Ramucirumab in metastatic colorectal cancer: evidence to date and place in therapy.
ABSTRACT: Colorectal cancer is the third most frequent cancer worldwide. Overall survival rates have improved greatly over the last few years due, at least in part, to the addition of targeted therapies to standard of care chemotherapy. Angiogenesis plays an important role in colorectal cancer, and therapies directed against the vascular endothelial growth factor (VEGF) axis have contributed significantly to improving the outcome of patients with metastatic colorectal cancer. Over the past few years, several new targeted antiangiogenic agents have been approved for this patient population, confirming the value of inhibiting tumour angiogenesis. The most recent among them is ramucirumab, a fully humanized monoclonal antibody that targets the extracellular domain of VEGF receptor 2. It has proven valuable in multiple tumour types including colorectal cancer. Several phase I and II clinical trials showed a favourable toxicity profile and promising clinical antitumour efficacy in colorectal cancer patients. In the phase III RAISE clinical trial, the addition of ramucirumab to FOLFIRI-based chemotherapy resulted in an improvement of overall survival in patients with metastatic colorectal cancer who had been previously treated with bevacizumab, oxaliplatin and a fluoropyrimidine. On the basis of these results, ramucirumab was approved by the US Food and Drug Administration for this setting. We present an overview of the key preclinical and clinical studies in the development of ramucirumab in the context of metastatic colorectal cancer.
Project description:Gastric cancer is currently the third most common cause of cancer deaths worldwide. Prognosis remains poor with most patients presenting with advanced or metastatic disease. A better understanding of angiogenesis has led to the investigation of drugs that inhibit the vascular endothelial growth factor (VEGF) pathway including anti-VEGF antibody therapy (eg, bevacizumab), inhibitors of angiogenic receptor tyrosine kinases (eg, sunitinib, sorafenib, apatinib, regorafenib), and inhibitors of vascular endothelial growth factor receptors (VEGFRs) (eg, ramucirumab). Ramucirumab, a VEGFR-2 inhibitor, is the first anti-angiogenic agent approved by the US Food and Drug Administration for use in the treatment of advanced gastric cancers. This review will focus on the clinical utility and potential use of ramucirumab in advanced gastric cancer.
Project description:The vascular endothelial growth factor (VEGF) and receptor is a therapeutic target because of the importance of this pathway in carcinogenesis. This pathway regulates and promotes angiogenesis as well as increases endothelial cell proliferation, permeability, and cancer survival. Ramucirumab is a new fully human monoclonal antibody that targets the VEGF receptor-2, an important key receptor implicated in angiogenesis. Ramucirumab has been approved for the treatment of second-line advanced or metastatic non-small cell lung cancer (NSCLC) in combination with the chemotherapy agent docetaxel. This was based on the result of the randomized trial REVEL of 1,253 patients with metastatic NSCLC previously treated with a platinum-based combination therapy. The authors observed a significant improvement in overall survival (OS) with an acceptable toxicities profile. In this study, patients were randomized to receive ramucirumab plus docetaxel or placebo with docetaxel. The combination of docetaxel and ramucirumab showed an improved OS (hazard ratio [HR]: 0.86; 95% CI: 0.75, 0.98). Median OS was 10.5 months in the ramucirumab arm versus 9.1 months in the placebo arm. Regarding side effects, the toxicity described on the ramucirumab arm were principally diarrhea, fatigue, and neutropenia. The most common (5%) adverse reactions of grade 3 and 4 in the ramucirumab arm were fatigue, neutropenia, febrile neutropenia, leukopenia, and hypertension. Adding ramucirumab to docetaxel improves QoL of patients, and does not impair symptoms or functioning. There are currently several trials in progress evaluating the effects of ramucirumab in combination with other drugs in patients with advanced NSCLC.
Project description:Ramucirumab (IMC-1121B) is a fully humanized IgG1 monoclonal antibody, targeting the extracellular domain of VEGF receptor 2 (VEGFR2). Numerous Phase I - II trials in various malignancies have shown promising clinical antitumor efficacy and tolerability. Most recently, the large Phase III REGARD trial evaluated ramucirumab in patients with refractory metastatic gastric cancer. Patients receiving ramucirumab experienced a median overall survival of 5.2 months compared to 3.8 months on placebo.The purpose of this article is to review the preclinical motivation for VEGFR2-targeted therapies and survey recent data from clinical trials involving ramucirumab, as well as highlight ongoing studies.Rational multi-target approaches to angiogenesis are needed to overcome resistance mechanisms. Predictive angiogenic biomarkers are also needed to optimize patient selection for novel anti-angiogenic agents.
Project description:The interaction between vascular endothelial growth factor and its receptor is an important therapeutic target due to the importance of this pathway in carcinogenesis. In particular, this pathway promotes and regulates angiogenesis as well as increases endothelial cell proliferation, permeability, and survival. Ramucirumab is a fully human monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2, the key receptor implicated in angiogenesis. Currently, ramucirumab is approved for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC) in combination with docetaxel. In a Phase III clinical trial, ramucirumab was shown to improve the overall survival in patients with disease progression, despite platinum-based chemotherapy for advanced NSCLC. This review describes the pharmacology, pharmacokinetics and dynamics, adverse event profile, and the clinical activity of ramucirumab observed in Phase II and III trials in NSCLC.
Project description:Anti-angiogenic therapy is one of the promising strategies for many types of solid cancers. Bevacizumab (Avastin), a recombinant humanized monoclonal antibody of vascular endothelial growth factor (VEGF) A, was approved for the first time as an anti-angiogenic drug for the treatment of metastatic colorectal cancer (CRC) by the Food and Drug Administration (FDA) in 2004. In addition, the other VEGF pathway inhibitors including small molecule tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), a soluble VEGF decoy receptor (aflibercept), and a humanized monoclonal antibody of VEGF receptor 2 (VEGFR2) (ramucirumab) have been approved for cancer therapy. Although many types of VEGF pathway inhibitors can improve survival in most cancer patients, some patients have little or no beneficial effect from them. The primary or acquired resistance towards many oncological drugs, including anti-VEGF inhibitors, is a common problem in cancer treatment. This review summarizes the proposed alternative mechanisms of angiogenesis other than the VEGF pathway. These mechanisms are involved in the development of resistance to anti-VEGF therapies in cancer patients.
Project description:INTRODUCTION:In 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in the second line setting of advanced or metastatic, gastric or gastroesophageal adenocarcinoma (GEAC) based on the result of Phase III clinical trials; REGARD and RAINBOW. AREAS COVERED:We briefly review the mechanisms of angiogenesis, anti-angiogenic therapy, and current status of advanced GEAC treatment then highlight the challenges and future prospects of novel molecular targeted agents. EXPERT OPINION:Although both the REGARD and RAINBOW trials met their primary endpoints of significantly prolonged overall survival (OS) and progression-free survival (PFS), the magnitude of the difference is still relatively modest. Given that ramucirumab alone has a marginal effect, a combination of paclitaxel and ramucirumab is strongly preferred as a second line therapy. To maximize the impact of ramucirumab in patients with GEAC, we can leverage the recent pharmacokinetics (PK) data of ramucirumab from the REGARD and RAINBOW trials. In addition, the quest for identifying biomarkers to select patients who are likely to benefit the most should continue. It is our firm belief that taxanes should no longer be added to the frontline regimens in most cases, given the success of the taxane/ramucirumab in the second line setting.
Project description:Background:The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo?+?FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods:Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results:Biomarker results were available from?>80% (n?=?894) of patients. Analysis of the ME subset determined a VEGF-D level of 115?pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME?+?MC populations found that the median OS in the ramucirumab?+?FOLFIRI arm compared with placebo?+?FOLFIRI showed an improvement of 2.4?months in the high VEGF-D subgroup [13.9?months (95% CI 12.5-15.6) versus 11.5?months (95% CI 10.1-12.4), respectively], and a decrease of 0.5?month in the low VEGF-D subgroup [12.6?months (95% CI 10.7-14.0) versus 13.1?months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions:The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration:NCT01183780.
Project description:Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) are believed to mediate angiogenesis in colorectal cancer (CRC). Ramucirumab (RAM; IMC-1121B) is a human IgG1 monoclonal antibody that inhibits VEGF ligand binding to VEGFR-2, inhibiting VEGFR-2 activation and signaling.Patients with metastatic CRC, Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function who had not received chemotherapy for metastatic disease received RAM and the modified FOLFOX-6 regimen every 2 weeks. Endpoints included progression-free survival (PFS), objective response rate, overall survival, and safety. The sample size was based on a potentially improved median PFS from 8 months to 11 months.Forty-eight patients received therapy. Median PFS was 11.5 months (95% confidence interval [CI]: 8.6-13.1 months). The objective response rate was 58.3% (95% CI: 43.21-72.39). The disease control rate (complete or partial response plus stable disease) was 93.8% (95% CI: 82.8-98.7). Median overall survival was 20.4 months (95% CI: 18.5-25.1 months). The most frequent grade 3-4 adverse events included neutropenia (grade 3: 33.3%; grade 4: 8.3%), hypertension (grade 3: 16.7%), and neuropathy (grade 3: 12.5%). Two patients died during the study due to myocardial infarction and cardiopulmonary arrest.RAM may enhance the efficacy of modified FOLFOX-6 chemotherapy with an acceptable safety profile in metastatic CRC.
Project description:Gastric cancer (GC) is the fifth-ranked cancer type by associated mortality. The proportion of early diagnosis is low, and most patients are diagnosed at the advanced stages. First-line therapy standardly includes fluoropyrimidines and platinum compounds with trastuzumab for HER2-positive cases. For recurrent disease, there are several alternative options including ramucirumab, a monoclonal therapeutic antibody that inhibits VEGF-mediated tumor angiogenesis by binding with VEGFR2, alone or in combination with other cancer drugs. However, overall response rate following ramucirumab or its combinations is 30%-80% of the patients, suggesting that personalization of drug prescription is needed to increase efficacy of treatment. We report here original tumor RNA sequencing profiles for 15 advanced GC patients linked with data on clinical response to ramucirumab or its combinations. Three genes showed differential expression in the tumors for responders versus nonresponders: CHRM3, LRFN1, and TEX15 Of them, CHRM3 was up-regulated in the responders. Using the bioinformatic platform Oncobox we simulated ramucirumab efficiency and compared output model results with actual tumor response data. An agreement was observed between predicted and real clinical outcomes (AUC ? 0.7). These results suggest that RNA sequencing may be used to personalize the prescription of ramucirumab for GC and indicate potential molecular mechanisms underlying ramucirumab resistance. The RNA sequencing profiles obtained here are fully compatible with the previously published Oncobox Atlas of Normal Tissue Expression (ANTE) data.
Project description:Regorafenib monotherapy is a potential option for metastatic colorectal cancer patients. However, the lack of predictive factors and the severe toxicities related to treatment have made its use in clinical practice challenging. Polymorphisms of VEGF and its receptor (VEGFR) genes might regulate angiogenesis and thus potentially influence outcome during anti-angiogenesis treatment such as regorafenib. Aim of our study was to evaluate the role of VEGF and VEGFR genotyping in determining clinical outcome for colorectal cancer patients receiving regorafenib. We retrospectively collected clinical data and samples (tumour or blood) of 138 metastatic colorectal cancer patients treated with regorafenib. We analysed the correlation of different VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs) with patients' progression-free survival (PFS) and overall survival (OS). Results from angiogenesis genotyping showed that only VEGF-A rs2010963 maintained an independent correlation with PFS and OS. Among clinical factors only ECOG PS was independently correlated with OS, whereas no correlation with PFS was evident. Grouping together those results allowed further patients stratification into 3 prognostic groups: favourable, intermediate and unfavourable. VEGF-A rs2010963 genotyping may represent an important tool for a more accurate selection of optimal candidates for regorafenib therapy.