Ramucirumab (Cyramza)

Number: 0883

Policy

Aetna considers ramucirumab (Cyramza) medically necessary for the following indications:  

  • Gastric, Gastro-esophageal Junction (GEJ), and Esophageal Adenocarcinoma - for treatment in members who are not surgical candidates or have unresectable locally advanced, recurrent or metastatic disease as subsequent therapy as a single agent or in combination with paclitaxel; or 

  • Non-Small Cell Lung Cancer (NSCLC) - for treatment of recurrent, advanced or metastatic NSCLC when either of the following criteria is met:

    • Used in combination with docetaxel as subsequent therapy; or
    • Used in combination with erlotinib for EGFR mutation postitive disease; or

  • Colorectal Cancer - for treatment of advanced or metastatic colorectal cancer in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) or irinotecan; or
     
  • Hepatocellular cancer - for treatment as subsequent therapy as a single agent in members who have an alpha fetoprotein (AFP) of greater than or equal to 400 ng/mL.

Aetna considers continuation of ramucirumab (Cyramza) medically necessary for members with an indication listed above who have not experienced disease progression or an unacceptable toxicity.

Aetna considers ramucirumab experimental and investigational for the treatment of the following indications (not an all-inclusive list):

  • Biliary tract cancer
  • Bladder (urothelial) cancer
  • Breast cancer
  • Chondrosarcoma
  • Gastric neuroendocrine carcinoma
  • Genitourinary tumor
  • Fallopian tube cancer
  • Head and neck cancer
  • Malignant pleural diseases (e.g., mesothelioma)
  • Melanoma
  • Ovarian cancer
  • Peritoneal carcinoma
  • Prostate cancer
  • Renal cell carcinoma
  • Rheumatoid arthritis
  • Soft tissue sarcoma
  • Thymic carcinoma.

Dosing Recommendations

Cyramza (ramucirumab) is available for injection as 100 mg/10 mL (10 mg/mL) or 500 mg/50 mL (10 mg/mL) solution in a single-dose vial

Gastric cancer

The recommended dosage of Cyramza, either as a single agent or in combination with weekly paclitaxel, is 8 mg/kg every 2 weeks administered by intravenous (IV) infusion over 60 minutes. If the first infusion is tolerated, all subsequent Cyramza infusions may be administered over 30 minutes. Continue until disease progression or unacceptable toxicity.

Non-Small Cell Lung Cancer

The recommended dosage is 10 mg/kg administered by IV infusion over 60 minutes on Day 1of a 21-day cycle prior to docetaxel infusion. If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes. Continue until disease progression or unacceptable toxicity.

Colorectal Cancer

The recommended dosage is 8 mg/kg every 2 weeks administered by IV infusion over 60 minutes prior to FOLFIRI administration. If the first infusion is tolerated, all subsequent Cyramza infusions may be administered over 30 minutes. Continue until disease progression or unacceptable toxicity.

Hepatocellular Carcinoma

The recommended dosage is 8 mg/kg every 2 weeks administered by IV infusion over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be administered over 30 minutes. Continue until disease progression or unacceptable toxicity.

Source: Eli Lilly, 2019

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. 

Ramucirumab is a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGFR ligands, VEGF‐A, VEGF‐C, and VEGF‐D. As a result, ramucirumab inhibits ligand‐stimulated activation of VEGF Receptor 2, thereby inhibiting ligand‐induced proliferation, and migration of human endothelial cells.

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).

Cyramza (ramucirumab) is approved by the U.S. Food and Drug Administration (FDA) for

  • Gastric Cancer: Cyramza as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine-or platinum-containing chemotherapy.
  • Non-Small Cell Lung Cancer (NSCLC): Cyramza, in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Cyramza.
  • Colorectal Cancer: Cyramza, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
  • Hepatocellular Cancer: Cyramza as a single agent, is indicated for the treatment of of hepatocellular carcinoma in patients who have an alpha fetoprotein of ≥400 ng/mL and have been treated with sorafenib.

The following adverse reactions are discussed in greater detail in the Prescribing Information:

  • Hemorrhage (Boxed Warning)
  • Arterial Thromboembolic Events
  • Hypertension
  • Infusion Related Reactions
  • Gastrointestinal Perforations
  • Impaired Wound Healing
  • Clinical Deterioration in Patients with Child‐Pugh B or C Cirrhosis
  • Reversible Posterior Leukoencephalopathy.

Compendial uses for ramucirumab include:

  • Esophageal adenocarcinoma
  • Colorectal cancer, advanced
  • NSCLC, EGFR mutation positive, in combination with erlotinib.

Colorectal Cancer

The FDA approved ramucirumab for use in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) chemotherapy for the treatment of patients with metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. 

The approval is based on the RAISE trial, a multinational, double-blind Phase III study which compared ramucirumab plus FOLFIRI to placebo plus FOLFIRI in people with metastatic colorectal cancer who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were randomized in a 1:1 ratio to receive ramucirumab plus FOLFIRI (n=536) or placebo plus FOLFIRI (n=536) every two weeks. Efficacy endpoints in the trial included the major efficacy outcome measure of overall survival (OS) and the supportive efficacy outcome measure of progression-free survival (PFS). 

In the RAISE trial, patients treated with the ramucirumab-FOLFIRI combination achieved a median OS, the study's primary endpoint, of 13.3 months as compared to those treated with placebo-FOLFIRI who achieved 11.7 months, a statistically significant improvement that reduced the risk of patient death by 15 percent (HR 0.85; 95% CI: 0.73-0.98; p = 0.023). The percentage of deaths at the time of analysis was 69 percent (372 patients) and 74 percent (397 patients) in the ramucirumab-plus-FOLFIRI and placebo-plus-FOLFIRI treatment arms, respectively. The ramucirumab combination also demonstrated a statistically significant improvement in the secondary endpoint of PFS over the placebo-FOLFIRI regimen, with a median PFS of 5.7 months vs. 4.5 months, respectively (HR 0.79; 95% CI: 0.70-0.90; p < 0.001). The percentage of events at the time of analysis was 89 percent (476 patients) and 92 percent (494 patients) in the ramucirumab-plus-FOLFIRI and placebo-plus-FOLFIRI treatment arms, respectively. In the RAISE trial, randomization was stratified by geographic region, tumor KRAS status, and time to disease progression after beginning first-line treatment (less than 6 months vs. greater than or equal to 6 months). The treatment effect was consistent across the pre-specified stratification factors. 

The labeling for Cyramza contains Boxed Warnings for hemorrhage, GI perforation, and impaired wound healing and additional Warnings and Precautions for arterial thromboembolic events, hypertension, infusion-related reactions, clinical deterioration in patients with Child-Pugh B or C cirrhosis, reversible posterior leukoencephalopathy syndrome, proteinuria including nephrotic syndrome, thyroid dysfunction, and embryofetal toxicity. The most common adverse reactions (all grades) observed in ramucirumab-plus-FOLFIRI-treated patients at a rate of ≥30 percent and ≥2 percent higher than placebo plus FOLFIRI were diarrhea (60% vs. 51%), neutropenia (59% vs. 46%), decreased appetite (37% vs. 27%), epistaxis (33% vs. 15%), and stomatitis (31% vs. 21%). The most common serious adverse events with ramucirumab plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%). 

Ramucirumab should be permanently discontinued in patients who experience severe bleeding or a GI perforation. Ramucirumab should be withheld prior to surgery and discontinued if a patient develops wound healing complications.

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.

Gastric and Esophageal Cancer

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.

See the "National Comprehensive Cancer Network" Drugs and Biologics Compendium (NCCN) (below) for recommendations for ramucirumab therapy. 

Hepatocellular Carcinoma

On May 10, 2019, the Food and Drug Administration approved ramucirumab as a single agent for hepatocellular carcinoma (HCC) in patients who have an alpha fetoprotein (AFP) of ≥ 400 ng/mL and have been previously treated with sorafenib. Approval was based on REACH‑2 (Zhu 2019; NCT02435433), a multinational, randomized, double-blind, placebo-controlled, multicenter study in 292 patients with advanced HCC with AFP ≥ 400 ng/mL who had disease progression on or after sorafenib or who were intolerant. Patients were randomized (2:1) to receive ramucirumab 8 mg/kg plus best supportive care (BSC) or placebo plus BSC every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity. The trial’s primary endpoint was overall survival (OS). The estimated median OS was 8.5 months (7.0, 10.6) for patients receiving ramucirumab and 7.3 months (5.4, 9.1) for those receiving placebo (HR 0.71; 95% CI: 0.53, 0.95; p=0.020). The most common adverse reactions observed in patients with HCC receiving single-agent ramucirumab (≥ 15% and ≥ 2% higher incidence than placebo) were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites. The most common laboratory abnormalities (≥ 30% and a ≥ 2% higher incidence than placebo) were hypoalbuminemia, hyponatremia, and thrombocytopenia.

Zhu et al (2019) stated patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations have poor prognosis. The authors aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and alpha-fetoprotein concentrations of 400 ng/mL or higher. REACH-2 was a randomized, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centers in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, alpha-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. The authors also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with alpha-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0-12·5), median overall survival (8·5 months [95% CI 7·0-10·6] vs 7·3 months [5·4-9·1]; hazard ratio [HR] 0·710 [95% CI 0·531-0·949]; p=0·0199) and progression-free survival (2·8 months [2·8-4·1] vs 1·6 months [1·5-2·7]; 0·452 [0·339-0·603]; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group. The proportion of patients with an objective response did not differ significantly between groups (nine [5%] of 197 vs one [1%] of 95; p=0·1697). Median time to deterioration in FHSI-8 total scores (3·7 months [95% CI 2·8-4·4] vs 2·8 months [1·6-2·9]; HR 0·799 [95% CI 0·545-1·171]; p=0·238) and ECOG performance statuses (HR 1·082 [95% CI 0·639-1·832]; p=0·77) did not differ between groups. Grade 3 or worse treatment-emergent adverse events that occurred in at least 5% of patients in either group were hypertension (25 [13%] in the ramucirumab group vs five [5%] in the placebo group), hyponatremia (11 [6%] vs 0) and increased aspartate aminotransferase (six [3%] vs five [5%]). Serious adverse events of any grade and cause occurred in 68 (35%) patients in the ramucirumab group and 28 (29%) patients in the placebo group. Three patients in the ramucirumab group died from treatment-emergent adverse events that were judged to be related to study treatment (one had acute kidney injury, one had hepatorenal syndrome, and one had renal failure). The authors concluded that REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and alpha-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To the authors’ knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma.

Non-Small Cell Lung Cancer

In a randomized, double-blind, multi-center, phase III clinical trial, Garon et al (2014) evaluated the safety and effectiveness of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV NSCLC after platinum-based therapy.  In this trial (REVEL), these investigators enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen.  Patients were randomly allocated (1:1) with a centralized, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes versus no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, withdrawal, or death.  The primary end-point was OS in all patients allocated to treatment.  These researchers assessed adverse events according to treatment received.  Between December 3, 2010, and January 24, 2013, these investigators screened 1,825 patients, of whom 1,253 patients were randomly allocated to treatment.  Median OS was 10.5 months (IQR 5.1 to 21.2) for 628 patients allocated ramucirumab plus docetaxel and 9.1 months (4.2 to 18.0) for 625 patients who received placebo plus docetaxel (HR 0.86, 95 % CI: 0.75 to 0.98; p = 0.023).  Median progression-free survival (PFS) was 4.5 months (IQR 2.3 to 8.3) for the ramucirumab group compared with 3.0 months (1.4 to 6.9) for the control group (0.76, 0.68 to 0.86; p < 0.0001).  These researchers noted treatment-emergent adverse events in 613 (98 %) of 627 patients in the ramucirumab safety population and 594 (95 %) of 618 patients in the control safety population.  The most common grade 3 or worse adverse events were neutropenia (306 patients [49 %] in the ramucirumab group versus 246 [40 %] in the control group), febrile neutropenia (100 [16 %] versus 62 [10 %]), fatigue (88 [14 %] versus 65 [10 %]), leucopenia (86 [14 %] versus 77 [12 %]), and hypertension (35 [6 %] versus 13 [2 %]).  The numbers of deaths from adverse events (31 [5 %] versus 35 [6 %]) and grade 3 or worse pulmonary hemorrhage (8 [1 %] versus 8 [1 %]) did not differ between groups.  Toxicities were manageable with appropriate dose reductions and supportive care.  The authors concluded that ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC.

On December 12, 2014, the FDA expanded the approved use of ramucirumab (Cyramza) to treat patients with metastatic NSCLC. Ramucirumab in combination with docetaxel, was approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. The labeling states that patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab.

The approval of ramucirumab plus docetaxel for metastatic NSCLC is based on a clinical study of 1,253 patients with previously treated and progressive lung cancer. Subjects were randomly assigned to receive ramucirumab plus docetaxel or a placebo plus docetaxel. Treatment was given until disease progression or development of intolerable side effects. The trial was designed to measure OS, the length of time a participant lived before death. Results showed that 50 % of the participants treated with ramucirumab plus docetaxel survived an average of 10.5 months from the start of treatment, compared to an average of 9.1 months from the start of treatment for 50 % of the participants who received placebo plus docetaxel.

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 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.

Other Indications

While ramucirumab for the treatment of unresectable or metastatic gastric cancer, EG junction adenocarcinoma, non-small cell lung lung cancer, and metastatic colorectal cancer 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.

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 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.

In a randomized, double-blind, placebo-controlled, multi-national, phase III clinical trial, Mackey et al (2015) evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer.  In this study, a total of 1,144 patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a 2-to-1 ratio to receive docetaxel 75 mg/m2 plus ramucirumab 10 mg/kg or docetaxel 75 mg/m2 plus placebo once every 3 weeks.  Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region.  An independent data monitoring committee oversaw the trial.  The primary end-point was investigator-assessed PFS.  Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (HR, 0.88; p = 0.077).  Median OS was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; p = 0.915).  Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis.  The authors concluded that addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.

In a phase II clinical trial, Penson et al (2014) investigated the effectiveness of ramucirumab in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.  Primary end-points were PFS at 6 months (PFS-6) and confirmed ORR.  Women who received greater than or equal to 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of less than 12 months with measurable disease were eligible.  Patients received 8 mg/kg ramucirumab intravenously every 2 weeks.  A total of 60 patients were treated; 1 patient remained on study as of September 2013.  The median age was 62 years (range of 27 to 80), and median number of prior regimens was 3.  Forty-five (75 %) patients had platinum refractory/resistant disease; 39 patients (65.0 %) had serous tumors.  PFS-6 was 25.0 % (n = 15/60, 95 % CI: 14.7 to 37.9 %).  Best overall response was: partial response (PR) 5.0 % (n = 3/60), stable disease (SD) 56.7 % (n = 34/60), and progressive disease 33.3 % (n = 20/60).  The most common treatment-emergent adverse events possibly related to study drug were headache (65.0 %; 10.0 % Grade greater than or equal to 3), fatigue (56.7 %; 3.3 % Grade greater than or equal to 3), diarrhea (28.3 %; 1.7 % Grade greater than or equal to 3), hypertension (25.0 %; 3.3 % Grade greater than or equal to 3), and nausea (20.0 %; no Grade greater than or equal to 3).  Two patients experienced intestinal perforations (3.3 % Grade greater than or equal to 3).  Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2.  The authors concluded that although anti-tumor activity was observed, the pre-determined efficacy end-points were not met.

Biliary Tract Cancer

Arkenau and colleagues (2018) stated that few therapeutic options exist for patients with advanced biliary tract cancer (BTC) following progression on gemcitabine-cisplatin.  Pre-clinical evidence suggested that simultaneous blockade of VEGFR-2 and programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) enhances anti-tumor effects.  In a non-randomized, open-label, phase-I clinical trial, these researchers evaluated the safety and efficacy of ramucirumab with pembrolizumab in biomarker-unselected patients with previously treated advanced or metastatic BTC.  Patients had previously treated advanced or metastatic adenocarcinoma of the gallbladder, intra-hepatic and extra-hepatic bile ducts, or ampulla of Vater.  Ramucirumab 8 mg/kg was administered intravenously on days 1 and 8 with intravenous pembrolizumab 200 mg on day 1 every 3 weeks.  The primary end-point was safety and tolerability of the combination; secondary end-points included ORR, PFS, and OS.  A total of 26 patients were treated at 12 centers in 5 countries.  Hypertension was the most common grade 3 treatment-related AE (TRAE), occurring in 5 patients; 1 patient experienced a grade 4 TRAE (neutropenia), and no treatment-related deaths occurred; ORR was 4 %.  Median PFS and OS were 1.6 months and 6.4 months, respectively.  The authors concluded that ramucirumab plus pembrolizumab revealed no unexpected safety findings in patients with advanced or metastatic biliary tract cancer, which was consistent with reports of other tumor cohorts within this phase-Ia/b trial.  Ramucirumab plus pembrolizumab did not demonstrate an improvement in OS when compared with historical controls in biomarker unselected, heavily pre-treated patients with advanced or metastatic biliary tract cancer.  Patients with PD-L1-positive tumors had improved OS compared with patients with PD-L1-negative disease.  These investigators noted that the survival signal in PD-L1-positive patients was interesting, but they were  limited by sample size and had no historical reference for the natural history of patients with PD-L1 positivity relative to the wider population, and it may represent selection bias.  Moreover, they stated that ramucirumab is concurrently being investigated in the phase-II setting for advanced or metastatic BTC in combination with gemcitabine-cisplatin for 1st-line treatment and as monotherapy in patients previously treated with a gemcitabine-based regimen.

Bladder (Urothelial) Cancer

In an open-label, 3-arm, randomized controlled phase II clinical trial, Petrylak and colleagues (2016) evaluated the safety and effectiveness of docetaxel monotherapy or docetaxel in combination with ramucirumab (VEGFR2 antibody) or icrucumab (VEGFR 1 antibody) after progression during or within 12 months of platinum-based regimens for patients with locally advanced or metastatic bladder (urothelial) carcinoma.  Patients were randomly assigned (1:1:1) to receive docetaxel 75 mg/m(2) intravenously (IV) on day 1 of a 3-week cycle (arm-A), docetaxel 75 mg/m(2) IV plus ramucirumab 10 mg/kg IV on day 1 of a 3-week cycle (arm-B), or docetaxel 75 mg/m(2) IV on day 1 plus icrucumab 12 mg/kg IV on days 1 and 8 of a 3-week cycle (arm-C).  Treatment continued until disease progression or unacceptable toxicity.  The primary end-point was investigator-assessed PFS.  A total of 140 patients were randomly assigned and treated in arm-A (n = 45), arm-B (n = 46), or arm-C (n = 49); PFS was significantly longer in arm-B compared with arm-A (median of 5.4 months; 95 % CI: 3.1 to 6.9 months versus 2.8 months; 95 % CI: 1.9 to 3.6 months; stratified HR, 0.389; 95 % CI: 0.235 to 0.643; p = 0.0002).  Arm-C did not experience improved PFS compared with arm-A (1.6 months; 95 % CI: 1.4 to 2.9; stratified HR, 0.863; 95 % CI: 0.550 to 1.357; p = 0.5053).  The most common grade 3 or worse adverse events (AEs) (arm-A, arm-B, and arm-C) were neutropenia (36 %, 33 %, and 39 %, respectively), fatigue (13 %, 30 %, and 20 %, respectively), febrile neutropenia (13 %, 17 %, and 6.1 %, respectively), and anemia (6.7 %, 13 %, and 14 %, respectively).  The authors concluded that the addition of ramucirumab to docetaxel met the pre-specified effectiveness end-point for prolonging PFS in patients with locally advanced or metastatic bladder carcinoma receiving 2nd-line treatment and warrants further investigation in the phase III clinical trials.

Aragon-Ching and Trump (2017) noted that progress has been slow in systemic management of locally advanced and metastatic bladder cancer over the past 20 years.  However, the recent approval of immunotherapy with atezolizumab and nivolumab for 2nd-line salvage therapy may usher in an era of more rapid improvement.  Systemic treatment is suboptimal and is an area of substantial unmet medical need.  The recent findings from the Cancer Genome Atlas project revealed promising pathways that may be amenable to targeted therapies.  Promising results with VEGF inhibitors (e.g., ramucirumab, sunitinib or bevacizumab), and HER2-targeted therapies, epidermal growth factor receptor inhibitors, and fibroblast growth factor receptor inhibitors, are undergoing clinical trials.

In a randomized, double-blind, phase-III clinical trial, Petrylak et al (2017) evaluated the safety and the efficacy of treatment with docetaxel plus either ramucirumab or placebo in patients with platinum-refractory advanced or metastatic urothelial carcinoma.  Patients were enrolled from 124 sites in 23 countries.  Previous treatment with 1 immune-checkpoint inhibitor was permitted.  Patients were randomized (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met.  The primary end-point was investigator-assessed progression-free survival (PFS), analyzed by intention-to-treat in the first 437 randomized patients.  Between July, 2015, and April, 2017, a total of 530 patients were randomly allocated either ramucirumab plus docetaxel (n = 263) or placebo plus docetaxel (n = 267); PFS was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median of 4.07 months [95 % CI: 2.96 to 4.47] versus 2.76 months [2.60 to 2.96]; hazard ratio [HR] 0.757, 95 % CI: 0.607 to 0.943; p = 0.0118).  A blinded independent central analysis was consistent with these results.  An objective response was achieved by 53 (24.5 %, 95 % CI: 18.8 to 30.3) of 216 patients allocated ramucirumab and 31 (14.0 %, 9.4 to 18.6) of 221 assigned placebo.  The most frequently reported treatment-emergent adverse events (AEs), regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhea, decreased appetite, and nausea.  These AEs occurred predominantly at grade 1 to 2 severity.  The frequency of grade 3 or worse AEs was similar for patients allocated ramucirumab and placebo (156 [60 %] of 258 versus 163 [62 %] of 265 had an AE), with no unexpected toxic effects; 63 (24 %) of 258 patients allocated ramucirumab and 54 (20 %) of 265 assigned placebo had a serious AE that was judged by the investigator to be related to treatment; 38 (15 %) of 258 patients allocated ramucirumab and 43 (16 %) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which 8(3 %) and 5 (2% ) deaths were deemed related to treatment by the investigator.  Sepsis was the most common AE leading to death on treatment (4 [2 %] versus none [0 %]); 1 fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab.  The authors concluded that to the best of their knowledge, ramucirumab plus docetaxel is the first regimen in a phase-III clinical trial to show superior PFS over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma.  They stated that these data validated inhibition of VEGFR-2 signaling as a potential new therapeutic treatment option for patients with urothelial carcinoma.

Chondrosarcoma

Jones and colleagues (2017) noted that chondrosarcoma is the most common bone sarcoma in adults.  Conventional chondrosarcoma, the commonest histological subtype, is largely resistant to anthracycline-based chemotherapy.  There have been anecdotal reports of durable clinical benefit with anti-angiogenic agents in this disease.  These investigators carried out a retrospective search of patients treated at 3 sarcoma referral centers to identify patients with advanced chondrosarcoma treated with anti-angiogenic agents.  They evaluated the safety and effectiveness of anti-angiogenic agents in advanced chondrosarcoma.  A total of 10 patients were identified; 7 with conventional, 1 each with clear cell, extra-skeletal mesenchymal chondrosarcoma and extra-skeletal myxoid chondrosarcoma.  The median PFS for patients with conventional and clear cell sarcoma was 22.6 months.  Median OS has not been met.  Anti-angiogenic therapy was well-tolerated in this series of patients.  The authors concluded that the findings of this retrospective study suggested that anti-angiogenic therapy can provide prolonged clinical benefit in advanced chondrosarcoma patients.  Moreover, they stated that further prospective trials are needed to precisely define the role of this class of agent in advanced chondrosarcoma (ramucirumab was one of the keywords of this trial).

Gastric Neuroendocrine Carcinoma

Koizumi and co-workers (2018) reported on the case of a 84-year old man who underwent total gastrectomy with D1 plus lymph node dissection in December 2015, with a diagnosis of Stage III B neuroendocrine carcinoma (NEC) of the stomach.  An abdominal computed tomography (CT) revealed swollen para-aortic lymph nodes and left adrenal grand in May 2016.  Since his serum level of CA19-9 was elevated, he was thus diagnosed as having recurrence, and was started chemotherapy with ramucirumab (RAM).  After introduction of the chemotherapy, his serum level of CA19-9 was decreased gradually and metastatic foci were also decreased in size.  Although the patient required relatively longer administration interval according to the severity of general fatigue, he continued the chemotherapy without severe adverse effects until he rejected further treatment in January 2017, and satisfactory therapeutic result was acquired.  While the prognosis of gastric NEC is reported to be very poor, no definitive therapeutic guideline is available at present. The authors stated that especially in elderly patients, considerable attention should be paid to the selection of chemotherapeutic agents because of their own adverse effects.  In the present case, RAM could be administered safely, and it appeared that RAM might become a useful therapeutic option for gastric NEC even in elderly patients.  These preliminary findings need to be further investigated.

Matsubara and colleagues (2018) noted that extra-pulmonary NEC is a rare disease, and there is no standard chemotherapy.  These investigators reported on the case of a 73-year old man who was diagnosed with advanced gastric NEC.  He received chemotherapy of irinotecan plus cisplatin, and amrubicin monotherapy.  After failure of 2nd-line chemotherapy, he received RAM plus paclitaxel; this treatment was chosen because VEGF 2 was strongly expressed in the tumor endothelial cells.  After 2 cycles, his NEC had markedly reduced in size, and he continued with this treatment for over 8 months.  In this case, the combination of an anti-angiogenic inhibitor and a cytotoxic agent was highly effective for gastric NEC.  This was a single-case study; and its findings were confounded by the combined use of RAM and paclitaxel.

Head and Neck Cancer

In a single-arm, non-randomized, open-label, dose-escalation, phase I clinical trial, Cao and colleagues (2017) evaluated the safety, tolerability, and pharmacokinetics (PK) of ramucirumab in Chinese patients with advanced solid tumors (including breast cancer as well as head and neck cancer) that were resistant to standard therapy or no standard therapy was available.  Dose escalation was a 3 + 3 design, with expansion in cohorts 2 and 3 for PK.  Ramucirumab was given intravenously at 3 different dosages:
  1. 6 mg/kg every 2 weeks,
  2. 10 mg/kg every 3 weeks, and
  3. 8 mg/kg every 2 weeks.
Safety analyses included all patients; PK, immunogenicity, and anti-tumor activity were also assessed.  Among 28 patients treated, 2 experienced dose-limiting toxicity (DLT), possibly related to ramucirumab.  No maximum tolerated dose (MTD) was determined.  All patients experienced at least 1 treatment-related adverse event (AE); grade 3 or higher AE was reported for 53.6 % (n = 15) of patients; PK analyses indicated that ramucirumab had low clearance, small volume of distribution, and long half-life in Chinese patients, as in other populations.  Immunogenicity was not detected.  No patient had complete response (CR)/PR, and 64.3 % (n = 18) had SD with a median duration of 5.55 months (95 % CI: 3.38 to 7.13 months).  The authors concluded that ramucirumab appeared to be well-tolerated in Chinese patients with advanced solid tumors; PK characteristics in Chinese patients were similar to those in other populations.  These investigators stated that preliminary anti-tumor activity was demonstrated in this phase I study, however, due to limited sample size (n = 28) and single‐arm design, no efficacy conclusion can be drawn from this study and further randomized trials are needed.

Lung Metastases from Gastric Cancer

In a retrospective study, Roviello and colleagues (2019) examined the activity of ramucirumab in combination with paclitaxel in patients with metastatic gastric cancer (GC) and lung metastases.  These researchers retrospectively reviewed clinical data from patients with GC treated in 2nd-line with ramucirumab and paclitaxel according to the presence or not of lung metastases.  A total of 31 patients were eligible; 5 (16.1 %) patients had lung metastases.  The median PFS was 156 days in patients without lung metastases compared with 54 days in patients with lung metastases.  The median OS also showed a trend in favor of patients without lung metastases.  The authors concluded that despite the small number of patients and the retrospective nature of the data, this analysis showed relatively poor efficacy of ramucirumab plus paclitaxel as a 2nd-line treatment in patients with lung metastases from GC.  These researchers stated that further studies are needed to evaluate novel treatments in this subset of patients.

Malignant Pleural Diseases (e.g., Mesothelioma)

Marquez-Medina and Popat (2016) stated that malignant pleural effusion (MPE) represents 15 to 35 % of pleural effusions and markedly worsens the prognosis and quality of life (QOL) of patients with cancer.  Malignant mesothelioma (MM) and lung adenocarcinoma are the most frequent primary and secondary causes, respectively, of MPE.  Effective treatments for cancer-related MPE are warranted in order to improve symptoms, reduce the number of invasive pleural procedures, and prolong patients’ life.  Since angiogenesis plays a key role in MPE development, these researchers examined the potential role of bevacizumab and other anti-angiogenic therapies in this review.  No relevant phase III clinical trials have specifically analyzed the benefit from adding bevacizumab to platinum-based chemotherapy in lung cancer-related MPE.  However, small retrospective series reported 71.4 to 93.3 % MPE control rate, a reduction in invasive procedures, and a safe profile with this combination.  Being approved for the 1st-line treatment of non-squamous advanced NSCLC, the addition of bevacizumab should be considered for patients presenting with MPE.  In MM, the addition of bevacizumab to platinum-based chemotherapy did not meet primary end-points in 2 phase II clinical trials.  However, the beneficial results on OS reported in comparison with historical cohorts and the statistically significant benefit on PFS and OS observed in the phase III MAPS trial foretell an eventual role for the combination of platinum/pemetrexed/bevacizumab as front-line systemic therapy for pleural MM.  To-date, no other anti-angiogenic drug has showed significant benefit in the treatment of patients with either MPE or MM.  However, new promising drugs such as ramucirumab or recombinant human endostar warrant further investigation.

Peritoneal Metastases from Gastric Cancer

Ishikawa and colleagues (2019) noted that ramucirumab (RAM) plus solvent-based (sb)-paclitaxel (PTX) is the standard 2nd-line chemotherapy for advanced GC (AGC).  The subset analysis of the ABSOLUTE trial, which confirmed non-inferiority of weekly nanoparticle albumin-bound (nab)-PTX to weekly sb-PTX, suggested that nab-PTX might have better efficacy than sb-PTX in patients with peritoneal metastasis.  These investigators retrospectively examined the safety and efficacy of RAM plus sb-PTX and nab-PTX in patients with peritoneal metastasis of AGC.  Patients with AGC who received RAM plus sb-PTX or nab-PTX as 2nd-line chemotherapy from June 2015 to February 2019 were included in the study; OS, PFS, response rate, and safety were assessed.  A total of 128 patients were included in this study (93 in the RAM plus sb-PTX group and 35 in the RAM plus nab-PTX group).  PFS was 4.1 months in the RAM plus sb-PTX group and 4.6 months in the RAM plus nab-PTX group (HR 0.90; 95 % CI: 0.58 to 1.41, p = 0.643).  OS was 8.9 months in the RAM plus sb-PTX group and 11.4 months in the RAM plus nab-PTX group (HR 0.95; 95 % CI : 0.56 to 1.62, p = 0.847).  A total of 62 and 31 patients had peritoneal metastasis in the RAM plus sb-PTX and the RAM plus nab-PTX groups, respectively.  RAM plus nab-PTX showed a slightly longer survival compared to RAM plus sb-PTX in patients with peritoneal metastasis (PFS 5.8 versus 3.5 months, HR 0.66; 95 % CI: 0.40 to 1.10, p = 0.109).  The authors concluded that the findings of this study suggested that RAM plus nab-PTX might be a more effective treatment for peritoneal metastasis of AGC.

Rheumatoid Arthritis

Abdel-Maged and colleagues (2019) stated that rheumatoid arthritis (RA) is a chronic and progressive autoimmune inflammatory disease associated with irreversible joint destruction that leads to permanent motor disability and compromised QOL.  However, the main cause of RA is still unknown though stimulation of immune system and cells plays pivotal role in disease development and progression.  Ramucirumab (RAM) is the monoclonal antibody against VEGF- receptor.  These investigators examined the therapeutic effect of RAM with or without methotrexate (MTX) against adjuvant-induced arthritis in rats.  Complete Freund's adjuvant (CFA)-induced arthritic rats were treated for 3 consecutive weeks with MTX or RAM alone and MTX-RAM co-therapy.  Arthritic score, gait score, ankle diameter, paw thickness, angiogenic, inflammatory cytokines, bone erosion markers, and apoptotic markers were assessed to evaluate the anti-arthritic effect.  RAM monotherapy exhibited anti-inflammatory, anti-angiogenic and anti-apoptotic effects similar to MTX alone to treat RA in the current study.  Furthermore, RAM alone had a protective effect on bone and cartilage health better than standard anti-rheumatic agent MTX.  Interestingly, combined therapy of MTX and RAM produced significant differences in comparison with MTX or RAM monotherapy in all tested parameters.  Moreover, the current study proved that MTX-RAM co-therapy has a synergistic effect.  These preliminary findings need to be further investigated.

Soft Tissue Sarcoma

In a phase II clinical trial, Chow and colleagues (2016) evaluated PK interaction potential between ramucirumab and paclitaxel in patients with advanced malignant solid tumors including breast carcinoma, soft tissue sarcoma, and urothelial carcinoma.  This study was designed to evaluate 2-way PK drug-drug interactions between ramucirumab and paclitaxel.  A total of 24 patients participated in Part A, which consisted of a 2-week monotherapy period in which paclitaxel 80 mg/m(2) was administered on day 1, followed by a 4-week cycle of combination treatment with ramucirumab (8 mg/kg on days 1 and 15; paclitaxel on days 1, 8, and 15).  Patients could continue to receive combination therapy with ramucirumab and paclitaxel.  In 16 patients in Part B, ramucirumab monotherapy was administered on day 1 of a 3-week cycle.  Patients could continue to receive ramucirumab monotherapy or combination therapy with paclitaxel.  Concomitant administration of ramucirumab had no effect on PK of paclitaxel, with ratios of geometric least squares (LS) means (with ramucirumab versus alone) of 1.09 (90 % CI: 0.93 to 1.29) for AUC(0-∞) and 0.97 (90 % CI: 0.83, 1.13) for maximum drug concentration (Cmax).  In addition, similar ramucirumab PK characteristics were observed with or without paclitaxel administration.  The ratios of geometric LS means of AUC(0-∞) and Cmax of ramucirumab (with paclitaxel versus alone) were 1.00 (90 % CI: 0.84 to 1.19) for AUC(0-∞) and 1.07 (90 % CI: 0.93 to 1.24) for Cmax, respectively.  The authors concluded that concomitant paclitaxel administration is unlikely to affect the PK of ramucirumab, and vice-versa.  The incidence and severity of AEs were consistent with the known safety profiles of paclitaxel and ramucirumab.

Thymic Carcinoma

Imbimbo and colleagues (2018) noted that thymic epithelial tumors are rare malignancies.  Thymic carcinoma represents about 20 % of all thymic epithelial tumors and has aggressive behavior, with a greater tendency to metastatic spread.  Thymic carcinoma is often diagnosed in advanced stages for which systemic treatment is the main therapeutic option.  The association of chemotherapy and anti-angiogenic agents in the 1st-line setting has never been investigated in this very rare cancer.  However, pre-clinical and clinical evidence has suggested that inhibition of angiogenesis could be beneficial.  The RELEVENT trial is a multi-center, open-label, single-arm, phase-II clinical trial that aimed at examining the activity and safety of ramucirumab combined with paclitaxel and carboplatin in chemotherapy-naive patients affected by thymic carcinoma or B3 thymoma with area of carcinoma.  The primary end-point of the trial is the ORR; PFS, OS, and safety are secondary end-points.  Patient-reported outcomes will be collected at each visit.  Furthermore, the mutational status of a subset of genes, polymorphisms, and selected micro-RNA expression will be evaluated.

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network Clinical Practice Guidelines on "Colon cancer" (NCCN, 2019) state that small intestine (small bowel adenocarcinoma) and appendiceal adenocarcinoma may be treated with systemic therapy according to NCCN guidelines for colon cancer. NCCN guidelines for anal carcinoma (NCCN, 2019) state that anal adenocarcinoma and anal melanoma is managed with NCCN guidelines for rectal cancer.

The NCCN Drugs & Biologics Compendium (2020) provides the following recommendations for ramucirumab (Cyramza):

  • Colon Cancer (adenocarcinoma) - (Category 2A)

    • Primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months

      • in combination with irinotecan
      • in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen

    • Subsequent therapy for progression of unresectable advanced or metastatic disease in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen in patients not previously treated with irinotecan-based therapy.

  • Esophageal and Esophagogastric Junction Cancers - (Category 1 for EGJ adenocarcinoma; 2A for esophageal adenocarcinoma)

    Palliative therapy for patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic adenocarcinoma and Karnofsky performance score ≥60% or ECOG performance score ≤2 as second-line or subsequent therapy in combination with paclitaxel (preferred) or as a single agent.

  • Gastric Cancer - (Category 1)

    Palliative therapy for locoregional disease in patients who are not surgical candidates, recurrent, or metastatic disease and Karnofsky performance score ≥60% or ECOG performance score ≤2 as second-line or subsequent therapy in combination with paclitaxel (preferred) or as a single agent.

  • Hepatocellular Carcinoma - (Category 1)

    Subsequent treatment as a single agent for progressive disease in patients (AFP ≥ 400 ng/mL only) who

    • have unresectable disease and are not a transplant candidate
    • are inoperable by performance status or comorbidity, or have local disease or local disease with minimal extrahepatic disease only
    • have metastatic disease or extensive liver tumor burden.

  • Non-Small Cell Lung Cancer -

    (Category 2A for first progression after initial systemic therapy; 2B for progression after subsequent systemic therapy)

    Subsequent systemic therapy in combination with docetaxel (if not already given) for recurrent, advanced or metastatic disease in patients with performance status 0-2.

    (Category 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease; 2A for all others)
    Therapy in combination with erlotinib for sensitizing EGFR mutation-positive recurrent, advanced or metastatic disease as

    • first-line therapy
    • continuation of therapy following disease progression on combination of erlotinib and ramucirumab for asymptomatic disease, symptomatic brain lesions, or isolated symptomatic systemic lesions.
  • Rectal Cancer  (adenocarcinoma) - (Category 2A)

    • Primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months

      • in combination with irinotecan
      • in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen.

    • Subsequent therapy for progression of unresectable advanced or metastatic disease in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen in patients not previously treated with irinotecan-based therapy.
Table: CPT Codes / HCPCS Codes / ICD-9 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

82105 Alpha-fetoprotein (AFP); serum
82107 Alpha-fetoprotein (AFP); AFP-L3 fraction isoform and total AFP (including ratio)
96413 Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
96415     each additional hour (List separately in addition to code for primary procedure)

HCPCS codes covered if selection criteria are met:

J9308 Injection, ramucirumab, 5 mg

Other HCPCS codes related to the CPB:

J0640 Injection, leucovorin calcium, per 50 mg
J8520 Capecitabine, oral, 150 mg
J8521 Capecitabine, oral, 500 mg
J9035 Injection, bevacizumab, 10 mg
J9190 Injection, fluorouracil, 500 mg [covered in combination with ramucirumab for metastatic small intestine adenocarcinoma, appendiceal adenocarcinoma, and anal adenocarcinoma, with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine]
J9206 Injection, irinotecan, 20 mg [covered in combination with ramucirumab for metastatic small intestine adenocarcinoma, appendiceal adenocarcinoma, and anal adenocarcinoma, with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine]
J9263 Injection, oxaliplatin, 0.5 mg
J9400 Injection, ziv-alfibercept, 1mg
Q5107 Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg

ICD-10 codes covered if selection criteria are met:

C15.3 - C20 Malignant neoplasm of esophagus, stomach, small intestine (including duodenum), colon, rectosigmoid junction and rectum
C21.0 - C21.8 Malignant neoplasm of anus [covered in combination of ramucirumab with FOLFIRI covered for metastatic small intestine adenocarcinoma, appendiceal adenocarcinoma, and anal adenocarcinoma, with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine]
C22.0 Liver cell carcinoma
C34.00 - C34.92 Malignant neoplasm of bronchus and lung [non-small cell lung cancer]

ICD-10 codes not covered for indications listed in the CPB (not all inclusive list):

C00.0 - C14.8 Malignant neoplasm of head, face and neck
C22.1 - C22.9 Malignant neoplasm of liver and intrahepatic bile ducts
C24.0 - C24.9 Malignant neoplasm of other and unspecified parts of biliary tract
C37 Malignant neoplasm of thymus
C38.4 Malignant neoplasm of pleura
C41.0 - C41.9 Malignant neoplasm of bone and articular cartilage of other and unspecified sites [chondrosarcoma]
C43.0 - C43.9 Malignant melanoma of skin
C45.0 - C45.9 Mesothelioma
C48.1 - C48.2 Malignant neoplasm of specified and unspecified parts of peritoneum
C49.9 Malignant neoplasm of connective and soft tissue, unspecified[soft tissue sarcoma]
C50.011 - C50.929 Malignant neoplasm of breast
C56.1 - C56.9 Malignant neoplasm of ovary
C57.00 - C57.02 Malignant neoplasm of fallopian tube
C61 Malignant neoplasm of prostate
C64.1 - C68.9 Malignant neoplasm of kidney and other and unspecified urinary organs
C67.0 - C67.9 Malignant neoplasm of bladder
C76.0 Malignant neoplasm of head, face and neck
C7A.092 Malignant carcinoid tumor of the stomach [gastric neuroendocrine carcinoma]
D03.0 - D03.9 Melanoma in situ
M05.00 - M06.9 Rheumatoid arthritis

The above policy is based on the following references:

  1. Abdel-Maged AE, Gad AM, Wahdan SA, Azab SS. Efficacy and safety of ramucirumab and methotrexate co-therapy in rheumatoid arthritis experimental model: Involvement of angiogenic and immunomodulatory signaling. Toxicol Appl Pharmacol. 2019;380:114702.
  2. Aprile G, Bonotto M, Ongaro E, et al. Critical appraisal of ramucirumab (IMC-1121B) for cancer treatment: From benchside to clinical use. Drugs. 2013;73(18):2003-2015.
  3. Aragon-Ching JB, Trump DL. Targeted therapies in the treatment of urothelial cancers. Urol Oncol. 2017;35(7):465-472.
  4. Arkenau HT, Martin-Liberal J, Calvo E, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced or metastatic biliary tract cancer: Nonrandomized, open-label, phase I trial (JVDF). Oncologist. 2018;23(12):1407-e136.
  5. Cao J, Ji D, Chen Z, et al. Phase I dose-escalation study of ramucirumab in Chinese patients with advanced solid tumors. Oncologist. 2017;22(6):638-e56. 
  6. Chow LQ, Smith DC, Tan AR, et al. Lack of pharmacokinetic drug-drug interaction between ramucirumab and paclitaxel in a phase II study of patients with advanced malignant solid tumors. Cancer Chemother Pharmacol. 2016;78(2):433-441.
  7. Eli Lilly & Co. Cyramza (ramucirumab) injection, for intravenous use. Prescribing Information. CYR-0003-USPI-20150424. Indianapolis, IN: Lilly; revised April 2015.
  8. Eli Lilly & Co. Lilly's Cyramza (ramucirumab) receives fourth FDA approval. Press Release. Indianapolis, IN: Lilly; April 24, 2015.
  9. Eli Lilly & Company. Cyramza (ramucirumab) injection, for intravenous use. Prescribing Information. Indianapolis, IN: Lilly; revised 2014.
  10. Eli Lilly and Company. Cyramza (ramucirumab) injection, for intravenous use. Prescribing Information. Indianapolis, IN: Eli Lilly and Company; revised November 2019.
  11. Fuchs CS, Tomasek J, Yong CJ; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31-39.
  12. Garcia JA, Hudes GR, Choueiri TK, et al. A phase 2, single-arm study of ramucirumab in patients with metastatic renal cell carcinoma with disease progression on or intolerance to tyrosine kinase inhibitor therapy. Cancer. 2014;120(11):1647-1655.
  13. Garcia-Carbonero R, Rivera F, Maurel J, et al. An open-label phase II study evaluating the safety and efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy for metastatic colorectal cancer. Oncologist. 2014;19(4):350-351.
  14. Garon EB, Cao D, Alexandris E, et al. A randomized, double-blind, phase III study of docetaxel and ramucirumab versus docetaxel and placebo in the treatment of stage IV non-small-cell lung cancer after disease progression after 1 previous platinum-based therapy (REVEL): Treatment rationale and study design. Clin Lung Cancer. 2012;13(6):505-509.
  15. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): A multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.
  16. Imbimbo M, Vitali M, Fabbri A, et al. RELEVENT Trial: Phase II trial of ramucirumab, carboplatin, and paclitaxel in previously untreated thymic carcinoma/B3 thymoma with area of carcinoma. Clin Lung Cancer. 2018;19(5):e811-e814.
  17. Ishikawa M, Iwasa S, Nagashima K, et al. Retrospective comparison of nab-paclitaxel plus ramucirumab and paclitaxel plus ramucirumab as second-line treatment for advanced gastric cancer focusing on peritoneal metastasis. Invest New Drugs. 2019 Jul 2 [Epub ahead of print].
  18. Jones RL, Katz D, Loggers ET, et al. Clinical benefit of antiangiogenic therapy in advanced and metastatic chondrosarcoma. Med Oncol. 2017;34(10):167.
  19. Kawazoe A, Shitara K. Trifluridine/tipiracil for the treatment of metastatic gastric cancer. Expert Rev Gastroenterol Hepatol. 2020 Jan 14:1-6 [Epub ahead of print].
  20. Koizumi N, Kobayashi H, Takagi T, Fukumoto K. An elderly case of recurrent neuroendocrine carcinoma of the stomach treated with ramucirumab. Gan To Kagaku Ryoho. 2018;45(3):557-559.
  21. Krupitskaya Y, Wakelee HA. Ramucirumab, a fully human mAb to the transmembrane signaling tyrosine kinase VEGFR-2 for the potential treatment of cancer. Curr Opin Investig Drugs. 2009;10(6):597-605.
  22. Mackey JR, Ramos-Vazquez M, Lipatov O, et al. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J Clin Oncol. 2015;33(2):141-148.
  23. Marquez-Medina D, Popat S. Closing faucets: The role of anti-angiogenic therapies in malignant pleural diseases. Clin Transl Oncol. 2016;18(8):760-768.
  24. Matsubara Y, Ando T, Hosokawa A, et al. Neuroendocrine carcinoma of the stomach: A response to combination chemotherapy consisting of ramucirumab plus paclitaxel. Intern Med. 2018;57(5):671-675.
  25. National Comprehensive Cancer Network (NCCN). Anal carcinoma. NCCN Clinical Practice Guidelines in Oncology. Version 2. 2018. Fort Washington, PA: NCCN; 2018.
  26. National Comprehensive Cancer Network (NCCN). Colon cancer. NCCN Clinical Practice Guidelines in Oncology. Version 1.2020. Fort Washington, PA: NCCN; 2019.
  27. National Comprehensive Cancer Network (NCCN). Esophageal and esophagogastric junction cancers. NCCN Clinical Practice Guidelines in Oncology. Version 4.2019. Fort Washington, PA: NCCN; 2019.
  28. National Comprehensive Cancer Network (NCCN). Gastric cancer. NCCN Clinical Practice Guidelines in Oncology. Version 4.2019. Fort Washington, PA: NCCN; 2019.
  29. National Comprehensive Cancer Network (NCCN). Hepatocellular Carcinoma. NCCN Clinical Practice Guidelines in Oncology, version 2.2019. Fort Washington, PA: NCCN; 2019.
  30. National Comprehensive Cancer Network (NCCN). Non-small cell lung cancer. NCCN Clinical Practice Guidelines in Oncology. Version 3. 2019. Fort Washington, PA: NCCN; 2019.
  31. National Comprehensive Cancer Network (NCCN). Rectal cancer. NCCN Clinical Practice Guidelines in Oncology. Version 1.2020. Fort Washington, PA: NCCN; 2019.
  32. Penson RT, Moore KM, Fleming GF, et al. A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. Gynecol Oncol. 2014;134(3):478-485.
  33. Petrylak DP, de Wit R, Chi KN, et al; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): A randomised, double-blind, phase 3 trial. Lancet. 2017;390(10109):2266-2277.
  34. Petrylak DP, Tagawa ST, Kohli M, et al. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: An open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016;34(13):1500-1509.
  35. Roviello G, Corona SP, Multari AG, et al. Poor outcome for patients with gastric cancer and lung metastases treated with ramucirumab and paclitaxel. Anticancer Drugs. 2019;30(7):e0789.
  36. Roviello G, Zanotti L, Cappelletti MR, et al. New molecular therapies in patients with advanced hepatocellular cancer in second line of treatment: Is a real defeat?: Results from a literature based meta-analysis of randomized trials. Crit Rev Oncol Hematol. 2016;108:62-68.
  37. Spratlin JL, Mulder KE, Mackey JR. Ramucirumab (IMC-1121B): A novel attack on angiogenesis. Future Oncol. 2010;6(7):1085-1094.
  38. Tovoli F, Lorenzo S, Barbera MA, et al. Postsorafenib systemic treatments for hepatocellular carcinoma: Questions and opportunities after the regorafenib trial. Future Oncol. 2017;13(21):1893-1905.
  39. U.S. Food and Drug Administration (FDA). FDA expands approved use of Cyramza to treat aggressive non-small cell lung cancer. Press Announcements. Silver Spring, MD: FDA; December 12, 2014.
  40. U.S. Food and Drug Administration (FDA). FDA approves Cyramza for stomach cancer. Press Announcement. Silver Spring, MD: FDA; April 21, 2014. 
  41. U.S. Food and Drug Administration (FDA). FDA approves ramucirumab for hepatocellular carcinoma. FDA News Release. Silver Spring, MD: FDA; May 10, 2019.
  42. Vahdat LT, Layman R, Yardley DA, et al. Randomized phase II study of ramucirumab or icrucumab in combination with capecitabine in patients with previously treated locally advanced or metastatic breast cancer. Oncologist. 2017;22(3):245-254.
  43. Wadhwa R, Elimova E, Shiozaki H, et al. Anti-angiogenic agent ramucirumab: Meaningful or marginal? Expert Rev Anticancer Ther. 2014;14(4):367-379.
  44. Zhu AX, Finn RS, Mulcahy M, et al. A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer. Clin Cancer Res. 2013;19(23):6614-6623.
  45. Zhu AX, Kang YK, Yen CJ, et al; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282-296.