K. Rihawi

Ramucirumab: preclinical research and clinical development

Ramucirumab (IMC-1121B, LY3009806), a fully humanized monoclonal antibody directed against the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), is a new therapeutic option that selectively inhibits the human VEGFR-2 with a much greater affinity than its natural ligands. Based on the promising results of both preclinical and early clinical studies, ramucirumab has been tested in different tumor types either alone or in combination with chemotherapy. While it has recently been granted its first US Food and Drug Administration approval for use as a single agent in patients with advanced or metastatic gastric cancer or gastroesophageal junction carcinoma, its role for metastatic breast cancer or advanced non-small-cell lung cancer is still debated. The aims of this review are to recall and discuss the most significant preclinical and clinical studies that led to the development of ramucirumab and to present the results of the randomized clinical trials that have tested its efficacy in different malignancies, including gastric and lung cancer.

Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: A critical insight

Advanced gastric cancer ranks second as the global leading cause of cancer-related death and improvements in systemic chemotherapy have reached a plateau. Advanced molecular sequencing techniques help identifying patients more likely to respond to targeted agents; nevertheless we are still far from major breakthroughs. Although antiangiogenic drugs have produced notable advances, redundant pathways or mechanisms of resistance may limit their efficacy. Novel compounds have been recently developed to specifically target VEGF receptors, PlGF, FGF, MET, and angiopoietin. Ramucirumab, a monoclonal antibody specifically directed against the VEGFR-2, has emerged as a novel therapeutic opportunity. REGARD and RAINBOW were the first phase III studies to report the value of this strategy in gastric cancer patients, and other ongoing trials are testing novel antiangiogenic compounds. The aim of our review is to present the state-of-the-art of novel antiangiogenic compounds in advanced gastric cancer, underlying the biology, their mechanism of action, and their clinical results.

Treatment-related gastrointestinal toxicities and advanced colorectal or pancreatic cancer: A critical update

Gastrointestinal toxicities (GIT), including oral mucositis, nausea and vomiting, and diarrhea, are common side effects of chemotherapy and targeted agents in patients with advanced colorectal cancer and pancreatic cancer. Being often underreported, it is still difficult to precisely establish their burden in terms of both patients quality of life and cancer care costs. Moreover, with the use of more intensive upfront combination regimens, the frequency of these toxicities is rapidly growing with a potential negative effect also on patients outcome, as a result of dose reductions, delays or even discontinuation of active treatments. Thus, identifying patients at higher risk of developing GIT as well as an optimal management are paramount in order to improve patients compliance and outcome. After the description of the main treatment-induced GIT, we discuss the current knowledge on the pathophysiology of these side effects and comment the scales commonly used to assess and grade them. We then provide a critical update on GIT incidence based on the results of key randomized trials conducted in patients with metastatic colorectal cancer and advanced pancreatic cancer.

MGMT promoter methylation status in brain metastases from colorectal cancer and corresponding primary tumors

BACKGROUND Brain metastases (BM) from colorectal cancer are usually associated with poor prognosis. The aim of this retrospective study is to evaluate MGMT promoter methylation in BM and their corresponding primary colorectal cancer tumors. MATERIALS & METHODS MGMT promoter methylation status was assessed by pyrosequencing in 53 consecutive patients resected for BM. A concordance analysis between BM and matched primary tumor was performed in 39 cases. RESULTS MGMT methylation was found in 34 (64.2%) BM and in 25 corresponding primary tumors (64.1%). Median survival after neurosurgery was independent from MGMT promoter methylation (163 days for those with methylated MGMT versus 193 days for the unmethylated). CONCLUSION Epigenetic MGMT promoter methylation was common and the concordance between primary and secondary lesions was high.

Role and mechanisms of resistance of epidermal growth factor receptor antagonists in the treatment of colorectal cancer

Introduction: Although epidermal growth factor receptor (EGFR) inhibitors have progressively become a relevant therapeutic arm in the treatment of patients with advanced colorectal cancer, the responses achieved are not durable and resistance invariably occurs. The advances in sequencing technology have allowed not only a more profound molecular tumor characterization but also the identification of the different molecular pathways involved in drug resistance and disease progression. These biological improvements have encouraged researchers to design clinical studies testing novel target therapies. Areas covered: After discussing the results of key Phase III randomized trials and providing commentary on the most promising novel agents (Sym004, MM-151, GA201 and MEHD7945A), the authors present the future steps ahead toward a real tailored treatment. Expert opinion: EGFR inhibitors are highly effective in the advanced disease setting. Although the negative predictive role of RAS and possibly BRAF mutations has already been established, more comprehensive efforts are needed to optimize the use of these drugs. At the same time, understanding the underlying biology will help basic scientists to develop new compounds able to overcome both primary and acquired resistance and help clinical researchers to test novel drugs within adequately designed trials whose results eventually are expected to reshape the overall treatment strategy.