Second-line Treatment For Advanced Gastric Cancer Research Articles

Efficacy and Safety of Low-Dose Apatinib Combined with Chemotherapy as Second-Line Treatment for Advanced Gastric Cancer: A Meta-Analysis

Introduction: At present, there are several studies on low-dose apatinib combined with chemotherapy as a second-line treatment of advanced gastric cancer (AGC), but the conclusions are controversial. Therefore, this meta-analysis aimed to evaluate the efficacy and safety of low-dose apatinib combined with chemotherapy as a second-line treatment of AGC. Methods: Nine databases were searched for records on apatinib combined with chemotherapy in treating AGC from inception to June 2022. The observation group received low-dose apatinib combined with chemotherapy, while the controls received chemotherapy alone or other non-placebo treatments. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. The relative risk (RR) and weighted mean difference (WMD) were used as effect sizes. Results: Eight studies involving 679 patients were included in this meta-analysis. The results of the meta-analysis showed that the observation group was superior to the controls in terms of ORR (RR = 1.38, 95% confidence interval [CI]: 1.05–1.81, p = 0.02), DCR (RR = 1.35, 95% CI: 1.20–1.53, p < 0.001), OS (WMD = 4.72, 95% CI: 0.71–8.72, p < 0.001), and PFS (WMD = 2.67, 95% CI: 1.7–3.63, p < 0.001). There were no significant differences between the two groups in adverse events of any grade except hypertension (RR = 2.82, 95% CI: 2.07–3.84, p < 0.001), hand-mouth syndrome (RR = 1.84, 95% CI: 1.84–2.48, p < 0.001), and proteinuria (RR = 3.63, 95% CI: 2.31–5.7, p < 0.001). Conclusion: Low-dose apatinib combined with chemotherapy as a second-line therapy is more effective in improving the efficacy of AGC compared to chemotherapy alone. However, this option has the potential to increase the risk of hypertension, hand-mouth syndrome, and proteinuria.

Efficacy and safety of second-line treatment for advanced gastric cancer: A network meta-analysis of randomized controlled trials.

e16018 Background: To evaluate the difference of curative effect between different treatment regimens in patients with advanced gastric cancer (AGC) who have previously received fluorouracil based first-line chemotherapy. Methods: We searched PubMed, PMC and EMBASE databases for published randomized controlled trials (RCTs). The number of people who reached the objective response rate (ORR) and the hazard ratio (HR) and its 95% confidence interval (CI) of progression-free survival (PFS) and overall survival (OS) were extracted. R (version 4.0.5) and R Studio were used to conduct meta-analysis of relevant data based on the Bayesian framework. Gemtc software package facilitates statistical analysis. To provide a ranking for each treatment regimen, surface under the cumulative ranking curve (SUCRA) was calculated. Survival analysis was conducted based on WinBUGS 14. STATA17.0 was used to draw the network diagram and funnel plot. Results: A total of 17 RCTs were included in this meta-analysis, and a total of 15 treatment regimens were used in the second-line treatment of AGC. There was no publication bias or other bias in the studies. Ramucirumab combined with paclitaxel and nab-paclitaxel weekly regimens have obvious advantages in efficacy and safety. Among them, ramucirumab combined with paclitaxel (83.6%) has great advantages in ORR, while the probability of anemia (36.6%) and anorexia (22.7%) is low, and the probability of leucopenia (66.6%) is high. However, the ORR of nab-paclitaxel weekly regimen (71.4%) is only second to that of ramucirumab combined with paclitaxel, and the probability of anemia (46.3%) and anorexia (44%) is also low, and the probability of leucopenia (53.8%) is high. In terms of OS and PFS, ramucirumab combined with paclitaxel has the best effect according to the probabilistic settlement table. Pembrolizumab and 5-Fu have poor therapeutic effects in terms of PFS. Conclusions: Ramucirumab combined with paclitaxel and nab-paclitaxel can significantly improve the survival outcome of patients with AGC. The effect of ramucirumab combined with paclitaxel is significantly better than that of paclitaxel, and the effect of nab-paclitaxel is only second to that of ramucirumab combined with paclitaxel. The safety of multi-drug combination should also be carefully considered. These findings may help clinicians better choose the second-line treatment strategy for patients with AGC.

Abstract 1082: Effect of doublet treatment versus single-agent treatment in gastric cancers with/without MET amplification or a MET exon 14 skipping mutation

Abstract Although conventional combination chemotherapy for advanced gastric cancer (GC) is associated with increased survival, it has major adverse effects, which necessitate the development of more effective, less toxic treatments. Combinations of multiple anti-cancer drugs, such as paclitaxel plus ramucirumab, have recently been used for the second-line treatment of advanced GC. This study evaluated the MET copy number variation (CNV), mutations, and gene and protein expression in human GC cells and the differential susceptibility of GC cells to single (tepotinib, ramucirumab, or paclitaxel) or doublet (tepotinib plus paclitaxel or ramucirumab plus paclitaxel) regimens. Compared to ramucirumab plus paclitaxel, tepotinib plus paclitaxel inhibited the growth of GC cells with a MET exon 14 skipping mutation and those without MET amplification but with phosphorylated MET in a dose-dependent manner with a concomitant induction of cell death. Tepotinib plus paclitaxel and ramucirumab plus paclitaxel similarly inhibited the growth of GC cells without a MET amplification or MET phosphorylation in a dose-dependent manner without inducing cell death. However, tepotinib alone or tepotinib plus ramucirumab was more effective in c-MET-positive GC cells (CNV &amp;gt; 30) than ramucirumab alone, paclitaxel alone, or ramucirumab plus paclitaxel. Our in vitro findings suggest that, compared to ramucirumab plus paclitaxel, tepotinib plus paclitaxel inhibits the growth of c-MET-positive GC cells, GC cells without a MET amplification but with phosphorylated MET, and those with MET mutations. Tepotinib alone was as effective as tepotinib plus paclitaxel in c-MET-positive GC cells. Clinical studies are required to confirm the therapeutic effects of these regimens. Citation Format: Dae Young Zang, sung-hwa sohn, Hee Jung Sul, Bum Jun Kim. Effect of doublet treatment versus single-agent treatment in gastric cancers with/without MET amplification or a MET exon 14 skipping mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1082.

Efficacy and safety of second-line therapy with apatinib combined with chemotherapy as second-line therapy in advanced gastric cancer: a single-arm, open-label, prospective, multicenter study.

BackgroundFor advanced gastric cancer (GC) patients who fail first-line treatment, chemotherapy alone is of limited benefit. Ramucirumab combined with paclitaxel and apatinib combined with docetaxel provided clinical benefit in previous studies, but the feasibility of apatinib combined with other chemotherapy agents remains unknown. The aim of the present study was to evaluate the efficacy and safety of apatinib combined with chemotherapy as a second-line treatment for advanced GC.MethodsPatients aged 18–75 years with histologically or cytologically confirmed advanced or metastatic GC or gastroesophageal junction adenocarcinoma that had progressed with first-line treatment were recruited and received apatinib 250 or 500 mg oral apatinib and chemotherapy regimens, including docetaxel, paclitaxel, tegafur, oxaliplatin, and capecitabine. Each treatment cycle was 28 days (4 weeks). During post-discontinuation follow-up, all patients were followed for survival [every 8 weeks (+0 to 7 days)] until disease progression, death, or study completion. Overall survival (OS) was the primary endpoint. Secondary endpoints were overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Adverse events (AEs) were also noted. Tumor response and progression were assessed according to RECIST 1.1. AEs were graded following the National Cancer Institute common terminology criteria for AEs (NCI-CTCAE 4.0).ResultsBetween August 31, 2016 and February 17, 2020, a total of 32 patients were enrolled in the present study, and 29 were evaluable. At the time of data cut-off, median follow-up was 7.00 months (IQR, 4.60–12.23 months). The ORR and DCR were 18.52% and 92.59%, respectively. The median PFS was 3.06 months, and the median OS was 6.93 months. In the population receipt of apatinib plus docetaxel, the median OS was 6.51 months. AEs were observed in 22 patients. Leukopenia was the most common AE (24.1%), followed by hypertension (24.1%) and neutropenia (17.2%). Patients did not develop any AEs that were grade 4 or higher.ConclusionsThe combination of apatinib and chemotherapy demonstrated clinical activity and acceptable toxicity as a second-line treatment for advanced GC, and may provide new second-line treatment options for advanced GC patients.

Abstract CT159: Open label, single-arm, multi-center phase Ib/II study to evaluate the safety and efficacy of nivolumab in combination with paclitaxel in Epstein-Barr virus (EBV)-related, or microsatellite instability-high (MSI-H), or programmed cell death ligand 1 (PD-L1) positive advanced gastric cancer (AGC)

Abstract Background: Pembrolizumab monotherapy did not improve overall survival compared with paclitaxel in second-line treatment for AGC in Keynote-061. Here, we report the results of patients (pts) with evaluable lesions treated with combination of nivolumab (Nivo) and paclitaxel (PTX) in AGC who progressed on first-line chemotherapy with a platinum and fluoropyrimidine. Methods: This open label, single arm, phase 1b/2 study is part of biomarker-integrated umbrella study conducted at multi-centers in South Korea. Phase 1b included 6 all-comer pts irrespective of biomarkers in a 3+3 design. In phase 2, 47 pts with either EBV-related, deficient mismatch repair (dMMR)/MSI-H or PD-L1 positive were enrolled. PD-L1 was defined as combined positive score (CPS) of &amp;gt;1. The primary endpoints were determining maximum tolerated dose (MTD) and recommended phase II dose (RP2D) for phase 1b, and progression-free survival (PFS) for phase 2. Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), PFS rate at 6 months and toxicity. Results: In phase 1b, dose limiting toxicities were not observed, and the RP2D was Nivo (3 mg/kg on days 1 and 15) combined with PTX (80 mg/m2 on days 1, 8 and 15) every 28 days. Phase 2 pts included CPS &amp;gt;1 (n=41), EBV positive (n=2), and 4 patients showed more than one biomarkers: CPS &amp;gt;1, EBV positive (n=2), CPS &amp;gt;1, dMMR/MSI-H (n=1), and CPS &amp;gt;1, EBV positive, dMMR/MSI-H (n=1). With a median follow-up period of 12.1 months, 7 pts remain on treatment (treatment duration: 1.1 to 23.1 months) as of August, 2020. In patients with measurable lesions (n=33), ORR was 24% (CR 9%, PR 15%) and DCR was 39%. Median duration of response was 18.4 months (95% CI, 3.2-19.8). Median PFS was 3.9 months (95% CI, 2.9-4.9) and PFS rate at 6 months was 32%. Median OS was 18.9 months (95% CI, 8.8-28.9). There was no statistical difference in PFS or OS by all biomarkers, including CPS cutoff for 1, 5, and 10. Of the 40 pts who had disease progression, 23 pts (49%) were treated with subsequent therapy. Treatment-related AEs (≥G3) occurred in 22 pts (47%), and immune-related AE (&amp;gt;G3) was observed in 3 pts (6%), including pneumonitis (G3) (n=1, 2%). Exploratory analysis of 13 cytokines from plasma at baseline showed an increase of interleukin-1 receptor antagonist (IL-1ra) (p=0.05), and increasing tendency of IL-8 and IL-12 in non-responders (PFS &amp;lt;3 mo.) compare to responders (PFS &amp;gt;8 mo.). Conclusion: Combination of Nivo and PTX demonstrated antitumor activity with manageable toxicity profiles as second-line treatment for AGC. Genomic analysis of tumor tissues by targeted next-generation sequencing are awaiting. Clinical trial information: NCT02951091 Citation Format: Rha Sun Young, Jii Bum Lee, Hyo Song Kim, Minkyu Jung, Choong-kun Lee, Sook Ryun Park, Dong-Hoe Koo, Hyun Woo Lee, Woo Kyun Bae, Hei Cheul Jeung, Hyun Cheol Chung. Open label, single-arm, multi-center phase Ib/II study to evaluate the safety and efficacy of nivolumab in combination with paclitaxel in Epstein-Barr virus (EBV)-related, or microsatellite instability-high (MSI-H), or programmed cell death ligand 1 (PD-L1) positive advanced gastric cancer (AGC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT159.

LDH as prognostic factor in second line treatment for advanced gastric cancer: The LINE study.

e16102 Background: Lactate dehydrogenase (LDH) is recognized as indirect marker of tumor hypoxia and angiogenesis for several solid tumors. Ramucirumab is the first antiangiogenic agent approved for second-line therapy in advanced gastric cancer (GC), alone or in association with chemotherapy. To date, no reliable biomarkers can predict the potential benefit from anti-VEGFR2 treatment. This retrospective multicenter study aimed to assess the prognostic role of baseline LDH levels in patients (pts) undergoing second-line treatment for advanced GC. Methods: The study analyzed a retrospective cohort of consecutive advanced GC pts treated with second line therapy at IRCCS, CRO of Aviano and at Mauriziano Hospital of Torino, Italy, from 2010 to 2020. LDH levels prior to second-line treatment were classified as low-normal or high and standardized according to the upper limit of the reference range. To better determine the optimal LDH cut-off value, ROC analysis was performed (using PFS &lt; 3 months as binary outcome). Normalized LDH values were subsequently sorted according to the ROC curve cut-off in order to test the association with overall survival (OS) through the Kaplan-Meier method and compared using the Log-Rank test. A multivariate Cox regression analysis assessed the prognostic impact of normalized LDH levels for OS calculated from the start of second line treatment. Results: Overall, 125 pts were enrolled. Of these, 81 pts (64.80%) received ramucirumab alone or plus paclitaxel as second line treatment, while 44 (35.20%) had taxanes or fluoropyrimidines combined with irinotecan. Median age was 68 years, 93% had an ECOG PS ≤ 1, 64.80% was first diagnosed with metastatic disease and 40.80% underwent primary tumor resection. Median second line PFS and OS were 4.2 and 7.9 months, respectively. Baseline LDH values were available for 99 pts. ROC analysis identified a normalized LDH value of 0.83 as the optimized cut-off point to define pts with poor prognosis. At univariate analyses, surgery of the primary tumor (HR 0.51, 95% CI 0.31-0.82, p = 0.005) was associated with better OS, while low-normal BMI ( &lt; 25 kg/m2) at second line start (HR 1.99, 95% CI 1.21-3.28, p = 0.007), normalized LDH values ≥ 0.83 (HR 1.86, 95% CI 1.13-3.07, p = 0.015) and PS &gt; 1 (HR 5.65, 95% CI 2.29-13.92, p &lt; 0.001) were associated with poorer outcome. At multivariable model, only PS &gt; 1 was independently associated with poor prognosis (HR 9.93, 95% CI 3.27-30.08, p &lt; 0.001). Subgroup analyses showed no significant heterogeneity in OS outcome according to normalized LDH levels between patients treated with or without ramucirumab. Conclusions: Elevated LDH levels are indicators of worse outcome in advanced gastric cancer pts. Notably, the LDH cut-off value identified a poor prognosis subgroup among pts with normal baseline levels, suggesting that current laboratory ranges could be suboptimal for patient stratification.

Results of a phase II trial of ramucirumab plus irinotecan as second-line treatment for patients with advanced gastric cancer (HGCSG 1603).

217 Background: Ramucirumab (RAM) is a fully human IgG1 monoclonal vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. The RAINBOW trial showed RAM plus paclitaxel (PTX) increased overall survival (OS) compared with PTX alone for advanced gastric cancer (AGC) in second-line treatment. WJOG 4007 trial demonstrated equivalent efficacy between irinotecan (IRI) and PTX. We conducted this trial to examine the efficacy and safety of RAM plus IRI combination therapy in the second-line treatment for AGC. Methods: This non-randomized, single arm, phase 2 trial was carried out at 22 institutes in Japan. AGC patients with refractory or intolerance to primary chemotherapy were eligible. RAM 8 mg/kg and IRI 150 mg/m2 combination therapy administered every two weeks were continued until progression or emergence of adverse events requiring discontinuation. The primary endpoint was progression-free survival (PFS) rate at six-month, the target was set as 16% with an expected threshold of 39%. A total of 35 cases are planned for registration. The secondary endpoints were OS, PFS, response rate (RR) and safety. This trial was registered with Japan Registry of Clinical Trials, number jRCTs011180029. Results: Between Jan 2018 and Sept 2019, 35 patients were enrolled. Median age was 70 (range, 47-80); female/male were 10/25; ECOG PS 0/1, 22/13. PFS rate at six months was 26.5% (95%C.I., 13.2-41.8%, p = 0.1353). Median PFS and OS were 4.2 (95%C.I., 2.5-5.4 months) and 9.6 months (95%C.I., 6.5-16.6 months), respectively. RR was 26% and disease control rate was 85%. Grade 3 or higher adverse events that occurred in more than 5% of patients were neutropenia (51%), leucopenia (43%), anemia (20%), anorexia (14%), febrile neutropenia (11%), diarrhea (9%), hypertension (9%), proteinuria (9%), hypokalemia (9%), hypoalbuminemia (9%), thrombocytopenia (6%), and hyponatremia (6%). No death and new safety signals with a causal relation to study treatment were observed. Conclusions: Although the primary endpoint was not achieved statistically, the results are clinically encouraging, especially take into account that more elderly patients enrolled in this trial. The combination of RAM plus IRI has anti-cancer activity and manageable safety profile in second-line treatment for patients with AGC. Clinical trial information: jRCTs011180029.

Second-line treatment in advanced gastric cancer: Data from the Spanish AGAMENON registry.

Second-line treatments boost overall survival in advanced gastric cancer (AGC). However, there is a paucity of information as to patterns of use and the results achieved in actual clinical practice. The study population comprised patients with AGC in the AGAMENON registry who had received second-line. The objective was to describe the pattern of second-line therapies administered, progression-free survival following second-line (PFS-2), and post-progression survival since first-line (PPS). 2311 cases with 2066 progression events since first-line (89.3%) were recorded; 245 (10.6%) patients died during first-line treatment and 1326/2066 (64.1%) received a second-line. Median PFS-2 and PPS were 3.1 (95% CI, 2.9-3.3) and 5.8 months (5.5-6.3), respectively. The most widely used strategies were monoCT (56.9%), polyCT (15.0%), ramucirumab+CT (12.6%), platinum-reintroduction (8.3%), trastuzumab+CT (6.1%), and ramucirumab (1.1%). PFS-2/PPS medians gradually increased in monoCT, 2.6/5.1 months; polyCT 3.4/6.3 months; ramucirumab+CT, 4.1/6.5 months; platinum-reintroduction, 4.2/6.7 months, and for the HER2+ subgroup in particular, trastuzumab+CT, 5.2/11.7 months. Correlation between PFS since first-line and OS was moderate in the series as a whole (Kendall's τ = 0.613), lower in those subjects who received second-line (Kendall's τ = 0.539), especially with ramucirumab+CT (Kendall's τ = 0.413). This analysis reveals the diversity in second-line treatment for AGC, highlighting the effectiveness of paclitaxel-ramucirumab and, for a selected subgroup of patients, platinum reintroduction; both strategies endorsed by recent clinical guidelines.

Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy

BackgroundPaclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. Methods and materialsPatients were randomized 1:1 to DHP107 (200mg/m2 orally twice daily days 1, 8, 15 every 4weeks) or i.v. paclitaxel (175mg/m2 day 1 every 3weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25. ResultsBaseline characteristics were balanced in the 236 randomized patients (n=118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7–4.0) months for DHP107 and 2.6 (95% CI 1.8–2.8) months for paclitaxel (hazard ratio [HR]=0.85; 95% CI 0.64–1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR=0.93; 95% CI 0.70–1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1−11.5) months for DHP107 versus 8.9 (95% CI 7.1–12.2) months for paclitaxel (HR=1.04; 95% CI 0.76–1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). ConclusionsDHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. ClinicalTrials.govNCT01839773.

Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05)

In Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC. Patients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40-60 mg/m(2)) on days 1-14 and intravenous irinotecan (150 mg/m(2)) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS). From February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78-1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group. The consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy. ClinicalTrials.gov ID: NCT00639327.

A randomized phase II factorial design trial of CPT-11 versus PTX versus each combination with S-1 in patients with advanced gastric cancer refractory to S-1: Final results of OGSG0701.

117 Background: S1 + platinum (SP) is recognized as standard first-line chemotherapy for advanced gastric cancer(AGC), and S1 monotherapy is suggested for frail AGC patients or adjuvant setting in Japan. However, taxane or CPT-11 were often employed as second-line treatment for the patients who were resistant to S1-containing regimen. A retrospective analysis has reported that S1 combination chemotherapy extended overall survival as second-line treatment for AGC. Methods: Patients with AGC who confirmed disease progression by imaging after the first-line therapy with S1 or SP were randomized in four groups; CPT-11 150 mg/m2, day1, q2w (Group A), PTX 80 mg/m2, day1, 8,15, q4w (Group B), CPT-11 80 mg/m2, day1, 15, S-1 80 mg/m2, day1-21, q5w (Group C1), PTX 50 mg/m2,day1, 8, S1 80 mg/m2, day1-14, q3w (Group C2). Primary endpoint was overall survival (OS), and secondary endpoints were progression free survival (PFS), overall response rate (ORR) and safety. Sample size was set at 100 to 120 to achieve 2 months improvement of OS by using CPT-11 or by adding S1 with approximately 80% probability of the correct selection. Results: From July 2008 to March 2012, 127 patients were enrolled. The OS was 11.3/11.3/14.6/10.5 months(M) (Group A/B/C1/C2), 11.8M in Group A+C1 and 11.1M in Group B+C2 (p=0.922, HR: 0.981 [0.679-1.419]), 11.3M in Group A+B and 11.1M in Group C1+C2 (p=0.808, HR: 0.952 [0.643-1.412]), respectively. The PFS was 3.0/4.4/3.8/3.5M (Group A/B/C1/C2), 3.6M in Group A+C1 and 4.1M in Group B+C2 (p=0.035, HR:0.674 [0.468-0.972]) 3.7M in Group A+B and 3.7M in Group C1+C2 (p=0.931, HR: 1.017 [0.643-1.412]). The ORR was 7.1/16.3/4.5/5.0% (Group A/B/C1/C2), 4.7%[1.7-15.2] in Group A+C1 and 12.7%[5.6-23.5] in Group B+C2 (p=0.241), 11.8%[5.8-20.6] in Group A+B and 4.6%[0.6-16.2] in Group C1+C2 (p=0.572).Major Grade 3/4 toxicity (Group A/B/C1/C2, %), was leukopenia (12/7/5/0), neutropenia (29/16/24/24), nausea (7/2/10/5), diarrhea (5/0/10/0), and fatigue (5/2/10/5). Conclusions: From our results, we do not recommend consecutive use of S1 but CPT-11 or PTX monotherapy as second-line treatment in AGC refractory to S1 or SP. Clinical trial information: 000000677.

O1-13-1 - Randomized Phase II Study of Cpt-11 Vs Ptx; +/- S1 in Advanced Gastric Cancer Refractory to S1 or S1 + Platinum(Ogsg0701)

Background: In Japan, S1 + platinum (SP) is recommended for advanced gastric cancer (AGC) patients as first-line setting, and S1 monotherapy is suggested for frail AGC patients or adjuvant setting. However, taxane or CPT-11 were often employed as second-line treatment for the patients who were resistant to S1-containing regimen. A retrospective analysis has reported that S1 combination chemotherapy extended overall survival as second-line treatment for AGC that was resistant to first-line S1-based chemotherapy.Methods: Patients with AGC who confirmed disease progression by imaging after the first-line therapy with S1 or SP were randomized in four groups. Treatment groups were divided as follows; CPT-11 alone (Group A), weekly paclitaxel (Group B), CPT-11 plus S1 (Group C1) and PTX plus S1 (Group C2). Primary endpoint was overall survival (OS), and secondary endpoints were progression free survival (PFS), response rate and safety. Sample size was set at 100 to 120 to achieve 2 months improvement of OS by using CPT-11 or by adding S1 with approximately 80% probability of the correct selection.Results: From July 2008 to March 2012, 127 patients were enrolled. The OS was 11.3/11.3/14.6/10.5 months(M) (Group A/B/C1/C2), 11.8M in Group A + C1 and 11.1M in Group B + C2 (p = 0.922, HR: 0.981 [0.679-1.419]), 11.3M in Group A + B and 11.1M in Group C1 + C2 (p = 0.808, HR: 0.952 [0.643-1.412]), respectively. The PFS was 3.0/4.4/3.8/3.5M (Group A/B/C1/C2), 3.6M in Group A + C1 and 4.1M in Group B + C2 (p = 0.035, HR:0.674 [0.468-0.972]) 3.7M in Group A + B and 3.7M in Group C1 + C2 (p = 0.931, HR: 1.017 [0.643-1.412]).Major Grade 3/4 toxicity (Group A/B/C1/C2, %), was leukopenia (12/7/5/0), neutropenia (29/16/24/24), nausea (7/2/10/5), diarrhea (5/0/10/0), and fatigue (5/2/10/5). There was one treatment-related death in Group A.Conclusions: From our results, we do not recommend consecutive use of S1 but CPT-11 or PTX monotherapy as second-line treatment in AGC patients who are refractory to S1 or SP.

Docetaxel plus oxaliplatin (DOCOX) as a second-line treatment after failure of fluoropyrimidine and platinum in Chinese patients with advanced gastric cancer

The fluoropyrimidine and platinum-based combination chemotherapy is now widely used as first-line therapy for advanced gastric cancer (AGC). Unfortunately, about half of all patients do not respond to the current first-line chemotherapy and furthermore, most patients who achieve response to first-line chemotherapy eventually experience disease progression. Although there is a need for effective salvage treatment after the failure of first-line chemotherapy, data on the safety and efficacy of second-line treatment in AGC is limited. The current study evaluated an experimental combination regimen of docetaxel (60 mg/m) as an intravenous infusion of less than 1 h, followed by oxaliplatin (130 mg/m) intravenously for less than 2 h. Both drugs were administered on day 1 of a 21-day cycle, in pretreated Chinese patients with AGC. The trial enrolled 48 patients of whom 46 (95.8%) were assessable for response. The median time to progression was 4.4 months (95% confidence interval (CI): 3.4-5.4 months) and the median overall survival was 7.2 months (95% CI: 6.6-12.1 months). Partial response was confirmed in 11 of 48 cases (22.9%; 95% CI: 10.9-34.9%) and no complete responses were seen. Significant hematologic toxicity was noted with grade 3 and grade 4 neutropenia occurring in 21.7 and 4.3% of patients, respectively, as well as grade 3 thrombocytopenia occurring in 4.3% of patients. Grade 3 febrile neutropenia occurred in 6.5% of the patients. There were no treatment-related deaths during on the study. In summary, docetaxel and oxaliplatin have modest activity with predictable hematologic toxicity when given as salvage therapy for Chinese patients treated earlier for AGC. Given the short duration of response more focus should be given to newer biologic agents and triplet regimens.