EJ.2 - Therapeutic Potential of Angiogenesis Inhibitors for Gastric Cancer

Abstract

Gastric adenocarcinoma (GC) is the fourth most common cancer worldwide (7.8% of cancers in 2008) but the second leading cause of cancer death (9.7% of cancer deaths). The highest mortality remains in Korea and Japan (31/100,000 and 23/100,000 respectively). However multiagent chemotherapy improves overall survival and quality of life (QoL) compared with best supportive care (BSC) alone.Attempts to improve these outcomes for treatment in AOGC have focused on targeting growth factor signalling pathways (such as the HER family, mTOR and tumour angiogenesis). In the first line setting, a phase III randomised trial of trastuzumab in HER2-positive AOGC/GOJ (ToGA trial) recently demonstrated a significantly improved median OS in combination with chemotherapy. By contrast blockade of HER- 1 has surprisingly not shown a benefit in combination with chemotherapy. A recent phase III study of everolimus, an inhibitor of the PI3K/Akt/mTOR pathway, also failed to demonstrate a significant improvement OS compared with placebo.As in most other cancers, VEGF and angiogenesis expression or pathway upregulation is of poor prognostic significance in GC. A randomised phase III trial of bevacizumab (anti-VEGF monoclonal antibody) in combination with chemotherapy (CX) in AOGC (AVAGAST) recently demonstrated significant improvement in the secondary efficacy endpoints of PFS (6.7 months vs. 5.3 months; HR = 0.80; p = 0.0037) and ORR (46% vs. 37%; p = 0.0315) with bevacizumab, but did not meet the primary endpoint of OS. Recently a randomised trial of Ramicurumab, a monoclonal antibody VEGFR2 inhibitor, showed a survival benefit compared to best supportive care, in second line therapy. The addition of ramucirumab significantly prolonged median overall survival—the primary endpoint—from 3.8 to 5.2 months (p = 0.0473), comparable to the survival benefit achieved by adding second-line cytotoxic chemotherapy to best supportive care. These two large clinical studies, together with some activity in Phase II studies of sunitinib and sorafenib, combined with a strong biological rationale, provide an impetus to continue exploring the role of antiangiogenic agents in the treatment of gastric cancer. Gastric adenocarcinoma (GC) is the fourth most common cancer worldwide (7.8% of cancers in 2008) but the second leading cause of cancer death (9.7% of cancer deaths). The highest mortality remains in Korea and Japan (31/100,000 and 23/100,000 respectively). However multiagent chemotherapy improves overall survival and quality of life (QoL) compared with best supportive care (BSC) alone. Attempts to improve these outcomes for treatment in AOGC have focused on targeting growth factor signalling pathways (such as the HER family, mTOR and tumour angiogenesis). In the first line setting, a phase III randomised trial of trastuzumab in HER2-positive AOGC/GOJ (ToGA trial) recently demonstrated a significantly improved median OS in combination with chemotherapy. By contrast blockade of HER- 1 has surprisingly not shown a benefit in combination with chemotherapy. A recent phase III study of everolimus, an inhibitor of the PI3K/Akt/mTOR pathway, also failed to demonstrate a significant improvement OS compared with placebo. As in most other cancers, VEGF and angiogenesis expression or pathway upregulation is of poor prognostic significance in GC. A randomised phase III trial of bevacizumab (anti-VEGF monoclonal antibody) in combination with chemotherapy (CX) in AOGC (AVAGAST) recently demonstrated significant improvement in the secondary efficacy endpoints of PFS (6.7 months vs. 5.3 months; HR = 0.80; p = 0.0037) and ORR (46% vs. 37%; p = 0.0315) with bevacizumab, but did not meet the primary endpoint of OS. Recently a randomised trial of Ramicurumab, a monoclonal antibody VEGFR2 inhibitor, showed a survival benefit compared to best supportive care, in second line therapy. The addition of ramucirumab significantly prolonged median overall survival—the primary endpoint—from 3.8 to 5.2 months (p = 0.0473), comparable to the survival benefit achieved by adding second-line cytotoxic chemotherapy to best supportive care. These two large clinical studies, together with some activity in Phase II studies of sunitinib and sorafenib, combined with a strong biological rationale, provide an impetus to continue exploring the role of antiangiogenic agents in the treatment of gastric cancer.