HER2-positive Gastric Cancer Patients With Liver Metastasis Clinical Trial
Official title:
Phase II Study of Neoadjuvant XELOX + Lapatinib in HER2(+) Gastric Cancer Patients With Liver Metastasis
We planned this study to investigate the efficacy and safety of XELOX (capecitabine and oxaliplatin) plus lapatinib treatment in HER2-positive gastric cancer patients with liver metastasis.
Gastric cancer is the leading cause of cancer death worldwide with the incidence of
18.9/100,000 per year and the mortality rate of 14.7/100,000 per year [1] and is the most
common malignancy in Korea[2]. Metastatic gastric cancer remains a therapeutic challenge for
medical oncologists due to poor prognosis. Several randomized phase III trials comparing
combination chemotherapy such as 5-fluorouracil (5-FU), doxorubicin, and mitomycin (FAM), or
5-FU, doxorubicin, and high-dose methotrexate (FAMTX) with best supportive care have
demonstrated significantly prolonged overall survival (8 - 10 months) for chemotherapy group
as compared to best supportive care alone (3 - 5 months)[3, 4].
In quest of a novel therapeutic target for gastric cancer, HER2 overexpression has been
tested and was reported in 6-35% of stomach and gastroesophageal tumors [5]. Trastuzumab, a
humanized monoclonal antibody which selectively targets HER2, has shown survival benefit in
patients with HER2(+) metastatic breast cancer [6-8]. The ToGA trial is the first randomized,
prospective, multicenter, phase III trial to study the efficacy and safety of trastuzumab in
HER2(+) GC [9]. Of 3,807 tumor samples screened for Her2 status, 22.1% were Her2 positive and
594 patients were randomized to receive chemotherapy alone or chemotherapy + trastuzumab.
The ToGA trial demonstrated a significant survival benefit in the transtuzumab +chemotherapy
when compared with chemotherapy alone arm: 13.5 vs. 11.1 months, respectively (p=0.0048; HR
0.74; 95% CI 0.60, 0.91). ORR was 47.3% in the trastuzumab + 5-FU/CDDP (or capecitabine/CDDP)
arm and 34.5% in the chemotherapy alone arm (p=0.0017). The ToGA trial is the first phase III
trial to demonstrate survival benefit from molecularly targeted agent in gastric cancer.
Of note, 70 - 80% of patients HER2 overexpressing breast cancer do not respond to trastuzumab
due to either primary or acquired resistance. One of the important mechanisms for trastuzumab
resistance is the accumulation of truncated forms of the HER2 receptor which lack the
extracellular trastuzumab-binding domain (Figure 2). P95HER2, an amino terminally truncated
carboxyl terminal fragments of HER2, is frequently found in HER2(+) breast cancer cell lines
and tumor specimens (~20%)[11]. Intriguingly, recent study showed that p95HER2 (+) breast
cancer cells were resistant to trastuzumab but remained sensitive to the antiproliferative
effects of the tyrosine kinase inhibitor lapatinib, both in vitro and in vivo[11]. In
addition, patients with p95HER2(+)breast cancer were resistant to trastuzumab with
significantly lower response rate when compared with full-length HER2(+) breast cancer (11.1%
vs 51.4%, respectively; P = 0.029).
We have surveyed the incidence of p95HER2 expression in fresh frozen tissues from gastric
cancer and found that > 60% of HER2 (3+) GC demonstrated p95HER2. Hence, the role of
lapatinib may be more promising than trastuzumab in GC HER2(+) patients with truncation.
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