Ramucirumab (IMC-1121B): A Novel Fully Human Monoclonal Antibody that Targets VEGFR-2

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Ramucirumab is an investigational immunoglobin G1 (IgG1) monoclonal antibody (mAb) currently under development. It uses only human cells, allowing it to avoid many of the adverse effects associated with murine or chimeric mAbs. Ramucirumab binds to human VEGFR-2, thus blocking VEGF binding and thwarting the angiogenic process. It is thought that inhibiting VEGFR-2 might yield superior outcomes in several solid tumors. Ramucirumab has demonstrated activity in vitro and in murine models against leukemia and ovarian cancer cell lines and in phase I and II clinical trials against breast and gastric cancer.

Ramucirumab inhibits VEGFR-2 expression from normal endothelial cells, as well as tumor endothelial cells, impairing endothelial healing and hypercoagulability. Preliminary data suggest that ramucirumab is well tolerated, with manageable adverse effects. The safety of ramucirumab has not been reported on extensively, however, and results from the many ongoing studies should shed light on this important area. Its specific targeting of VEGFR-2 suggests it may have a narrower adverse effects profile than broadspectrum TKIs.

VEGF inhibition increases the risk of bleeding events, as seen with bevacizumab (Avastin), another mAb that inhibits VEGF expression. Hypertension and renal toxicities are also not unexpected with ramucirumab. Based on safety data from trials of bevacizumab, investigators decided to exclude certain patient populations from subsequent trials of ramucirumab. These include patients who have brain metastases, a recent history of thrombotic events, non-healing wounds/ulcers, major blood vessel encasement or invasion.

PHASE III: BREAST CANCER

In this multicenter, multinational study sponsored by ImClone LLC, investigators plan to accrue 1113 patients with recurrent HER2-negative locally advanced or metastatic breast cancer (MBC) or inoperable breast cancer. Patients will be randomized to receive docetaxel plus the investigational agent ramucirumab or placebo. Patients must not have received prior therapy for their recurrence or MBC. Treatment will continue until evidence of progressive disease or unacceptable toxicity. Patients will be assessed every 6 weeks until progressive disease and every 6 months thereafter for at least 36 months after discontinuing the study. ClinicalTrials.gov ID: NCT00703326.

PHASE III: GASTRIC CANCER

Investigators hope to assess overall survival of patients with metastatic gastric cancer (including cancers of the gastroesophageal junction) who are randomized to receive treatment with ramucirumab and best supportive care (BSC) or placebo and BSC. They plan to enroll 615 patients whose disease has progressed following first-line treatment with a platinum- or fluoropyrimidine-based chemotherapy regimen. Treatment will continue until evidence of progressive disease, unacceptable toxicity or failure to adhere to protocol. Secondary outcome measures include progression-free survival, objective response, duration of response, quality of life, and safety. ClinicalTrials.gov ID: NCT00917384.

PHASE II: PROSTATE CANCER

Investigators seek to determine whether the investigational agent IMC-A12 or ramucirumab plus mitoxantrone and prednisone are effective in metastatic androgen-independent prostate cancer in patients whose disease has progressed after docetaxel-based chemotherapy. In this randomized study, 132 patients will be randomized to receive one of the two experimental drugs plus mitoxantrone and prednisone. Treatment will continue until evidence of disease progression, intolerable toxicities, or death. IGF-IR and VEGFR-2 mediated pathways may contribute to prostate cancer pathogenesis. Patients with other malignancies are excluded from participation. ClinicalTrials. gov: NCT00683475.

PHASE II: GLIOBLASTOMA

In this interventional open-label study sponsored by the National Cancer Institute and ImClone LLC, investigators plan to enroll 80 patients with brain and central nervous system tumors, particularly recurrent glioblastoma multiforme. One group will receive ramucirumab administered intravenously; the other group will receive anti-PDGFR alpha monoclonal antibody IMC-3G3. Both treatments will be continued until disease progression or unacceptable toxicity. The primary outcome measure for this trial is progression-free survival at 6 months. Secondary outcome measures include objective tumor response rate, overall survival, acute and late toxicities, and Pharmacokinetic and pharmacodynamic profiles and immunogenicity. ClinicalTrials.gov ID: NCT00895180.

VEGF & VEGF Receptors

VEGF is a polypeptide found on chromosome 6p12. Cells trigger production of this protein to stimulate the growth of new blood vessels, a vital function that promotes healing when blood vessels are injured or occluded or when tissue is hypoxic. Various cellular receptors and oncogenes contribute to increased VEGF expression. VEGF overexpression sometimes leads to vascular disease or the unchecked growth of malignant tumors.

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Most cancerous tumors secrete VEGF, which signals angiogenesis and facilitates survival of a tumor’s existing vasculature. VEGF signaling enables tumors to establish their own vascular support network, securing an unimpeded supply of nutrients and oxygen. This facilitates tumor growth and infiltration into surrounding tissues. Tumor vasculature associated with high levels of VEGF expression is typically abnormal, with leaky pericytes, tortuousness, and hyperpermeability. The tumor’s immature and abnormal vessels can impede the effective delivery of anticancer compounds.

Current understanding is that there are five VEGF ligands, identified as VEGF-A through VEGF-E. The first to be discovered was VEGF-A, which is considered the most critical to neovascularization and is typically referred to simply as VEGF. This protein binds to VEGF receptors (VEGFRs) 1 and 2 on the surface of endothelial cells (Figure). VEGFR-2 has also been found on the surface of tumor cells in some malignancies. The binding of VEGF to VEGFR-2 causes dimerization and activation through transphosphorylation.

Endothelial cells in tumor blood vessels can express VEGFR-1, VEGFR-2, and VEGFR-3, though they primarily express VEGFR-2. The upregulation of VEGFR-2 is common during tumor formation and growth. VEGFR-2 expression is said to be 3- to 5-fold higher in tumor vasculature than in normal vasculature. It is believed that, of the three VEGFRs, only VEGFR-2 triggers intracellular signaling, making it a useful pathway to target for inhibition.