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. 相似文献
Introduction: First-line treatment with platinum-based chemotherapy has been the standard treatment for non-small-cell lung cancer (NSCLC) during the past decades. The development of new targeted drugs based on molecular alterations (EGFR, ALK, and ROS1) has led to important outcome benefits, but not for squamous cell carcinoma (SCC). However, the aberrant function of the EGFR pathway in SCC may be important in the development of the tumor and has been explored in preclinical and clinical studies as a potential target.
Areas covered: Necitumumab is a human IgG1 anti-EGFR antibody that binds to the receptor and inhibits further pathway activation, thereby inhibiting cell differentiation, proliferation and migration. The phase III SQUIRE trial was a randomized study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone for first-line stage IV squamous NSCLC, showing a higher overall survival and better disease control with the addition of necitumumab. Despite the good results, the lack of robust predictive biomarkers makes the selection of the patients who will benefit the most complex.
Expert opinion: Necitumumab plus cisplatin-gemcitabine is a first-line treatment option in SCC that improves overall survival and preserves the patient’s quality of life with a manageable toxicity profile. 相似文献
The inhibition of angiogenesis through vascular endothelial growth factor (VEGF) receptor targeting is a strategy that is relatively tumour selective. The high selectivity achieved with neutralising antibodies, soluble receptors and ribozymes reduces the risk of adverse reactions not related to VEGF inhibition itself. Small-molecule, orally-active protein kinase inhibitors provide an attractive alternative for chronic therapy, although specifically targeting a small subset of protein kinases from the ~ 550 expressed in mammalian cells is a challenge. Current efforts have resulted in promising clinical data for several synthetic VEGF receptor kinase inhibitors, of which PTK787/ZK222584 and ZD6474 are proceeding into large size clinical trials. It seems likely that blockers of the VEGF signalling pathway will be unsuitable for monotherapy, and that their role will be as an adjunct to additional antiangiogenic agents together with directly-acting antitumour agents or radiation therapy. Caution is needed with combinations of antiVEGF therapies and cytotoxic agents, as coadministration of cytotoxic agents with either the kinase inhibitor SU5416 or the VEGF antibody avastin appears to be associated with bleeding and thrombotic adverse events. 相似文献
Platelet-derived growth factor receptor alpha (PDGFRα) is believed to be associated with cell survival. We examined (i) whether PDGFRα blockade enhances the antitumor activity of taxanes in ovarian carcinoma and (ii) potential biomarkers of response to anti-PDGFRα therapy.
Methods
PDGFRα expression in 176 ovarian carcinomas was evaluated with tissue microarray and correlated to survival outcome. Human-specific monoclonal antibody to PDGFRα (IMC-3G3) was used for in vitro and in vivo experiments with or without docetaxel. Gene microarrays and reverse-phase protein arrays with pathway analyses were performed to identify potential predictive biomarkers.
Results
When compared to low or no PDGFRα expression, increased PDGFRα expression was associated with significantly poorer overall survival of patients with ovarian cancer (P = 0.014). Although treatment with IMC-3G3 alone did not affect cell viability or increase apoptosis, concurrent use of IMC-3G3 with docetaxel significantly enhanced sensitization to docetaxel and apoptosis. In an orthotopic mouse model, IMC-3G3 monotherapy had no significant antitumor effects in SKOV3-ip1 (low PDGFRα expression), but showed significant antitumor effects in HeyA8-MDR (high PDGFRα expression). Concurrent use of IMC-3G3 with docetaxel, compared with use of docetaxel alone, significantly reduced tumor weight in all tested cell lines. In protein ontology, the EGFR and AKT pathways were downregulated by IMC-3G3 therapy. MAPK and CCNB1 were downregulated only in the HeyA8-MDR model.
Conclusion
These data identify IMC-3G3 as an attractive therapeutic strategy and identify potential predictive markers for further development. 相似文献