Paclitaxel For Advanced Gastric Cancer Research Articles

A phase 1 study to evaluate the safety and preliminary efficacy of minnelide given alone or in combination with paclitaxel in advanced gastric cancer.

4033 Background: Minnelide is a water-soluble disodium salt variant of triptolide, an HSP70 inhibitor. Studies using pancreatic cancer cell lines and human xenograft transplants demonstrated that Minnelide prevents tumor progression, increases survival, and causes tumor regression. This study aims to evaluate the safety and antitumor activity of Minnelide and its combination with paclitaxel in patients with advanced gastric cancer (AGC). Methods: This open-label, single-center, dose-escalation phase I study recruited adult patients with previously treated advanced gastric cancer. Patients received Minnelide per oral (PO) daily starting with 1.0 mg for 3weeks and 1week rest schedule, escalating to 1.25mg, and 1.5mg. In combination Regimen, patients received Minnelide starting at a dose of 0.25 mg and escalating by 0.25mg to 1.25mg plus paclitaxel 60-80 mg/m2 intravenously on Day 1, 8, and 15 of each cycle, administered in 4-week cycles. The primary objective was to assess the safety and determine the recommended phase II dose (RP2D). Secondary objectives included preliminary efficacy using RECIST v1.1, and survival analysis. Results: Among Regimen A (n = 11), two patients experienced dose-limiting toxicity (DLTs) (Minnelide 1.5 mg: Grade 3 abdominal pain). No DLTs occurred in combination treatment, Regimen B & C (n=25). The MTD was Minnelide 1.25 mg once daily for 21days Q4 weeks as monotherapy. The most common Grade ≥3 AEs were neutropenia (19.4%) and abdominal pain (11.1%). In Regimen C, 71.5% achieved either a partial response or a stable disease with the median PFS of 4.5 months, and the median OS of 10.7 months. Notably, patients without previous exposure to paclitaxel (n = 4) in the last 2 cohorts of Regimen C, had a confirmed ORR of 50.0%, DCR of 75.0%, the median PFS was 5.3 months (95% CI NE-NE) and the median OS has not reached as some of the patients are still receiving treatment. Conclusions: The combination of Minnelide plus paclitaxel as salvage treatment in AGC patients showed meaningful clinical activity with a manageable safety profile. Based on this Phase I experience a Phase II will be initiated in AGC patients. Clinical trial information: NCT05566834 .

Abstract 6410: An exosomal microRNA signature predicts the efficacy of ramucirumab plus paclitaxel in advanced gastric cancer: Findings from the prospective IVY trial

Abstract Purpose: With rapid advances in the development of effective therapeutic regimens in patients with advanced gastric cancer, it is imperative to establish individualized treatment approaches that can help identify patient subsets that have the highest likelihood of response to a specific regimen. Although ramucirumab plus paclitaxel therapy is the standard second-line treatment for patients with advanced gastric cancer, biomarkers that can help predict therapeutic response are still lacking. This longitudinal study aimed to establish a liquid-biopsy assay that can predict response to ramucirumab plus paclitaxel therapy in patients with advanced gastric cancer. Experimental Design: A prospective observational multicenter study (named the IVY study) enrolled 115 patients who received ramucirumab plus paclitaxel treatment. We collected serum specimens prior to the initiation of the treatment regimen. Patients were divided into responders and non-responders according to the response evaluation criteria in solid tumors (RECIST). We performed small RNA-sequencing (sRNA-Seq) in a subset of 28 patients with and without response to identify exosomal microRNA-based biomarkers that allowed risk stratification and response prediction in patients with advanced gastric cancer. Results: The sRNA-Seq analysis and rigorous bioinformatic approaches using machine-learning algorithms allowed us to identify a panel of 10 exosomal microRNAs that robustly predicted resistance to ramucirumab plus paclitaxel treatment (AUC: 0.83). The panel of exosomal miRNAs was also shown to have a robust prognostic value for predicting survival outcomes in gastric cancer patients treated with ramucirumab plus paclitaxel, and Cox proportional hazards regression analysis showed that patients classified as high risk on the panel of exosomal miRNAs independent poor prognostic factor (OS: HR = 2.74, 95% CI = 1.56-4.81, P < 0.01, RFS: HR = 1.84, 95% CI = 1.16-2.92, P < 0.01). Following logistic regression and backward elimination, we trained a clinically feasible 5 exosomal miRNA signature by combining it with the Body Mass Index data, an independent clinical predictor (AUC: 0.84). We subsequently successfully validated the performance of this signature in the prospective clinical trial cohort (AUC: 0.87). Finally, we established a prognostic risk nomogram based on the circulating exosomal miRNA signature for a non-invasive and personalized pre-therapeutic selection approach. Conclusions: We have developed a novel liquid biopsy-based assay that allows robust prediction of response to ramucirumab plus paclitaxel treatment in gastric cancer patients, and our assay provides a framework for a personalized medicine approach that can provide risk-based management and treatment for each patient prior to the initiation of therapy. Citation Format: Katsutoshi Shoda, Caiming Xu, Yoh Asahii, Takeshi Nagasaka, Daisuke Ichikawa, Ajay Goel. An exosomal microRNA signature predicts the efficacy of ramucirumab plus paclitaxel in advanced gastric cancer: Findings from the prospective IVY trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6410.

Effect of ramucirumab plus paclitaxel in advanced gastric cancer according to the status of programmed cell death-ligand 1 (PD-L1) expression.

Ramucirumab, an anti-vascular endothelial growth factor receptor (VEGFR) monoclonal antibody (mAb), inhibits angiogenesis and reduces tumor activity. Programmed cell death-ligand 1 (PD-L1) might act upon VEGFR2 to induce cancer cell angiogenesis and metastasis. Herein, we investigated the efficacy of combining ramucirumab and paclitaxel according to the status of PD-L1 expression in patients with advanced gastric cancer (AGC). This analysis included AGC patients who received ramucirumab plus paclitaxel as 2nd line therapy between December 1, 2018, and February 28, 2022, at Samsung Medical Center. All patient data analyses included an evaluation of PD-L1 expression using the combined positive score (CPS). We analyzed the efficacy and the survival of patients according to their PD-L1 expression. We included 117 patients in this analysis, and 80 patients (68.4%) had a PD-L1 CPS of one or more, 37 (31.6%) had five or more, and 19 (16.2%) had ten or more scores. Progression-free survival (PFS) and overall survival (OS) did not differ significantly between patients with a PD-L1 CPS of less than one and one or more {PD-L1 <1% vs. PD-L1 ≥1%; PFS: median 3.6 months [95% confidence interval (CI): 2.4-4.8 months] vs. median 4.1 months (95% CI: 3.5-4.7 months), P=0.93; PD-L1 <1% vs. PD-L1 ≥1%; OS: median 7.0 months (95% CI: 5.4-8.6 months) vs. median 8.1 months (95% CI: 6.4-9.8 months), P=0.32}. PFS and OS did not differ significantly between patients with a PD-L1 CPS of less than 5 and 5 or more [PD-L1 <5% vs. PD-L1 ≥5%; PFS: 3.9 months (95% CI: 3.3-4.5 months) vs. 4.4 months (95% CI: 3.0-5.8 months), P=0.57; OS: 7.4 months (95% CI: 6.5-8.3 months) vs. 10.0 months (95% CI: 1.1-18.9 months), P=0.07]. Interestingly, with a PD-L1 CPS cutoff of 10, PFS and OS did differ significantly [PD-L1 <10% vs. PD-L1 ≥10%; PFS: 3.8 months (95% CI: 3.3-4.3 months) vs. 5.7 months (95% CI: 4.1-7.3 months), P=0.05; OS: 7.2 months (95% CI: 6.5-7.9 months) vs. 18.9 months (95% CI: 6.5-31.3 months), P=0.04]. No biomarkers have been established to predict survival times after ramucirumab plus paclitaxel treatment. This analysis suggests that a PD-L1 CPS cutoff of 10 might be novel a biomarker to predict the survival of AGC patients treated with ramucirumab and paclitaxel.

Association between gene expression signatures and clinical outcomes of pembrolizumab versus paclitaxel in advanced gastric cancer: exploratory analysis from the randomized, controlled, phase III KEYNOTE-061 trial

BackgroundIn the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction...

Bintrafusp alfa plus paclitaxel for advanced gastric cancer as a second-line treatment: An open label, single-arm, phase Ib/II study.

374 Background: Anti-PD-1 monotherapy did not improve overall survival compared with paclitaxel in second-line treatment for advanced gastric cancer (AGC) in KEYNOTE-061 trial. Recent studies suggest that inhibition of transforming growth factor beta (TGF-β) signaling reverses immunosuppressive tumor microenvironment into improved responses to cancer immunotherapy. Especially, genomically stable subtype of AGC showed the increased level of TGF-β pathway. Here, we report the results of phase Ib/II trial of bintrafusp alfa (M7824), a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII fused to a human IgG1 mAb blocking PD-L1, in combination with paclitaxel as a 2nd line treatment for AGC. Methods: This investigator-initiated, single-arm, open-label, phase Ib/II study enrolled HER2-negative, histologically confirmed AGC patients with evaluable disease who failed prior palliative 1st line treatment. Prior immune checkpoint inhibitor was not allowed. Phase 1b was planned to enroll 3 to 12 patients in a 3+3 design (bintrafusp alfa 1200mg on days 1 and 15 plus paclitaxel 80 mg/m2 (level 1) or 70 mg/m2 (level -1) on days 1, 8 and 15) every 28 days). The primary endpoints were to determine recommended phase II dose (RP2D) for phase Ib, and progression-free survival (PFS) at 6 months for phase II. Secondary endpoints included PFS, OS, ORR, DCR, and safety. Exploratory endpoints included immune-related biomarker changes from serial liquid biopsies (NCT04835896). Results: In phase 1b, dose limiting toxicities were not observed, and the RP2D was determined as dose level 1. During phase II, enrollment was stopped after 30 patients were recruited, following negative readouts from bintrafusp alfa trials in other indications. With a median follow-up duration of 10.9 months (95% CI 9.5–12.6), 7 patients remained on treatment (treatment duration range: 1.0 to 15.1 months) as of September, 2022. Median PFS was 3.8 months (95% CI, 2.6-7.8) and PFS rate at 6 months was 36.7% (95% CI, 20.1-53.4). Median OS was 9.6 months (95% CI, 4.1-not reached). In patients with measurable lesions (n=25), ORR was 28% (PR, n=7) and DCR was 68%. No patient was EBV-related. Patients with MSI-H (n=3; mPFS, 7.8 months; mOS, not reached) or PD-L1-positive (CPS≥1) (n=9; mPFS, 7.8 months; mOS, not reached) showed durable efficacy. Treatment-related AEs (≥G3) occurred in 23 pts (76.7%), including anemia (G3, n=12, 40%) and neutropenia (G3, n=9, 30%). Immune-related AE included urticaria (G3, n=2, 6.7%; G2, n=4, 13.3%), rash (G3, n=1, 3.3%), and pneumonitis (G3, n=1, 3.3%). Conclusions: Combination of bintrafusp alfa and paclitaxel was feasible with modest efficacy as 2nd line treatment for AGC. There was subset of patients with durable responses. Analyses of targeted next-generation sequencing from serial ctDNA sampling are ongoing. Clinical trial information: NCT04835896 .

Genomic profiling as a response predictor of second-line treatment in advanced gastric cancer patients: Post-hoc analyses of two phase Ib/II trials.

351 Background: Targeted panel next-generation sequencing (NGS) is now actively performed in clinics to guide treatment decisions for advanced cancer patients. However, NGS profilings of advanced gastric cancer (AGC) do not provide relevant genomic biomarkers that could predict response to second-line treatment for AGC patients yet. Methods: Two paclitaxel-based phase Ib/II trials as a second-line treatment for AGC patients were included: GSK2636771 (PI3Kβ selective inhibitor) and paclitaxel for AGC patients with PI3K/Akt pathway alterations (PTEN trial, NCT02615730, presented at GI ESMO 2021) and nivolumab and paclitaxel for EBV-related, dMMR/MSI-H or PD-L1 positive AGC (K-umbrella-003 trial, NCT02951091, presented at AACR 2021). Pre-treatment tumor tissue samples from two trials were subjected to the in-house panel sequencing using CancerMaster Panel V2 (Kwon et al., GI ASCO 2021) that covers 524 genes for single nucleotide variants, 143 for copy-number variations, and 18 for fusions. Baseline genomic alterations were compared with each patient’s response and survival. Oncogenic signaling pathways were annotated manually according to previous reports. Tumor mutation burden (TMB) and Human leukocyte antigen (HLA) profilings were also performed. Results: Baseline tumor tissues from 54 patients (24 from PTEN trial, 30 from K-umbrella-003 trial) were available for NGS. In patients treated with GSK2636771 and paclitaxel, patients with PIK3R1 M326I mutation (n = 3) showed longer PFS (8.1 vs 2.8 months, P= 0.041), and patients without MYC Q48H (n = 13) showed better PFS (4.8 vs 2.6 months, P= 0.013). Genetic alterations in epigenetic pathway were found in 13 patients (54.2%) and showed worse PFS (2.8 vs 5.0 months, P = 0.04). In patients treated with nivolumab and paclitaxel, patients with RTK/RAS pathway alterations excluding deletions (n = 21, 70%) showed significantly longer PFS (4.1 vs 2.6 months, P = 0.0085), and patients with HLA-A02 supertype (n = 11, 36.7%) showed significantly longer PFS (12.4 vs. 2.7 months, P = 0.0068). In both studies, TMB-high was not related to the survival and there were no common predictive genomic alterations. Conclusions: We observed that specific NGS-based genomic alterations such as single gene mutations, altered signaling pathways and HLA genotyping were potential predictors of each targeted agent or immunotherapy as a 2nd line treatment of AGC patients, regardless of paclitaxel. Further correlative studies within AGC trials for exploring predictive biomarkers are warranted. Clinical trial information: NCT02615730; NCT02951091.

Molecular mechanisms of synergistic action of Ramucirumab and Paclitaxel in Gastric Cancers cell lines

Ramucirumab is approved both as monotherapy and in combination with Paclitaxel for advanced gastric cancer in patients with disease progression after chemotherapy. In tumor cells, the VEGFA-VEGFR2 binding activates autocrine survival and migration signaling in angiogenesis independent manner. The present in vitro study investigated the effects of single and combined treatments with Ramucirumab and Paclitaxel on cell growth and migration highlighting the mechanisms underlying the interaction between the two drugs in gastric cancer cells. Cell growth and motility were investigated in human gastric cancer cell lines characterized by different tumorigenicity. The inhibitory effect on cell growth exerted by both drugs was potentiated by their combination and was synergistic. Ramucirumab was able to enhance the inhibitory effect exerted by Paclitaxel on cell cycle progression. A synergistic action was also observed in the expression of proteins crucial for cell motility, microtubule organization and epithelial-mesenchymal transition. Furthermore, synergistic inhibition of VEGFR2 expression was obtained by the drug combination. These findings highlighted the importance of the combined treatment to strongly inhibit all the main molecules of both PI3K/Akt/mTOR and MAPK pathways thus preventing possible reactivations due to cross-talk phenomena. The combined treatment with Ramucirumab seems to be a promising option to overcome the Paclitaxel resistance.

Impact of Oxaliplatin-Induced Neuropathy on Subsequent Paclitaxel for Advanced Gastric Cancer

Purpose: Several studies have shown that fluoropyrimidine plus oxaliplatin (SOX) is non-inferior to fluoropyrimidine plus cisplatin as first-line chemotherapy for advanced gastric cancer. We investigated retrospectively the choice of second-line regimen, along with the proportion and feasibility of paclitaxel-containing regimen, in the subsequent treatment of patients with advanced gastric cancer treated with SOX as first-line chemotherapy. Materials and Methods: We retrospectively analyzed the impact of oxaliplatin-induced neuropathy on both the choice of subsequent regimens and feasibility of subsequent chemotherapy with paclitaxel, focusing on patients with advanced gastric cancer who received S-1 plus oxaliplatin as first-line chemotherapy. Results: Twenty-seven from a total of 31 patients enrolled into the phase 2 and phase 3 study assessing S-1 plus oxaliplatin were analyzed (4 patients were deemed ineligible). Among 24 patients that had received second-line treatment, paclitaxel was not selected in 2 patients due to oxaliplatin-induced neuropathy. Paclitaxel was selected as second-line chemotherapy in 16 patients, as third-line chemotherapy in 6 patients and fourth-line chemotherapy in one patient. Severity of sensory neuropathy was grade 0/1/2/3 in 11/10/2/0 patients, respectively, immediately before treatment with paclitaxel, while the worst toxicity profile during paclitaxel treatment was grade 0/1/2/3 in 7/13/1/2 patients, respectively. Although there were no patients requiring dose reductions of paclitaxel due to neuropathy, 2 patients discontinued paclitaxel use due to grade 3 sensory neuropathy after 4 or 8 administrations of paclitaxel. Conclusion: Oxaliplatin-induced neuropathy during first-line chemotherapy may affect the choice and feasibility of subsequent chemotherapy with paclitaxel in advanced gastric cancer patients.

Impact of peripheral neuropathy induced by platinum in first-line chemotherapy on second-line chemotherapy with paclitaxel for advanced gastric cancer.

Fluoropyrimidine plus platinum, followed by paclitaxel (PTX) plus ramucirumab is a recommended treatment strategy for advanced gastric cancer (AGC). We investigated how peripheral neuropathy (PN), induced by platinum in first-line chemotherapy, affected the tolerability of second-line chemotherapy with PTX (2nd-PTX). The subjects were AGC patients who received second-line chemotherapy with PTX (2nd-PTX) after the failure of platinum-based chemotherapy between March 2015 and June 2018. We retrospectively reviewed PN severity, and dose reduction and/or discontinuation due to PN during 2nd-PTX, and compared the cumulative incidence of grade 2 PN between the two groups according to first-line chemotherapy containing oxaliplatin (L-OHP) or cisplatin (CDDP). The L-OHP and CDDP groups consisted of 50 patients each. PN severity before 2nd-PTX was grade 1/2 in 46/12% of patients in the L-OHP group, and 100/0% in the CDDP group. The worst grades of chemotherapy-induced PN during 2nd-PTX were grades 1/2/3 in 40/34/14% of patients in the L-OHP group, and 36/18/0% in the CDDP group. Median time to grade 2 PN after starting second-PTX was 2.5months in the L-OHP group and 8.6months in the CDDP group (hazard ratio 3.34, p = 0.002). The frequencies of a PN-related dose reduction and/or discontinuation of PTX were 18% in the L-OHP group and 8% in the CDDP group (p = 0.234). The severity of PN and tolerability of 2nd-PTX may be affected by first-line chemotherapy with L-OHP or CDDP for AGC.

Impact of peripheral neuropathy induced by platinum in first-line chemotherapy on second-line chemotherapy containing paclitaxel for advanced gastric cancer.

132 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of platinum and paclitaxel (PTX) persisting for long time. In the Gastric Cancer Treatment Guideline (Japanese Gastric Cancer Association, 2018), first-line chemotherapy with fluoropyrimidine plus platinum followed by taxane based chemotherapy is recommended. It is not well known how much CIPN by platinum in the first-line chemotherapy affect the tolerability of second-line chemotherapy containing PTX (second-PTX). Methods: The subjects were advanced gastric cancer patients who received second-PTX after the platinum-containing first-line chemotherapy between March 2015 and June 2018. Patients were divided into two groups according to prior platinum: oxaliplatin (prior L-OHP) and cisplatin (prior CDDP) groups. CIPN was graded according to CTCAE ver.4. Severity of CIPN, dose reduction and discontinuation due to CIPN during the second-PTX were compared between the two groups. Results: 109 patients (50 prior L-OHP group and 59 prior CDDP group) were included in this retrospective study. The severity of CIPN just before second-PTX was 46% for grade 1 and 12% for grade 2 in the prior L-OHP group, and 8.5% and 0% in the prior CDDP group. The initial dose of PTX was reduced in 59 % of the prior L-OHP and in 39 % of the prior CDDP group. The worst grade of CIPN during second-PTX was 40% for grade 1, 34% for grade 2, 14% for grade 3 in the prior L-OHP group, and 33.9%, 20.3%, 0% in the prior CDDP group. Median time to grade 2 neuropathy during second-PTX was 2.5 months in the prior L-OHP group and 8.6 months in the prior CDDP group (p = 0.0004). CIPN-related dose reduction of PTX were 12.0% in the prior L-OHP group and 3.4% in the prior CDDP group (p = 0.177). Discontinuation of second-PTX due to CIPN were 10.0% in the prior L-OHP group and 5.1% in the prior CDDP group (p = 0.541). Conclusions: The severity of CIPN and tolerability of the second-PTX may be affected by prior platinum, L-OHP or CDDP, in the first-line chemotherapy for advanced gastric cancer.

Advances in the treatment of gastric cancer.

To review the recent literature regarding treatment of gastric cancer. Addition of postoperative radiation therapy to perioperative chemotherapy offers no survival benefit. Fluoropyrimidines, in particular 5-fluorouracil (5-FU), are the backbone for gastric cancer chemotherapy. S-1, an oral prodrug of 5-FU, has become the mainstay for gastric cancer chemotherapy in Japan. In a Japanese adjuvant chemotherapy trial, addition of docetaxel to standard S-1 chemotherapy improved disease-free survival; this regimen will become their new standard for adjuvant therapy. Microsatellite instability (MSI) high status is emerging as a favorable prognostic marker in resected gastric cancer and may indicate a group of patients who do not gain additional benefit from treatment with adjuvant chemotherapy. In metastatic gastric cancer, the addition of ramucirumab, an antivascular endothelial growth factor receptor 2-targeted antibody, to first-line chemotherapy did not improve survival over chemotherapy alone. Trifluridine/tipiracil treatment in chemotherapy-refractory gastric cancer improved survival compared to placebo and will emerge as a late-line therapy option. Phase II and III trials indicate activity for the immune checkpoint inhibitors pembrolizumab and nivolumab in chemotherapy-refractory gastric cancer and have led to US regulatory approval for pembrolizumab in chemotherapy-refractory programmed death ligand 1-positive or MSI-high gastric cancer, and approval in Japan for nivolumab in chemotherapy-refractory gastric cancer. However, a phase III trial in advanced gastric cancer failed to show a survival benefit for pembrolizumab over conventional paclitaxel. The poly ADP ribose polymerase inhibitor, olaparib, added to second-line paclitaxel in advanced gastric cancer failed to improve overall survival compared with paclitaxel alone. Perioperative or postoperative adjuvant chemotherapy without radiation therapy remains the standard of care in gastric cancer. Addition of docetaxel to adjuvant S-1 will likely emerge as a new care standard. Pembrolizumab and nivolumab improve survival and now are treatment options in chemotherapy-refractory gastric cancer, especially for programmed death ligand 1-positive or MSI-high cancers.

Analysis of predictive factors of ramucirumab plus paclitaxel for advanced gastric cancer.

185 Background: Ramucirumab (RAM) is a novel anti-VEGF antibody approved in 2015 in Japan. Predictive factors for RAM in combination with paclitaxel (PTX) remain largely unknown. Methods: We reviewed 77 consecutive advanced gastric cancer patients who were treated with RAM plus PTX between June 2015 and June 2016 in our institution. We evaluated treatment outcome and analyzed potential predictive factors by univariate and multivariate analyses. Results: Median age was 67 years (range 35-83) and 51 % of the patients were male. The ECOG performance status (PS) was ≥ 2 in 8 patients. 89% (69/77) patients were treated as second line chemotherapy. Objective response rate (ORR) in patients who have measurable disease was 52 % (17/33). Median progression free survival (PFS) and overall survival (OS) and was 6.0 months (95% confidence interval [CI] = 4.3-7.1) and 10.4 months (95% CI 6.8-13.6), respectively. The most frequent adverse events were peripheral neuropathy (44%), G3 ≥ neutropenia (34%), hypertension (32%) and bleeding (27%). At multivariate analysis, hypertension was independent factor for OS (Hazard ratio [HR] = 0.35, 95% CI = 0.14-0.90, P = 0.03). Also, bleeding (HR = 0.23, 95% CI = 0.09-0.55, P = 0.001) was independent factor for PFS and hypertension (HR = 0.47, 95% CI = 0.22-1.02, P = 0.06) had trend toward to show better PFS. Conclusions: RAM plus PTX showed promising efficacy for advanced gastric cancer. RAM related toxicities such as hypertension and bleeding/hemorrhage were independent factors for better outcome. Further investigation is warranted to verify our analysis.

Association between ABCB1 G2677T/A polymorphisms and chemosensitivity of paclitaxel in advanced gastric cancer

To investigate the association between ABCB1 polymorphisms and chemosensitivity of paclitaxel in Chinese advanced gastric cancer(AGC) patients. Clinical data and peripheral blood prior to chemotherapy of 412 AGC patients treated with first-line capecitabine plus paclitaxel(pactitaxel group, n=268) or cisplatin(cisplatin group, n=268) in Peking University Cancer Hospital from December 2008 to April 2013 were retrospectively collected. ABCB1 G2677T/A polymorphisms were determined using PCR amplification and Sanger Sequencing. Clinical response evaluation and survival analysis were performed using RECIST1.1 criteria and Kaplan-Meier curve, respectively. The associations of ABCB1 G2677T/A polymorphisms with clinical response and survival were analyzed statistically. The genotypes of ABCB1 were detected in all the patients and the frequency of wild type(G2677G), single allele variants(G2677T+G2677A), and two allele variants (T2677T+T2677A+A2677A) was 22.8%(94/412), 49.8%(205/412), and 27.4%(113/412), respectively. In paclitaxel group, the disease control rate(DCR)[89.9%(116/129)] and median progression-free survival(PFS)(190 days) of patients with single allele variants of G2677T/A were significantly higher than those of wild type patients[76.1%(51/67) and 110 days, all P<0.05], and did not differ statistically from those with two allele variants. In cisplatin group, no significant differences were observed among patients with different genotypes of ABCB1 in terms of the DCR or PFS(all P>0.05). ABCB1 G2677T/A polymorphisms are associated with chemosensitivity of paclitaxel in gastric cancer.

Association between CHFR methylation and chemosensitivity of paclitaxel in advanced gastric cancer

Aberrant methylation of CHFR (Checkpoint with forkhead associated and ring finger) gene was frequently happened in cancer and had been reported to be associated with the sensitivity of microtubule inhibitors in several cancer cells containing gastric cancer cells in vitro experiments [1]. However, the clinical significance of CHFR methylation and chemosensitivity of microtubule inhibitors (paclitaxel or docetaxel) in gastric cancer patients was investigated only in few studies with limited samples, and the conclusion was controversial [2, 3]. In this study, we aimed to investigate the association between CHFR methylation and the sensitivity of paclitaxel in Chinese advanced gastric cancer (AGC) patients to identify the potential predictor of paclitaxel. Tumor or matched non-tumor biopsies prior chemotherapy from 117 AGC patients receiving paclitaxel plus capecitabine (cohort 1, n = 59) or cisplatin plus capecitabine (cohort 2, n = 58) were retrospectively collected and analyzed for CHFR methylation status by MethyLight assay. We further investigated the association between CHFR methylation and the sensitivity of paclitaxel in AGC patients to identify its predictive significance. This study was approved by the Ethics Committee of Peking University Cancer Hospital and was performed according to the Declaration of Helsinki Principles. The median age of patients was 59 years with all patients had been evaluable for clinical response. The percentage of responders and non-responders was 36.8 and 63.2 %, respectively. Among all 117 patients, 46 patients had tumor tissues and matched non-tumor tissues. CHFR methylation occurred frequently in gastric cancer tissues (35/117, 29.9 %) compared to nontumor tissues (0/46, 0 %; P\ 0.001). For all patients, no significant differences were found between CHFR methylation and age, gender, histological differentiation, Lauren classification, metastasis, or HER2 status (all P[ 0.05). We analyzed the correlation between CHFR methylation and chemosensitivity of paclitaxel in clinical cohorts. However, no significant differences were seen between CHFR methylation and clinical response in all patients or any clinical cohort (P[ 0.05) as shown in Table 1. Up to August 2013, the median PFS and OS for all patients were 143 and 288 days, respectively. There were no differences of PFS or OS between patients with positive and negative methylation of CHFR in all patients (Table 1). For cohort 1, the median PFS and OS in patients with positive methylation of CHFR were 165 and 283 days, which had no difference with those (154 and 335 days) in patients with negative methylation of CHFR (Table 1). Also, the same results were seen in cohort 2 (Table 1). This study demonstrated that CHFR methylation was frequent and specific in gastric cancer tissues, while absent in non-tumor tissues. Our results verified that no correlation was found between CHFR methylation and paclitaxel chemosensitivity in clinical cohorts, which helped to disabuse the inconclusive results. The correlation between CHFR methylation and prognosis of patients needed to be further validated in large samples. M. Wang L. Shen (&) Department of GI Oncology, Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China e-mail: lin100@medmail.com.cn

6586 POSTER Metronomic Combination Chemotherapy With S-1 and Biweekly Paclitaxel for Advanced Gastric Cancer

6586 POSTER Metronomic Combination Chemotherapy With S-1 and Biweekly Paclitaxel for Advanced Gastric Cancer

A phase I study of S-1 administration and a 24-h infusion of cisplatin plus paclitaxel in patients with advanced gastric cancer

4074 Background: S-1 may have a major role in the treatment of gastric cancer as single agent or as a component of combination chemotherapy in Japan. We previously reported a multicentric phase II study of S-1 combined with a 24-h infusion of cisplatin in patients with advanced gastric cancer. This combination was active, safe and had the possibility of being combined with other anticancer drug. Combination chemotherapy with S-1 and cisplatin plus paclitaxel for advanced gastric cancer might yield a stronger antitumor effect. The objective of this study was to determine the dose-limiting toxicity (DLT), the maximum tolerated dose (MTD), the recommended dose (RD), and the preliminary antitumor activity of S-1 and cisplatin plus paclitaxel for advanced gastric cancer. Methods: Paclitaxel was administered on day 1. A fixed dose of S-1 (70 mg/m2/day) was orally administered for 14 consecutive days from day 1, and a 24-h infusion of a fixed dose of cisplatin (60 mg/m2) was administered on day 14 of every 28-day cycle. Four dose escalation levels of paclitaxcel were studied (120, 140, 160, and 180 mg/m2). The DLT was defined as any of the following: grade 3 neutropenia lasting more than 5 days, grade 4 hematological toxicity, grade 3 non-hematological toxicity, or treatment delay of greater than 2 weeks as a result of toxicity. Results: Twenty patients were enrolled. Hematological and non- hematological toxicity of over grade 2 was not observed at dose level 1 and 2. Three patients started at dose level 3. One developed grade 3 neutropenia for 5 days following by grade 2 neutropenia lasted more than 10 days. Five more patients were added at this level. The treatment was delayed over 2 weeks in 1 out of 8 patients. Three patients started at dose level 4. One developed grade 3 neutropenia and needed longer than 14 days to recover. Three patients added this level. In total, at dose level 4 the treatment was delayed over 2 weeks in 3 out of 6 patients as a result of neutropenia. We considered level 4 is the MTD and the RD of paclitaxcel was 160 mg/m2 (dose level 3). The overall response rate was 75%. Conclusions: Triple combination chemotherapy consisting of S-1, cisplatin, and paclitaxel showed a tolerable dose of adverse reactions and favorable antitumor activity for gastric cancer. No significant financial relationships to disclose.