The investigators suggested that this higher discontinuation rate and lower drug exposure might have impacted upon the PFS assessment. It is difficult to establish why a differential effect was seen with ramucirumab treatment and oesophageal malignancy GC and GOJ malignancy. remains low, with less than one in five individuals surviving for more than 5 years. For advanced disease the prognosis is particularly bleak, having a median overall survival (OS) of only 3 months with best supportive care, and approximately 12 months with first-line combination chemotherapy. Current standard of care The first-line standard of care for metastatic or inoperable locally advanced gastro-oesophageal malignancy consists of a doublet of a platinum and a fluoropyrimidine, or a triplet with the help of epirubicin or a taxane. In 2010 2010 the practice changing ToGA trial led to the addition of trastuzumab to the standard doublet for those individuals who are Human being Epidermal Growth Element Receptor 2 (HER2) positive, approximately 20% of individuals with advanced gastro-oesophageal malignancy [Bang 2010]. The addition of trastuzumab with this study resulted in a median OS of 16 weeks for the subgroup of HER2-positive individuals with HER2 3+ on immunohistochemistry (IHC) screening or HER2 2+ on IHC with positive HER2 on fluorescence hybridization screening. As yet, however, there is no standard targeted first-line treatment for HER2-bad individuals. There BML-190 is less international consensus concerning second-line treatment, but irinotecan, docetaxel and weekly paclitaxel are all used in BML-190 this situation [Kang 2012; Thuss-Patience 2011; Ford 2014; Hironaka 2013]. Across the studies performed with this establishing the OS with best supportive care offers ranged from 2.4 to 3.8 months, whereas the OS with single-agent chemotherapy has been between 4 and 9.5 months. However, it must be noted the top limit of survival quoted here is from the Japanese study of paclitaxel irinotecan where approximately 80% of patients went on to have third-line chemotherapy. In the other studies, OS was between 4 and 5.3 months (Figure 1). Open in a separate window Physique 1. Overall survival with second-/subsequent-line chemotherapy in BML-190 advanced gastric malignancy. *Hironaka [2013]: paclitaxel irinotecan. $,Ford [2014]: docetaxel best supportive care (BSC). ?Kang [2012]: docetaxel or irinotecan BSC. Thuss-Patience [2011]: irinotecan BSC. ?Fuchs [2014]: ramucirumab placebo. **Wilke [2014]: paclitaxel and ramucirumab paclitaxel. This benefit with second-line chemotherapy was further supported by a meta-analysis conducted in 2013 of over 400 patients treated with second-line docetaxel or irinotecan, in which a significant reduction in the risk of death was observed with salvage chemotherapy [hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.52C0.79; 0.0001] [Kim 2015] (Table 1). Table 1. Grades 3C4 adverse events in second or subsequent collection chemotherapy for advanced gastro-oesophageal malignancy. [2013]: paclitaxel irinotecan. $Ford [2014]: docetaxel BSC. ?Kang [2012]: docetaxel or irinotecan BSC. Thuss-Patience [2011]: irinotecan BSC. ?Six episodes of febrile neutropenia in both irinoptecan and docetaxel arms. **COUGAR-02 reported all gastrointestinal toxicities as a composite endpoint. In the COUGAR-02 study, 21% experienced at least one grade 4 toxicity with docetaxel compared with 4% in BSC. BSC, best supportive care; NR, not reported. Targeted therapies In recent years, the elucidation of various molecular pathways involved in the development of GC has led to a multitude of studies of targeted therapies. There is, as yet, no single clear molecular driver for gastro-oesophageal malignancy, but following the success of the ToGA trial discussed above, agents targeting the vascular endothelial growth factor (VEGF) angiogenesis pathway, the hepatocyte growth factor pathway (MET), the phosphoinositide 3 kinase inhibitor/mammalian target of rapamycin (PI3K/mTOR) pathway and other agents targeting the epidermal growth factor receptor family (EGFR) have all been investigated (Table 2). Table 2. Phase III studies of targeted therapies in GC and GOJC. BSC3552.11.35.23.8GRANiTEPreviously treated advanced GCmTOREverolimus BSC6565.44.31.71.4RAINBOWPreviously treated advanced GC/GOJCVEGF/angiogenesisPaclitaxel +/C ramucirumab6654.42.99.67.4In progress: first lineMETGASTRICHER2-unfavorable and MET-positive metastatic GECMETFOLFOX+/C onartuzumab800JACOBHER2-positive advanced GC/GOJC(EGFR)XP-T +/C pertuzumab780HELOISEHER2-positive advanced GC/GOJC(EGFR)XP-T standard high dose400RILOMETMET-positive advanced GC/GOJCMETECX +/C rilotumumab450In progress: second or subsequent lineGATSBYPreviously treated advanced GC/GOJC(EGFR)TDM1 taxane412INTEGRATE (phase II)Previously treated advanced GC/GOJCVEGF/angiogenesisRegorafenib BSC150 Open in a separate window BSC, best supportive care; CF/X, cisplatin, 5FU/capecitabine; EGFR, epidermal growth factor receptor; EOX, epirubicin, oxaliplatin and capecitabine; FOLFOX, 5FU, folinic acid, oxaliplatin; ECX, epirubicin, cisplatin and capecitabine; GC, gastric malignancy; GEC, GOJ, gastro-oesophageal junction; GOJC, gastro-oesophageal junction malignancy; HER2, Human Epidermal Growth Factor Receptor 2; MET, hepatocyte growth factor pathway; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3 kinase inhibitor; OS, overall survival; PFS, progression-free survival; TDM1, trastuzumab emtansine; ENTPD1 VEGF, vascular endothelial growth factor; XP, capecitabine and platinum; XP-T, capecitabine, platinum and trastuzumab. So far, these trials of targeted brokers have been disappointing, with only trastuzumab in the first-line setting.