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Background
Angiogenesis is a hallmark of malignancy, and attempts to inhibit this process have characterized the age of biologic anti-cancer therapies for solid tumors. Vascular endothelial growth factor receptor-2 (VEGFR-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, specifically inhibits VEGFR-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 (Spratlin et al, 2010).
In an international, randomized, multi-center, placebo-controlled, phase III clinical trial (the REGARD trial), Fuchs et al (2014) examined if ramucirumab prolonged survival in patients with advanced gastric cancer. These researchers carried out this phase III trial between October 6, 2009 and January 26, 2012 at 119 centers in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24 to 87 years with advanced gastric or gastro-esophageal (GE) junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1) to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary end-point was overall survival (OS). Analysis was by intention-to-treat. A total of 355 patients were assigned to receive ramucirumab (n = 238) or placebo (n = 117). Median OS was 5.2 months (IQR 2.3 to 9.9) in patients in the ramucirumab group and 3.8 months (1.7 to 7.1) in those in the placebo group (hazard ratio [HR] 0.776, 95 % confidence intervals [CI]: 0.603 to 0.998; p = 0.047). The survival benefit with ramucirumab remained unchanged after multi-variable adjustment for other prognostic factors (multi-variable HR 0.774, CI: 0.605 to 0.991; p = 0.042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16 %] versus 9 [8 %]), whereas rates of other adverse events were mostly similar between groups (223 [94 %] versus 101 [88 %]). Five (2 %) deaths in the ramucirumab group and 2 (2 %) in the placebo group were considered to be related to study drug. The authors concluded that ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or GE junction adenocarcinoma progressing after first-line chemotherapy. They stated that these findings validated VEGFR-2 signaling as an important therapeutic target in advanced gastric cancer.
On April 21, 2014, the Food and Drug Administration (FDA) approved ramucirumab (Cyramza) to treat patients with advanced gastric cancer or gastro-esophageal junction adenocarcinoma. Ramucirumab is intended for patients with unresectable cancer or metastatic cancer after being treated with a fluoropyrimidine- or platinum-containing therapy. The safety and effectiveness of ramucirumab were evaluated in a clinical trial of 355 participants with unresectable or metastatic gastric or gastro-esophageal (EG) junction cancer; 2/3 of trial participants received ramucirumab while the remaining participants received a placebo (the REGARD Trial). Results from a second clinical trial that evaluated the effectiveness of ramucirumab plus paclitaxel versus paclitaxel alone also showed an improvement in OS. Common side effects experienced by ramucirumab-treated participants during clinical testing include diarrhea and hypertension. The recommended ramucirumab dose and schedule is 8 mg/kg administered as a 60-minute intravenous infusion every 2 weeks.
While ramucirumab for the treatment of unresectable or metastatic gastric cancer or EG junction adenocarcinoma has been approved by the FDA, its effectiveness for other types of solid tumors has yet to be established.
Krupitskaya and Wakelee (2009) stated that ramucirumab was well-tolerated on weekly and fortnightly schedules in phase I clinical trials in patients with advanced cancers; mechanism-related dose-limiting toxicities were hypertension and deep venous thrombosis. Stable disease was also observed in several patients treated on either schedule, and several patients on the weekly schedule exhibited partial responses. At the time of publication, ramucirumab was undergoing assessment in phase II trials as a monotherapy in hepato-cellular carcinoma (HCC), renal cell carcinoma (RCC) and ovarian cancer. Ramucirumab was also in phase II trials in combination with dacarbazine in melanoma, with mitoxantrone/prednisone in prostate cancer, with carboplatin/paclitaxel in non-small-cell lung cancer (NSCLC) and with oxaliplatin/folinic acid/5-fluorouracil in colorectal cancer (CRC). A phase III trial in combination with docetaxel in breast cancer (BC) was also ongoing.
Aprile et al (2013) noted that ramucirumab is emerging as a novel anti-angiogenic agent. Starting with pre-clinical data and early clinical results, these researchers discussed the development of the novel compound across multiple cancers (including gastro-intestinal malignancies, BC, lung carcinoma, and genitourinary tumors), and presented available data from randomized phase II and phase III trials. REGARD was the first phase III study to report on the efficacy of single-agent ramucirumab in patients with refractory metastatic gastric cancer.
Garon et al (2012) described the treatment rationale and study-related procedures for the a randomized, double-blind, phase III study of docetaxel and ramucirumab versus docetaxel and placebo in the treatment of stage IV NSCLC following disease progression after one prior platinum-based therapy (REVEL) study. This international, randomized, placebo-controlled, double-blinded phase III trial examines the safety and effectiveness of ramucirumab treatment administered in combination with docetaxel, as compared with docetaxel administered with placebo, in patients with stage IV NSCLC whose disease progressed during or after first-line platinum-based chemotherapy with or without maintenance treatment. The primary end-point is OS; secondary end-points include progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), patient-reported outcomes, and assessment of safety and tolerability of ramucirumab. Eligible patients (enrollment n = 1,242) are randomized at a 1:1 ratio to receive either docetaxel (75 mg/m(2)) plus ramucirumab (10 mg/kg) (Arm A) or docetaxel (75 mg/m(2)) plus placebo (Arm B). Both drugs are administered via intravenous infusion once every 3 weeks until evidence of disease progression, unacceptable toxicity, non-compliance, or patient's consent withdrawal. Safety and effectiveness will be compared between the study arms and in patient subgroups including patients with non-squamous versus squamous tumor histology and patients who received prior bevacizumab treatment. Multiple blood and tumor tissue biomarker samples are collected during the study. The goal of the REVEL study is to demonstrate that ramucirumab in combination with docetaxel improves OS of patients with NSCLC with progressive disease after first-line therapy, and to advance the knowledge of the role of angiogenesis blockade in patients with NSCLC by identifying patients who are likely to experience maximum benefit based on extensive clinical biomarker correlative analysis.
In a phase II study, Zhu and colleagues (2013) evaluated the safety and effectiveness of ramucirumab as first-line therapy in patients with advanced HCC and explored potential circulating biomarkers. Adults with advanced HCC and no prior systemic treatment received ramucirumab 8 mg/kg every 2 weeks until disease progression or limiting toxicity. The primary end-point was PFS; secondary end-points included ORR and OS. Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients. A total of 42 patients received ramucirumab. Median PFS was 4.0 months [95 % CI: 2.6 to 5.7], ORR was 9.5 % (95 % CI: 2.7 to 22.6; 4/42 patients had a partial response), and median OS was 12.0 months (95 % CI: 6.1 to 19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95 % CI: 0.5 to 9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95 % CI: 6.1 to 23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade greater than or equal to 3 toxicities included hypertension (14 %), gastro-intestinal hemorrhage and infusion-related reactions (7 % each), and fatigue (5 %). There was 1 treatment-related death (gastro-intestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2. The authors concluded that ramucirumab monotherapy may confer anti-cancer activity in advanced HCC with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and soluble VEGFR-2 that are consistent with those seen with other anti-VEGF agents.
Wadhwa et al (2014) stated that ramucirumab is being investigated in many malignancies including gastric cancer. The phase III trial in patients with advanced breast cancer failed to improve the primary end-point.
In an open-label, phase II study, Garcia-Carbonero et al (2014) evaluated the safety and effectiveness of ramucirumab (RAM) combined with mFOLFOX-6 as first-line therapy for metastatic CRC. Patients with metastatic CRC, Eastern Cooperative Oncology Group performance status 0 to 1, and adequate organ function who had not received chemotherapy for metastatic disease received RAM and the modified FOLFOX-6 regimen every 2 weeks. End-points included PFS, ORR, OS, and safety. The sample size was based on a potentially improved median PFS from 8 months to 11 months. A total of 48 patients received therapy. Median PFS was 11.5 months (95 % CI: 8.6 to 13.1 months). The ORR was 58.3 % (95 % CI: 43.21 to 72.39). The DCR (complete or partial response plus stable disease) was 93.8 % (95 % CI: 82.8 to 98.7). Median OS was 20.4 months (95 % CI: 18.5 to 25.1 months). The most frequent grade 3 to 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. The authors concluded that RAM may enhance the effectiveness of modified FOLFOX-6 chemotherapy with an acceptable safety profile in metastatic CRC.
In a single-arm, phase II clinical trial, Garcia et al (2014) examined the safety and effectiveness of ramucirumab in patients with tyrosine kinase inhibitors (TKIs)-resistant/intolerant metastatic RCC (mRCC). Patients received ramucirumab 8 mg/kg every 2 weeks until they developed disease progression or intolerable toxicity. The primary end-point was the best ORR; additional end-points included the DCR, PFS, the median duration of OS, and safety. A total of 39 patients with RCC received ramucirumab monotherapy. Prior TKI therapy included sunitinib (59 % of patients), sunitinib and sorafenib (30.8 % of patients), and sorafenib (10.3 % of patients). The ORR was 5.1 % (95 % CI: 0.6 % to 17.3 %). The 12-week DCR was 64.1 % (95 % CI: 47.2 % to 78.8 %). The median PFS was 7.1 months (95 % CI: 4.1 to 9.7 months), and the median OS was 24.8 months (95 % CI: 18.9 to 32.6 months). Grade 3 or higher adverse events that occurred in greater than or equal to 5 % of patients included grade 3 hypertension (7.7 %) and proteinuria (5.1 %). There was 1 on-study death from multi-organ failure. The authors concluded that although the study did not meet its primary end-point of greater than or equal to 15 % ORR, ramucirumab was associated with evidence of anti-tumor activity in patients with TKI-resistant/intolerant mRCC. Ramucirumab was safe and well-tolerated.
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