e15000 Background: FS-1502 is an antibody-drug conjugate composed of an anti-HER2 antibody, linker, and Monomethylauristatin F. In this study, we conducted an open-label, multicenter, two-cohort phase II trial to evaluate the efficacy and safety of FS-1502 in HER2- positive locally advanced or metastatic gastric or gastroesophageal junction cancer. Methods: Pts with HER2-positive (IHC 3+ or 2+/FISH+) who had received ≥1 prior treatment regimens were eligible and received FS-1502 2.3 mg/kg alone every 3 weeks. The study consists of Cohort 1 for pts received ≥2 lines of previous therapy and Cohort 2 for pts only received first-line of previous therapy, respectively. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), duration of response, disease control rate, and safety. Results: At data cutoff (Dec 24,2023), 46 pts were enrolled (intent-to-treat [ITT]), 35 pts were confirmed HER2-positive (IHC 3+ or IHC 2+/ISH+, Efficacy Evaluable Set [ES]) by central laboratory. In the ES, the median age was 58.3 years, 48.6% were IHC3+ and primary tumor location in 77.1% of pts was GC. 45.7% (16/35) pts had assigned to cohort 1 and 54.3% (19/35) pts had assigned to cohort 2. In cohort 1, median study follow-up time was 10.1 months, the investigator-assessed ORR was 37.5% (95% CI, 15.2-64.6), median PFS and OS were 4.3 months (95% CI, 1.5-5.8 months) and 10.0 months (95% CI,5.1-NA months), respectively. In cohort 2, median study follow-up time was 12.5 months, the investigator-assessed ORR was 52.6% (95% CI, 28.9-75.6). PFS and OS were 4.4 months (95% CI, 3.0-7.3 months) and 14.6 months (95% CI, 8.7-NA months), respectively. Grade≥3 treatment-related TEAEs were reported in 12 (26.1%) pts, ≥5% were hypokalemia (6.5%) and fatigue(6.5%). No adverse events leading to drug discontinuation or death. Efficacy and safety data are shown in table. Conclusions: FS-1502 showed promising activity with tolerable and manageable safety profile, which warrants further development in HER2-postive, advanced gastric or gastroesophageal junction adenocarcinoma who had received ≥1 prior treatment regimens. [Table: see text]
23 Background: CDH1 germline mutations are found to be associated with the development of hereditary diffuse gastric cancer (HDGC) and the early-onset diffuse gastric cancer (EODGC). But the impact of CDH1 gene mutations and large deletions on HDGC and EODGC has not been fully determined in Asians. Although the incidence of gastric cancer is relatively high in China, the detection rate of CDH1 germline mutations in Chinese patients with EODGC is rare compared to that in European patients. Methods: We investigated the mutation status of the CDH1 gene in 57 Chinese EODGC patients younger than 40 years old who met the clinical criteria for HDGC. Polymerase chain reaction-direct sequencing was performed, and multiplex ligation-dependent probe amplification (MLPA) was used to evaluate the patients with negative sequencing results. Associations between mutation, clinicopathologic, and overall survival data were analyzed by SPSS 19. Results: The germline mutations of CDH1gene were identified in 51 (89.5%) of the 57 EODGC patients. The nonsense mutation in exon 13 (c.2200T>C, p.Ala692*) occurred in fourty-six EODGC patients. The missense mutations were detected in twenty patients (Eighteen in exon 5: c.778G>C, p.Glu218Asp; Two in exon 12: c.2012C>G, p.Leu630Val). No deletion or duplication in any patient. Most of the patients carrying the CDH1 mutation in exon 13 had lymph node metastasis when compared with patients lacking CDH1 mutation (87.2% vs 60.0%) ( P < 0.05 ). EODGC patients, lacking germline CDH1 alterations, showed a longer median overall survival (mOS) than patients carrying CDH1 mutation in exon 13 ( P < 0.05 ). Moreover, the presence of CDH1 mutation in exon 13 was associated with the incidence of neural invasion ( P < 0.05 ). Conclusions: This study reveals novel CDH1 mutations in Chinese EODGC patients which had been poorly investigated. The presence of CDH1 mutation in EODGC patients may result in lymph node metastasis and poor prognosis. More research is needed to determine additional genetic targets that trigger EODGC.
2514 Background: To explore the safety and synergistic anti-tumor effect of fruquintinib (a VEGFR inhibitor) in combination with sintilimab (an anti-PD-1 Ab) in patients (pts) with advanced colorectal cancer (CRC) and other solid tumors. Methods: This is an ongoing phase Ib/II, multicenter, two-stage study. Pts with variety cancer types, including CRC, were enrolled and is continuously enrolling in the study. For this interim analysis, all pts were analyzed for safety whereas only CRC pts were analyzed for efficacy. MMR status were analyzed for all enrolled CRC pts. Stage 1 was classical “3+3” dose escalation with pts assigned to one of the following 4 cohorts, fruquintinib taken orally at 3mg (Cohort A, 3 weeks on/ 1 week off), 4mg (Cohort B, 3 weeks on/ 1 week off), 5mg-intermittent (Cohort C, 2 weeks on/ 1 week off) or 3mg-continuous (Cohort E, once daily), while sintilimab was given at 200mg intravenously with Q4W in Cohort A and Cohort B whereas Q3W in Cohort C and Cohort E. DLT was observed for 28 days. Stage 2 was dose expansion with pts receiving 5mg-intermittent or 3mg-continuous fruquintinib plus sintilimab (200mg, Q3W). The primary endpoints were safety and tolerability and secondary endpoint was objective response rate (ORR). Results: As of Jan 5, 2021, 44 CRC pts which failed to at least 2 previous lines of therapy containing fluoropyrimidine, oxaliplatin or irinotecan were enrolled. They received either 5mg-intermittent or 3mg-continous dosage (n = 22, each), the ORR was 22.7% (10/44, 95% CI: 11.5-37.8%) with 27.3% (6/22, 95% CI: 10.7-50.2%) in 5mg-intermittent group and 18.2% (4/22, 95% CI: 5.2-40.3%) in 3mg-continuous group. With a median follow-up time of 8.3 (range: 0-9.6) months, the K-M estimated median PFS was 6.8 (95% CI:5.6-NA) months and 4.3 (95% CI:3.5-NA) months for 5mg-intermittent group and 3mg-continuous group, respectively. Overall, 60 pts were enrolled for safety analysis, including 23 in stage1 and 37 (only CRC) in stage 2. In stage 1, all pts experienced TEAEs, 52.2% of which were ≥ grade 3. The most frequently reported TEAEs were TSH increasing (73.9%), fecal occult blood positive (56.5%), and Palmar-plantar erythrodysaesthesia syndrome (PPES) (56.5%). SAEs occurred in 8 (34.8%) pts and no treatment-related death was reported. One patient in Cohort B reported manageable DLT. In stage 2, all pts experienced TEAEs, 18 (48.6%) pts experienced ≥ grade 3 TEAEs with 6 (31.6%) in 5mg-intermittent group and 12 (66.7%) in 3mg-continuous group. The most common TEAEs were proteinuria (45.9%) and TSH increasing (37.8%). TEAEs leading to either fruquintinib or sintilimab discontinuation occurred in 3 (5%) pts each. Conclusions: Fruquintinib plus sintilimab showed promising efficacy and favorable safety profile in advanced CRC. Clinical trial information: NCT03903705.
To evaluate the effect of Supportan, an enteral nutrition (EN) specific for tumor patients, on the nutritional status and immune function of late-staged gastric cancer patients undergoing chemotherapy.Sixty-six late-staged gastric cancer patients undergoing chemotherapy were randomly divided into EN group (n=33) and control group (n=33). During chemotherapy, the patients in EN group received Supportan and the patients in the control group received basic diet. On the 14th day before chemotherapy and after chemotherapy, nutritional status and cell immune indicators were evaluated.As for nutrition indicators, there were no significant differences in EN group before and after chemotherapy (P > 0.05). Total protein, hemoglobin, prealbumin and transferrin significantly decreased after chemotherapy compared with those before chemotherapy in the control group (P< 0.01). The levels of CD4(+), CD8(+) T cells and CD4/CD8 were significantly increased, and NK cells, serum levels of IL-1, IL-6 were significantly decreased after chemotherapy in EN group (P< 0.01). The levels of IL-6 and TNF-alpha were significantly higher after chemotherapy than those before chemotherapy in the control group(P< 0.01). Curative effects of immune nutrition in EN group were superior to that in the control group, however, the differences were not statistically significant. The incidences of nausea, vomiting and marrow inhibition in Supportan group was lower compared with those in the control group, but with no significant difference.Supportan can prevent malnutrition of the late-staged gastric cancer patients undergoing chemotherapy, and improve immune function and alleviate adverse effects of chemotherapy.
e15079 Background: To study the correlation between the type and frequency of exon variants in E- cadherin (CDH1) gene and clinical characteristics of early-onset diffuse gastric cancer (EODGC) in Chinese patients. Methods: Peripheral blood samples were collected from 57 EODGC patients (age≤40 years) who underwent resection surgery for primary tumor. DNA was extracted from peripheral blood leucocytes and polymerase chain reaction amplification (PCR) was performed to amplify and sequence the CDH1 gene. Statistical analysis was performed using the SPSS 19 software package for Windows. Results: Missense variant in exon 5 was observed in 18 of the 57 EODGC patients with a variant frequency of 31.6%, while 2 patients (3.5% variant frequency) had variant in exon 12. Synonymous variant in exon 13 with a variant frequency 80.7% was observed in 46 patients. No significant correlation was observed between the missense variants in exon 5 and clinical pathological characteristics of the patients. Lymph node metastasis in patients with the exon 13 missense variant was significantly higher than those without variant (87% vs. 64%, P=0.07). The median overall survival (mOS) of 46 patients with synonymous variant in exon 13 was 34 months, while no death was observed in patients without variant (N=11, P=0.046). Conclusions: Missense variants in the exon 13 of CDH1 gene lead to lower survival rate in Chinese EODGC patients. Variants in other exons are not correlated with clinical or pathological characteristics.
Colorectal cancer (CRC) is one of the most common and serious types of malignancy worldwide. The embryonic ectoderm development (EED) gene is important to maintain transcriptional repressive states of genes over successive cell generations. The present study aimed to investigate the association between EED methylation and CRC. A total of 111 CRC tissue samples, 111 paired para-tumor tissues and 20 colorectal normal tissues were obtained for EED methylation assay, which was performed using a quantitative methylation-specific polymerase chain reaction. The percentage of methylated reference was calculated to represent the DNA methylation level. A dual-luciferase reporter gene assay was used to detect the gene promoter activity of a EED fragment. The current results revealed a significant difference in the EED methylation levels among tumor, para-tumor and normal colorectal tissues (tumor vs. para-tumor vs. normal, 5.03±4.61 vs. 8.65±11.50 vs. 40.12±45.31; F=45.014; P<0.0001). The dual-luciferase reporter gene assay demonstrated that the transcriptional activity of recombinant pGL3-EED plasmid was significantly higher compared with that of the pGL3-Basic control vector (fold-change, 3.15; P=0.014), which suggests the EED fragment can promote gene expression. In conclusion, the present study demonstrated that EED hypomethylation may be an important factor associated with CRC.
To analyze the correlation between sequential aspects of the phosphoinositide-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway by immunohistochemistry in the primary lesion of gastric cancer, clinicopathologic factors, and survival in Chinese patients to explore the role of sequential analysis of multiple targets in prognoses.Immunohistochemistry was performed to examine the expression of PI3K, phosphorylated-AKT (p-AKT), and phosphorylated-mTOR (p-mTOR) in 59 primary lesion samples ranging from Stages I to IV after gastrectomy. The correlation between sequential expression of multiple targets, and clinicopathologic factors and survival was analyzed.The positive expression rates of PI3K, p-AKT, and p-mTOR were 49%, 58%, and 56%, respectively. There were eleven cases with three biomarkers positive (19%), 22 cases with two biomarkers positive (37%), and 19 cases with only one biomarker positive (32%). Seven cases (12%) were all negative. Multi-factorial Cox regression analysis showed that neural invasion, vascular invasion, size of the tumor, lymph nodes affected, metastasis, carbohydrate antigen 19-9 level, and PI3K/p-AKT/p-mTOR simultaneous expression were independent prognostic parameters. The risk of death for the cases with two biomarkers positive was 0.367 times that for the cases with three biomarkers positive (P=0.166). The risk of death for the cases with only one biomarker positive was 0.105 times that for the cases with three biomarkers positive (P=0.058). The risk of death for the cases with three biomarkers negative was 0.017 times that for the cases with three biomarkers positive (P=0.022).Our study generated the hypothesis that patients with gastric cancer with simultaneous expression of PI3K/p-AKT/p-mTOR had worse outcome. But we need more rigorous validation in a larger data set.
In the past 15 years, we have seen few therapeutic advances for patients with pancreatic cancer, which is the fourth leading cause of cancer-related death in the United States.Currently, only about 6% of patients with advanced disease respond to standard gemcitabine therapy, and median survival is only about 6 mo.Moreover, phase Ⅲ trials have shown that adding various cytotoxic and targeted chemotherapeutic agents to gemcitabine has failed to improve overall survival, except in cases in which gemcitabine combined with erlotinib show minimal survival benefit.Several metaanalyses have shown that the combination of gemcitabine with either a platinum analog or capecitabine may lead to clinically relevant survival prolongation, especially for patients with good performance status.Meanwhile, many studies have focused on the pharmacokinetic modulation of gemcitabine by fixed-dose administration, and metabolic or transport enzymes related to the response and toxicity of gemcitabine.Strikingly, a phase Ⅲ trial in 2010 showed that, in comparison to gemcitabine alone, the FOLFIRINOX regimen in patients with advanced disease and good performance status, produced better median overall survival, median progression-free survival, and ob-jective response rates.This regimen also resulted in greater, albeit manageable toxicity.
To investigate the expression of multidrug resistance (MDR) gene-associated proteins (MRP) in gastric carcinoma, and their effects on the postoperative adjuvant chemotherapy and the prognosis of patients.The expressions of ToPo II, MRP, GST-pi in 99 patients with gastric carcinoma were detected by immunohistochemistry. The expression and its relationship to the pathological data were analyzed. The positive expression of MRP and GST-pi, and the negative expression of ToPo II were considered as risk factors. Patients were divided into two groups: a high risk drug-resistant group (2-3 risk factors) and the low risk drug-resistant group (0-1 risk factors). Postoperative recurrence, survival rate, and efficacy of adjuvant chemotherapy were compared between two groups.The positive rate of ToPo II was 74.7%, and the expression was associated with types and differentiation of the tumor. The positive rate of GST-pi was 49.5%, and the expression was related to the gender and the differentiation. The positive rate of MRP was 40.4%, and there was no relationship between the MRP expression and the pathological finding. There were no significant differences in the recurrence, time to recurrence, and the 5-year survival rate between the positive and negative group of the three proteins (P>0.05). Recurrence was found in 25 cases(55.6%) in the high risk drug-resistant group and the mean time to recurrence was (15.2+/-8.1) months. The time to recurrence was shorter in the low risk drug-resistant group [(21.3+/-11.1) months, P<0.05] , but there was no significant difference in the recurrence rate between two groups (P>0.05). The 5-year survival rate of the high risk drug-resistant group and the low risk drug-resistant group was 44.4% and 55.6% (P>0.05). The 5-year survival rates of patients with or without chemotherapy in the high risk drug-resistant group were 45.8% and 42.9% (P>0.05). The 5-year survival rates of patients with or without chemotherapy in the low risk drug-resistant group were 70.4% and 40.7%. The survival rate of patients with chemotherapy was higher than that of the patients without chemotherapy (P<0.05).The expression of ToPo II, MRP and GST-pi is associated with the efficacy of postoperative adjuvant chemotherapy. Chemotherapy appears to be more beneficial to patients with low risk drug-resistance.
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