER2-), CLDN18.2-positive (CLDN18.2+) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and CLDN18.2+ advanced pancreatic adenocarcinoma. In March 2024, zolbetuximab was approved in Japan for the treatment of patients with HER2-, CLDN18.2+ unresectable, advanced/recurrent gastric cancer (the gastric cancer indication includes GEJ cancer). Zolbetuximab is also undergoing regulatory review for HER2-, CLDN18.2+ advanced gastric or GEJ adenocarcinoma in the USA, the EU, China, Australia and several other countries. This article summarizes the milestones in the development of zolbetuximab leading to this first approval for the treatment of patients with CLDN18.2+ gastrointestinal malignancies.

A Cost-Effectiveness Analysis of Adjuvant Nivolumab for Patients with Resected Esophageal Cancer or Gastroesophageal Junction Cancer in France.

Esophageal and gastroesophageal junction cancer (EC/GEJC) is a poor prognosis disease with a high risk of recurrence even in patients curatively resected. Adjuvant nivolumab is currently used for patients with completely resected (R0) EC/GEJC who have residual pathologic disease following prior neoadjuvant chemoradiotherapy. This study aimed to determine the cost effectiveness of nivolumab in this indication in France according to the collective perspective excluding indirect costs. A simplified four-health-state semi-Markov model was developed to model EC/GEJC patients who have residual disease after neoadjuvant chemoradiotherapy followed by R0 over a 15-year time horizon, comparing adjuvant nivolumab versus surveillance, which was the recommended French clinical practice before immunotherapy arrival. Time-to-recurrence (TTR) from CheckMate 577 was used to inform transition from disease-free to post-recurrence health state; patients who recurred were split according to the distribution of type of recurrence observed during the trial. Post-recurrence survival (PRS) according to the type of recurrence was derived from a real-world registry. Adjuvant treatment with nivolumab led to an incremental survival gain of 1.19 years (+34%), mostly in the disease-free state, an incremental cost of €48,634 and QALY of 0.98 resulting in an incremental cost-utility ratio (ICUR) of €49,572/QALY with limited uncertainty. 'Cure assumption' at 5years had an important impact on the results (€41,115/QALY; -17%), as that tends to increase life-years and QALYs while costs remain the same. Probabilistic sensitivity analyses confirmed reference ICUR (€52,542/QALY) with 80% probability of nivolumab being cost effective at a willingness-to-pay threshold of €75,000/QALY. Our analysis suggests that adjuvant nivolumab is cost effective in the treatment of EC/GEJC patients who have residual disease after neoadjuvant CRT followed by R0 resection. Compared with previously evaluated cost-effectiveness analyses for other immune-checkpoint inhibitors indicated in metastatic settings, ICUR appears particularly low in this early setting thanks to the important impact on health outcomes and capped treatment duration.

Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial

In Asia, adjuvant chemotherapy after gastrectomy with D2 or more extensive lymph-node dissection is standard treatment for people with pathological stage III gastric or gastro-oesophageal junction (GEJ) cancer. We aimed to assess the efficacy and safety of adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy administered in this setting. ATTRACTION-5 was a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial conducted at 96 hospitals in Japan, South Korea, Taiwan, and China. Eligible patients were aged between 20 years and 80 years with histologically confirmed pathological stage IIIA-C gastric or GEJ adenocarcinoma after gastrectomy with D2 or more extensive lymph-node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and available tumour tissue for PD-L1 expression analysis. Patients were randomly assigned (1:1) to receive either nivolumab plus chemotherapy or placebo plus chemotherapy via an interactive web-response system with block sizes of four. Investigational treatment, either nivolumab 360 mg or placebo, was administered intravenously for 30 min once every 3 weeks. Adjuvant chemotherapy was administered as either tegafur-gimeracil-oteracil (S-1) at an initial dose of 40 mg/m2 per dose orally twice per day for 28 consecutive days, followed by 14 days off per cycle, or capecitabine plus oxaliplatin consisting of an initial dose of intravenous oxaliplatin 130 mg/m2 for 2 h every 21 days and capecitabine 1000 mg/m2 per dose orally twice per day for 14 consecutive days, followed by 7 days off treatment. The primary endpoint was relapse-free survival by central assessment. The intention-to-treat population, consisting of all randomly assigned patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of trial drug, was used for analysis of safety endpoints. This trial is registered with ClinicalTrials.gov (NCT03006705) and is closed. Between Feb 1, 2017, and Aug 15, 2019, 755 patients were randomly assigned to receive either adjuvant nivolumab plus chemotherapy (n=377) or adjuvant placebo plus chemotherapy (n=378). 267 (71%) of 377 patients in the nivolumab group and 263 (70%) of 378 patients in the placebo group were male; 110 (29%) of 377 patients in the nivolumab group and 115 (31%) of 378 patients in the placebo group were female. 745 patients received assigned treatment (371 in the nivolumab plus chemotherapy group; 374 in the placebo plus chemotherapy group), which was the safety population. Median time from first dose to data cutoff was 49·1 months (IQR 43·1-56·7). 3-year relapse-free survival was 68·4% (95% CI 63·0-73·2) in the nivolumab plus chemotherapy group and 65·3% (59·9-70·2) in the placebo plus chemotherapy group; the hazard ratio for relapse-free survival was 0·90 (95·72% CI 0·69-1·18; p=0·44). Treatment-related adverse events occurred in 366 (99%) of 371 patients in the nivolumab plus chemotherapy group and 364 (98%) of 374 patients in the placebo plus chemotherapy group. Discontinuation due to adverse events was more frequent in the nivolumab plus chemotherapy group (34 [9%] of 371 patients) than the placebo plus chemotherapy group (13 [4%] of 374 patients). The most common treatment-related adverse events were decreased appetite, nausea, diarrhoea, neutrophil count decreased, and peripheral sensory neuropathy. The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer. Ono Pharmaceutical and Bristol Myers Squibb.

PCR251 A Conceptual Disease Model for Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer (aGC/GEJC): Results From a Targeted Literature Review and Patient Interviews

PCR251 A Conceptual Disease Model for Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer (aGC/GEJC): Results From a Targeted Literature Review and Patient Interviews

Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer.

Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.