Pretreated Gastric Cancer Research Articles

Safety and preliminary efficacy of MIL93 in patients with advanced solid tumors: The monotherapy part of a phase 1 trial.

798 Background: Claudin18.2 (CLDN18.2) is specifically expressed in the tight junction of gastric epithelial cells, and has been identified as a promising target in gastric and pancreatic cancer as well as several other malignancies. MIL93 is a humanized afucosylated IgG1 monoclonal antibody targeting CLDN18.2 with enhanced ADCC function, which demonstrated superior activity compared with zolbetuximab in vitro and in vivo, respectively. We conducted a multicenter, dose escalation and expansion phase 1 study of MIL93 for advanced solid tumors. Methods: We enrolled pts aged 18 years or older with advanced solid tumors whose disease had progressed after standard systemic treatments in the monotherapy part of this study. Pts were required to have measurable lesion as per RECIST v1.1; ECOG PS score of 0-1 and adequate organ functions. In the dose escalation phase, 6 dose levels (0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg and 30mg/kg, Q3W) of MIL93 were conducted for assessment. Accelerated titration was adopted for the first 2 dose levels, and the 3+3 design was used afterwards. In the dose expansion phase, pts with CLDN18.2-positive cancers received the selected RP2D. The primary objectives were the safety and tolerability, dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MIL93. Secondary objectives included pharmacokinetics, immunogenicity and preliminary efficacy. Results: At the data cut-off date (August 9, 2022), 30 pts were enrolled from 6 centers in China. MIL93 was well-tolerated for the dosages tested (0.3mg/kg through 30mg/kg Q3W). DLT was observed in one pt during the 3-week window at 30mg/kg. However, none of the three additional patients at 30mg/kg had DLT, and MTD has not been reached. In further expansion study 9 additional pts were enrolled into the expansion phase at the 20 mg/kg Q3W dose and 3 pts were enrolled into the dose escalation at the 10mg/kg Q2W. The most common TEAE occurring in ≥20% of pts were nausea (60%), hypoalbuminemia (46.7%), vomiting (43.3%), anemia (36.7%), hyponatremia (33.3%), hypocalcemia (23.3%), decreased appetite (23.3%), asthenia (23.3%), aspartate aminotransferase increased (20.0%). Serious adverse events (SAEs) were observed in 9 (30%) pts, and MIL93-related SAEs occurred in 6 (20%) pts including hypoalbuminemia/hypoproteinemia, malnutrition, anorexia and vomiting. No treatment related Grade 4 or 5 event was reported. Among the 25 pts who had at least one post-treatment radiological evaluation, 2 gastric cancer pts who progressed on multiple lines of therapies achieved partial response (PR). The disease control rate (DCR) reached 44%. Conclusions: MIL93 had a manageable and tolerable safety profile in patients with advanced solid tumors and preliminary anti-tumor activity in 2 heavily pretreated gastric cancer pts. Combination of MIL93 and standard treatment in selected tumor types is currently underway. Clinical trial information: NCT04671875 .

The Role and Expression of Angiogenesis-Related miRNAs in Gastric Cancer.

Simple SummaryThe aberrant expression of several micro RNAs (miRNAs) has been shown to be involved in neoplastic angiogenesis, which is a crucial mechanism in gastric cancer onset and progression. In this review, the possible prognostic and predictive roles of angiogenesis-related miRNAs as novel biomarkers of gastric cancer have been evaluated, but neither tissue nor circulating biomarkers have shown a predictive role for response to anti-angiogenic treatment. Nevertheless, we consider that in future studies, miRNAs should be evaluated as candidate biomarkers with prognostic and predictive features.Gastric cancer (GC) is the fifth most frequently diagnosed malignant tumor and the third highest cause of cancer mortality worldwide. For advanced GC, many novel drugs and combinations have been tested, but results are still disappointing, and the disease is incurable in the majority of cases. In this regard, it is critical to investigate the molecular mechanisms underlying GC development. Angiogenesis is one of the hallmarks of cancer with a fundamental role in GC growth and progression. Ramucirumab, a monoclonal antibody that binds to vascular endothelial growth factor-2 (VEGFR-2), is approved in the treatment of advanced and pretreated GC. However, no predictive biomarkers for ramucirumab have been identified so far. Micro RNAs (miRNAs) are a class of evolutionarily-conserved single-stranded non-coding RNAs that play an important role (via post-transcriptional regulation) in essentially all biologic processes, such as cell proliferation, differentiation, apoptosis, survival, invasion, and migration. In our review, we aimed to analyze the available data on the role of angiogenesis-related miRNAs in GC.

Immune Checkpoint Inhibitors in Pre-Treated Gastric Cancer Patients: Results from a Literature-Based Meta-Analysis.

Immunotherapy has recently changed the treatment of several cancers. We performed a literature-based meta-analysis of randomised controlled trials to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in metastatic gastric cancer. The main outcome was overall survival. Based on age (cut-off agreed at 65 years), tumour location (gastric vs. gastro-oesophageal junction), programmed death-ligand 1 (PD-L1) status, sex and Eastern Cooperative Oncology Group (ECOG) status (1 vs. 0), we scheduled a subgroup analysis for the overall survival. Three studies were included in the analysis for a total of 1456 cases (811 cases were in the experimental group and 645 cases in the control group). The pooled analysis showed improved overall survival in the experimental arm in the absence of statistical significance (hazard ratio (HR) = 0.87, 95% CI: 0.64–1.18; p = 0.37). The subgroup of patients with PD-L1-positive tumours (HR = 0.82 vs. 1.04) and gastro-oesophageal junction cancer (HR = 0.82 vs. 1.04) showed a statistically significant advantage of overall survival. This study supports the efficacy of immune checkpoint inhibitors in the subgroup of patients with metastatic gastric cancer with PD-L1-positive and gastro-oesophageal junction tumour location. Future studies are needed with the aim of identifying reliable predictive biomarkers of ICI efficacy.

Targeted therapy in gastric cancer: Review of literature

Gastric cancer (GC) is the second leading cause of cancer-related death, and despite having improved treatment modalities over the last decade, for most patients, only modest improvements have been seen in overall survival. Conventional chemotherapy and radiation have shown limited efficacy for advanced gastric cancer, showing an overall survival (OS) rate of ~10 months. Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is the first approved molecularly targeted agent for HER2-overexpressing gastric cancer, which was found to prolong the OS and the progression free survival (PFS) of patients. Angiogenesis is a vital process in the progression and metastasis of solids tumors including gastric adenocarcinoma. Monoclonal antibodies, soluble receptors, and small molecule tyrosine kinase inhibitors have been developed to inhibit tumor angiogenesis: The recent REGARD trial RAINBOW trial for advanced pretreated gastric cancer confirmed the survival advantage of this anti-angiogenic agent in gastric cancer.

Safety, pharmacokinetics and efficacy of RC48-ADC in a phase I study in patients with HER2-overexpression advanced solid cancer.

e16059 Background: Trastuzumab combined with chemotherapy is the standard first-line regimen in HER2- overexpression advanced gastric cancer, and there is no established therapy in the second-line setting. RC48-ADC is a novel humanized anti-HER2 antibody conjugated with Monomethyl Auristatin E (MMAE) via a cleavable linker, which has showed high specificity and potency in vivo and in vitro models of gastric cancer and other solid tumors. Methods: This was an open-label, dose-escalation and dose-expansion study in pts with HER2-overexpression (defined as IHC 2+ or 3+) advanced solid cancers. The dose escalation phase was initialed by accelerated titration (0.1 and 0.5 mg/kg) and then switched to 3+3 scheme (1.0, 2.0 and 2.5 mg/kg, Q2W). In dose expansion phase, pts were given at 2.0mg/kg Q2W. Results: As of Jan 29, 2018, 22 pts (21 gastric cancers and 1 breast cancer) in dose escalation (0.1 - 2.5 mg/kg Q2W, n = 19; 2.0 mg/kg Q3W, n = 3) and 14 pts (11 gastric cancers, 2 urothelial cancers and 1 bile duct cancer) in dose expansion were available for analysis. MTD was not reached at doses up to 2.5 mg/kg Q2W. 35 pts (97.2%) experienced TRAEs, most commonly leucopenia (61.1%), neutropenia (52.8%), fatigue (50.0%), numbness (44.4%), AST elevation (30.6%) and ALT elevation (27.8%). 11 pts (30.6%) developed Grade 3-4 TRAEs including leucopenia (11.4%), neutropenia (11.4%), numbness (11.1%) and fatigue (5.6%), which resolved with dose reduction and supportive care. Anticancer activity was observed in 2.0 and 2.5mg/kg cohort of 24 evaluable pts, reporting 33.3% ORR and 58.3% DCR. 2 PRs were assessed in 1 pt with urothelial cancer and 1 with bile duct cancer. ORR was 40% in low HER2-expression (IHC 2+/FISH-, n = 5) pts and 29.4% in high HER2-expression (IHC 2+/FISH+ or IHC 3+, n = 17) pts. Furthermore, an ORR of 30% and DCR of 60% was found in 10 gastric pts receiving 2.0 or 2.5 mg/kg who had progressed to trastuzumab-based regimens. Conclusions: RC48-ADC has presented a manageable safety profile. It has severity-limited myelosuppression and low liver toxicities. Pts with trastuzumab- pretreated gastric cancer exhibit good response. Dose expansion is on progress. Clinical trial information: NCT02881190.

M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with pretreated recurrent or refractory gastric cancer: Preliminary results from a phase I trial.

100 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report preliminary results in Asian patients with heavily pretreated gastric cancer. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02699515, patients with recurrent or refractory unresectable stage IV gastric or gastroesophageal junction adenocarcinoma for which no standard therapy exists or standard therapy has failed receive M7824 1200 mg q2w until confirmed progressive disease, unacceptable toxicity or trial withdrawal. The primary objective is safety; secondary objectives include best overall response (BOR) per RECIST v1.1. Results: As of 6 September 2017, 31 heavily pretreated patients with advanced gastric cancer (67.7% received ≥3 prior anticancer therapies) received M7824 for a median duration of 6.1 (range: 2-30) weeks (median number of M7824 infusions: 3 [range: 1-13]); 8 patients remained on treatment. Four patients (12.9%) experienced grade 3 treatment-related adverse events (anemia and diarrhea 1 each and 2 rash). No treatment-related grade 4 AEs occurred. One grade 5 event (total 5 doses received) was considered possibly treatment related, but suspected rupture of preexisting thoracic aortic aneurysm was cited as other probable cause by the investigator. There were 5 confirmed partial responses (4 ongoing after 4-6 months of follow-up) based on investigator assessment of BOR (overall response rate: 16.1%). This is an ongoing study; updated data will be presented. Conclusions: These preliminary data show that M7824 resulted in a manageable safety profile in heavily pretreated Asian patients with gastric cancer. Early signs of clinical efficacy are encouraging. Clinical trial information: NCT02699515.

Hepatic arterial infusion chemotherapy for liver metastases from gastric cancer: an analysis in Western patients.

The advantage of administering chemotherapy by hepatic arterial infusion is the achievement of high drug concentrations in the liver. Oxaliplatin, irinotecan and 5-flourouracil are active agents in advanced gastric cancer. Therefore a retrospective analysis was performed to investigate the effects of these drugs administered by hepatic arterial infusion in heavily pretreated gastric cancer patients with predominant hepatic metastases. Very limited data about hepatic arterial infusion exist in western gastric cancer patients. Seven patients with advanced gastric cancer were included in the retrospective analysis. All patients had proven progressive disease prior to initiation of hepatic arterial infusion. All had an ECOG performance status of < or =2 and had received at least two previous systemic chemotherapy regimens, including the combination of cisplatin/5-fluorouracil. Patients were given chemotherapy by hepatic arterial infusion: 5-fluorouracil, 600 mg/m2, together with folinic acid, 300 mg/m2/2 h, followed by oxaliplatin, 85 mg/m2/2 h, every 2 weeks. Fifty-four cycles of hepatic arterial infusion (range, 2-21) with a median treatment duration of 6 cycles were administered in 7 patients. The treatment was feasible and safe, no grade 3-4 toxicity was observed. One patient showed stabilization of liver metastases over 7 months. In 6 of the 7 patients there was radiologically proven progressive disease after a median treatment time of 10 weeks. Chemotherapy by hepatic arterial infusion is modestly effective in heavily pretreated gastric cancer patients. Hepatic arterial infusion has a very favorable toxicity profile and can be safely administered even in elderly patients. It might be an additional therapeutic option and should be further investigated. The literature on hepatic arterial infusion in gastric cancer patients is reviewed.

Immunotherapy for Esophageal and Gastric Cancer.

PD-L1 upregulation occurs in approximately 40% of gastroesophageal cancers. However, unlike other solid tumors, there is minimal PD-L1 expressed on the cancer cells; rather, expression occurs predominantly on infiltrating myeloid cells. Preliminary clinical data involving single-agent PD-1/PD-L1 inhibitors in metastatic gastroesophageal cancer have reported response rates of 22%-27% for patients with PD-L1+ tumors and 10%-17% for unselected patients. The phase III ONO-4538-12 (ATTRACTION 2) trial has demonstrated an improved overall survival for nivolumab compared with placebo for patients with heavily pretreated gastric cancer. In the future, we will need better biomarkers to select those most likely to respond and/or identify patients who may need combination immunotherapeutics or alternate strategies. A number of subsets of gastric cancer with different immune signatures, most notably tumors positive for Epstein-Barr virus and microsatellite instability, have been identified, with approximately 50% and 94% PD-L1+ staining seen on tumor cells and immune cells in the EBV subtype and approximately 33% and 45% PD-L1+ staining seen on tumor cells and immune cells in MSI high tumors. Both subtypes demonstrate PD-L1+ immune cells with tumor-infiltrating patterns, unlike the more commonly seen PD-L1+ immune cells at the invasive margin. PD-L2 expression has been reported in 52% of esophageal adenocarcinomas but little is known about the expression of other immune checkpoints. Additional factors that suggest gastroesophageal cancers may respond to checkpoint inhibition include the high somatic mutation burden and the link with chronic inflammation. Here we provide a comprehensive review of the checkpoint inhibitor data published to date in advanced esophagogastric cancers and rationalize how the immune microenvironment in these diverse tumors can explain response or resistance to immunotherapeutics.

Immunotherapy for Esophageal and Gastric Cancer

PD-L1 upregulation occurs in approximately 40% of gastroesophageal cancers. However, unlike other solid tumors, there is minimal PD-L1 expressed on the cancer cells; rather, expression occurs predominantly on infiltrating myeloid cells. Preliminary clinical data involving single-agent PD-1/PD-L1 inhibitors in metastatic gastroesophageal cancer have reported response rates of 22%-27% for patients with PD-L1+ tumors and 10%-17% for unselected patients. The phase III ONO-4538-12 (ATTRACTION 2) trial has demonstrated an improved overall survival for nivolumab compared with placebo for patients with heavily pretreated gastric cancer. In the future, we will need better biomarkers to select those most likely to respond and/or identify patients who may need combination immunotherapeutics or alternate strategies. A number of subsets of gastric cancer with different immune signatures, most notably tumors positive for Epstein-Barr virus and microsatellite instability, have been identified, with approximately 50% and 94% PD-L1+ staining seen on tumor cells and immune cells in the EBV subtype and approximately 33% and 45% PD-L1+ staining seen on tumor cells and immune cells in MSI high tumors. Both subtypes demonstrate PD-L1+ immune cells with tumor-infiltrating patterns, unlike the more commonly seen PD-L1+ immune cells at the invasive margin. PD-L2 expression has been reported in 52% of esophageal adenocarcinomas but little is known about the expression of other immune checkpoints. Additional factors that suggest gastroesophageal cancers may respond to checkpoint inhibition include the high somatic mutation burden and the link with chronic inflammation. Here we provide a comprehensive review of the checkpoint inhibitor data published to date in advanced esophagogastric cancers and rationalize how the immune microenvironment in these diverse tumors can explain response or resistance to immunotherapeutics.

614O - Final results of the FAST study, an international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without the anti-CLDN18.2 antibody IMAB362 as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma

Background: IMAB362, a chimeric monoclonal antibody that mediates specific killing of cancer cells expressing the tight junction protein Claudin18.2 (CLDN18.2) by activation of immune effector mechanisms, has demonstrated single-agent activity and tolerability in patients ( pts) with heavily pretreated gastric cancer. Methods: Pts with advanced/recurrent gastric and GEJ cancer were centrally evaluated for CLDN18.2 expression by immunohistochemistry (CLAUDETECT® 18.2 Histology Kit). Eligible pts had a CLDN18.2 expression of ≥2+ in ≥40% tumor cells, an ECOG PS of 0–1 and were not eligible for trastuzumab. Pts were randomized 1:1 to first-line EOX (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 d1, and capecitabine 625 mg/m2 bid, d1–21; qd22) with or without IMAB362 (loading dose 800 mg/m2, then 600 mg/m2 d1, qd21). An exploratory arm (N = 85) was added to investigate a higher dose IMAB362 (1000 mg/m2) plus EOX. The primary study endpoint was PFS (Arm1 vs 2,70% power, hazard ratio [HR] 0.72, 1-sided p = 0.1). Here we present the final study results.

Advances in Systemic Therapy for Metastatic or Advanced Gastric Cancer.

In recent years, various new agents have been investigated for the treatment of advanced gastric cancer (AGC). The anti-HER2 antibody trastuzumab has been shown to prolong the overall survival of patients with HER2-positive AGC and has become a standard treatment. However, lapatinib, or ado-trastuzumab emtansine (T-DM1), did not show survival benefit in AGC, although it has shown remarkable efficacy for HER2-positive breast cancer. The efficacy of the anti-vascular endothelial growth factor receptor monoclonal antibody ramucirumab for pretreated gastric cancer is a milestone for antiangiogenic therapy for AGC. Early clinical trials of TAS-118, TAS-102, and STAT3 inhibitors; IMAB362 (anti-Claudin 18.2); and immune checkpoint inhibitors are all encouraging. These findings warrant further evaluation in larger clinical trials.

FAST: An international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without IMAB362, a first-in-class anti-CLDN18.2 antibody, as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma.

LBA4001 Background: Claudin18.2 (CLDN18.2) is a tight junction protein expressed by several cancers including gastric and GEJ adenocarcinoma. IMAB362 is a chimeric monoclonal antibody that mediates specific killing of CLDN18.2-positive cancer cells by activation of immune effector mechanisms. IMAB362 has demonstrated single-agent activity and was safe and tolerable in patients (pts) with pretreated gastric cancer. Methods: Pts with advanced/recurrent gastric and GEJ cancer were centrally evaluated for CLDN18.2 expression by IHC (validated CLAUDETECT18.2 Kit). Eligible pts had a CLDN18.2 expression of ≥ 2+ in ≥ 40% tumor cells, an ECOG PS of 0–1 and were not eligible for trastuzumab. Pts were randomized 1:1 to first-line EOX (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 d1, and capecitabine 625 mg/m2 bid, d1–21; qd22) with or without IMAB362 (loading dose 800 mg/m2, then 600 mg/m2 d1, qd21). The study was extended by an exploratory Arm3 (N = 85) to investigate a high dose IMAB362 (1000 mg/m2) plus EOX, (not subject here). The primary study endpoint was PFS (Arm 1 v 2, 70% power, HR 0.72, 1-sided p = 0.1). Results: 730 pts were consented, of whom 352 pts (48%) were tested CLDN18.2+ per protocol criteria. Of those, 161 pts (median age, 58 yrs; male 64%; gastric, 80%; GEJ, 16%; esophageal, 4%) were randomized into Arms1 and 2. The study met its endpoints. IMAB362 plus EOX improved PFS (median 5.7 v 7.9 mon; HR 0.5; 95% CI 0.35–0.78, 1-sided p = 0.001) and OS (median 8.7 v 12.5 mon; HR 0.5, 95% CI 0.28–0.73) compared to EOX alone. In the subpopulation with very high CLDN18.2 expression ( ≥ 2+ intensity in ≥ 70% tumor cells), efficacy was more pronounced (PFS, 6.1 vs 9.1 mon; HR 0.46; OS, 9.3 v 16.6 mon; HR 0.44). Most common IMAB362-related adverse events included vomiting, neutropenia, and anemia, which were mostly of NCI-CTC grade 1/2. Grade 3/4 events were not significantly increased by IMAB362. Conclusions: IMAB362 combined with first-line chemotherapy exhibited a clinically relevant benefit in PFS and OS and a favorable risk/benefit profile. Clinical trial information: NCT01630083.

Ramucirumab: successfully targeting angiogenesis in gastric cancer.

Gastric cancer is the fourth most common cancer globally and represents the second most common cause of cancer-related mortality. Early detection, aggressive surgical resection, and postoperative adjuvant therapy have led to survival improvement for early-stage gastric cancer, particularly in Asian countries. Unfortunately, advanced gastric cancer continues to pose a formidable challenge with few gains being reported recently. Trastuzumab was the first targeted agent to be approved for the treatment of advanced gastric cancer in 2010. The failure of the AVAGAST trial was a setback for antiangiogenic therapy for this disease. Ramucirumab is a monoclonal antibody that binds to VEGF-R2 and prevents its activation. The recent REGARD trial was a randomized phase III trial of ramucirumab vs. placebo for patients with advanced, pretreated gastric cancer that met its primary endpoint of increased overall survival. The toxicity of ramucirumab was modest in this setting, with an increased risk of grade 3 or higher hypertension (8% vs. 3%, with ramucirumab and placebo, respectively). The subsequent RAINBOW trial of paclitaxel plus ramucirumab vs. paclitaxel plus placebo for advanced pretreated gastric cancer confirmed the survival advantage of this antiangiogenic agent in gastric cancer. Ramucirumab is the first FDA-approved therapy for advanced gastric cancer after prior chemotherapy.

Salvage chemotherapy in gastric cancer—more than a straw?

The benefit of salvage chemotherapy in gastric cancer refractory to first-line platinum and fluoropyrimidine therapy was previously unknown. A randomized multicentre study has shown that irinotecan or docetaxel administered as single agents improved survival compared with best supportive care alone. Hence, salvage chemotherapy is now a proven option in pretreated gastric cancer.

Hepatic Arterial Infusion Chemotherapy for Liver Metastases from Gastric Cancer: An Analysis in Western Patients

The advantage of administering chemotherapy by hepatic arterial infusion is the achievement of high drug concentrations in the liver. Oxaliplatin, irinotecan and 5-flourouracil are active agents in advanced gastric cancer. Therefore a retrospective analysis was performed to investigate the effects of these drugs administered by hepatic arterial infusion in heavily pretreated gastric cancer patients with predominant hepatic metastases. Very limited data about hepatic arterial infusion exist in western gastric cancer patients. Seven patients with advanced gastric cancer were included in the retrospective analysis. All patients had proven progressive disease prior to initiation of hepatic arterial infusion. All had an ECOG performance status of < or =2 and had received at least two previous systemic chemotherapy regimens, including the combination of cisplatin/5-fluorouracil. Patients were given chemotherapy by hepatic arterial infusion: 5-fluorouracil, 600 mg/m2, together with folinic acid, 300 mg/m2/2 h, followed by oxaliplatin, 85 mg/m2/2 h, every 2 weeks. Fifty-four cycles of hepatic arterial infusion (range, 2-21) with a median treatment duration of 6 cycles were administered in 7 patients. The treatment was feasible and safe, no grade 3-4 toxicity was observed. One patient showed stabilization of liver metastases over 7 months. In 6 of the 7 patients there was radiologically proven progressive disease after a median treatment time of 10 weeks. Chemotherapy by hepatic arterial infusion is modestly effective in heavily pretreated gastric cancer patients. Hepatic arterial infusion has a very favorable toxicity profile and can be safely administered even in elderly patients. It might be an additional therapeutic option and should be further investigated. The literature on hepatic arterial infusion in gastric cancer patients is reviewed.

Capecitabine and doxorubicin combination chemotherapy as salvage therapy in pretreated advanced gastric cancer

The aim of this study was to evaluate the activity and the safety of a combination regimen of capecitabine and doxorubicin as salvage chemotherapy in advanced gastric cancer patients who had undergone one or two prior chemotherapy regimens. Patients received capecitabine, 2,500 mg/m(2)/day PO for 14 days (D1-14) and doxorubicin, 30 mg/m(2) IV on day 1 every 3 weeks until disease progression. The response was evaluated according to RECIST criteria, and the toxicity was evaluated by NCI-CTC (version 2.0). Forty-five patients were enrolled. Twenty-six patients were treated as second-line chemotherapy and the remaining patients as third-line chemotherapy. A total of 152 cycles of chemotherapy (median 2, range 1-12) were administered. Median dose intensities of capecitabine and doxorubicin were 11,326 and 9.6 mg/m(2)/week, respectively. The overall response rate was 6.7% (95% CI, 4.1-12.5%) and the disease control rate was 46.7% (95% CI, 28.6-87.1%) according to an intent-to-treat analysis. The median progression-free survival was 11.3 weeks (95% CI, 5.6-16.7 weeks). The median overall survival was 29.1 weeks (95% CI, 18.3-39.9 weeks) with one-year survival rate of 24%. Severe (grade III/IV) hematologic and non-hematologic toxicity was uncommon and included nausea/vomiting in five (11.1%), neutropenia in two (4.4%), anemia in one (2.2%), and hand-foot syndrome in one patient (2.2%). The combination of capecitabine and doxorubicin is a feasible salvage regimen in advanced pre-treated gastric cancer.

Irinotecan (CPT-11) and Mitomycin-C (MMC) as Second-Line Therapy in Advanced Gastric Cancer

The aim of this study was to evaluate the activity and toxicity of a combination regimen of CPT-11 and mitomycin-c as second-line chemotherapy for pretreated patients with advanced, metastatic, or both, gastric adenocarcinoma. Patients with pretreated metastatic disease or early relapsed after adjuvant chemotherapy were enrolled. Entry criteria included histologic/cytologic diagnosis of gastric adenocarcinoma, age 18 to 75 years, performance status > or =70 (Karnofsky scale), bi-dimensionally measurable disease. Patients received CPT-11 and mitomycin-c at the dosage of 150 mg/m2 on days 1 and 15, and 8 mg/m2 on day 1, respectively, every 4 weeks. The disease evaluation was done every 3 cycles. Among the 38 patients we observed, 1 (3%) complete response and 11 (29%) partial responses for an overall response rate of 32% according to an intent-to-treat analysis. The median duration of response was 6.5 months. The median time to progression was 4 months with a median overall survival 8 months. All patients were evaluable for toxicity and the only grade 3-4 observed toxicities were leukopenia (8%), neutropenia (21%), and anemia (5%). The combination of CPT-11 and mitomycin-c is an active and well tolerated second-line treatment in pretreated gastric cancer patients. Further studies are needed to test its role in first-line treatment.

Phase II study of low-dose paclitaxel and cisplatin as second-line therapy in 5-fluorouracil and platinum pretreated gastric cancer

4194 Background: Paclitaxel has shown promising activity as a single agent in gastric cancer and has synergism with cisplatin in human gastric cancer cell lines. This study was performed to evaluate the efficacy and toxicity of an outpatient regimen composed of low-dose paclitaxel and cisplatin in patients with metastatic or relapsed gastric cancer who had progressed disease during or after treatment with 5-fluorouracil (5-FU) and platinum compounds. Methods: Patients with documented progression on or within 6 months of 5-FU and platinum-based chemotherapy were enrolled. As second-line treatment, paclitaxel 145 mg/m2 was administered intravenously over 3 hours, followed by cisplatin 60 mg/m2 on day 1 every 3 weeks in the outpatient setting. Results: Between October 2002 and June 2004, 28 patients (25 male and 3 female) were enrolled. As first-line treatment, 24 patients received 5-FU/cisplatin and 4 patients received 5-FU/oxaliplatin/leucovorin. Median age was 62.5 years. Of these patients, 8 (29%) had partial responses. Six (21%) had stable disease and 12 (43%) had progressive disease. Two patients (7%) were not evaluable because of early drop-out from this study due to treatment-related toxicities. With the median follow-up duration of 10.5 months, the median time to progression (TTP) in all patients was 2.9 months (95% confidence interval [CI]: 1.9∼3.9 months) and the TTP in responders was 4.3 months (95% CI: 3.1∼5.5 months). The median overall survival was 9.1 months (95% CI: 7.0∼11.2 months). The most common hematologic toxicity was grade 1∼2 anemia (43%). Grade 3 leucopenia developed in 7% and no other grade 3∼4 hematologic toxicity or neutropenic sepsis were observed. The most common non-hematologic toxicities were peripheral neuropathy (32%) and emesis (25%). One case (4%) of grade 4 emesis and 2 cases (7%) of grade 3 peripheral neuropathy were developed; 2 (7%) patients were dropped out from this study due to toxicities. No other grade 3∼4 non-hematological toxicities were observed. Conclusions: As second-line treatment, low-dose paclitaxel and cisplatin chemotherapy in the outpatient setting was active and had acceptable toxicities. No significant financial relationships to disclose.

Irinotecan combined with infusional 5-fluorouracil and folinic acid (folfiri) in patients with metastatic gastric cancer resistant to cisplatin-containing chemotherapy

4146 Background: irinotecan is an active drug for pretreated gastric cancer patients. It resulted particularly effective when combined with cisplatin, but no reference regimen exists for patients progressive after cisplatin. Activity and toxicity of FOLFIRI is well known in metastatic colorectal cancer patients. Therefore, we studied the tolerability and activity of this regimen in patients with metastatic gastric carcinoma progressive after chemotherapy containing cisplatin. Patients and methods: Patients with histologically proven gastric cancer, measurable or evaluable disease, age ≤ 75 years, PS 0–2 (ECOG), were enrolled. The regimen included irinotecan 180 mg/m2 i.v. over 90' + Folinic Acid 200 mg/m2 i.v. over two hours + 5-Fluorouracil (5-FU) 400 mg/m2 i.v. bolus + 5-FU 2400 mg/m2 i.v. continuous infusion over 46 hours, and was repeated every two weeks. Restaging was performed after 4 courses. Responsive patients could be treated until progression. Results: From June 2002 to August 2003 twenty-seven consecutive patients were treated. Informed consent was obtained from all patients. Progressive disease after a cisplatin-based first-line chemotherapy or within six months after a neo-/adjuvant chemotherapy was present in all patients. Previous treatments were: Epirubicin,Cisplatin,5-FU (ECF) in 15 patients, Taxotere,Cisplatin,5-FU (TCF) in five, Taxotere,Cisplatin (TC) in seven. Four out of the 27 patients were refractory to neo-/adjuvant chemotherapy. Eighty-eight courses were administered (median per patient 5; range 1–14). Grade (G) 4 neutropenia in two patients was the only G3–4 toxicity. Quality of life evaluation in over half of the patients is ongoing. Five objective responses and nine stable diseases were obtained (intent to treat). Four patients showed a stable disease for > four months. One patient is not evaluable because too early. Conclusion: FOLFIRI is a proposable second-line chemotherapy in metastatic gastric cancer patients resistant to cisplatin-containing chemotherapy. Phase II and III studies in chemotherapy-naive patients are warranted. No significant financial relationships to disclose.