53considered negative since the primary end point of improving the
overall survival was not met (12.2 months versus 10.5 months,
hazard ratio = 0.91, 95% confidence interval (CI) = 0.73–1.12;
p = 0.3492). Nonetheless, the response rate was significantly higher
with lapatinib (53% vs 39%; p = 0.0031) and robust overall survival
benefit was demonstrated in the exploratory subgroup of Asian
patients (16.5 months vs 10.9 months, HR = 0.68, 95% CI = 0.48–
0.96; p = 0.0261) as well as younger patients (12.9 months vs
9.0 months, HR =0.69, 95% CI = 0.51–0.94; p = 0.0141). Unlike
other studies, no significant correlation was observed between
HER2 status and survival benefit though.
Dual HER2 blockage with trastuzumab and pertuzumab
appears to be a feasible approach and result of the use in breast
cancer is promising [ 10 ]. Pertuzumab is referred to as HER2
dimerization inhibitor, and it binds to the HER2 receptor at site
different from trastuzumab. The phase III JACOB study is ongo-
ing to evaluate pertuzumab plus trastuzumab and chemotherapy as
first-line therapy for HER2-positive advanced gastric cancer (clini-
cal trial number NCT01358877).
The role of anti-HER2 therapy beyond disease progression is
controversial. Small clinical series have suggested the safety and
efficacy of continuing trastuzumab after initial failure but high-
level evidence is lacking [ 11 – 13 ]. So far, only lapatinib and TDM-1
have been reported in phase III randomized setting. Two hundred
and sixty-one Asian patients were randomized in the TyTAN study
that compares paclitaxel with or without lapatinib [ 14 ]. Only 5–6%
of patients have received prior trastuzumab. No significant differ-
ence between the two study arms was observed with regard to
overall survival and progression-free survival despite a higher treat-
ment response was noted (OR 3.85; p < 0.001). Although all
patients in the study are HER2 positive (by FISH), the survival
benefit may be diluted by over 30% of the patients in the study who were
HER2 low (with scores = “0/1+” as detected by immunohisto-
chemistry). Diarrhea was a common side effect in other studies
with lapatinib.
Trastuzumab emtansine (T-DM1) is an antibody-drug conju-
gate, composed of trastuzumab linked by a stable linker to the
tubulin inhibitor emtansine. Emtansine itself is too toxic if given
in the usual route but the antibody-drug conjugate delivery allows
intracellular release of cytotoxic emtansine-containing catabolites
in HER2-positive cancer cells and induces mitotic arrest and
apoptosis [ 15 ]. TDM-1 has proven efficacy in trastuzumab-
pretreated metastatic breast cancer and in general has a favorable
toxicity profile [ 16 , 17 ]. In the phase II/III GATSBY study,
patients with HER2-positive metastatic gastric or esophagogastric
adenocarcinoma were randomized to receive either TDM-1 or
paclitaxel after failure of prior chemotherapy [ 18 ]. About 80% of
patients in both arms have received prior anti-HER2 therapy.
Target Therapy of Esophageal Adenocarcinoma