D ru g Eva lu a tio n

Jennifer L Spratlin†1, Karen E Mulder1 & John R Mackey1 1 Department of Medical Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada † Author for correspondence: Address n Tel.: +1 780 432 8513 n Fax: +1 780 432 8888 n [email protected]

integrity [2,11–13] . VEGF–VEGFR-2 interaction inhibition is consequently a promising target for anticancer treatment. Preclinical in vivo models show inhibition of tumor growth and metastases when VEGF–VEGFR interactions and VEGFR signal transduction pathway are blocked with anti-VEGF antibodies, VEGF-based immunotoxins, soluble VEGFRs, small-molecule VEGFR-2 tyrosine kinase inhibitors (TKIs) or anti-VEGF antisense ribonucleic acid expression [14–16] . In vivo animal data are complemented by positive results with a number of these compounds in human trials [17] . Ramucirumab (IMC-1121B ; ImClone Systems Corporation, Branchburg, NJ, USA) is a fully human, IgG1 monoclonal antibody that binds the extracellular domain of VEGFR-2, thereby blocking VEGF–VEGFR‑2 interaction [18] . Phase I, single-agent studies of ramucirumab have been completed, and Phase II and III clinical trials are underway. This article describes the available pharmacokinetics (PK), pharmacodynamics (PD), toxicity and efficacy data of ramucirumab and places this novel drug in the context of clinically available antiangiogenic agents.

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Angiogenesis is the physiologic process of new blood vessel formation, which is coopted by many human malignancies to meet the metabolic requirements of macroscopic solid tumors. Although modulated by various inhibitors and inducers, including matrix metalloproteases, PDGF-b, TNF-a and TGF, angiogenesis is principally driven by interactions between VEGFs and VEGF receptors (VEGFRs), with persistent upregulation of this process being an important factor in the pathology of cancer growth and metastasis [1–5] . Of the VEGF family of ligands, consisting of VEGF (VEGF-A), VEGF-B, VEGF-C, VEGF-D, VEGF-E and PIGF, VEGF is known to be the essential regulator of tumor angiogenesis and endothelial proliferation, permeability and survival [1,6,7] . VEGF binds primarily to two structurally similar tyrosine kinase receptors with high affinity, VEGFR-1 (fms-like tyrosine kinase-1) and VEGFR-2 (kinase insert domain-containing receptor) [8,9] . Once bound, receptor dimerization and autophosphorylation occurs, followed by a cascade of signaling events eventually leading to activation of downstream proteins and effector molecules. VEGFR-2 expression is upregulated several fold in the tumor vasculature of endothelial cells [10] . Emerging data suggest a critical role for VEGF binding to VEGFR-2 triggering the full spectrum of VEGF-induced biological modifications, including proliferation, migration and vascular endothelial cell differentiation, in addition to key changes in vascular permeability and

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Angiogenesis is a critical hallmark of malignancy, and attempts to inhibit this process have characterized the age of biologic anticancer therapies for solid tumors. VEGF receptor-2 is the premier receptor responsible for many of the cancer- driven VEGF-induced spectrum of biologic changes, including modification of blood vessel structure and function, proliferation and migration. Unlike all clinically approved angiogenesis inhibitors, the fully human monoclonal antibody ramucirumab (IMC-1121B) specifically and potently inhibits VEGF receptor-2. Phase I clinical trials have shown safety across a wide range of ramucirumab doses with impressive, albeit early, evidence of both stable disease and partial responses in a variety of tumor types. In this article, we review the current data on ramucirumab and make comparisons with commercially available antiangiogenic agents.

10.2217/FON.10.75 © 2010 Future Medicine Ltd

Overview of the market

Angiogenesis inhibitors, most notably bevacizumab, sunitinib and sorafenib, are US FDA approved for the treatment of several cancer indications. Bevacizumab, a recombinant humanized antibody to VEGF was the first FDA-approved novel antiangiogenic agent. Future Oncol. (2010) 6(7), xxx–xxx

Drug Evaluation

Future Oncology

Ramucirumab (IMC-1121B): a novel attack on angiogenesis

Keywords n

angiogenesis

n antiangiogenic

agent monoclonal antibody n VEGFR2 n IMC-1121B n

part of

ISSN 1479-6694

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Drug Evaluation

Spratlin, Mulder & Mackey

was well tolerated with minimal toxicity, including dose-related hypertension (HTN) and treatment-emergent dermal hemangiomata [37] . No dose-limiting toxicities (DLTs) were recorded. Biologic activity was confirmed by biopsies showing nonphosphorylated VEGFR-2 with bound CPD791. IMC-1121, a chimeric antiVEGFR-2 antibody, has also been evaluated in a Phase I clinical trial and was well tolerated with only minor grade 1 bleeding documented in four out of 14 patients with no DLTs [36] . Favorable antitumor and dynamic contrastenhanced (DCE) MRI results, observed although human antichimeric antibodies, were detected in half of patients exposed to drug. Consequently, the IMC-1121 chimeric antibody was fully humanized and further developed as IMC-1121B (ramucirumab). There are three Phase I clinical trials, one of which is published and the other two being presented in abstract form, evaluating the safety, PK, PD and early efficacy of ramucirumab in patients with advanced cancer refractory to standard-of-care treatments [39,40] . In addition, nine Phase II and two Phase III studies have enrolled patients; the status and patient demographics of these trials are summarized in Table 1.

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Initially approved in the first- and secondline settings for metastatic colorectal cancer based on both progression free and overall survival data, bevacizumab is also indicated in metastatic, nonsquamous non-small-cell lung cancer (NSCLC), metastatic breast cancer, glioblastoma and metastatic renal cell carcinoma (RCC) [19–25] ; although an overall survival advantage was seen in nonsquamous NSCLC when combined with chemotherapy, bevacizumab did not extend survival in the other disease settings and was approved based on improvement in progression-free survival or in objective response rate. There are several small-molecule TKIs to VEGFRs at various stages of clinical development; most have multiple intracellular targets accounting for some of the additional observable toxicities not directly related to VEGFR-2 inhibition. These compounds exert their effects via reversible, competitive inhibition of the ATP-binding domain. The most notable approved drugs in this category are sunitinib and sorafenib [26–29] . Sunitinib inhibits VEGFR-1, VEGFR-2, PDGF receptor, c-KIT, FLT3 and RET, thereby modulating many of the processes involved not only in angiogenesis but also in tumor progression and metastasis [30–32] . Approved for gastrointestinal stromal tumors after progression or intolerance to imatinib mesylate and in the setting of advanced RCC, sunitinib has also demonstrated preclinical activity in colorectal, NSCLC, melanoma, epidermoid and leukemic cell lines resulting in tumor regression. Early clinical trials have also documented antitumor activity in these and other tumors [27,28,30,33] . Like sunitinib, sorafenib is a multitargeted TKI, inhibiting VEGFRs and PDGF receptor‑b on the cell surface as well as Raf-1 and wild-type and mutant B-Raf, intracellular serine–threonine kinases responsible in part for cell proliferation and angiogenesis, and can also induce apoptosis [34,35] . Sorafenib was FDA approved in 2005 for use in advanced RCC and was more recently approved for advanced hepatocellular cancer [28,29] . Targeting the extracellular domain of VEGFR-2 is a novel approach that has been explored in preclinical models and in earlystage clinical trials. Although ramucirumab is the most advanced in development, other clinically tested VEGFR-2 inhibitors include IMC-1121 (ImClone, NJ, USA) and CDP791 (UCB, Brussels, Belgium) [36–38] . CPD791, a PEGylated di-Fab fragment against VEGFR-2,

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Future Oncol. (2010) 6(7)

Introduction to the compound Chemistry

Ramucirumab, the most clinically advanced direct inhibitor of VEGFR-2, specifically binds the extracellular VEGF-binding domain of VEGFR-2 with low picomolar affinity [41] . Ramucirumab development began to identify and develop an antibody with potent VEGFR-2 affinity, and as such, a bacteriophage library of human Fab fragments from nonimmunized human donors was probed against VEGFR-2 [42] . Clone 1121 was identified as having a binding affinity to VEGFR-2 of more than 30-fold [43] . Ramucirumab (IMC-1121B) was created via further cloning and genetic changes. Ramucirumab is expressed in the GS-NS0 mouse myeloma cell line and potently inhibits VEGF–VEGFR-2 interaction with an IC50 of 0.8–1.0 nM. For patient administration, ramucirumab dose is calculated based on bodyweight and mixed with normal saline to a maximum volume of 250 ml. Pharmacodynamics

Proof-of-concept studies have been undertaken to determine the benefit of inhibiting VEGFR-2 using DC101, a rat antimouse future science group


Drug Evaluation

Table 1. Overview of ramucirumab clinical trials. Clinical trial

Phase Therapy

CP12-0401 CP12-0402 CP12-0816/NCT010005355

I I I

CP12-0604/NCT00533702 CP12-0605/NCT00515697

II II

CP12-0708/NCT00735696

II

IMC CP12-0709/ NCT00862784 IMC CP12-0710/ NCT00627042 CP12-0711/NCT00721162

II

Patient population

II

Single-agent R

CP12-0712/NCT01017731 IMC CP18-0601/ NCT00683475

II II

Single-agent R IMC-A12 or R plus mitoxantrone and prednisone

IMCL-CP-19-0801/ NCT00895180 IMC CP12-0606/TRIO-012/ NCT00703326

II

IMC CP12-0715/ NCT00917384

III

R or anti-PDGF receptor-a monoclonal antibody IMC-3G3 Randomized, double-blind study of R plus docetaxel versus placebo plus docetaxel Randomized R plus best supportive care (BSC) versus placebo plus BSC

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antibody directed at FLK-1, the murine homolog of human VEGFR-2. In vitro, DC101 is both antiangiogenic and antitumorigenic and inhibits metastatic growth in animal models, even with resected primary tumors [40,44–46] . In addition, DC101 demonstrated multiple signs of target inhibition, including reduced microvessel density, tumor necrosis, increased apoptosis and decreased proliferation [16,47] . In preclinical studies, ramucirumab potently inhibited VEGF binding to VEGFR-2 with a binding affinity constant of ramucirumab to VEGFR-2 of 5 × 10 -11 M [48] . Furthermore, ramucirumab demonstrates inhibition of VEGF-stimulated VEGFR-2 activation, proliferation of human endothelial cells, VEGF-migration of human leukemia cells, and VEGF-induced phosphorylation of VEGFR-2 in human umbilical vein and porcine aortic endothelial cells overexpressing VEGFR-2 [43,49] . The clinical PD data for ramucirumab report on serum VEGF, soluble VEGFR-1 (sVEGFR-1), and soluble VEGFR-2 (sVEGFR-2) levels, as well as DCE-MRI studies. Shortly after initial future science group

Persistent or recurrent epithelial ovarian, Fallopian tube or primary peritoneal carcinoma Treatment-refractory cancer patients Metastatic androgen-independent prostate cancer following progression on docetaxel-based therapy Recurrent glioblastoma multiforme

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R: Ramucirumab.

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II

Treatment-refractory cancer patients Treatment-refractory cancer patients Japanese patients refractory to other cancer therapies R with or without dacarbazine Metastatic melanoma Single-agent R every 2 weeks Metastatic renal cell carcinoma flowing failure of anti-VEGF receptor-2 therapy R plus paclitaxel and carboplatin First line in stage IIIB/IV non‑small‑cell lung cancer R in combination with 5-fluorouracil/FA Colorectal cancer and oxaliplatin Single-agent R Untreated liver cancer

III

Single-agent R once weekly Single-agent R once every 2 or 3 weeks Single-agent R once every 2 or 3 weeks

Previously untreated HER2-negative, unresectable, locally recurrent or metastatic breast cancer Previously treated metastatic gastric cancer

Status of trial Published Closed to accrual Actively accruing Closed to accrual Closed to accrual

Actively accruing Actively accruing Closed to accrual Closed to accrual

Actively accruing Actively accruing

Approved – not yet active Actively accruing

Actively accruing

ramucirumab infusion, VEGF-A concentrations increase between 1.5- and 3.5-fold higher than baseline values and remain elevated as long as ramucirumab is present [39] . These changes imply that ramucirumab binds VEGFR-2, thereby preventing circulating VEGF-A receptor binding. Both the CP12-0402 and CP12-0605 studies show similar preliminary results [40,50] . By contrast, sVEGFR-1 and -2 decrease postramucirumab dosing but recover to near baseline levels thereafter [39] . None of the observable changes in VEGF-A, sVEGFR-1 or sVEGFR-2 appear to be dose dependent. In patients treated with ramucirumab, there appears to be good correlation between the dose level, dose intensity and number of DCEMRI-responding patients, with patients from the highest dose cohorts showing a significant decrease in tumor perfusion and vascularity [39] . Other studies using TKIs inhibiting both VEGFR-1 and VEGFR-2 have shown similar results [51–54] . In contrast to other exclusive VEGFR-2-directed therapies (which include IMC-1C11 and CDP791), decreased perfusion www.futuremedicine.com

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Drug Evaluation


Pharmacokinetics & metabolism

was observed with weekly ramucirumab therapy across multiple tumor types and various sites of metastatic disease [39] . Four heavily pretreated patients experienced a partial response (PR), one each with melanoma, gastric, uterine leiomyosarcoma, and ovarian primaries. A total of 30% of patients had stable disease (SD) exceeding 24 weeks. Approximately 10% of patients who participated in the trial received the drug for over 2 years, establishing long-term drug tolerability. There were no complete responses (CRs). In comparison with other anti-VEGF therapies evaluated in Phase I clinical trials, the IMC-1121B efficacy and toxicity profiles appeared similar if not superior to those of other agents (Table 2) . A disease control rate (CR plus PR plus SD) of 73% was observed in this trial, well above that seen with other antiangiogenic agents when evaluated in Phase I, single-agent clinical trials. These data provide proof of principle that VEGFR-2 blockade with an antibody is an effective strategy.

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parameters were noted but were short lived and did not show a reduction in tumor vascular flow or permeability [36,37] . The CP12-0401 study did not, however, assess the effects of ramucirumab past the first treatment cycle; thus, the duration of these changes is unknown. Furthermore, there is no clear correlation between the DCEMRI results, VEGF-A, sVEGFR-1 or sVEGFR-2 levels. These findings demonstrate the ongoing challenges of understanding the mechanisms by which anti-VEGF therapies exert their effects on tumor vasculature and emphasize the need for additional research to determine whether DCEMRI can serve as a quantitative biomarker for drug efficacy.

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Preclinical ramucirumab PK studies were on cynomolgus monkeys using repeat-dose studies [18] . PK parameters were nonlinear and typical for monoclonal antibodies. With increasing IMC-1121B dose, the half-life increased, the clearance decreased and the steady state volume of distribution increased and was equal to vascular space, while the AUC0-∞ and Cmax increased greater than the proportional dose increase. The limit of quantitation using the ELISA assay was 1 ng/ml. Immunogenicity evaluating for antibodies versus IMC-1121B using a double-antigen radiometric assay in cynomolgus monkeys showed mixed results in these studies, with no particular pattern of increased immunogenicity with increasing dose. Similar PK data have been generated from the Phase I study dosing ramucirumab weekly [39] . Ramucirumab clearance decreased disproportionately as dose increased; this effect was less evident at doses of more than 8 mg/ kg, implying saturation of clearance mechanisms. Half-life ranged from 200 to 300 h and increased disproportionately as dose increased, with interpatient variability. There was negligible drug accumulation. Importantly, the target trough level (20 µg/ml) determined from preclinical xenograft studies required for antitumor activity was achieved in this dose-finding study as well as subsequently analyzed trials including CP12-0402, CP12‑0604, CP12-0605 and IMCL CP12-0710 [48] . Clinical efficacy Phase I studies

Ramucirumab currently has limited available efficacy results at this time, but the data that have been published and reported are promising. Encouraging objective antitumor activity 4


Phase II studies

Preliminary efficacy data from the Phase II study of ramucirumab in patients with advanced RCC who have failed VEGFR-2 TKI inhibition were presented at the fall 2009 European Society for Medical Oncology (ESMO) meeting [50] . To date, 39 patients with a median age of 59 years (range: 36–91 years) have been treated with ramucirumab 8 mg/kg intravenously every 2 weeks. Although there were no CRs, two (5%) and 26 (67%) patients achieved PR and SD, respectively. A disease control rate of 72% (CR plus PR plus SD) was observed, similar to the disease control rate recorded in the CP120401 Phase I study and impressive in the setting of a group of patients who had previously been treated with anti-VEGF therapy (53 and 35% of patients with previous sunitinib, and sunitinib and sorafenib exposure, respectively) demonstrating ramucirumab activity in heavily pretreated cancer patients. Safety & tolerability

Overall, ramucirumab administration has been safe and tolerable with little need for dose modifications. The only fully published data report that 60% of patients, irrespective of attribution, experienced grade 3–5 adverse events, which included HTN, proteinuria, deep venous thrombosis (DVT), headache, anorexia, vomiting, dyspnea and an increase in alkaline phosphatase [39] . DLTs in that trial included one episode of HTN and one DVT at the 16 mg/kg dose level. future science group


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developed proteinuria, which has generally been of low grade and reversible with drug interruption or discontinuation. Significant proteinuria (up to 8 g per 24 h) has been reported, however, and this uncommon toxicity requires close monitoring. Both venous and arterial thromboses have been reported with the use of ramucirumab, but data are limited, with only five venous events (two DVT, one subclavian vein thrombosis, one vena cava thrombosis and one vein disorder not otherwise specified) as well as two arterial events (one peripheral arterial thrombosis and one thrombosis not otherwise specified) occurring in ramucirumab-treated subjects. A total of 11 incidences of hemorrhage have been reported across trials as of 1 June 2009. These range from duodenal ulcer hemorrhage, hemoptysis, bleeding from metastatic sites, worsening epistaxis and CNS bleeding. Many of these events have been reported as unrelated and are most likely to be due to primary tumors or metastatic lesions

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As of 1 June 2009, across all trials, there have been 230 serious adverse events; of those, 60 events were considered to be possibly, probably or definitely related to ramucirumab, including six deaths (one each of cardiac arrest, gastrointestinal hemorrhage, hepatic failure, intestinal perforation, respiratory failure and sepsis) (Table 3) [48] . As expected with ramucirumab’s mechanism of action, HTN, proteinuria, thrombotic event, and bleeding have been reported. The most upto-date information from Phase I and II clinical trials indicates that 44 out of 227 patients (19%) developed ramucirumab-related HTN. Across the trials, the incidence has been relatively inconsistent, and the majority of patients who experienced ramucirumab-related HTN tended to have preexisting comorbidities or HTN. Approximately 10% (24% in the two Phase I studies and 2–5% in the ongoing Phase II studies) of patients across the reported trials have

Drug Evaluation

Table 2. Comparison of ramucirumab with other antiangiogenic agents in Phase I trials.

Ramucirumab

37

0.001

Bevacizumab

25

–

Sunitinib

40

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HTN, DVT and headache Proteinuria, vomiting and amylasemia None Anemia, dyspnea, intracranial bleeding and tumor hemorrhage Asthenia, nausea, Fatigue, HTN, bullous vomiting, HTN, PE, skin toxicity, elevated lipase/amylase, decrease phlebitis, neutropenia, thrombocytopenia, skin LVEF, edema, toxicity, tumor-related thrombocytopenia and fistulas and anemia tumor necrosis Fatigue, anorexia, Rash, HTN, dyspnea, fatigue, HFS, abdominal diarrhea, rash/ desquamation, HFS, cramping, diarrhea, retrosternal pain, edema nausea and alopecia of uvula and anorexia Diarrhea, rash, nausea, Diarrhea, HTN, rash, HTN, fatigue, anorexia, folliculitis, CHF, PE, DVT and hypophosphatemia, bowel ischemia increased ALT, bowel obstruction, colitis, fatigue and thrombocytopenia HTN, hypertensive crisis, Fatigue, diarrhea, nausea, dysphonia, hypoglycemia and hypertension, vomiting elevated bilirubin and anorexia

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173

0.03‡–0.09 §

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Sorafenib

†

Other grade 3/4 toxicities

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Antiangiogenic Patients VEGFR-2 IC50 DLTs agent (n) (µM)

ZD6474

77

0.04 §

AZD2171

83

0.001§

Efficacy

Ref.

CR (%)

PR (%)

SD (%)

0 (0)

4 (11)

23 (62)

[45]

0 (0)

0 (0)

12 (48)

[57]

0 (0)

7 (18)

7 (18)

[61–62]

0 (0)

2 (1)

55 (31)

[58–60]

0 (0)

0 (0)

31 (40)

[63]

0 (0)

2 (2)

22 (27)

[64]

Cellular IC50 assays in human umbilical vascular endothelial cells and HL60 and HEL leukemia cell lines. Cellular IC50 assays in NIH-3T3 cells and serum-starved human umbilical vascular endothelial cells, determined from inhibition of receptor phosphorylation assays and ligand‑dependent cell kinase assays. § Noncellular IC50 values: determined from biochemical assays (including those to inhibit recombinant tyrosine kinase, receptor phosphorylation activity using 96-well ELISA, scintillation proximity-based assays and other assays). CHF: Congestive heart failure; CR: Complete response; DLT: Dose-limiting toxicity; DVT: Deep vein thrombosis; HFS: Hand–foot syndrome; HTN: Hypertension; LVEF: Left ventricular ejection fraction; PE: Pulmonary embolism; PR: Partial response; SD: Stable disease; VEGFR: VEGF receptor. † ‡

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Drug Evaluation


Table 3. Frequency of related serious adverse events across ramucirumab trials. Number Toxicity of events Infusion-related reaction Proteinuria and hypertension Febrile neutropenia and gastrointestinal hemorrhage Chest pain, fatigue, myocardial infarction and acute renal failure Anorexia, bronchospasm, cardiac arrest, cardiorespiratory arrest, duodenal ulcer hemorrhage, encephalopathy, epitaxis, flushing, hemoptysis, headache, hepatic failure, hypotension, intestinal perforation, left ventricular dysfunction, leucopenia, nausea, peripheral edema, pelvic venous thrombosis, peripheral sensory neuropathy, thrombocytopenia, pleuritic pain, pneumothorax, proctalgia, pulmonary embolism, pyrexia, respiratory failure, sepsis, supraventricular tachycardia, syncope, tumor flare, tumor hemorrhage and vomiting

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5 4 3 2 1

also observed in 23% of patients treated with CDP791, a pegylated antibody fragment binding VEGFR-2 [38] . In the cases associated with CDP791, the hemangiomata tended to appear after at least three cycles of therapy and were only seen in patients treated at relatively high doses of the drug [38] . Biopsy of one of the lesions associated with CPD791 showed endothelial cells, VEGFR-2 expression and CDP791 binding in areas of nonphosphorylated VEGFR-2, suggesting that the drug was pharmacologically active [38] . None of the patients who developed these lesions discontinued therapy as a result of the hemangiomata, whereas the skin toxicity did regress after treatment cessation. The only other VEGFR-2-targeted agent that has been tested clinically, IMC-1C11, a chimeric monoclonal antibody, did not cause hemangiomata when tested in humans, and this toxicity has not been reported with bevacizumab or the small-molecule TKIs inhibiting the VEGF pathway [36,55– 63] . The mechanism by which these hemangiomata occur and the patient characteristics that may promote their development have yet to be delineated. Although these may be mechanistically related to specific inhibition of VEGFR-2, their development is likely to be multifactorial, including the possibility of an intrinsic defect in local endothelial cells and/or aberrant activity in circulating hemangioblasts and endothelial cells when exposed to agents blocking VEGFR-2 [64] .

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in these patients. To date, because of the multifactorial issues, including primary cancer and metastatic sites, use of antiplatelet therapies, and the background incidence of bleeding and clotting in cancer patients and the paucity of data from controlled trials, it is not possible to definitively attribute these events to ramucirumab therapy. For frequency and severity of these mechanism-based toxicities see Table 4 [48] . Other reported toxicities of interest from the published Phase I study (CP12-0401) included embolism and dermal hemangiomata (both at the 4 mg/kg dose level). A patient with melanoma developed grade 2 emboli to the fingers and toes during the eighth cycle of ramucirumab treatment. Doppler ultrasound at the time demonstrated an absence of clotting in the arterial systems. The patient was treated with full-dose aspirin, and hypercoaguable work-up was negative. The patient was re-challenged with ramucirumab but emboli persisted, precluding further dosing despite a confirmed partial response. The patient was treated with low-molecular-weight heparin, and no further recurrences were noted. A second patient in the same cohort with colorectal cancer experienced grade 1 hemangiomata to the scalp, fingers and torso, with the first of these lesions documented in the 2-week observation period of cycle 1. Pathology showed a vascular lesion. Similar lesions appeared between cycle 4 week 3 and cycle 7 week 4, at which point the patient was discontinued from study for progressive disease. A further biopsy of a finger lesion showed lobular capillary hemangioma. Multiple benign hemangiomata is an unusual toxicity that may be unique to VEGFR-2 inhibition with an antibody. Hemangiomata were

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Comparison with other antiangiogenic agents

Ramucirumab has not been compared head-tohead with other antiangiogenic agents. However, when the data of other anti-VEGF therapies evaluated in Phase I clinical trials are compared with the available data for ramucirumab, the efficacy and toxicity profile of ramucirumab appears similar if not superior to that of other agents (Table 2) . Bevacizumab, a recombinant human monoclonal antibody to VEGF and perhaps the most familiar drug in this class, did not have any partial responses when evaluated in its initial singleagent Phase I clinical trial [55] . In this trial, one RCC patient had a minor response not reaching PR criteria with 12 out of 25 patients achieving stability of disease. Two patients on this study had serious grade 3–4 bleeding events, one with intracranial hemorrhage and the other with tumor hemorrhage; two other patients reported minor hemoptysis. Only two episodes of grade 1–2 HTN were documented, and proteinuria was not observed. future science group


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antiangiogenic treatments, and expected based on the drugs mechanism of action, although fewer DLTs were recorded with ramucirumab administration compared with other agents (Table 2) [55,57–63,65–67] . Ramucirumab did not cause any toxicities of grade 4 or higher in this patient population. Notably, asthenia/fatigue was not a major occurrence in patients who were exposed to ramucirumab, which was also the case with CPD791 and IMC-1C11, the other clinically tested VEGFR-2-directed therapies, whereas this was a major concern for antiangiogenic TKIs, contributing not only to DLTs in the studies evaluating these compounds but also to a significant number of adverse events. Similar findings were noted with the frequency of hand–foot syndrome, only observed in 5% of courses with ramucirumab, not encountered with CDP791 or IMC-1C11, and commonly documented with TKIs, most notably sorafenib, where hand–foot syndrome occurred in more than 50% of patients at higher dose levels (Table 2) [57] . Regulatory affairs

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Sunitinib, a small molecule inhibiting VEGFR-2 among other receptor tyrosine kinases, with similar VEGFR-2 IC50 inhibitory concentrations to IMC-1121B (4 and 1 nM, respectively, for sunitinib and IMC-1121B), was studied in two Phase I trials as a single agent using either a 2-week on, 1-week off or 4-week on, 2-week off regimen [59,60] . A total of 40 patients were evaluated across these trials, with DLTs including grade 4 elevation of lipase and amylase, grade 3 fatigue and HTN, and grade 2 bullous skin changes and decrease in left ventricular ejection fraction. In addition, asthenia was prominent with cumulative administration of sunitinib. Objective responses included those involving three RCC patients, one gastrointestinal stromal tumor, one neuroendocrine tumor, one primary unknown adenocarcinoma and one papillary thyroid cancer. Sorafenib, another oral multitargeted kinase inhibitor with activity against VEGFR-2 activity, albeit slightly less potent than ramucirumab (IC50 vs VEGFR-2 30 nM) [65] , has been examined in four single-agent Phase I clinical trials [56–58,66] . Sorafenib was generally well tolerated with commonly experienced toxicities of fatigue, anorexia, diarrhea, rash, desquamation and hand–foot reactions. A total of 17 out of 173 patients across these trials met the criteria for DLT and included skin toxicities, fatigue, diarrhea and HTN. Only two of 137 patients reached PR, although 28% had disease stability while on treatment. The other clinically advanced drugs in this class are ZD6474 and AZD2171. Again, the most prominent DLT seen with ZD6474, a dual anti-VEGF and anti-EGF receptor targeted small molecule, was HTN; efficacy was limited to achievement of disease stability [61–63,67] . AZD2171, an oral selective inhibitor of VEGFR-1, VEGFR-2 and VEGFR-3 tyrosine kinase activity, reported a modest disease control rate of 29% in its single‑agent Phase I trial [62] . Toxicities associated with ramucirumab were tolerable across the entire dosing range. The DLTs encountered, with the exception of DVT, were similar to those observed with other

Drug Evaluation

Ramucirumab is currently not approved for any indication. Ongoing Phase II and III studies will direct licensing applications.

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Conclusion

Ramucirumab is a fully human IgG1 monoclonal antibody that selectively binds to the extrac ellular VEGF-binding domain of VEGFR-2. The maximum tolerated dose of ramucirumab was 13 mg/kg intravenously weekly. Importantly, the predefined C min (20 µg/ml), selected a priori based on preclinical xenograft efficacy and PD data, was met in all but the lowest of dose levels in Phase I studies. As such, and since ramucirumab clearance appears saturated at 8 mg/ kg, further studies will focus on the evaluation of ramucirumab using 8 mg/kg. Ramucirumab shows efficacy and tolerability that appears more favorable than the Phase I results from several commercially available antiangiogenic drugs, although no head-to-head trials have been undertaken yet.

Table 4. Significant ramucirumab-related toxicities by grade and frequency. Toxicity/grade

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Total

Denominator

Percentage

Hypertension Proteinuria Thrombotic events Bleeding

8 7 1 0

16 10 3 3

19 3 3 4

1 1 0 1

0 0 0 1

44 21 7 9

227 217 104 213

19.4 9.7 6.7 4.2



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Drug Evaluation


Future perspective

Update of ongoing Phase III clinical trial of Ramucirumab in breast cancer: Mackey J, Gelmon K, Martin M et al.: TRIO-012: a multicenter, multinational, randomized, double-blind Phase III study of IMC-1121B plus docetaxel versus placebo plus docetaxel in previously untreated patients with HER2-negative, unresectable, locally recurrent or metastatic breast cancer. Clin. Breast Cancer 9(4), 258–261 (2009).

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Financial & competing interests disclosure

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Ramucirumab is in evaluation in Phase II and III trial settings, both alone and in combination with traditional chemotherapeutic agents in a variety of tumor types. Early trial success with this novel and specific antiangiogenic drug show encouraging tolerability across a range of doses without reported long-lasting toxicities, and has signs of considerable anticancer activity. Although clinical development is still ongoing, and the oncology community must wait for the results of Phase II and III studies to determine the absolute and relative clinical value of this drug, early indications suggest a highly favorable risk–benefit ratio. Further studies will focus on identification and validation of a predictive biomarker for benefit from ramucirumab, although such a marker has not yet been demonstrated for the licensed antiangiogenic drugs. Ultimately, ramucirumab will require formal Phase III comparison studies to definitively demonstrate its place relative to other anti-VEGF strategies.

antibodies targeting vascular endothelial growth factor. BioDrugs 23(5), 289–304 (2009).

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Information resources

Hsu JY, Wakelee HA: Review of monoclonal

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Executive summary

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Ramucirumab is a novel, fully human IgG1 monoclonal antibody directed at the extracellular domain of VEGFR-2 ultimately blocking the VEGF–VEGFR-2 interaction at nanomolar concentrations. n Ramucirumab has shown promise in terms of tolerable toxicity and early efficacy in Phase I clinical trials; further Phase II and III clinical trials are underway.

Overview of the market

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Ramucirumab is an antiangiogenic agent unlike any other licensed antiangiogenic as it directly attacks VEGFR-2; the other commonly used angiogenesis agents that attack the VEGF ligand are small molecules directed at multiple intracellular tyrosine kinases. n Bevacizumab, sunitinib and sorafenib are among the approved antiangiogenic agents for various tumor types, including colon, lung, breast and glioblastoma, for either a progression-free survival or overall survival benefit, although there is controversy among physicians as to their clinical utility relative to the high drug-acquisition costs. n None of the approved antiangiogenic agents had as high efficacy signals or better tolerability in Phase I clinical trials.

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Pharmacodynamics & pharmacokinetics

Ramucirumab potently inhibits VEGF binding to VEGFR-2. VEGF-A concentrations increase 1.5- to 3.5-fold post-ramucirumab infusion presumably owing to drug binding to the receptor; soluble VEGFR-1 and soluble VEGFR-2 decrease post-ramucirumab exposure then return to baseline. n There is good correlation between ramucirumab dose level and the number of patients demonstrating response via dynamic contrast‑enhanced MRI. n Ramucirumab has a half-life of 200–300 h. n The C value of what was predetermined from in vitro studies to be the efficacious biologic dose was achieved at all but the lowest min doses in Phase I clinical trials. n Saturation of clearance mechanisms was demonstrated by ramucirumab clearance decreasing disproportionately with increasing dose. n n

Clinical efficacy There are only early efficacy results available for ramucirumab; nonetheless, these results are very promising, with a disease control rate of 73 and 72% in the published Phase I and Phase II renal cell carcinoma study, respectively. n Ramucirumab continues to be investigated in Phase II and Phase III clinical trials as a single agent and in combination with some traditional chemotherapies. n

Regulatory affairs Ramucirumab is not approved for use, although ongoing registration trials are currently accruing patients.

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