Trials For Advanced Gastric Cancer Research Articles

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.

External validity of docetaxel triplet trials in advanced gastric cancer: are there patients who still benefit?

BackgroundThe purpose of our study was to develop an online calculator to estimate the effect of docetaxel triplets (DPF) in first line of advanced gastric cancer (AGC), and to assess the external validity of docetaxel trials in individual patients.MethodsThe study includes patients with HER2(-) AGC treated with platin and fluoropyrimidine (PF) or with DPF in first line. Treatment effect and interactions were assessed using Bayesian accelerated failure time models.ResultThe series comprises 1376 patients; 238 treated with DPF and 1138 with PF between 2008 and 2019. DPF was associated with increased progression-free survival (PFS) and overall survival (OS) with time ratio (TR) 1.27 (95% credible interval [CrI], 1.15–1.40), and TR 1.19 (95% CrI, 1.09–1.27), respectively. Serious adverse events were more common with DPF, particularly hematological effects (32% vs 22%). Younger participants received greater DPF dose density without achieving greater disease control, while severe toxicity was likewise higher. DPF yielded superior OS in Lauren intestinal (TR 1.27, 95% CrI, 1.08–1.11) vs diffuse subtype (TR 1.17, 95% CrI, 1.09–1.24) and the probability of increasing OS > 15% was 90% vs 67% in each subtype, respectively. The effect dwindles over time, which can be attributed to pathological changes and clinical practice changes.ConclusionOur study confirms the effect of DPF is highly dependent on several clinical–pathological variables, with discreet and gradually declining benefit over platinum doublets in later years, at the expense of increased toxicity. These results may help to underpin the idea that external validity of AGC trials should be revised regularly.

A Biomarker Analysis of Nivolumab in Previously Treated Advanced Gastric Cancer (WJOG10417GTR)

Abstract Background Nivolumab (anti-PD-1 mAb) is a promising drug that survival benefit has been proven in a phase III trial for advanced gastric cancer in third- or later line treatment. In Japan, nivolumab was approved for unresectable advanced gastric cancer in 2017, and its monotherapy is recommended as the standard treatment in the third or later line treatment in the Gastric Cancer Treatment Guidelines 2018. However, the response rate of the nivolumab monotherapy is only about 10%, and no therapeutic efficacy has been seen in about a half of the treated patients. In addition, pembrolizumab (also anti-PD-1 mAb) failed to show superiority to the weekly-paclitaxel in the Keynote-061 trial for PD-L1-positive (CPS > 1%) advanced gastric cancer. Thus, since the treatment efficacy of blocking PD-1 in gastric cancer is limited, it is urgently necessary for the treatment selection to establish more useful biomarkers. Methods The WJOG10417GTR is a translational research using fresh and unfrozen specimens harvested from gastric cancer patients treated with nivolumab monotherapy. Peripheral blood, endoscopic biopsy samples are collected at 3 time points (before initiating treatment, about 1 month after treatment, and at disease progression), and systems oncoimmunology is being conducted by analyzing gene expression, pathological features of tumor tissues, soluble molecules in plasma, and phenotypes of immune cells by flow cytometry. Then, the relationship between these data and the clinicopathological characteristics including the response to nivolumab will be statistically evaluated. Eleven hospitals are collaborating in this study toward the goal of 100 patient’s enrollment in July 2018. Thirty-three patients have been registered until May 2019.

Surgical treatment strategy for advanced gastric cancer

There are large amount of gastric cancer patients in China, and because of current medical care situation in China, most of the patients have been diagnosed with advanced stage. Surgery is still an important method for patients with advanced gastric cancer, to cure or improve their survival. For lymph node dissection of resectable advanced gastric cancer, D2 radical resection as a standard progressive lymph node dissection of gastric cancer is gradually accepted by East Asian countries and more and more western countries. As recommended by the 8th AJCC-TNM staging, ≥16 lymph nodes for pathological examination are needed to provide better survival, and ≥30 lymph nodes allows better evaluation for prognosis. After years of research, surgical experts have found that D1+ is not suitable for advanced gastric cancer. The III phase clinical trials for advanced gastric cancer, JLSSG 0901 in Japan and KLASS-02 in Korea, have been carried out to confirm that the long-term survival of laparoscopic surgery is no worse than traditional open surgery. CLASS-01 III phase study performed by Chinese laparoscopic gastroenterological study group compared the efficacy between laparoscopic and open distal gastrectomy with D2 lymph node dissection for advanced gastric cancer. The short-term report showed that the laparoscopic surgery has favorable safety, effectiveness, and satisfactory oncologic effect. With the development of conversion therapy, IV stage gastric cancer was divided into 4 types: potential resectable metastasis, borderline resectable metastasis, incurable metastasis and unresectable metastasis. And it is proposed that patients of the 2nd, and some of the 3rd and 4th types are suitable for conversion therapy. Surgery should be performed when tumor has maximal response to chemotherapy. In addition, palliative resection or short circuited surgery may be selected for patients who are refractory to conversion therapy or have some complications such as pyloric stenosis or obstruction, perforation of the tumor, or massive hemorrhage that cannot be alleviated.

An Analytics Approach to Designing Combination Chemotherapy Regimens for Cancer

Cancer is a leading cause of death worldwide, and advanced cancer is often treated with combinations of multiple chemotherapy drugs. In this work, we develop models to predict the outcomes of clinical trials testing combination chemotherapy regimens before they are run and to select the combination chemotherapy regimens to be tested in new phase II and phase III clinical trials, with the primary objective of improving the quality of regimens tested in phase III trials compared to current practice. We built a database of 414 clinical trials for advanced gastric cancer and use it to build statistical models that attain an out-of-sample R2 of 0.56 when predicting a trial’s median overall survival (OS) and an out-of-sample area under the curve (AUC) of 0.83 when predicting if a trial has unacceptably high toxicity. We propose models that use machine learning and optimization to suggest regimens to be tested in phase II and phase III trials. Though it is inherently challenging to evaluate the performance of such models without actually running clinical trials, we use two techniques to obtain estimates for the quality of regimens selected by our models compared with those actually tested in current clinical practice. Both techniques indicate that the models might improve the efficacy of the regimens selected for testing in phase III clinical trials without changing toxicity outcomes. This evaluation of the proposed models suggests that they merit further testing in a clinical trial setting. This paper was accepted by Noah Gans, stochastic models and systems.

Molecular Biomarker Study in a Randomised Phase III Trial of Irinotecan Plus S-1 versus S-1 for Advanced Gastric Cancer (GC0301/TOP-002)

AimsGastric cancer is a common and heterogeneous disease; however, global standard and biomarkers for selecting chemotherapy regimens have not been established. This study was designed retrospectively to identify molecular biomarkers for irinotecan plus S-1 (IRI-S) and S-1 therapy from subset analyses in GC0301/TOP-002, a randomised phase III trial for advanced gastric cancer. Materials and methodsParaffin-embedded primary tumour specimens were collected from 126 of 326 randomised patients in GC0301/TOP-002. The mRNA was measured for thymidylate synthase, dihydropyrimidine dehydrogenase, topoisomerase I, excision repair cross-complementing gene 1 (ERCC1) and thymidine phosphorylase; categorised into low and high to analyse their association with efficacy end points. ResultsThere was no significant difference in each mRNA between S-1 and IRI-S groups, whereas there were differences among some clinical characteristics. Multivariate analyses for overall survival showed that mRNA levels were not correlated with prognosis. By comparison, between IRI-S and S-1 arms, low thymidylate synthase, low ERCC1 and high thymidine phosphorylase were associated with better prognosis for IRI-S versus S-1 (hazard ratio = 0.653, 0.702 and 0.709, respectively; P < 0.15 for each interaction). ConclusionLow thymidylate synthase, low ERCC1 and high thymidine phosphorylase are candidates for predictive biomarkers for first-line treatment in advanced gastric cancer by IRI-S. Further study is warranted to confirm these results in other clinical trials and cohort studies.

Controlling angiogenesis in gastric cancer: A systematic review of anti-angiogenic trials

PurposeAngiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of anti-angiogenic agents in gastric cancer. DesignA systematic search of PubMed, Embase and conference databases is performed to identify clinical trials with specific anti-angiogenic agents in gastric cancer treatment ResultsThe risk of disease progression (37–52%) and death (19–22%) with ramucirumab as second-line treatment decreases in phase III trials in advanced gastric cancer. No significant improvement in overall survival (OS) with the addition of bevacizumab to chemotherapy is shown. Bevacizumab or ramucirumab combined with traditional chemotherapy is associated with higher adverse event rate compared to chemotherapy alone. Except for apatinib, phase II trials of other tyrosine kinase inhibitors (TKIs) may improve overall response rate, but there are no significant improvements in OS and progression-free survival (PFS) when combined with chemotherapy. ConclusionPhase III trials in advanced gastric cancer have demonstrated improved outcome with ramucirumab as second-line treatment. Most of the other studies on anti-angiogenic agents in gastric cancer have reported improvement in response rate but not in OS compared to chemotherapy alone. Future research is expected in optimizing the anti-angiogenic therapy combined with traditional treatment.

Novel Targeted Therapy for Advanced Gastric Cancer

Despite its decreasing incidence in western countries, the care of gastric cancer remains a concern. As gastric cancer is often diagnosed at an advanced stage, the prognosis of patients with advanced disease remains dismal. Recent trials in advanced gastric cancer have been focused on targeted therapies. Agents targeting EGFR1 and HER2 have been widely tested. The addition of trastuzumab to cisplatin/fluoropyrimidine-based combination chemotherapy significantly improved survival in patients with HER2 positive advanced gastric cancer, which is now the new standard of care by recent ToGA trial. Other agents targeting VEGF, the PI3K–Akt–mTOR pathway, and other biological pathways have also been investigated in clinical trials, but showed little impact on the survival of patients. This review will focus on the recent progress in targeted agents for the treatment of AGC and summarize the current clinical evidence and ongoing trials supporting the use of targeted agents in the treatment of patients with AGC.

Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan Clinical Oncology Group Trial JCOG9912

BackgroundSince the best chemotherapy regimen for each patient with advanced gastric cancer is uncertain, we aimed to identify molecular prognostic or predictive biomarkers from biopsy specimens in JCOG9912, a randomized phase III trial for advanced gastric cancer. Patients and methodsEndoscopic biopsy specimens from primary lesions were collected in 445 of 704 randomized patients in JCOG9912. We measured the mRNA expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase, dihydropyrimidine dehydrogenase, and five other genes, then, categorized them into low and high groups relative to the median, and examined whether gene expression was associated with efficacy end point. ResultsMultivariate analyses showed that high ERCC1 expression [HR 1.37; 95% confidence interval (CI) 1.08–1.75; P = 0.010], performance status ≥1 (HR 1.45; 95% CI 1.13–1.86; P = 0.004), and number of metastatic sites ≥2 (HR 1.66; 95% CI 1.28–1.86; P < 0.001) were associated with a poor prognosis, and recurrent disease (versus unresectable; HR 0.75; 95% CI 0.56–1.00; P = 0.049) was associated with a favorable prognosis. None of these molecular factors were a predictive marker for choosing irinotecan plus cisplatin or 5-fluorouracil rather than S-1. ConclusionThese correlative analyses suggest that ERCC1 is an independent prognostic factor for overall survival in the first-line treatment of gastric cancer. Clinical Trial NumberC000000062, www.umin.ac.jp.

Evolving Standards of Care in Advanced Gastric Cancer

Despite its decreasing incidence in western countries, the care of gastric cancer remains a concern, as many patients are diagnosed with advanced disease. Whereas localized gastric cancer has benefited from advances in surgical management and perioperative chemotherapy, patients with unresectable or metastatic disease have a poor prognosis. However, advances in chemotherapy have still arisen, with the onset of more convenient and active schedules of treatment, but no significant breakthrough has been achieved in terms of survival. Recent trials in advanced gastric cancer have been focusing on targeted therapies. This article aims to focus on the current state of the art in terms of chemotherapy for advanced gastric cancer, as well as to describe and explain the rationale and hopes for newer therapies that are currently under investigation.

6513 POSTER Reporting Patient Characteristics and Stratification Factors in Randomized Trials of Systemic Chemotherapy for Advanced Gastric Cancer

Background There is no consensus on which patient characteristics are the most suitable to report or to be used as stratification factors in clinical trials for advanced gastric cancer (AGC), to our knowledge.

Reporting patient characteristics and stratification factors in randomized trials of systemic chemotherapy for advanced gastric cancer

There is no consensus on which patient characteristics are the most suitable to report or to be used as stratification factors in clinical trials for advanced gastric cancer (AGC), to our knowledge. We conducted a comprehensive review of published randomized trials for AGC to examine the patient characteristics that were reported. Among the 67 analyzed trials, age, gender, performance status, proportion of patients with measurable disease, and previous gastrectomy were frequently reported (>69%). Histology, number of disease sites, and adjuvant treatment were reported in less than 50% of trials. Although the reporting of second-line chemotherapy has increased in recent trials, it remains at less than 50%. Notably, recent trials have tended to include patients with better performance status and less locally advanced disease, with Asian trials more frequently including patients with more diffuse histology and less locally advanced disease or liver metastasis than non-Asian trials. Stratification was conducted in approximately 60% of the trials, using quite variable stratifying factors. Inconsistency exists in the reporting of patient characteristics, the characteristics themselves, and the use of stratification factors in clinical trials for AGC. A consensus set of important patient characteristics and strata may be necessary to conduct and interpret quality randomized studies.

Progression-free survival and time to progression as surrogate markers of overall survival in patients with advanced gastric cancer: Literature-based analysis of 36 randomized trials.

103 Background: We evaluated the potential of progression-free survival (PFS) and time to progression (TTP) to act as surrogates of overall survival (OS) in clinical trial settings by a comprehensive literature-based analysis. Methods: Randomized trials of systemic chemotherapy for advanced gastric cancer were identified by comprehensive electronic and manual search. Correlations between PFS/TTP and OS were evaluated. Results: Thirty-six trials with a total of 83 treatment arms and 10,484 patients were selected for analysis. The nonparametric Spearman rank correlation coefficient (p) between median PFS/TTP and OS was 0.70 (95% CI, 0.59 to 0.82) and the correlation coefficient between hazard ratios in PFS/TTP and OS was 0.80 (95% CI, 0.68 to 0.92). Correlation tended to be higher in non-Asian (p = 0.80; 0.61-0.98) than Asian trials (p = 0.67; 0.39-0.94), higher in trials reporting PFS (p = 0.85; 0.72-0.97) than in those reporting TTP (p = 0.60; 0.24-0.97), and higher in trials in patients with measurable lesions only (p = 0.91; 0.77-1.00) than in those including non-measurable lesions (p = 0.71; 0.50-0.93), albeit that none of these differences was significant. Conclusions: Our results indicate that improvements in PFS/TTP in advanced gastric cancer strongly correlate with improvements in OS. PFS/TTP may be an appropriate surrogate for OS in clinical trials for advanced gastric cancer. No significant financial relationships to disclose.

Drug Development in Advanced Esophagogastric Cancer: The Art of Extrapolation

Drug Development in Advanced Esophagogastric Cancer: The Art of Extrapolation

Novel Perspectives for the Treatment of Gastric Cancer: From a Global Approach to a Personalized Strategy

Although recent advances have been made, surgery still remains the mainstay of any curative treatment for gastric cancer patients, with radical gastrectomy representing the procedure of choice. However, patients with locally advanced disease show high rates of locoregional or distant recurrence even after potentially curative resections. According to global results presented in the setting of locally advanced resectable gastric carcinoma, perioperative chemotherapy may be considered a valuable option. On the other hand, clinical trials for advanced gastric cancer seem to suggest that a limit in efficacy has been reached for standard chemotherapy. Interesting data are expected from the development of targeted agents that, similarly to other cancer sites, showed appealing results in gastric cancer as well. Along with new effective therapeutic opportunities, better clinical and molecularly driven patient selection will represent the cornerstone of the global care for these patients.

Evaluation of heterogeneities in baseline risks and treatment effects among hospitals: Additional result of JCOG9912 phase III trial for advanced gastric cancer

6638 Background: JCOG9912 phase III trial demonstrated the treatment effect of irinotecan plus cisplatin (CP) regimen or S-1 regimen compared with 5-FU regimen for advanced gastric cancer (ASCO2007...

Disparities in Gastric Cancer Chemotherapy Between the East and West

There are still remarkable disparities in the treatment of gastric cancer between the East and West. Treatment outcomes for this disease have improved in Japan due to early detection and surgical resection with systematic node dissections, such as D2, whereas gastric cancer remains a virulent disease in Western countries. Differences in the types of surgery and their outcomes affect how adjuvant trials are conducted and interpreted. Recent Western randomized trials demonstrated the significant survival benefit of adjuvant chemoradiotherapy or intensive combination chemotherapy. However, baseline surgical quality and outcomes were quite different from those in Japan, and Japanese surgical/medical oncologists have not accepted the Western results. Several disparities are also evident in the results of chemotherapy trials for advanced gastric cancer. Although similar results were obtained with randomized studies using older regimens, the interpretation of the results differed between Japan and other countries. A combination of cisplatin and fluorouracil was used as the reference arm in ongoing randomized trials in most countries, whereas single-agent fluorouracil or S-1 alone was used in Japanese trials. Two triplet regimens have already demonstrated significant prolongation of survival in Western studies. However, these benefits seem to be marginal and these regimens may be replaced by newer regimens, which will soon be available in Europe and Asia, where a total of 2,600 patients have been accrued. Although these disparities between regions must be overcome, it is time for both Eastern and Western investigators to pursue further benefits by incorporating new agents into treatment regimens.

Gemcitabine (GEM) plus oxaliplatin, folinic acid, and 5-fluorouracil (FOLFOX-4) in patients with advanced gastric cancer

oxaliplatin in combination with folinic acid (FA) and infusional 5-fluorouracil (5-FU) has shown significant anti-tumor activity in gastric cancer patients (FOLFOX). Previous studies have shown that gemcitabine (GEM), a new fluorinated anti-metabolite, enhances the individual anti-tumor activity of either 5-FU or oxaliplatin. We have therefore designed a multi-center phase II trial in order to test a novel GEM+FOLFOX-4 regimen in patients with metastatic gastric cancer. we enrolled 36 patients, 28 males and 8 females, with an average age of 64.4 years (range 37-78), who received bi-weekly treatment with GEM (1,000 mg/m2 on day 1), levo-FA (100 mg/m2 on days 1 and 2), a 5-FU (400 mg/m2) bolus injection followed by 22-h continuous infusion (800 mg/m2) on days 1 and 2, and oxaliplatin 85 mg/m2 in a 4-6 h intravenous (i.v.) infusion before the second FUFA administration on day 2. the most frequent side effect was grade 1-2 hematological toxicity and late sensorial neurotoxicity. Two patients developed hypersensitivity to oxaliplatin while another developed an aseptic eosinophilic pneumonitis. Two patients refused to continue the treatment after two cycles of chemotherapy and were lost at the follow-up. Among the remaining 34 patients four achieved a complete response, 15 a partial response, 12 had a stable disease and three progressed. these results may grant the rationale to evaluate this multi-drug combination in randomized phase III trials in advanced gastric cancer.

Relatively low expression of multidrug resistance-1 (MDR-1) and its possible clinical implication in gastric cancers.

The mechanism of drug resistance of gastric cancer cells has rarely been investigated. We specifically examine the magnitude and the biologic significance of multidrug resistance-1 (MDR-1) expression in human gastric cancer. All patients had previously been treated in prospective clinical trials for advanced gastric cancer in our institution. Patients with adequate prechemotherapy gastric cancer tissues for immunohistochemical studies by a C219 monoclonal antibody were selected for the determination of the expression rate of MDR-1. The results were designated as negative or positive by the independent interpretation of two pathologists. A subgroup of patients who had been treated with doxorubicin- or etoposide-containing regimens were selected for further correlation with drug sensitivity. Between 1990 and 1996, a total of 60 patients, 38 men and 22 women with a median age of 55 years, were studied. Eight (13.3%; 95% confidence interval, 6%-25%) of them had MDR-1 expression. None of the pertinent clinicopathologic features, including the histopathologic types of the tumors and the extent of the diseases, correlated with the expression of MDR-1. Among the 30 patients who had received doxorubicin- or etoposide-containing combination chemotherapy, 3 (10%; 95% confidence interval, 3%-27%) were designated positive for MDR-1 expression. None of the 3 patients responded to chemotherapy, whereas 19 (70.4%) of the 27 patients who had not expressed MDR-1 did respond (p=0.041 by Fisher's exact test). We conclude that the expression of MDR-1 in gastric cancer is relatively low. Its expression, however, is clinically relevant and is useful in predicting the chemoresistance of patients with gastric cancer receiving doxorubicin- or etoposide-containing combination chemotherapy.