Prognosis of HER2 over-expressing gastric malignancy patients with liver metastasis. In the TOXAG phase II trial, security and tolerability of oxaliplatin, capecitabine and trastuzumab combination and radiotherapy as adjuvant therapy in surgically resected HER2-positive gastric or gastroesophageal junction malignancy are being evaluated [38]. Finally, RTOG 1010 phase III is usually enrolling patients with esophageal HER2-positive adenocarcinoma in order to establish the efficacy of adding trastuzumab to chemoradiation [39]. In the mean time, novel HER-2 inhibitors are also being analyzed in gastric malignancy: lapatinib ditosylate, a dual anti-EGFR and anti-HER-2 tyrosine kinase inhibitor, was firstly tested in the TRIO-013/LOGiC trial designed to evaluate the efficacy and safety of the oral inhibitor in combination with capecitabine and oxaliplatin as first-line treatment of advanced or metastatic HER2-positive esophagogastric malignancy. In this study, 545 patients were randomized 1:1 to receive CAPOX q21 (oxaliplatin 130 mg/sqm, day 1, capecitabine 850 mg/sqm/bid days 1-14) plus lapatinib (1,250 mg daily given constantly) or placebo. The primary endpoint was not met with an HR for OS of 0.91 (95% CI 0.73-1.12; = 0.35), and a median OS of 12.2 months for standard treatment = 0.0381). Overall Response Rate (ORR) was 53% (95% CI, 46.4-58.8) in the experimental arm and 39% (95% CI, 32.9-45.3, = 0.0031) in the placebo arm [40]. In the open-label, phase III TyTAN trial, 261 HER2-positive advanced gastric malignancy Asian patients were randomized to receive weekly paclitaxel with or without lapatinib, as second-line treatment. Once again, no benefit was demonstrated in terms of OS (HR 0.84, 95% CI 0.64-1.11; = 0.10) or PFS (HR 0.85, 95%CI 0.63-1.13; = 0.24) for the use of lapatinib, though a statistically significant improvement in RR was noted (27% v 9%, OR 3.85, 95%CI 1.80-8.87; = 0.001) [41]. Possible reasons for these unfavorable results are the high proportion of patients with IHC HER-2 1+score, which might have diluted the benefit of lapatinib in patients with IHC HER-2 3+ score, as well as the different rate of potentially active third-line treatments between study arms. Moreover, in TRIO-013/LOGiC trial, no correlation was observed between IHC status and OS benefit. Despite these uncertainties, lapatinib was not approved for gastric malignancy. Key results of the most important randomized trials are summarized in Table ?Table2.2. Ongoing studies might better determine its role in combination with other targeted brokers. Pertuzumab, a recombinant, humanized immunoglobulin IgG1 monoclonal antibody which binds to the extracellular domain of HER-2 preventing its heterodimerization with other members of the HER-family (HER-1, HER-3, and HER-4), has been studied to overcome trastuzumab resistance. Pertuzumab and trastuzumab bind to distinct epitopes of HER-2 without competing with each other and have complementary mechanisms of HER-2 signaling disruption, resulting in synergistic antiproliferative activity both and = 0.00176.7 = 0.000213.8 = 0.0046LOGiC “type”:”clinical-trial”,”attrs”:”text”:”NCT00680901″,”term_id”:”NCT00680901″NCT00680901Capecitabine + Oxaliplatin + LapatinibCapecitabine + Oxaliplatin + PlaceboIIIIOS53 (95% CI 46.6-59.3) vs. 40 (95% CI 33.6-46.4)6.0 = 0.1012.2 = 0.3492TyTAN “type”:”clinical-trial”,”attrs”:”text”:”NCT00486954″,”term_id”:”NCT00486954″NCT00486954Paclitaxel + LapatinibPaclitaxel + PlaceboIIIIIOS27 vs. 9 OR = 3.85, 95% CI 1.80-8.87, < 0.0015.4 = 0.244111.0 = 0.2088GATSBY "type":"clinical-trial","attrs":"text":"NCT01641939","term_id":"NCT01641939"NCT01641939TDM-1 3.6 mg/kg q21 or TDM-1 2.4 mg/kg q7Paclitaxel or DocetaxelII/IIIIIOS20.6 vs 19.62.7 2.9 HR=1.13, 95% CI 0.89-1.43, = 0.317.9 8.6 HR= 1.15, 95% CI 0.87-1.51, = 0.86 Open in a separate window 5-FU: 5-fluorouracil, CI: confidence interval, HR: hazard ratio, OR: odds ratio, iv: intravenous, ORR: overall response rate, OS: overall survival, PFS: progression-free survival, TDM-1: trastuzumab emtansine. One of the possible mechanisms associated with trastuzumab resistance is the deregulation of HER-2 downstream signal, including the PI3K/AKT/mTOR pathway. It is well known that PIK3CA mutations and PTEN inactivation result in constitutive activation of the downstream signals [49]. Everolimus, an orally administered mTOR inhibitor, showed enhanced 5-FU-induced apoptosis in gastric cancer cells with HER-2 amplification and promising activity in preclinical and early clinical trials [50, 51]: such results, however, have not been confirmed in the phase III GRANITE-1 trial. [52]. It is uncertain whether the combination of HER2-targeted agents and mTOR inhibitors might provide benefit in patients with HER2-positive gastric cancer who became resistant: the identification of predictive biomarkers remains crucial for optimizing efficacy. Afatinib, an oral irreversible inhibitor of tyrosine kinase receptors targeting HER-1, HER-2 and HER-4, may help overcoming trastuzumab resistance. Preliminary data of a phase II study enrolling patients with metastatic HER2-positive (IHC 3+ or FISH >2.0) esophagogastric cancer with disease progression whilst on a trastuzumab-containing regimen have been recently presented [53, 54] with demonstration of a 40% disease control. As pan-HER inhibitors have shown significant antitumor effects as well as in xenograft model of HER2-positive gastric cancer [55], the efficacy and safety of dacomitinib, an irreversible pan-HER tyrosine kinase inhibitor, was investigated in advanced gastric cancer patients. Twenty-seven pretreated gastric cancer patients.2011;29:3030C6. [39]. Meanwhile, novel HER-2 inhibitors are also being studied in gastric cancer: lapatinib ditosylate, a dual anti-EGFR and anti-HER-2 tyrosine kinase inhibitor, was firstly tested in the TRIO-013/LOGiC trial designed to evaluate the efficacy and safety of the oral inhibitor in combination with capecitabine and oxaliplatin as first-line treatment of advanced or metastatic HER2-positive esophagogastric cancer. In this study, 545 patients were randomized 1:1 to receive CAPOX q21 (oxaliplatin 130 mg/sqm, day 1, capecitabine 850 mg/sqm/bid days 1-14) plus lapatinib (1,250 mg daily given continuously) or placebo. The primary endpoint was not met with an HR for OS of 0.91 (95% CI 0.73-1.12; = 0.35), and a median Chloramphenicol OS of 12.2 months for standard treatment = 0.0381). Overall Response Rate (ORR) was 53% (95% CI, 46.4-58.8) in the experimental arm and 39% (95% CI, 32.9-45.3, = 0.0031) in the placebo arm [40]. In the open-label, phase III TyTAN trial, 261 HER2-positive advanced gastric cancer Asian patients were randomized to receive weekly paclitaxel with or without lapatinib, as second-line treatment. Once again, no benefit was demonstrated in terms of OS (HR 0.84, 95% CI 0.64-1.11; = 0.10) or PFS (HR 0.85, 95%CI 0.63-1.13; = 0.24) for the use of lapatinib, though a statistically significant improvement in RR was noted (27% v 9%, OR 3.85, 95%CI 1.80-8.87; = 0.001) [41]. Possible reasons for these negative results are the high proportion of patients with IHC HER-2 1+score, which might have diluted the benefit of lapatinib in patients with IHC HER-2 3+ score, as well as the different rate of potentially active third-line treatments between study arms. Moreover, in TRIO-013/LOGiC trial, no correlation was observed between IHC status and OS benefit. Despite these uncertainties, lapatinib was not approved for gastric cancer. Key results of the most important randomized trials are summarized in Table ?Table2.2. Ongoing studies might better define its role in combination with other targeted agents. Pertuzumab, a recombinant, humanized immunoglobulin IgG1 monoclonal antibody which binds to the extracellular domain of HER-2 preventing its heterodimerization with other members of the HER-family (HER-1, HER-3, and HER-4), has been studied to overcome trastuzumab resistance. Pertuzumab and trastuzumab bind to distinct epitopes of HER-2 without competing with each other and have complementary mechanisms of HER-2 signaling disruption, resulting in synergistic antiproliferative activity both and = 0.00176.7 = 0.000213.8 = 0.0046LOGiC “type”:”clinical-trial”,”attrs”:”text”:”NCT00680901″,”term_id”:”NCT00680901″NCT00680901Capecitabine + Oxaliplatin + LapatinibCapecitabine + Oxaliplatin + PlaceboIIIIOS53 (95% CI 46.6-59.3) vs. 40 (95% CI 33.6-46.4)6.0 = 0.1012.2 = 0.3492TyTAN “type”:”clinical-trial”,”attrs”:”text”:”NCT00486954″,”term_id”:”NCT00486954″NCT00486954Paclitaxel + LapatinibPaclitaxel + PlaceboIIIIIOS27 vs. 9 OR = 3.85, 95% CI 1.80-8.87, < 0.0015.4 = 0.244111.0 = 0.2088GATSBY "type":"clinical-trial","attrs":"text":"NCT01641939","term_id":"NCT01641939"NCT01641939TDM-1 3.6 mg/kg q21 or TDM-1 2.4 mg/kg q7Paclitaxel or DocetaxelII/IIIIIOS20.6 vs 19.62.7 2.9 HR=1.13, 95% CI 0.89-1.43, = 0.317.9 8.6 HR= 1.15, 95% CI 0.87-1.51, = 0.86 Open in a separate window 5-FU: 5-fluorouracil, CI: confidence interval, HR: hazard ratio, OR: odds ratio, iv: intravenous, ORR: overall response rate, OS: overall survival, PFS: progression-free survival, TDM-1: trastuzumab emtansine. One of the possible mechanisms associated with trastuzumab resistance is the deregulation of HER-2 downstream transmission, including the Chloramphenicol PI3K/AKT/mTOR pathway. It is well known that PIK3CA mutations and PTEN inactivation result in constitutive activation of the downstream signals [49]. Everolimus, an orally given mTOR inhibitor, showed enhanced 5-FU-induced apoptosis in gastric malignancy cells with HER-2 amplification and encouraging activity in preclinical and early medical.Prognostic implications of modified human being epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. of HER-2 as prognostic and predictive factor in these malignancies. FLOT only in perioperative establishing [36]. Moreover, the INNOVATION phase II study is assessing the activity of trastuzumab or trastuzumab plus pertuzumab in addition to perioperative standard chemotherapy [37]. In the TOXAG phase II trial, security and tolerability of oxaliplatin, capecitabine and trastuzumab combination and radiotherapy as adjuvant therapy in surgically resected HER2-positive gastric or gastroesophageal junction malignancy are being evaluated [38]. Finally, RTOG 1010 phase III is definitely enrolling individuals with esophageal HER2-positive adenocarcinoma in order to set up the effectiveness of adding trastuzumab to chemoradiation [39]. In the mean time, novel HER-2 inhibitors will also be being analyzed in gastric malignancy: lapatinib ditosylate, a dual anti-EGFR and anti-HER-2 tyrosine kinase inhibitor, was firstly tested in the TRIO-013/LOGiC trial designed to evaluate the effectiveness and safety of the oral inhibitor in combination with capecitabine and oxaliplatin as first-line treatment of advanced or metastatic HER2-positive esophagogastric malignancy. In this study, 545 individuals were randomized 1:1 to receive CAPOX q21 (oxaliplatin 130 mg/sqm, day time 1, capecitabine 850 mg/sqm/bid days 1-14) plus lapatinib (1,250 mg daily given continually) or placebo. The primary endpoint was not met with an HR for OS of 0.91 (95% CI 0.73-1.12; = 0.35), and a median OS of 12.2 months for standard treatment = 0.0381). Overall Response Rate (ORR) was 53% (95% CI, 46.4-58.8) in the experimental arm and 39% (95% CI, 32.9-45.3, = 0.0031) in the placebo arm [40]. In the open-label, phase III TyTAN trial, 261 HER2-positive advanced gastric malignancy Asian individuals were randomized to receive weekly paclitaxel with or without lapatinib, as second-line treatment. Once again, no benefit was demonstrated in terms of OS (HR 0.84, 95% CI 0.64-1.11; = 0.10) or PFS (HR 0.85, 95%CI 0.63-1.13; = 0.24) for the use of lapatinib, though a statistically significant improvement in RR was noted (27% v 9%, OR 3.85, 95%CI 1.80-8.87; = 0.001) [41]. Possible reasons for these bad results are the high proportion of individuals with IHC HER-2 1+score, which might possess diluted the benefit of lapatinib in individuals with IHC HER-2 3+ score, as well as the different rate of potentially active third-line treatments between study arms. Moreover, in TRIO-013/LOGiC trial, no correlation was observed between IHC status and OS benefit. Despite these uncertainties, lapatinib was not authorized for gastric malignancy. Key results of the most important randomized tests are summarized in Table ?Table2.2. Ongoing studies might better determine its role in combination with additional targeted providers. Pertuzumab, a recombinant, humanized immunoglobulin IgG1 monoclonal antibody which binds to the extracellular website of HER-2 avoiding its heterodimerization with additional members of the HER-family (HER-1, HER-3, and HER-4), has been studied to conquer trastuzumab resistance. Pertuzumab and trastuzumab bind to unique epitopes of HER-2 without competing with each other and have complementary mechanisms of HER-2 signaling disruption, resulting in synergistic antiproliferative activity both and = 0.00176.7 = 0.000213.8 = 0.0046LOGiC “type”:”clinical-trial”,”attrs”:”text”:”NCT00680901″,”term_id”:”NCT00680901″NCT00680901Capecitabine + Oxaliplatin + LapatinibCapecitabine + Oxaliplatin + PlaceboIIIIOS53 (95% CI 46.6-59.3) vs. 40 (95% CI 33.6-46.4)6.0 = 0.1012.2 = 0.3492TyTAN “type”:”clinical-trial”,”attrs”:”text”:”NCT00486954″,”term_id”:”NCT00486954″NCT00486954Paclitaxel + LapatinibPaclitaxel + PlaceboIIIIIOS27 vs. 9 OR = 3.85, 95% CI 1.80-8.87, < 0.0015.4 = 0.244111.0 = 0.2088GATSBY "type":"clinical-trial","attrs":"text":"NCT01641939","term_id":"NCT01641939"NCT01641939TDM-1 3.6 mg/kg q21 or TDM-1 2.4 mg/kg q7Paclitaxel or DocetaxelII/IIIIIOS20.6 vs 19.62.7 2.9 HR=1.13, 95% CI 0.89-1.43, = 0.317.9 8.6 HR= 1.15, 95% CI 0.87-1.51, = 0.86 Open in a separate window 5-FU: 5-fluorouracil, CI: confidence interval, HR: risk ratio, OR: odds ratio, iv: intravenous, ORR: overall response rate, OS: overall survival, PFS: progression-free survival, TDM-1: trastuzumab emtansine. One of the possible mechanisms associated with trastuzumab resistance is the deregulation of HER-2 downstream transmission, including the PI3K/AKT/mTOR pathway. It is well known that PIK3CA mutations and PTEN inactivation result in constitutive activation of the downstream signals [49]. Everolimus, an orally given mTOR inhibitor, showed enhanced 5-FU-induced apoptosis in gastric malignancy cells with HER-2 amplification and encouraging activity in preclinical and early medical tests [50, 51]: such results, however, have not been confirmed in the phase III GRANITE-1 trial. [52]. It is uncertain whether the mix of HER2-targeted agencies and mTOR inhibitors may provide advantage in sufferers with HER2-positive gastric cancers who became resistant: the id of predictive biomarkers continues to be essential for optimizing efficiency. Afatinib, an dental irreversible inhibitor of tyrosine kinase receptors concentrating on HER-1, HER-2 and HER-4, can help conquering trastuzumab level of resistance. Preliminary data of the phase II research enrolling sufferers with metastatic HER2-positive (IHC 3+ or Seafood >2.0) esophagogastric cancers with disease development whilst on the trastuzumab-containing regimen have already been recently presented [53, 54] with demo of the 40% disease control. As pan-HER inhibitors show significant antitumor results as well such as xenograft style of HER2-positive gastric cancers [55],.2003;22 abstr 3584. to determine the efficiency of adding trastuzumab to chemoradiation [39]. On the other hand, book HER-2 inhibitors may also be being examined in gastric cancers: lapatinib ditosylate, a dual anti-EGFR and anti-HER-2 tyrosine kinase inhibitor, was first of all examined in the TRIO-013/Reasoning trial made to evaluate the efficiency and safety from the dental inhibitor in conjunction with capecitabine and oxaliplatin as first-line treatment of advanced or metastatic HER2-positive esophagogastric cancers. In this research, 545 sufferers had been randomized 1:1 to get CAPOX q21 (oxaliplatin 130 mg/sqm, time 1, capecitabine 850 mg/sqm/bet times 1-14) plus lapatinib (1,250 mg daily provided regularly) or placebo. The principal endpoint had not been fulfilled with an HR for Operating-system of 0.91 (95% CI 0.73-1.12; = 0.35), and a median OS of 12.2 months for regular treatment = 0.0381). General Response Price (ORR) was 53% (95% CI, 46.4-58.8) in the experimental arm and 39% (95% CI, 32.9-45.3, = 0.0031) in the placebo arm [40]. In the open-label, stage III TyTAN trial, 261 HER2-positive advanced gastric cancers Asian sufferers were randomized to get every week paclitaxel with or without lapatinib, as second-line treatment. Once more, no advantage was demonstrated with regards to Operating-system (HR 0.84, 95% CI 0.64-1.11; = 0.10) or PFS (HR 0.85, 95%CI 0.63-1.13; = 0.24) for the usage of lapatinib, though a statistically significant improvement in RR was noted (27% v 9%, OR 3.85, 95%CI 1.80-8.87; = 0.001) [41]. Feasible known reasons for these harmful email address details are the high percentage of sufferers with IHC HER-2 1+rating, which might have got diluted the advantage of lapatinib in sufferers with IHC HER-2 3+ rating, aswell as the various rate of possibly active third-line remedies between research arms. Furthermore, in TRIO-013/Reasoning trial, no relationship was noticed between IHC position and OS advantage. Despite these uncertainties, lapatinib had not been accepted for gastric cancers. Key results of the very most essential randomized studies are summarized in Desk ?Desk2.2. Ongoing research might better specify its role in conjunction with various other targeted agencies. Pertuzumab, a recombinant, humanized immunoglobulin IgG1 monoclonal antibody which binds towards the extracellular area of HER-2 stopping its heterodimerization with various other members from the HER-family (HER-1, HER-3, and HER-4), continues to be studied to get over trastuzumab level of resistance. Pertuzumab and trastuzumab bind to distinctive epitopes of HER-2 without contending with one another and also have complementary systems of HER-2 signaling disruption, leading to synergistic antiproliferative activity both and = 0.00176.7 = 0.000213.8 = 0.0046LOGiC “type”:”clinical-trial”,”attrs”:”text”:”NCT00680901″,”term_id”:”NCT00680901″NCT00680901Capecitabine + Oxaliplatin + LapatinibCapecitabine + Oxaliplatin + PlaceboIIIIOS53 (95% CI 46.6-59.3) vs. 40 (95% CI 33.6-46.4)6.0 = 0.1012.2 = 0.3492TyTAN “type”:”clinical-trial”,”attrs”:”text”:”NCT00486954″,”term_id”:”NCT00486954″NCT00486954Paclitaxel + LapatinibPaclitaxel + PlaceboIIIIIOS27 vs. 9 OR = 3.85, 95% CI 1.80-8.87, < 0.0015.4 = 0.244111.0 = 0.2088GATSBY "type":"clinical-trial","attrs":"text":"NCT01641939","term_id":"NCT01641939"NCT01641939TDM-1 3.6 mg/kg q21 or TDM-1 2.4 mg/kg q7Paclitaxel or DocetaxelII/IIIIIOS20.6 vs 19.62.7 2.9 HR=1.13, 95% Rabbit polyclonal to ZNF33A CI 0.89-1.43, = 0.317.9 8.6 HR= 1.15, 95% CI 0.87-1.51, = 0.86 Open up in another window 5-FU: 5-fluorouracil, CI: confidence interval, HR: threat ratio, OR: odds ratio, iv: intravenous, ORR: overall response rate, OS: overall survival, PFS: progression-free survival, TDM-1: trastuzumab emtansine. Among the feasible systems connected with trastuzumab level of resistance may be the deregulation of HER-2 downstream indication, like the PI3K/AKT/mTOR pathway. It really is popular that PIK3CA mutations and PTEN inactivation bring about constitutive activation from the downstream indicators [49]. Everolimus, an orally implemented mTOR inhibitor, demonstrated improved 5-FU-induced apoptosis in gastric cancers cells with HER-2 amplification and appealing activity in preclinical and early scientific studies [50, 51]: such outcomes, however, never have been verified in the stage III GRANITE-1 trial. [52]. It really is uncertain if the mix of HER2-targeted real estate agents and mTOR inhibitors may provide advantage in individuals with HER2-positive gastric tumor who became resistant: the recognition of predictive biomarkers continues to be important for optimizing.Tumor Med. HER2-positive adenocarcinoma to be able to set up the effectiveness of adding trastuzumab to chemoradiation [39]. In the meantime, book HER-2 inhibitors will also be being researched in gastric tumor: lapatinib ditosylate, a dual anti-EGFR and anti-HER-2 tyrosine kinase inhibitor, was first of all examined in the TRIO-013/Reasoning trial made to evaluate the effectiveness and safety from the dental inhibitor in conjunction with capecitabine and oxaliplatin as first-line treatment of advanced or metastatic HER2-positive esophagogastric tumor. In this research, 545 individuals had been randomized 1:1 to get CAPOX q21 (oxaliplatin 130 mg/sqm, day time 1, capecitabine 850 mg/sqm/bet times 1-14) plus lapatinib (1,250 mg daily provided consistently) or placebo. The principal endpoint had not been fulfilled with an HR for Operating-system Chloramphenicol of 0.91 (95% CI 0.73-1.12; = 0.35), and a median OS of 12.2 months for regular treatment = 0.0381). General Response Price (ORR) was 53% (95% CI, 46.4-58.8) in the experimental arm and 39% (95% CI, 32.9-45.3, = 0.0031) in the placebo arm [40]. In the open-label, stage III TyTAN trial, 261 HER2-positive advanced gastric tumor Asian individuals were randomized to get every week paclitaxel with or without lapatinib, as second-line treatment. Once more, no advantage was demonstrated with regards to Operating-system (HR 0.84, 95% CI 0.64-1.11; = 0.10) or PFS (HR 0.85, 95%CI 0.63-1.13; = 0.24) for the usage of lapatinib, though a statistically significant improvement in RR was noted (27% v 9%, OR 3.85, 95%CI 1.80-8.87; = 0.001) [41]. Feasible known reasons for these adverse email address details are the high percentage of individuals with IHC HER-2 1+rating, which might possess diluted the advantage of lapatinib in individuals with IHC HER-2 3+ rating, aswell as the various rate of possibly active third-line remedies between research arms. Furthermore, in TRIO-013/Reasoning trial, no relationship was noticed between IHC position and OS advantage. Despite these uncertainties, lapatinib had not been authorized for gastric tumor. Key results of the very most essential randomized tests are summarized in Desk ?Desk2.2. Ongoing research might better establish its role in conjunction with additional targeted real estate agents. Pertuzumab, a recombinant, humanized immunoglobulin IgG1 monoclonal antibody which binds towards the extracellular site of HER-2 avoiding its heterodimerization with additional members from the HER-family (HER-1, HER-3, and HER-4), continues to be studied to conquer trastuzumab level of resistance. Pertuzumab and trastuzumab bind to specific epitopes of HER-2 without contending with one another and also have complementary systems of HER-2 signaling disruption, leading to synergistic antiproliferative activity both and = 0.00176.7 = 0.000213.8 = 0.0046LOGiC “type”:”clinical-trial”,”attrs”:”text”:”NCT00680901″,”term_id”:”NCT00680901″NCT00680901Capecitabine + Oxaliplatin + LapatinibCapecitabine + Oxaliplatin + PlaceboIIIIOS53 (95% CI 46.6-59.3) vs. 40 (95% CI 33.6-46.4)6.0 = 0.1012.2 = 0.3492TyTAN “type”:”clinical-trial”,”attrs”:”text”:”NCT00486954″,”term_id”:”NCT00486954″NCT00486954Paclitaxel + LapatinibPaclitaxel + PlaceboIIIIIOS27 vs. 9 OR = 3.85, 95% CI 1.80-8.87, < 0.0015.4 = 0.244111.0 = 0.2088GATSBY "type":"clinical-trial","attrs":"text":"NCT01641939","term_id":"NCT01641939"NCT01641939TDM-1 3.6 mg/kg q21 or TDM-1 2.4 mg/kg q7Paclitaxel or DocetaxelII/IIIIIOS20.6 vs 19.62.7 2.9 HR=1.13, 95% CI 0.89-1.43, = 0.317.9 8.6 HR= 1.15, 95% CI 0.87-1.51, = 0.86 Open up in another window 5-FU: 5-fluorouracil, CI: confidence interval, HR: risk ratio, OR: odds ratio, iv: intravenous, ORR: overall response rate, OS: overall survival, PFS: progression-free survival, TDM-1: trastuzumab emtansine. Among the feasible systems connected with trastuzumab level of resistance may be the deregulation of HER-2 downstream sign, like the PI3K/AKT/mTOR pathway. It really is popular that PIK3CA mutations and PTEN inactivation bring about constitutive activation from the downstream indicators [49]. Everolimus, an orally administered mTOR inhibitor, showed enhanced 5-FU-induced apoptosis in gastric cancer cells with HER-2 amplification and promising activity in preclinical and early clinical trials [50, 51]: such results, however, have not been confirmed in the phase III GRANITE-1 trial. [52]. It is uncertain whether the combination of HER2-targeted agents and mTOR inhibitors might provide benefit in patients with HER2-positive gastric cancer who became resistant: the identification of predictive biomarkers remains crucial for optimizing efficacy. Afatinib, an oral irreversible inhibitor of tyrosine kinase receptors targeting HER-1, HER-2 and HER-4, may help overcoming trastuzumab resistance. Preliminary data of a phase II study enrolling patients with metastatic HER2-positive (IHC 3+ or FISH >2.0) esophagogastric cancer with disease progression whilst on a trastuzumab-containing regimen have been recently presented [53, 54] with demonstration of.