Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/02/15 For personal use only.
Drug Profile
Anti-angiogenic agent ramucirumab: meaningful or marginal? Expert Rev. Anticancer Ther. 14(4), 367–379 (2014)
Roopma Wadhwa1, Elena Elimova1, Hironori Shiozaki1, Kazuki Sudo1, Mariela A Blum1, Jeannelyn S Estrella2, Qiongrong Chen1, Shumei Song1 and Jaffer A Ajani*1 1 Department of GI Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd (FC10.3022), Houston, TX 77030, USA 2 Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA *Author for correspondence: Tel.: +1 713 745 1163 Fax: +1 713 792 2828 [email protected]
Ramucirumab (IMC-1121B) targets VEGFR-2. Ramucirumab is being investigated in many malignancies including gastric cancer. The Phase III trial in patients with advanced breast cancer failed to improve the primary end point The REGARD trial, a Phase III study, in patients with advanced gastric cancer in the second line setting, had a marginal improvement in overall survival but did not achieve the expected hazard ratio target (of 0.69) and the median duration of therapy with ramucirumab was meager 8 weeks (only 2 weeks longer than the placebo’s). Other notable agents in the second line setting are docetaxel and irinotecan. Preliminary results of the RAINBOW trial suggest that ramucirumab may be providing more than marginal advantage. In this review, we briefly summarize the process of angiogenesis and address the emerging cost-benefit issues that surround all newly developed agents including ramucirumab. KEYWORDS: advanced gastric cancer • angiogenesis • breast cancer • cost-benefit • IMC-1121B • ramucirumab • VEGF
There has been considerable progress in the understanding of molecular pathways in oncology, which led to the discovery of a variety of antiangiogenic agents. Bevacizumab has been approved by US FDA for resistant cases of Glioblastoma [1] as well as to be used in combination with other drugs in the treatment of metastatic colorectal cancer [2], metastatic renal cancer [3] and selected cases of nonsmall cell lung cancer [4]. Trastuzumab is one of the targeted agents already approved for HER-2-positive gastric cancer patients led by the positive results of ToGA trial [5]. Ramucirumab is a monoclonal antibody that utilizes an additional method of disrupting VEGF signaling and is an upcoming candidate on the horizon. It has been investigated in various solid tumors including advanced gastric cancer. Due to the progressive improvement in development of antiangiogenic agents, a brief discussion about angiogenesis and its mechanisms would be worth it. Angiogenesis & its role in cancer
Angiogenesis is a complex interplay between multiple signaling pathways and under normal physiological conditions, a state of balance exists between proangiogenic and antiangiogenic
informahealthcare.com
10.1586/14737140.2014.896207
components (tumor dormancy [6]). The process of angiogenesis involves local vascular basement membrane degradation, pericyte dissociation from the capillary, migration of tip cells toward the angiogenic stimulus, formation of endothelial cell tube by proliferation and alignment of endothelial cells, and finally, stabilization of the vessel by pericytes and/or smooth muscle association and basement membrane deposition [7]. Physiologically, angiogenesis is relevant in embryogenesis, wound healing, endometrial regeneration during menstrual cycle and ovulation [8]. On a pathological basis, disease states, like most cancers, macular degeneration, diabetic retinopathy and rheumatoid arthritis, all undergo angiogenesis [8]. The role of angiogenesis in tumor development and metastasis was first suggested by Judah Folkman in 1971 [9,10]. During tumor progression, the balance between proangiogenic and antiangiogenic factors inclines toward proangiogenic sequel (angiogenic switch). It was Folkman’s observation that a tumor that is
Drug Profile
Anti-angiogenic agent ramucirumab: meaningful or marginal? Expert Rev. Anticancer Ther. 14(4), 367–379 (2014)
Roopma Wadhwa1, Elena Elimova1, Hironori Shiozaki1, Kazuki Sudo1, Mariela A Blum1, Jeannelyn S Estrella2, Qiongrong Chen1, Shumei Song1 and Jaffer A Ajani*1 1 Department of GI Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd (FC10.3022), Houston, TX 77030, USA 2 Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA *Author for correspondence: Tel.: +1 713 745 1163 Fax: +1 713 792 2828 [email protected]
Ramucirumab (IMC-1121B) targets VEGFR-2. Ramucirumab is being investigated in many malignancies including gastric cancer. The Phase III trial in patients with advanced breast cancer failed to improve the primary end point The REGARD trial, a Phase III study, in patients with advanced gastric cancer in the second line setting, had a marginal improvement in overall survival but did not achieve the expected hazard ratio target (of 0.69) and the median duration of therapy with ramucirumab was meager 8 weeks (only 2 weeks longer than the placebo’s). Other notable agents in the second line setting are docetaxel and irinotecan. Preliminary results of the RAINBOW trial suggest that ramucirumab may be providing more than marginal advantage. In this review, we briefly summarize the process of angiogenesis and address the emerging cost-benefit issues that surround all newly developed agents including ramucirumab. KEYWORDS: advanced gastric cancer • angiogenesis • breast cancer • cost-benefit • IMC-1121B • ramucirumab • VEGF
There has been considerable progress in the understanding of molecular pathways in oncology, which led to the discovery of a variety of antiangiogenic agents. Bevacizumab has been approved by US FDA for resistant cases of Glioblastoma [1] as well as to be used in combination with other drugs in the treatment of metastatic colorectal cancer [2], metastatic renal cancer [3] and selected cases of nonsmall cell lung cancer [4]. Trastuzumab is one of the targeted agents already approved for HER-2-positive gastric cancer patients led by the positive results of ToGA trial [5]. Ramucirumab is a monoclonal antibody that utilizes an additional method of disrupting VEGF signaling and is an upcoming candidate on the horizon. It has been investigated in various solid tumors including advanced gastric cancer. Due to the progressive improvement in development of antiangiogenic agents, a brief discussion about angiogenesis and its mechanisms would be worth it. Angiogenesis & its role in cancer
Angiogenesis is a complex interplay between multiple signaling pathways and under normal physiological conditions, a state of balance exists between proangiogenic and antiangiogenic
informahealthcare.com
10.1586/14737140.2014.896207
components (tumor dormancy [6]). The process of angiogenesis involves local vascular basement membrane degradation, pericyte dissociation from the capillary, migration of tip cells toward the angiogenic stimulus, formation of endothelial cell tube by proliferation and alignment of endothelial cells, and finally, stabilization of the vessel by pericytes and/or smooth muscle association and basement membrane deposition [7]. Physiologically, angiogenesis is relevant in embryogenesis, wound healing, endometrial regeneration during menstrual cycle and ovulation [8]. On a pathological basis, disease states, like most cancers, macular degeneration, diabetic retinopathy and rheumatoid arthritis, all undergo angiogenesis [8]. The role of angiogenesis in tumor development and metastasis was first suggested by Judah Folkman in 1971 [9,10]. During tumor progression, the balance between proangiogenic and antiangiogenic factors inclines toward proangiogenic sequel (angiogenic switch). It was Folkman’s observation that a tumor that is
