Evaluation of pembrolizumab monotherapy in patients with previously treated advanced salivary gland carcinoma in the phase 2 KEYNOTE-158 study.

AIM: We evaluated pembrolizumab monotherapy in patients with advanced salivary gland carcinoma on the phase 2 KEYNOTE-158 study (NCT02628067). METHODS: Eligible patients had histologically/cytologically confirmed advanced salivary gland carcinoma with prior failure or intolerance to standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1., and ECOG performance status 0-1. Patients were enrolled irrespective of tumour PD-L1 expression. Patients received pembrolizumab 200 mg Q3W for up to 35 cycles (∼2 years). Radiographic imaging occurred every 9 weeks through month 12, then every 12 weeks. PD-L1 positivity was defined as combined positive score ≥1 (evaluated using PD-L1 IHC 22C3 pharmDx). The primary endpoint was objective response rate per RECIST v1.1. RESULTS: In total, 109 patients were enrolled (PD-L1-positive, 25.7%). At the data cutoff (October 5, 2020), median follow-up was 53.3 (range, 50.8-56.3) months. Objective response rate was 4.6% (95% CI, 1.5-10.4%) among all patients (complete response, n = 1; partial response, n = 4) and was 10.7% (95% CI, 2.3-28.2%) in patients with PD-L1-positive disease and 2.6% (95% CI, 0.3-9.1%) in patients with PD-L1-negative disease. Duration of response was ≥24 months for all 5 responders; median duration of response was not reached (range, 25.1-49.8+ months). Median progression-free survival and overall survival were 4.0 (95% CI, 2.6-4.2) and 21.1 (95% CI, 15.9-25.5) months, respectively. Treatment-related adverse events occurred in 75.2% (grade 3-4, 15.6%; grade 5, 0%) of patients. Immune-mediated adverse events occurred in 22.0% of patients (grade 3, 5.5%; grade 4-5, 0). CONCLUSIONS: A small subset of patients with advanced salivary gland carcinoma treated with pembrolizumab had a response; all had response duration ≥2 years. The safety profile of pembrolizumab was manageable.

Evolution of predictive and prognostic biomarkers in the treatment of advanced gastric cancer.

Despite new therapeutic options, advanced gastric cancer remains associated with a poor prognosis compared with other cancers. Recent gains in the treatment of gastric cancer were accompanied by the identification of novel biomarkers associated with various cellular pathways and corresponding diagnostic technologies. It is expected that the standardization of clinical workflow and technological refinements in biomarker assessment will support greater personalization and further improve treatment outcomes. In this article, we review the current state of prognostic and predictive biomarkers in gastric cancer.

Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial.

BACKGROUND: In the phase 3 KEYNOTE-061 study (cutoff: 10/26/2017), pembrolizumab did not significantly prolong OS vs paclitaxel as second-line (2L) therapy in PD-L1 combined positive score (CPS) ≥ 1 gastric/GEJ cancer. We present results in CPS ≥ 1, ≥ 5, and ≥ 10 populations after two additional years of follow-up (cutoff: 10/07/2019). METHODS: Patients were randomly allocated 1:1 to pembrolizumab 200 mg Q3W for ≤ 35 cycles or standard-dose paclitaxel. Primary endpoints: OS and PFS (CPS ≥ 1 population). HRs were calculated using stratified Cox proportional hazards models. RESULTS: 366/395 patients (92.7%) with CPS ≥ 1 died. Pembrolizumab demonstrated a trend toward improved OS vs paclitaxel in the CPS ≥ 1 population (HR, 0.81); 24-month OS rates: 19.9% vs 8.5%. Pembrolizumab incrementally increased the OS benefit with PD-L1 enrichment (CPS ≥ 5: HR, 0.72, 24-month rate, 24.2% vs 8.8%; CPS ≥ 10: 0.69, 24-month rate, 32.1% vs 10.9%). There was no difference in median PFS among treatment groups (CPS ≥ 1: HR, 1.25; CPS ≥ 5: 0.98; CPS ≥ 10: 0.79). ORR (pembrolizumab vs paclitaxel) was 16.3% vs 13.6% (CPS ≥ 1), 20.0% vs 14.3% (CPS ≥ 5), and 24.5% vs 9.1% (CPS ≥ 10); median DOR was 19.1 months vs 5.2, 32.7 vs 4.8, and NR vs 6.9, respectively. Fewer treatment-related AEs (TRAEs) occurred with pembrolizumab than paclitaxel (53% vs 84%). CONCLUSION: In this long-term analysis, 2L pembrolizumab did not significantly improve OS but was associated with higher 24-month OS rates than paclitaxel. Pembrolizumab also increased OS benefit with PD-L1 enrichment among patients with PD-L1-positive gastric/GEJ cancer and led to fewer TRAEs than paclitaxel. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02370498.

Safety and Antitumor Activity of α-PD-L1 Antibody as Monotherapy or in Combination with α-TIM-3 Antibody in Patients with Microsatellite Instability-High/Mismatch Repair-Deficient Tumors.

PURPOSE: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors. However, 50%-60% do not respond to single-agent anti-programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6-12 months. This phase Ib trial evaluated safety and antitumor activity of anti-PD-L1 antibody LY3300054 monotherapy or in combination with anti-TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors. PATIENTS AND METHODS: Eligible patients ≥18 years without prior anti-PD-1/PD-L1 therapy received LY3300054 monotherapy (N = 40) or combination (N = 20); patients with PD-1/PD-L1 inhibitor-resistant/refractory tumors received the combination (N = 22). LY3300054 (700 mg) and anti-TIM-3 antibody (cycles 1-2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability. RESULTS: Eighty-two patients were enrolled. Most had colorectal (n = 39, 47.6%) or endometrial (n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. CONCLUSIONS: LY3300054 monotherapy and combined LY3300054/anti-TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor-naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor-resistant/refractory MSI-H/dMMR tumors.

Maintenance avelumab versus continuation of first-line chemotherapy in gastric cancer: JAVELIN Gastric 100 study design.

Avelumab is a human anti-PD-L1 IgG1 monoclonal antibody that has shown antitumor activity in early phase studies in advanced/metastatic gastric/gastroesophageal junction cancer, including as first-line maintenance therapy. Here, we describe the design of JAVELIN Gastric 100 (NCT02625610), an open-label, Phase III trial. A total of 499 patients with locally advanced/metastatic HER2- gastric/gastroesophageal junction cancer adenocarcinoma, who had achieved at least stable disease following 12 weeks of first-line oxaliplatin/fluoropyrimidine chemotherapy, have been randomized 1:1 to receive avelumab maintenance therapy or continue chemotherapy. The primary objective is to demonstrate superior overall survival in all randomized patients or in the PD-L1+ population. Secondary objectives are to demonstrate superiority for progression-free survival and objective response rate, compare quality of life measures, and determine safety.

Efficacy and Safety of Ixabepilone and Capecitabine in Patients With Advanced Triple-negative Breast Cancer: a Pooled Analysis From Two Large Phase III, Randomized Clinical Trials.

INTRODUCTION: The purpose of this study was to evaluate the safety and efficacy of ixabepilone plus capecitabine in patients with metastatic or locally advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS: We conducted a pooled analysis of patients with TNBC enrolled in 2 phase III trials (NCT00080301 and NCT00082433), pretreated or resistant to an anthracycline and a taxane. In each study, patients were randomized to receive ixabepilone 40 mg/m2 (3-hour intravenous infusion, day 1), plus oral capecitabine 1000 mg/m2 twice daily (days 1-14), or capecitabine alone 1250 mg/m2 twice daily (days 1-14), every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. RESULTS: In the subset of patients with TNBC (N = 443), the addition of ixabepilone to capecitabine compared with capecitabine alone prolonged median progression-free survival from 1.7 months to 4.2 months (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.52-0.78; P < .0001), and doubled the objective response rate from 15% (95% CI, 10.4%-20.5%) to 31% (95% CI, 24.4%-38.0%). The median overall survival was similar (9.0 vs. 10.4 months; HR, 0.88; 95% CI, 0.72-1.08; P = .1802). A similar pattern of efficacy between arms was observed in the overall pooled population (N = 1973). The safety profile was comparable between the pooled TNBC subset and the overall pooled population. Adverse events observed with combination therapy were generally manageable and consistent with the safety profiles of the individual agents. CONCLUSION: Adding ixabepilone to capecitabine is effective in prolonging progression-free survival and improving objective response rate compared with capecitabine alone in patients with advanced TNBC previously treated with anthracyclines and taxanes.

Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.

BACKGROUND: Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. METHODS: This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498. FINDINGS: Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2-10·7) with pembrolizumab and 8·3 months (7·6-9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66-1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4-2·0) with pembrolizumab and 4·1 months (3·1-4·2) with paclitaxel (HR 1·27, 95% CI 1·03-1·57). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. INTERPRETATION: Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

MET in gastric cancer with liver metastasis: The relationship between MET amplification and Met overexpression in primary stomach tumors and liver metastasis.

BACKGROUND AND OBJECTIVES: Although MET amplification/overexpression was observed in a subset of gastric cancer (GC) patients, the relationship between MET amplification/overexpression in primary GC and liver metastasis was unclear. METHODS: GC samples and matched liver metastases (N = 47) were analyzed by fluorescence/silver in-situ hybridization (FISH/SISH) and by immunohistochemistry for MET amplification and MET expression, respectively. MET-copy number (CN) and Met expression data from The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD, N = 356) were also analyzed. RESULTS: Significant overlap existed between MET amplification and Met expression in both primary stomach tumors (P = 0.013) and liver metastasis (P = 0.001). In TCGA-STAD, MET-CN (≥4 copies) and MET expression were also positively correlated (r = 0.761; P = 0.017). Comparative analysis revealed a strong association between MET expression and MET amplification (85% concurrence) in primary stomach tumors and matched liver metastasis. MET status in synchronous liver metastasis (N = 36) was correlated with primary stomach tumors. However, a significant correlation between primary tumors and liver metastases was not observed in patients with metachronous liver metastasis. Survival analyses revealed that both MET amplification and MET overexpression were prognostic of poor outcomes. CONCLUSIONS: MET amplification and Met overexpression were positively correlated in GC. MET status should be re-evaluated in GC patients with liver metastasis, especially for metachronous metastasis.

Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial.

PURPOSE: To evaluate the efficacy of adding lapatinib to capecitabine and oxaliplatin (CapeOx) in patients with previously untreated human epidermal growth factor receptor 2 (HER2) -amplified advanced gastroesophageal adenocarcinoma. PATIENTS AND METHODS: Patients with HER2-positive advanced gastroesophageal adenocarcinoma were randomly assigned at a one-to-one ratio to CapeOx plus lapatinib 1,250 mg or placebo daily. Primary end point was overall survival (OS) in patients with centrally confirmed HER2 amplification in the primary efficacy population. RESULTS: A total of 545 patients were randomly assigned, and 487 patients comprised the primary efficacy population. Median OS in the lapatinib and placebo arms was 12.2 (95% CI, 10.6 to 14.2) and 10.5 months (95% CI, 9.0 to 11.3), respectively, which was not significantly different (hazard ratio, 0.91; 95% CI, 0.73 to 1.12). Median progression-free survival in the lapatinib and placebo arms was 6.0 (95% CI, 5.6 to 7.0) and 5.4 months (95% CI, 4.4 to 5.7), respectively (hazard ratio, 0.82; 95% CI, 0.68 to 1.00; P = .0381). Response rate was significantly higher in the lapatinib arm: 53% (95% CI, 46.4 to 58.8) compared with 39% (95% CI, 32.9 to 45.3) in the placebo arm (P = .0031). Preplanned exploratory subgroup analyses showed OS in the lapatinib arm was prolonged in Asian and younger patients. No correlation was observed between HER2 immunohistochemistry status and survival. There were increased toxicities in the lapatinib arm, particularly diarrhea. CONCLUSION: Addition of lapatinib to CapeOx did not increase OS in patients with HER2-amplified gastroesophageal adenocarcinoma. There were clear differences in the effect of lapatinib depending on region and age. Future studies could examine this correlation.

Sunitinib in metastatic renal cell carcinoma: an ethnic Asian subpopulation analysis for safety and efficacy.

AIMS: We evaluated and compared the safety and efficacy of sunitinib in Asian and non-Asian patients with metastatic renal cell carcinoma enrolled in a previously reported global expanded access program. METHODS: Previously treated and treatment-naïve patients received open-label sunitinib at a starting dose of 50 mg/day for 4 weeks, followed by 2 weeks off treatment, in repeated 6-week cycles. Safety was assessed regularly, tumor measurements were performed per local practice, and survival data collected where possible. RESULTS: Data were available for 212 Asian patients from Asian sites (Asian-A), 113 Asian patients from non-Asian sites (Asian-O) and 4046 non-Asian patients. The most common grade 3/4 treatment-related adverse events were neutropenia, thrombocytopenia, hand-foot syndrome, diarrhea, asthenia and fatigue. The incidence of many adverse events was greater in Asian-A than in Asian-O or non-Asian patients. Sunitinib efficacy was comparable between Asian and non-Asian patients, with an objective response rate of 18% versus 14%; median progression-free survival of 8.7 versus 10.9 months; and overall survival of 18.9 versus 18.4 months, respectively. CONCLUSIONS: Sunitinib demonstrated tolerable safety and similar efficacy in Asian and non-Asian patients. Geographic differences in the reported frequency of specific adverse events were noted across Asian patients.

Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group.

PURPOSE: Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II. PATIENTS AND METHODS: Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m(2) per day (level 1), 900 mg/m(2) per day (level 2), 1,200 mg/m(2) per day (level 3), and 1,400 mg/m(2) per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response. RESULTS: Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m(2) without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036). CONCLUSION: Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.

Biweekly gemcitabine-paclitaxel, gemcitabine-carboplatin, or gemcitabine-cisplatin as first-line treatment in metastatic breast cancer after anthracycline failure: a phase II randomized selection trial.

BACKGROUND: The primary objective of this multicenter, open-label, randomized, parallel, phase II selection trial was to compare the objective tumor response to biweekly (every 2 weeks) gemcitabine/paclitaxel, gemcitabine/carboplatin, and gemcitabine/cisplatin as first-line treatment for metastatic breast cancer. PATIENTS AND METHODS: Eligible patients with stage IV disease who relapsed after anthracycline failure were randomly assigned in a 1:1:1 ratio to gemcitabine (2,500 mg/m2) plus paclitaxel 150 mg/m2 (n = 49); plus carboplatin, area under the curve = 2.5 mg/mL × min (n = 47); or plus cisplatin 50 mg/m2 (n = 51). Study therapy continued up until a maximum of 8 cycles and follow-up continued for 24 months. RESULTS: All patients were analyzed for efficacy and one patient was excluded from the safety analyses. The objective response was 26.5% [95% confidence interval (CI) 14.9-41.1] for gemcitabine/paclitaxel, 17.0% (95% CI 7.6-30.8) for gemcitabine/carboplatin, and 15.7% (95% CI 7.0-28.6) for gemcitabine/cisplatin. The adjusted odds ratio for tumor response was 0.33 (95% CI 0.10-1.06), P = 0.063 for gemcitabine/carboplatin versus gemcitabine/paclitaxel; 0.26 (95% CI 0.08-0.86), P = 0.027 for gemcitabine/cisplatin versus gemcitabine/paclitaxel; and 0.77 (95% CI 0.24-2.52), P = 0.671 for gemcitabine/cisplatin versus gemcitabine/carboplatin. There were no significant differences in overall survival or progression-free survival (P > 0.05). Grade 3 or 4 drug-related adverse events varied between groups and the majority of deaths (94.9%; 74/78) were related to disease progression. CONCLUSIONS: The gemcitabine-based treatments had comparable activity and tolerability. Similar survival characteristics and different toxicity profiles suggested that gemcitabine-platinum may be evaluated further in patients after anthracycline failure.

Phase II study of sunitinib as second-line treatment for advanced gastric cancer.

PURPOSE: This phase II, open-label, multicenter study assessed the oral, multitargeted, tyrosine kinase inhibitor sunitinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma who had received prior chemotherapy. EXPERIMENTAL DESIGN: Patients received sunitinib 50 mg/day on Schedule 4/2 (4 weeks on treatment, followed by 2 weeks off treatment). The primary endpoint was objective response rate; secondary endpoints included clinical benefit rate, duration of response, progression-free survival (PFS), overall survival (OS), pharmacokinetics, pharmacodynamics, safety and tolerability, and quality of life. RESULTS: Of 78 patients enrolled, most had gastric adenocarcinoma (93.6%) and metastatic disease (93.6%). All were evaluable for safety and efficacy. Two patients (2.6%) had partial responses and 25 patients (32.1%) had a best response of stable disease for ≥6 weeks. Median PFS was 2.3 months (95% confidence interval [CI], 1.6-2.6 months) and median OS was 6.8 months (95% CI, 4.4-9.6 months). Grade ≥ 3 thrombocytopenia and neutropenia were reported in 34.6% and 29.4% of patients, respectively, and the most common non-hematologic adverse events were fatigue, anorexia, nausea, diarrhea, and stomatitis. Pharmacokinetics of sunitinib and its active metabolite were consistent with previous reports. There were no marked associations between baseline soluble protein levels, or changes from baseline, and measures of clinical outcome. CONCLUSIONS: The progression-delaying effect and manageable toxicity observed with sunitinib in this study suggest that although single-agent sunitinib has insufficient clinical value as second-line treatment for advanced gastric cancer, its role in combination with chemotherapy merits further study.

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.

BACKGROUND: Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. METHODS: ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. FINDINGS: 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. INTERPRETATION: Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. FUNDING: F Hoffmann-La Roche.

A phase I/II and pharmacogenomic study of pemetrexed and cisplatin in patients with unresectable, advanced gastric carcinoma.

This phase I/II study was conducted to determine the maximum recommended dose of pemetrexed when given in combination with a fixed dose of cisplatin, and the efficacy, toxicity and association of 5,10-methylenetetrahydrofolate reductase (MTHFR) variants with this pemetrexed--cisplatin combination, in patients with unresectable, advanced gastric carcinoma. Patients 18-70 years of age, with stage IV disease or post-surgery recurrence, no earlier palliative chemotherapy, 0 or 1 Eastern Cooperative Oncology Group performance status, were included. The cisplatin dose was 75 mg/m. In phase I, the initial dose of pemetrexed was 600 mg/m, escalated in 100 mg/m increments. In phase II, efficacy, including overall response rate, overall survival, as well as toxicity and MTHFR pharmacogenetics were investigated. Phase I enrolled 16 patients; 700 mg/m was defined as pemetrexed recommended dose. Thirteen serious adverse events were reported; the most common grade 3/4 toxicities were haematologic (10 of 13, 76.9%). Phase II enrolled 73 patients, 69 qualified for safety and 68 for efficacy analysis; 65 for pharmacogenomic analysis. Overall response rate was 23.5% (14.1%, 35.4%), disease control rate 55.9%, median overall survival 11.8 months (95% confidence interval, 7.2-18.5 months), progression-free survival 4.9 months (95% confidence interval, 2.8-7.1 months), and median response duration 5.4 months. Patients with MTHFR A1298C variants had median overall survival of 6.6 months, significantly shorter than patients with the wild type (median 18.5 months, P=0.001). The pemetrexed--cisplatin combination in patients with advanced gastric cancer generates modest efficacy and a manageable toxicity profile. The reduced overall survival in patients with MTHFR A1298C polymorphism variants deserves further investigation.

Alteration of hTERT full-length variant expression level showed different gene expression profiles and genomic copy number changes in breast cancer.

We analyzed hTERT splicing patterns with respect to telomerase activity in breast cancer. Using a cDNA microarray in 22 cell lines, we observed the difference in expression profiling based on the different levels of full-length variant expression with 71 selected genes. Using 33 known genes that act with the telomerase complex, we performed unsupervised clustering with all cell lines, and found a clustering tendency related to the full-length variant expression level. Using array-based CGH, highly altered genomic copy number changes were found more often in MCF-7 (159 genes) than in MDA-MB-231 (109 genes) and MDA-MB-435 (49 genes), suggesting more genomic changes in MCF-7 cells. On comparing MCF-7 with MDA-MB231 and MDA-MB-435 cell lines, we identified 8 genes with different copy numbers, including dystroglycan, which is located in the p12-21.2 area of chromosome 3. In conclusion, alterations in the level of the full-length variant of hTERT showed different gene expression profiles and genomic copy number changes in breast cancer, which require further study into their cause-and-effect relationship.

Infusional fluorouracil, etoposide, and cisplatin (FEP) in advanced and relapsed gastric cancer.

We evaluated the efficacy and tolerability of a combination chemotherapy including infusional fluorouracil (5-FU), etoposide, and cisplatin (FEP) in 89 patients with advanced/relapsed gastric cancer. Primary endpoints were progression-free and overall survival. Secondary endpoints were response rates, response duration, and toxicity. The treatment schedule was as follows: 5-FU 1,000 mg/m2 and etoposide 100 mg/m2 were administered on 3 consecutive days and cisplatin at 80 mg/m2 was administered on day 2, and repeated every 3 weeks. The median times to progression and overall survival were 4 and 8 months, respectively. One-year progression-free and overall survival rates were 10% and 33%, respectively. The overall response rate for 25 eligible patients with measurable disease was 20% (5/25, complete response 2, partial response 3) with median response duration of 7 months. Median actual dose intensities of 5-FU, etoposide, and cisplatin were 700 mg/m2/wk, 70 mg/m2/wk, and 21 mg/m2/wk, respectively. Median relative dose intensities of 5-FU, etoposide, and cisplatin were 0.70, 0.70, and 0.63, respectively. In conclusion, the FEP regimen was found to produce therapeutic results similar to those of other combination chemotherapeutic studies and to have an acceptable toxicity. This regimen could be used as one of the options for advanced gastric cancer chemotherapy in patients unsuitable for doxorubicin-based regimens.