1 Introduction

Angiogenesis, the formation of new blood vessels, is critical for the growth, invasion and metastasis of solid tumours [1–5]. Vascular endothelial growth factor (VEGF) ligands and receptors play a key role in angiogenesis and have emerged as targets for the development of novel anticancer agents. Binding of the ligands VEGF-A, VEGF-C and VEGF-D to vascular endothelial growth factor receptor-2 (VEGFR-2 or kinase insert domain receptor [KDR]) on the endothelial cells of tumours initiates signalling cascades that lead to angiogenesis, endothelial cell proliferation and migration, and increased vascular permeability [6, 7]. Inhibition of VEGFR-2 activation by blocking the binding of these ligands is therefore expected to prevent the formation of new blood vessels and thereby limit the supply of nutrients to the tumour, thus causing the death of the tumour cells.

Expression of VEGF has been found to correlate with increased vascular involvement and lymph node and hepatic metastases, and hence poor prognosis, in gastric cancer [8]. VEGF is therefore an attractive target for the treatment of advanced or metastatic gastric cancer, for which treatment options are limited and overall survival durations short, particularly for patients who have disease progression on combination chemotherapy [6]. Bevacizumab, a monoclonal antibody targeting VEGF-A, was found to improve progression-free survival and response rate in patients with advanced gastric cancer in the first-line setting when added to chemotherapy in the phase III AVAGAST study; however, it did not significantly improve overall survival, the study’s primary endpoint [9]. It has been suggested that targeting VEGFR-2 may be a more effective strategy, as this would also block the binding and pro-angiogenic activity of VEGF-C and VEGF-D [10].

Features and properties of ramucirumab

Alternative names

Anti-flk-1 monoclonal antibody – ImClone; Anti-KDR monoclonal antibody – ImClone; Anti-CEGFR 2 monoclonal antibody – ImClone; Cyramza™; IMC 1121; IMC 1121B; IMC 1C11 – ImClone; IMC-1121; IMC-1121 B: IMC-1121B; IMC-1C11 0 ImClone; IMC1121 B; IMC1121-B; IMC1121B; LY 3009806; LY-3009806; LY3009806

Class

Monoclonal antibodies

Mechanism of action

Vascular endothelial growth factor receptor-2 antagonist

Route of administration

IV infusion

Pharmacodynamics

Elevates serum VEGF concentrations following infusion; decreases tumour perfusion and vascularity

Immunogenicity

Anti-ramucirumab antibodies detected by ELISA in 7.4 % of patients in clinical trials, including neutralizing antibodies in 1 patient

Pharmacokinetics

Cmin of 50 and 74 μg/mL, respectively, after 3 and 6 biweekly doses of 8 mg/kg; dose-dependent elimination and non-linear exposure; steady state t1/2 of 200–300 h for doses of 8–16 mg/kg

Adverse events

 

 Most frequenta

Hypertension, diarrhoea, headache, hyponatremia, proteinuria

 Occasionalb

Neutropenia, epistaxis, rash, anaemia, severe haemorrhage, intestinal obstruction, arterial thromboembolic events

 Rare

Gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome

ATC codes

 

 WHO ATC code

L01X-C (monoclonal antibodies)

 EphMRA ATC code

L1X3 (Antineoplastic monoclonal antibodies)

Chemical name

Immunoglobulin G1, anti-(human vascular endothelial growth factor receptor type VEGFR-2 extracellular domain) (human monoclonal IMC-1121B γ-chain), disulfide with human monoclonal IMC-1121B κ-chain, dimer

  1. a5 % or more patients in REGARD and at least 2 % higher than placebo
  2. b1–5 % of patients in REGARD

Ramucirumab (Cyramza™ [US]), a fully human immunoglobulin G1 (IgG1) monoclonal antibody that inhibits the function of VEGFR-2, received its first global approval in the US on April 21 2014 for use as monotherapy in the treatment of advanced or metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma in patients who have experienced disease progression on or after fluoropyrimidine- or platinum-containing chemotherapy [11]. The approved labelling carries a black box warning regarding the increased risk of haemorrhage in patients taking ramucirumab, including severe and sometimes fatal events [12].

Ramucirumab is approved for use as an 8 mg/kg intravenous (IV) infusion to be administered over 60 minutes every 2 weeks, and is available in single-dose vials containing either 100 mg/10 mL or 500 mg/50 mL (both 10 mg/mL) [12]. Treatment with ramucirumab should be continued until disease progression or unacceptable toxicity occurs. To prevent infusion-related reactions, all patients should receive an IV histamine H1 antagonist such as diphenhydramine hydrochloride prior to each ramucirumab infusion. Patients who have experienced a grade 1 or 2 infusion reaction should also receive dexamethasone (or equivalent) and acetaminophen prior to each infusion and the infusion rate should be reduced by 50 % in these patients. Treatment interruption is required for patients who develop severe hypertension (until controlled with medical management) or proteinuria (urine protein levels of ≥2 g/24 h); for patients with proteinuria, ramucirumab can be restarted at a reduced dose of 6 mg/kg every 2 weeks after urine protein levels return to <2 g/24 h, with further reduction to 5 mg/kg every 2 weeks if proteinuria recurs. Treatment should also be interrupted prior to surgery due to the potential for wound healing complications, and should not be restarted until the wound is fully healed. Treatment with ramucirumab should be discontinued in patients who develop grade 3 or 4 infusion-related reactions, severe hypertension that cannot be controlled with antihypertensive agents, urine protein levels of >3 g/24 h or nephrotic syndrome, or arterial thromboembolism, gastrointestinal perforation or grade 3 or 4 haemorrhage.

The approval of ramucirumab in the US was based on results from the REGARD trial (NCT00917384; EudraCT2008-005964-15). This randomized, double-blind, phase III trial compared ramucirumab plus best supportive care (BSC) with placebo plus BSC in 355 patients with advanced gastric or gastro-oesophageal junction cancer with disease progression on or after platinum- or fluoropyrimidine-based chemotherapy in the US, Australia, Canada, Egypt, Europe, Latin America, New Zealand, South Africa, South-East Asia and India.

A regulatory application seeking approval for ramucirumab monotherapy in the treatment of advanced gastric cancer in patients with disease progression after initial chemotherapy has also been submitted in the EU [13]. Ramucirumab has been granted orphan drug status for the treatment of gastric cancer and hepatocellular carcinoma in the US and the EU [14–17].

Ramucirumab is also in development for a number of other solid tumour indications. It was in phase III development worldwide for metastatic breast cancer, but Eli Lilly decided not to submit regulatory applications for this indication after the phase III ROSE trial (NCT00703326, TRIO-012) failed to meet its primary endpoint [18].

1.1 Company Agreements

Ramucirumab is being developed by Eli Lilly (formerly ImClone Systems). ImClone Systems became a wholly-owned subsidiary of Eli Lilly in November 2008 [19], and has since merged and integrated into Eli Lilly.

In May 2014, Eli Lilly selected Biologics Inc’s Oncology Pharmacy Services to be the exclusive specialty pharmacy provider of ramucirumab in the US [20].

In April 2003, ImClone and Dyax Corporation entered into an antibody library license agreement. Under the terms of the agreement, ImClone had a non-exclusive licence to Dyax’s antibody phage display library and patent rights. In return, Dyax received an upfront licence fee and annual technology licence fee payments for up to 4 years. ImClone was to also pay Dyax clinical milestone payments and royalties on sales of any products arising from use of the library. Financial terms of the agreement were not disclosed [21, 22]. Cambridge Antibody Technology and Dyax have cross-patent licensing agreements in place.

2 Scientific Summary

2.1 Pharmacodynamics

Ramucirumab specifically binds VEGFR-2 and blocks the binding of VEGFR-A, VEGF-C and VEGF-D, thus inhibiting the VEGFR ligand-induced proliferation and migration of endothelial cells [12]. Analysis of the structure of ramucirumab showed that it directly blocks VEGF ligand binding at VEGFR-2 via binding at opposite ends of VEGFR-2 by two Fab fragments [23].

Ramucirumab doses of 2–16 mg/kg produced non-dose-dependent increases in VEGF-A and decreases in sVEGFR-1 and sVEGFR-2 in a study in 37 patients with advanced solid tumours [24]. Tumour perfusion and vascularity were decreased in 69 % of 13 evaluable patients, and was consistent across all target lesions in patients with multiple tumours assessed.

Treatment with ramucirumab 8 mg/kg every 2 weeks increased serum VEGF and placental growth factor levels and produced a rapid and transient decrease in soluble VEGFR-2 levels in patients with advanced hepatocellular carcinoma (HCC) in a phase II study [25]. A relationship between the change in sVEGFR-1 from baseline to day 8 and progression-free and overall survival was observed, with patients who had decreases in sVEGFR-1 appearing to have better outcomes.

2.2 Immunogenicity

Anti-ramucirumab antibodies were detected by enzyme-linked immunosorbent assay (ELISA) in 33 of 443 (7.4 %) of patients treatment with ramucirumab in clinical trials for whom post-baseline serum samples were available, with neutralizing antibodies in one patient [12]. It should be noted that this assay has limitations regarding the detection of anti-ramucirumab antibodies in the presence of ramucirumab.

2.3 Pharmacokinetics

In patients with advanced gastric or gastro-oesophageal cancer receiving ramucirumab 8 mg/kg every 2 weeks, geometric means of the minimum ramucirumab concentrations (Cmin) after the third and sixth doses were 50 μg/mL and 74 μg/mL, respectively [12].

Non-compartmental pharmacokinetic analysis from a phase I trial of ramucirumab in 37 patients with advanced solid tumours showed dose-dependent elimination and non-linear exposure, consistent with saturable clearance, at doses of 2–16 mg/kg [24]. Target trough levels required for anti-tumour activity (≥20 μg/mL, determined from preclinical xenograft studies) were exceeded at all dose levels. After the first infusion in cycle 1, the mean half-life (t1/2) ranged from 68.4–123 hours, mean Cmin was 6.83–177 μg/mL, mean maximum plasma concentration (Cmax) was 43.7–558 μg/mL and mean area under the plasma concentration-time curve (AUC0-∞) was 3,914–67,871 h · μg/mL. At steady state, the t1/2 for doses of 8–16 mg/kg was approximately 200–300 hours. Minimal accumulation was observed over ≥32 cycles of treatment.

There have been no dedicated studies of the effects of renal or hepatic impairment on the pharmacokinetics of ramucirumab, nor have formal drug interaction studies been conducted [12].

Clinical trials of ramucirumab conducted by Eli Lilly

Drugs

Indication

Patient subgroup

Study phase

Status

Study location

Trial identifiers

Ramucirumab ± best supportive care (BSC)

Gastric cancer

Metastatic disease; monotherapy; second-line therapy or greater

III

Completed

US, Argentina, Australia, Bosnia & Herzegovina, Brazil, Canada, Chile, Colombia, Croatia, Czech Republic, Egypt, Guatemala, India, Indonesia, Italy, South Korea, Lebanon, Malta, Mexico, New Zealand, Philippines, Poland, Romania, Russia, South Africa, Spain, Taiwan, Thailand, Turkey, UK

NCT00917384 (REGARD)

Paclitaxel ± ramucirumab

Gastric cancer

Metastatic disease; combination therapy; second-line therapy or greater

III

Enrolment completed

US, Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Chile, Estonia, France, Germany, Hungary, Israel, Italy, Japan, South Korea, Lithuania, Mexico, Poland, Portugal, Romania, Russia, Singapore, Spain, Taiwan, UK

NCT01170663 (RAINBOW)

Ramucirumab + docetaxel

Breast cancer

First-line therapy; combination therapy; metastatic disease

III

Enrolment completed

US, Australia, Belgium, Brazil, Canada, Croatia, Czech Republic, Egypt, Germany, Ireland, Israel, South Korea, Lebanon, New Zealand, Peru, Poland, Russia, Serbia, Slovakia, South Africa, Spain, Taiwan, UK

NCT00703326 (ROSE)

Ramucirumab ± FOLFIRI (fluorouracil + folinic acid + irinotecan)

Colorectal cancer

Metastatic disease; combination therapy; second-line therapy or greater

III

Enrolment completed

US, Argentina, Australia, Austria, Belgium, Czech Republic, Denmark, Finland, France, Greece, India, Italy, Japan, Puerto Rico, Romania, South Korea, Spain, Sweden, Taiwan

NCT01183780 (RAISE)

Ramucirumab ± best supportive care (BSC)

Hepatocellular carcinoma

Second-line therapy or greater

III

Enrolment completed

US, Austria, Australia, Belgium, Brazil, Bulgaria, Canada, Czech Republic, Finland, France, Germany, Hong Kong, Hungary, Israel, Italy, Japan, Netherlands, Norway, Philippines, Portugal, Romania, Spain, Sweden, Switzerland, Taiwan, Thailand

NCT01140347 (REACH)

Ramucirumab + docetaxel

Non-small cell lung cancer

Second-line therapy or greater; combination therapy; late-stage disease

III

Enrolment completed

US, Argentina, Austria, Brazil, Canada, France, Germany, Greece, Hungary, India, Israel, Italy, Mexico, Netherlands, New Zealand, Norway, Poland, Puerto Rico, Romania, Russia, Spain, South Korea, Sweden, Switzerland, Taiwan, Turkey, UK

NCT01168973 (REVEL)

Ramucirumab + docetaxel or docetaxel ± icrucumab

Bladder cancer, (+pelvic cancer, renal cancer, urethral cancer)

Second-line therapy or greater

II

Enrolment completed

US, Canada

NCT01282463

Ramucirumab

Renal Cancer

Metastatic disease; monotherapy

II

Completed

US

NCT00515697

Ramucirumab

Gastric cancer (including gastro-oesophageal junction adenocarcinoma)

Metastatic disease; monotherapy; second-line therapy or greater

II

Recruiting

Japan

NCT01983878

Ramucirumab + mFOLFOX6 (oxaliplatin + folinic acid + fluorouracil)

Gastric cancer, Oesophageal cancer

Combination therapy

II

Enrolment completed

US

NCT01246960

Ramucirumab ± eribulin

Breast cancer

Combination therapy; second-line therapy or greater; late-stage disease

II

Enrolment completed

US

NCT01427933

Ramucirumab + capecitabine

Breast cancer

Combination therapy; second-line therapy or greater; late-stage disease

II

Enrolment completed

US

NCT1234402

Ramucirumab + mFOLFOX6

Colorectal cancer

First-line therapy; metastatic disease; combination therapy

II

Completed

Canada, Spain

NCT00862784

Ramucirumab + mFOLFOX6

Colorectal cancer

Second-line therapy; metastatic disease; combination therapy

II

Completed

US, Canada

NCT01111604

Icrucumab + mFOLFOX6

Ramucirumab ± dacarbazine

Malignant melanoma

First-line therapy; metastatic disease

II

Completed

US

NCT00533702

Ramucirumab + docetaxel

NSCLC

Second-line therapy or greater; combination therapy; late-stage disease

II

Recruiting

Japan

NCT01703091

Ramucirumab + pemetrexed + carboplatin + cisplatin OR Ramucirumab + gemcitabine + carboplatin + cisplatin

NSCLC

First-line therapy; combination therapy; late-stage disease

II

Enrolment completed

US, Belgium, Canada, Germany, Poland, UK

NCT01160744

Ramucirumab + paclitaxel + carboplatin

NSCLC

First-line therapy; combination therapy; late-stage disease

II

Completed

US, UK

NCT00735696

Ramucirumab

Ovarian cancer (+fallopian tube cancer, primary peritoneal carcinoma)

Second-line therapy or greater; monotherapy)

II

Enrolment completed

US, UK

NCT00721162

Ramucirumab + mitoxantrone + prednisone

Prostate cancer

Second-line therapy or greater; hormone refractory; metastatic disease

II

Completed

US

NCT00683475

Ramucirumab

Renal cancer

Monotherapy; metastatic disease; second-line therapy or greater

II

Completed

US

NCT00515697

Ramucirumab + FOLFIRI (irinotecan + folinic acid + fluorouracil)

Solid tumours

Combination therapy

II

Enrolment completed

US

NCT01634555

Ramucirumab + paclitaxel

Solid tumours

First-line therapy

II

Enrolment completed

US

NCT01515306

Ramucirumab

Solid tumours

Combination therapy

II

Enrolment completed

US

NCT01017731

Ramucirumab + docetaxel

Solid tumours

Combination therapy

II

Completed

US

NCT01567163

2.4 Therapeutic Trials

2.4.1 Gastric Cancer and Gastro-Oesophageal Junction Adenocarcinoma

Ramucirumab significantly prolonged overall survival in patients with advanced gastric or gastro-oesophageal junction cancer in the REGARD trial (NCT00917384) [26]. Patients in this study, all of whom had experienced disease progression after first-line platinum- or fluoropyrimidine-containing chemotherapy, were randomized to treatment with ramucirumab 8 mg/kg (n = 238) or placebo (n = 117) by IV infusion every 2 weeks, in addition to BSC. Median overall survival durations for the ramucirumab and placebo groups were 5.2 months and 3.8 months, respectively (hazard ratio [HR] 0.776, 95 % confidence interval [CI] 0.603–0.998; P = 0.047). The difference in overall survival remained significant after adjustment for other prognostic factors (HR 0.774, 95 %CI 0.605–0.991; P = 0.042). Estimated overall survival rates for ramucirumab versus placebo at 6 and 12 months were 41.8 % vs 31.6 % and 17.6 % vs 11.8 %, respectively. The median progression-free survival duration was also significantly increased with ramucirumab (2.1 vs 1.3 months; HR 0.483, 95 %CI 0.376–0.620; P < 0.0001). Disease control rates for ramucirumab and placebo were 49 % and 23 %, respectively (P < 0.0001). One patient (<1%) in the ramucirumab group had a complete response and seven (3 %) had partial responses, compared with three partial responses (3 %) in the placebo group; in addition, stable disease was achieved in 45 % and 21 % of patients in the ramucirumab and placebo groups, respectively. Quality of life (QOL) data were available at 6 weeks for 114 (48 %) patients in the ramucirumab group and 29 (25 %) placebo-treated patients; data were unavailable for the majority of patients due to treatment discontinuation. Stable or improved QOL was reported by 34 % of ramucirumab recipients, compared with 13 % of the placebo group (P = 0.23).

Combination therapy with ramucirumab plus paclitaxel significantly improved overall and progression-free survival in patients with gastric or gastro-oesophageal junction cancer who had disease progression on or within 4 months after platinum- or fluoropyrimidine-containing chemotherapy in the RAINBOW trial (NCT01170663) [27]. This phase III trial enrolled a total of 665 patients who were randomized to receive ramucirumab 8 mg/kg (n = 330) or placebo (n = 335) by IV infusion, every 2 weeks in addition to paclitaxel 80 mg/m2 on days 1, 8 and 15 of a 4-week cycle. The median overall survival duration (primary endpoint) in the ramucirumab plus paclitaxel and placebo plus paclitaxel groups were 9.63 and 7.36 months, respectively (HR 0.807, 95 %CI 0.678–0.962; P = 0.0169). Median progression-free survival durations for the ramucirumab plus paclitaxel and placebo plus paclitaxel groups were 4.40 and 2.86 months, respectively (HR 0.635, 95 %CI 0.536–0.752; P < 0.0001), with median times to progression of 5.5 and 3.0 months, respectively (P < 0.0001). The objective response rate in the ramucirumab plus paclitaxel group was 28 %, compared with 16 % for placebo plus paclitaxel (P = 0.0001).

2.4.2 Breast Cancer

The addition of ramucirumab to first-line therapy with docetaxel did not achieve the primary endpoint of prolonging progression-free survival in patients with HER2-negative unresectable, locally recurrent or metastatic breast cancer in the phase III ROSE trial (NCT00703326) [28]. A total of 1,144 patients were randomized 2:1 to receive ramucirumab 10 mg/kg plus docetaxel 75 mg/m2 (n = 759) or placebo plus docetaxel 75 mg/m2 (n = 385), every 3 weeks until disease progression or unacceptable toxicity occurred. After a median follow-up duration of 16.2 months, progression-free survival durations in the ramucirumab and placebo arms were 9.5 months and 8.2 months, respectively (HR 0.88, 95 %CI 0.75–1.01; P = 0.077). There was also no significant difference in median overall survival between the ramucirumab and placebo groups (27.3 vs 27.2 months; HR 1.01, 95 %CI 0.83–1.23; P = 0.915). However, the median time to progression was significantly longer for ramucirumab versus placebo (9.7 vs 8.2 months; HR 0.78, 95 %CI 0.65–0.93; P = 0.034 and the objective response and disease control rates were higher for ramucirumab (44.7 % vs 37.9 %; P = 0.027 and 86.4 % vs 81.3 %; P = 0.022, respectively).

2.4.3 Colorectal Cancer

The combination of ramucirumab 8 mg/kg plus the modified FOLFOX-6 (folinic acid, fluorouracil, oxaliplatin) regimen, given every 2 weeks, was evaluated in an open-label phase II study in 48 patients with metastatic colorectal cancer (NCT00862784) [29, 30]. The median progression-free survival was 11.5 months (95 %CI 8.6–13.1 months), compared with an expected progression-free survival duration of 8 months. The median overall survival duration was 20.4 months (95 %CI 18.5–25.1 months). Objective response and disease control rates were 58.3 % and 93.8 %, respectively.

A phase Ib study (NCT01286818) evaluated the effects of ramucirumab 8 mg/kg every 2 weeks in combination with the FOLFIRI (fluorouracil, folinic acid, irinotecan) regimen in six Japanese patients with metastatic colorectal cancer who had disease progression on or after first-line treatment with bevacizumab, oxaliplatin and a fluoropyrimidine [31]. The median progression-free survival duration was 7.3 months (95 %CI 1.2–10.9 months). One patient had a partial response and four had stable disease.

2.4.4 Hepatocellular Carcinoma

First-line treatment with ramucirumab (8 mg/kg every 2 weeks) as monotherapy produced a median progression-free survival duration of 4.0 months (95 %CI 2.6–5.7 months) in a phase II study in 42 patients with advanced HCC [25]. Partial responses were observed in four patients (9.5 %), with a median response duration of 14.1 months. Another 25 patients (59.5 %) had stable disease, giving a disease control rate of 69.0 %. The median overall survival duration was 12.0 months (95 %CI 6.1–19.7 months). Overall survival rates at 1 year and 2 years were 49.4 % and 23.4 %, respectively. Among patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median overall survival durations for those with Child-Pugh A and B cirrhosis were 18.0 months (95 %CI 6.1–23.5 months) and 4.4 months (95 %CI 0.5–9.0 months), respectively; corresponding values for median progression-free survival were 4.2 months (95 %CI 2.6–6.7 months) and 2.6 months (95 %CI 0.5–6.2 months).

2.4.5 Lung Cancer

Combination therapy with ramucirumab plus first-line pemetrexed- and platinum-based chemotherapy demonstrated clinical activity in patients with non-small cell lung cancer (NSCLC) but did not achieve the primary endpoint of prolonging progression-free survival in a phase II study (NCT01160744) [32]. A total of 140 patients with non-squamous stage IIIb/IV NSCLC and no prior chemotherapy or anti-VEGF therapy were randomized to receive pemetrexed plus carboplatin or cisplatin either alone (arm A, n = 71) or in combination with ramucirumab 10 mg/kg (arm B, n = 69), every 3 weeks for 4–6 cycles; those without disease progression then received maintenance therapy with pemetrexed (arm A) or pemetrexed plus ramucirumab (arm B). Median progression-free survival durations for arms A and B were 5.6 months and 7.2 months, respectively (HR 0.75, 90 %CI 0.55–1.03; P = 0.132). Objective response rates in arms A and B were 38 % and 49.3 %, respectively (P = 0.18); this included one complete response in arm B. The disease control rate was significantly higher for patients treated with ramucirumab (86 % vs 70 % for arm A; P = 0.031). At the time of the final analysis for progression-free survival, the median overall survival duration was 10.4 months for arm A, compared with 13.9 months for arm B (HR 0.83, 90 %CI 0.56–1.22; P = 0.43).

The combination of ramucirumab plus paclitaxel and carboplatin was evaluated in another open-label phase II study in patients with advanced lung cancer [33]. Patients in this study received ramucirumab 10 mg/kg, paclitaxel 200 mg/m2 and carboplatin AUC = 6 every 3 weeks for up to 6 cycles, followed by ramucirumab maintenance. An interim analysis of 15 patients showed an objective response rate of 67 % (one complete response and nine partial responses) and median progression-free survival of 5.7 months.

2.4.6 Melanoma

Ramucirumab, alone or in combination with dacarbazine, demonstrated modest activity in a randomized, open-label phase II study in chemotherapy-naïve patients with metastatic malignant melanoma (NCT00533702) [34]. A total of 102 patients were treated with ramucirumab 10 mg/kg every 3 weeks as monotherapy or in combination with dacarbazine 1000 mg/m2 every 3 weeks. Median progression-free survival durations for the monotherapy and combination therapy arms were 1.7 and 2.6 months, respectively; however, the study was not powered to compare treatments. Partial response and stable disease rates for the monotherapy group were 4 % and 42 %, respectively; corresponding values for the combination therapy group were 17 % and 37 %.

2.4.7 Ovarian Cancer

Ramucirumab monotherapy was evaluated in an open-label phase II study in 60 patients with persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer [35]. Patients in this study, who had previously received platinum-based chemotherapy, received ramucirumab 8 mg/kg every 2 weeks. The 6-month progression-free survival rate was 34.2 % (95 %CI 21.7–47.0 %). Three patients (5 %) had a partial response (median duration 5.6 months) and 34 (57 %) had stable disease. Three patients (5 %) were not evaluable for response and 20 (33 %) had progressive disease. The median progression-free and overall survival durations were 3.5 months (95 %CI 2.3–5.3 months) and 11.1 months (95 %CI 8.3–17.0 months), respectively.

2.4.8 Prostate Cancer

Ramucirumab and cixutumumab, a fully human IgG1 monoclonal antibody targeting insulin-like growth factor, were evaluated in a phase II trial in patients with metastatic castration-resistant prostate cancer who had disease progression on docetaxel-based therapy [36]. A total of 132 patients were randomized to receive IV ramucirumab 6 mg/kg (n = 66) or cixutumumab 6 mg/kg (n = 66), once weekly in addition to IV mitoxantrone 12 mg/m2 every 3 weeks and oral prednisone 5 mg twice daily, for up to 12 cycles. Median follow-up durations for the ramucirumab and cixutumumab groups were 21.8 and 22.7 months, respectively. Median confirmed progression-free survival and overall survival durations were 6.7 months (95 %CI 4.5–8.3 months) and 13.0 months (95 %CI 9.5–16.0 months), respectively, for the ramucirumab group and 4.1 months (95 %CI 3.0–5.6 months) and 10.8 months (95 %CI 6.5–13.0 months), respectively, for the cixutumumab group. Prostate-specific antigen response rates in the ramucirumab and cixutumumab groups were 22.0 % and 18.4 %, respectively.

2.4.9 Renal Cancer

Ramucirumab demonstrated activity in tyrosine kinase inhibitor-refractory metastatic clear cell renal cell carcinoma in a multicentre phase II study [37]. Patients who had progressive disease or intolerance to prior sorafenib and/or sunitinib therapy (n = 40) received ramucirumab 8 mg/kg every 2 weeks. At an interim analysis there were two confirmed partial responses and 19 (49 %) patients had stable disease lasting >5 months; the median progression-free survival at the time of analysis was 6 months.

2.5 Adverse Events

Prescribing information for ramucirumab carries a black box warning regarding the risk of haemorrhagic events, including serious and sometimes fatal events [12]. It also contains warnings and precautions regarding the risks of arterial thromboembolic events, hypertension, infusion-related reactions, gastrointestinal perforations, impaired wound healing, reversible posterior leukoencephalopathy syndrome (RPLS) and clinical deterioration in patients with Child-Pugh B or C cirrhosis.

In the REGARD study, the most common adverse events of any grade occurring in >5 % of ramucirumab recipients with a difference of ≥2 % from the placebo group were hypertension (16 % vs 8 % for placebo; grade 3–4, 8 % vs 3 %), diarrhoea (14 % vs 9 %; grade 3–4, 1 % vs 2 %), headache (9 % vs 3 %; no grade 3–4 events) and hyponatremia (6 % vs 2 %; grade 3–4, 3 % vs 1 %) [12]. Clinically relevant adverse events occurring in 1–5 % of ramucirumab recipients were neutropenia (4.7 % vs 0.9 % for placebo), epistaxis (4.7 % vs 0.9 %), rash (4.2 % vs 1.7 %), intestinal obstruction (2.1 % vs 0 %) and arterial thromboembolic events (1.7 % vs 0 %). Proteinuria occurred in 8 % of ramucirumab recipients, compared with 3 % of patients in the placebo group, and two patients discontinued ramucirumab due to this event. Gastrointestinal perforation and infusion-related reactions occurred in 0.8 % and 0.4 % of patients, respectively. The most frequently reported serious adverse events in the ramucirumab group were anaemia (3.8 % and intestinal obstruction (2.1 %).

Overall rates of adverse events in the REGARD study were similar for ramucirumab versus placebo [26]. Grade 3–4 adverse events occurred in 57 % of patients in the ramucirumab group and 58 % in the placebo group. Although grade 3–4 arterial thromboembolic events were more frequent in the ramucirumab group (1 % vs 0 % for placebo), the difference was not statistically significant (P = 0.55). No increases in haemorrhage, venous thrombosis, proteinuria, infusion-related reactions, gastrointestinal perforation or fistula formation were seen with ramucirumab versus placebo. There were five deaths in the ramucirumab group (2 %) and two in the placebo group (2 %) that were considered to be related to study medication.

In the RAINBOW trial, grade 3 or higher adverse events occurring in >5 % of patients receiving ramucirumab in combination with paclitaxel were neutropenia (40.7 % of patients vs 18.8 % for placebo plus paclitaxel), leukopenia (17.4 % vs 6.7 %), hypertension (14.1 % vs 2.4), anaemia (9.2 % vs 10.3 %), fatigue (7.0 % vs 4.0 %), abdominal pain (5.5 % vs 3.3 %) and asthenia (5.5 % vs 3.3 %) [27]. Febrile neutropenia occurred in 3.1 % of patients treated with ramucirumab plus paclitaxel, compared with 2.4 % in the placebo plus paclitaxel group.

2.6 Ongoing Clinical Trials

There are several ongoing phase II and III trials of ramucirumab in different solid tumour indications:

  • Randomized, double-blind, multinational phase III trial of ramucirumab versus placebo, in combination with paclitaxel, in patients with gastric cancer and gastro-oesophageal junction cancer who had disease progression on or within 4 months after platinum- or fluoropyrimidine-containing chemotherapy (RAINBOW; NCT01170663) [38]

  • Randomized, double-blind, multinational phase III trial of ramucirumab plus docetaxel versus placebo plus docetaxel in patients with unresectable locally recurrent or metastatic breast cancer who have not received prior chemotherapy (ROSE; NCT00703326; TRIO-012) [39]

  • Randomized, double-blind, multinational phase III trial of ramucirumab versus placebo, in combination with a FOLFIRI regimen, in patients with metastatic colorectal cancer that has progressed after first-line therapy (RAISE; NCT01183780) [40]

  • Randomized, double-blind, multinational phase III trial of second-line ramucirumab and BSC versus BSC alone in patients with HCC previously treated with sorafenib (REACH; NCT01140347) [41]

  • Randomized, double-blind, multinational phase III trial of ramucirumab versus placebo, in combination with docetaxel, in patients with stage IV NSCLC with disease progression after one prior platinum-based regimen (REVEL; NCT01168973) [42]

  • Randomized, open-label, multicentre phase II study of ramucirumab or icrucumab with docetaxel or docetaxel alone as second-line therapy for bladder, urethra, ureter or renal pelvis carcinoma (NCT01282463) [43]

  • Open-label, single-arm, phase II trial of ramucirumab monotherapy in Japanese patients with metastatic gastric cancer or gastro-oesophageal junction cancer with disease progression after first-line platinum- or fluoropyrimidine-containing chemotherapy (NCT01983878) [44]

  • Randomized, double-blind, phase II study of ramucirumab versus placebo, in combination with mFOLFOX6 regimen in patients with gastric, oesophageal and gastro-oesophageal cancer (NCT01246960) [45]

  • Randomized, open-label, multicentre phase II trial of ramucirumab plus eribulin versus eribulin monotherapy in patients with unresectable, locally-recurrent or metastatic breast cancer who had previously been treated with anthracycline and taxane therapy (NCT01427933) [46]

  • Randomized, open-label, phase II trial of ramucirumab or icrucumab in combination with oral capecitabine in patients with unresectable, locally advanced or metastatic breast cancer who had previously been treated with anthracycline and taxane therapy (NCT01234402) [47]

  • Randomized, double-blind, phase II trial of ramucirumab plus docetaxel versus placebo plus docetaxel in Japanese patients with stage IV NSCLC who had disease progression after one prior platinum-based regimen (NCT01703091) [48]

  • Randomized, multinational, open-label phase II trial of ramucirumab in combination with platinum-based chemotherapy as first-line treatment for recurrent or advanced NSCLC (NCT01160744) [49]

  • Phase II non-randomized, open-label trial of ramucirumab in patients with persistent or recurrent ovarian cancer, fallopian tube cancer, and primary peritoneal carcinoma (NCT00721162) [50]

  • Three phase II trials of ramucirumab in patients with solid tumours are also ongoing (NCT01634555, NCT01515306, NCT01017731) [51–53]

3 Current Status

Ramucirumab received its first global approval on April 21 2014 for use as monotherapy in the treatment of advanced or metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma who have experienced disease progression on or after fluoropyrimidine- or platinum-containing chemotherapy in the US.