Ramucirumab (Cyramza)

Number: 0883

Policy

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

• Palliative therapy for individuals with Karnofsky performance score geater than or equal to 60 % or Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to 2 as a single agent or in combination with paclitaxel as second-line therapy for esophageal adenocarcinoma, esopha-gogastric junction (EGJ) adenocarcinoma, or gastric adenocarcinoma; or
• Subsequent therapy (if not already given) in combination with docetaxel for metastatic non-small cell lung cancer (NSCLC) in persons with ECOG performance status 0 to 2 who have not previously received docetaxel
  
  
  • following progression on a first-line cytotoxic regimen; or
    
  • for further progression on a systemic immune checkpoint inhibitor or other systemic therapy; or 
    
    
• In combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) or irinotecan for the treatment of colorectal cancer, small intestine adenocarcinoma, appendiceal adenocarcinoma, and anal adenocarcinoma as
  
  
  • primary treatment for persons 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; or
    • in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen; or
  • subsequent therapy after first progression for unresectable advanced or metastatic disease in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen for disease not previously treated with irinotecan-based regimens. 

Aetna considers ramucirumab therapy not medically necessary for members that have experienced disease progression while on ramucirumab.

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
• Hepatocellular cancer
• Malignant pleural diseases (e.g., mesothelioma)
• Melanoma
• Ovarian cancer
• Peritoneal carcinoma
• Prostate cancer
• Renal cell carcinoma
• Soft tissue sarcoma
• Thymic carcinoma.

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 (1) the treatment of advanced or metastatic gastric cancer or gastro‐esophageal junction adenocarcinoma, as a single‐agent, or in combination with paclitaxel, on or after prior fluoropyrimidine‐ or platinum‐containing chemotherapy; (2) in combination with docetaxel, for the treatment of patients with metastatic non‐small cell lung cancer (NSCLC) with disease progression on or after platinum‐based chemotherapy; (3) in combination with FOLFIRI, for the treatment of metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

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.

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.

The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium (NCCN, 2018) recommends ramucirumab as palliative therapy for patients with Karnofsky performance score greater than or equal to 60% or ECOG performance score less than or equal to 2 as a single agent or in combination with paclitaxel as preferred second-line therapy for esophageal adenocarcinoma, esophagogastric junction (EGJ) adenocarcinoma, or gastric adenocarcinoma.

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.

The NCCN Drug and Biologics Compendium (NCCN, 2018) recommends ramucirumab as subsequent therapy (if not already given) in combination with docetaxel for metastatic non-small cell lung cancer (adenocarcinoma (with mixed subtypes); squamous cell carcinoma; large cell carcinoma) in patients with performance status 0-2 who have not previously received docetaxel

• Following progression on a first-line cytotoxic regimen
• For further progression on a systemic immune checkpoint inhibitor or other systemic therapy. 

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.

The NCCN Drugs and Biologics Compendium (NCCN, 2018) recommend ramucirumab in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen for colorectal cancer as

• Therapy for patients with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months
• Subsequent therapy after first progression for unresectable advanced or metastatic disease for disease not previously treated with irinotecan-based regimens.

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.

Other Indications

NCCN guidelines on colon cancer (NCCN, 2018) 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, 2018) state that anal adenocarcinoma is managed with NCCN guidelines for rectal cancer.

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.

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.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) does not list bladder cancer as a recommended indication of ramucirumab.

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).

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) does not list chondrosarcoma as a recommended indication of ramucirumab.

Head and Neck Cancer

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.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) does not list malignant pleural mesothelioma as a recommended indication of ramucirumab.

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.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) does not list soft tissue sarcoma as a recommended indication of ramucirumab.

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.

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.

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.

Appendix

Recommended Dosing

Ramucirumab is available as Cyramza in 100-mg and 500-mg vials.

The recommended dose of Cyramza (ramucirumab) for colorectal cancer is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue Cyramza (ramucirumab) until disease progression or unacceptable toxicity.

The recommended dose of Cyramza (ramucirumab) for non-small cell lung cancer is 10 mg/kg on day 1 of a 21‐day cycle administered as an intravenous infusion over 60 minutes. Continue Cyramza (ramucirumab) until disease progression or unacceptable toxicity.

The recommended dose of Cyramza (ramucirumab) for gastric cancer is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue Cyramza (ramucirumab) until disease progression or unacceptable toxicity.

Please reference the Prescribing Information for specific recommendations regarding dose modifications secondary to toxicity.

Karnofsky Performance Status Scale

• 100 - Normal; no complaints; no evidence of disease.
• 90 - Able to carry on normal activity; minor signs or symptoms of disease.
• 80 - Normal activity with effort; some signs or symptoms of disease.
• 70 - Cares for self; unable to carry on normal activity or to do active work.
• 60 - Requires occasional assistance, but is able to care for most of his personal needs.
• 50 - Requires considerable assistance and frequent medical care.
• 40 - Disabled; requires special care and assistance.
• 30 - Severely disabled; hospital admission is indicated although death not imminent.
• 20 - Very sick; hospital admission necessary; active supportive treatment necessary.
• 10 - Moribund; fatal processes progressing rapidly.
• 0 - Dead.

Eastern Cooperative Oncology Group (ECOG)Score

• 0 - Asymptomatic (Fully active, able to carry on all predisease activities without restriction)
• 1 - Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work)
• 2 - Symptomatic, <50% in bed during the day (Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours)
• 3 - Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours)
• 4 - Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair)
• 5 - Death.
  
  

The above policy is based on the following references: