Page 97 - Read Online
P. 97

Toihata et al. J Cancer Metastasis Treat 2018;4:24  I  http://dx.doi.org/10.20517/2394-4722.2017.82                          Page 3 of 10

               Table 1. Clinical trials testing targeted therapies for esophagogastric junction and gastric adenocarcinoma
                                                                   Outcome
                                      Patients                              Outcome  Outcome Primary
                Trial         Target               Treatment     (EGJ + gastric                      Refs
                                       (EGJ)                                 (EGJ)  (gastric) endpoint
                                                                    cases)
                1st line
                   ToGA      HER2       594    XP vs.              Positive  Negative  Positive  OS  [6]
                                        (106)  XP + trastuzumab
                   LOGiC     HER2       545    CapeOx vs.          Negative  Negative  Negative  OS  [18]
                                        (49)   CapeOx + lapatinib
                   EXPAND    EGFR       904    XP vs.              Negative  Negative  Negative  OS  [24]
                                        (144)  XP + cetuximab
                   REAL3     EGFR       553    EOC vs.             Negative  Negative  Positive  OS  [26]
                                        (169)  EOC + panitumumab
                   RILOMET-1  MET       609    ECX vs.             Negative  Negative  Positive  OS  [27]
                                        (124)  ECX + rilotumumab
                   METGastric  MET/HGF  562    mFOLFOX6 vs.        Negative  Negative  Negative  OS  [29]
                                        (130)  mFOLFOX6+onartuzumab
                   AVAGAST   VEGFR-A    774    XP i.               Negative  Negative  Negative  OS  [17,49]
                                        (130)  XP + bevacizumab
                2nd line
                   RAINBOW   VEGFR2     665    Paclitaxel vs.      Positive  Positive  Positive  OS  [7]
                                        (137)  paclitaxel + ramucirumab
                   REGARD    VEGFR2     355    Placebo vs.         Positive  Negative  Negative  OS  [14]
                                        (90)   paclitaxel + ramucirumab
                   TyTAN     HER2       261    Paclitaxel or docetaxel vs.  Negative  Negative  Negative  OS  [19]
                                        (2)    trastuzumab-emtansine
                   GATSBY    HER2       345    Paclitaxel vs.      Negative  Negative  Negative  OS  [31]
                                        (110)  paclitaxel + lapatinib
                   GRANITE-1  mTOR      656    Placebo vs.         Negative  Negative  Negative  OS  [50,51]
                                        (187)  everolimus

               CapeOx: capecitabine and oxaliplatin; EGFR: epidermal growth factor receptor; ECX: epirubicin, cisplatin and capecitabine; EOC:
               epirubicin, oxaliplatin and capecitabine; HER2: human epidermal growth factor 2; HGF: hepatocyte growth factor; mFOLFOX6: leucovorin,
               fluorouracil and oxaliplatin; mTOR: mechanistic target of rapamycin; OS: overall survival; PFS: progression-free survival; VEGF-A: vascular
               endothelial growth factor A; VEGFR2: vascular endothelial growth factor receptor 2; XP: capecitabine and cisplatin

               with confirmed survival benefit in phase III trials. In this section, we focus on the results of phase III clinical
               trials.

               Trastuzumab (anti-HER2 antibody)
               Trastuzumab is a monoclonal antibody targeting HER2. In 2010, ToGA trial [phase III, including EGJ
               (n = 106) and advanced gastric adenocarcinoma (n = 478)] was to assess the efficacy and safety of trastuzumab
               plus first-line chemotherapy (XP or FP) of advanced HER2 positive 106 EGJ and 478 gastric adenocarcinoma.
               HER2 status was tested by IHC and FISH. HER2 positivity was defined as samples with 3+ by IHC, or those
               with both 2+ IHC and FISH positive. HER2 positivity was frequently observed in tumors located at EGJ,
               compared to those in stomach (33.2% for EGJ vs. 20.9% for stomach; P < 0.001). Median OS was significantly
               longer in trastuzumab plus chemotherapy groups than in chemotherapy alone [median 13.8 months
               (95% CI 12-16) vs. median 11.1 months (95% CI 10-13), HR 0.74; 95% CI 0.60-0.91; P = 0.0046]. However, in
               a subgroup analysis of EGJ adenocarcinoma, there were no survival benefit of trastuzumab (trastuzumab
               plus chemotherapy groups vs. chemotherapy alone, HR 0.67; 95% CI 0.42-1.08). The most common adverse
               events in both groups were nausea, vomiting and neutropenia. Rate of overall grade 3-4 adverse events (68%
               in trastuzumab plus chemotherapy groups vs. 68% in chemotherapy alone) and cardiac adverse events (6% in
                                                                                                        [6]
               trastuzumab plus chemotherapy groups vs. 6% in chemotherapy alone) did not differ between the groups .
               NCCN guideline recommends the addition of trastuzumab to any chemotherapy combination for patients
               with HER2-positive tumors.


               Ramucirumab (VEGFR-2 inhibitor)
               Ramucirumab is a human IgG1 monoclonal antibody VEGFR-2 antagonist. The REGARD trial and the
   92   93   94   95   96   97   98   99   100   101   102