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Ramucirumab (Cyramza)

Number: 0883



Policy

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

  • Palliative therapy for patients with Karnofsky performance score ≥60% or ECOG performance score ≤2 as a single agent or in combination with paclitaxel as second-line therapy for esophageal adenocarcinoma, esophagogastric junction (EGJ) adenocarcinoma, or gastric adenocarcinoma; 
  • Subsequent therapy in combination with docetaxel for metastatic non-small cell lung cancer (NSCLC) following progression on a cytotoxic regimen for patients with performance status 0-2 who have not previously received docetaxel.
  • 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.

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

  • Breast cancer
  • Genitourinary tumor
  • Fallopian tube cancer
  • Hepatocellular cancer
  • Melanoma
  • Ovarian cancer
  • Peritoneal carcinoma
  • Prostate cancer
  • Renal cell 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.  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).

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) Drug and Biologics Compendium (NCCN, 2015) recommends ramucirumab as palliative therapy for patients with Karnofsky performance score ≥60% or ECOG performance score ≤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 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 progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), patient-reported outcomes, and assessment of safety and tolerability of ramucirumab.  Eligible patients (enrollment n = 1,242) are randomized at a 1:1 ratio to receive either docetaxel (75 mg/m(2)) plus ramucirumab (10 mg/kg) (Arm A) or docetaxel (75 mg/m(2)) plus placebo (Arm B).  Both drugs are administered via intravenous infusion once every 3 weeks until evidence of disease progression, unacceptable toxicity, non-compliance, or patient's consent withdrawal.  Safety and effectiveness will be compared between the study arms and in patient subgroups including patients with non-squamous versus squamous tumor histology and patients who received prior bevacizumab treatment.  Multiple blood and tumor tissue biomarker samples are collected during the study.  The goal of the REVEL study is to demonstrate that ramucirumab in combination with docetaxel improves OS of patients with NSCLC with progressive disease after first-line therapy, and to advance the knowledge of the role of angiogenesis blockade in patients with NSCLC by identifying patients who are likely to experience maximum benefit based on extensive clinical biomarker correlative analysis.

The NCCN Drug and Biologics Compendium (NCCN, 2015) recommends ramucirumab for subsequent therapy in combination with docetaxel for metastatic non-small cell lung cancer following progression on a cytotoxic regimen for patients with performance status 0-2 who have not previously received docetaxel.

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.

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 (2014) 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.

Appendix

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.
CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB :
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:
C9025 Injection, ramucirumab, 5 mg
Other HCPCS codes related to the CPB:
J8520 Capecitabine, oral, 150 mg
J8521 Capecitabine, oral, 500 mg
J9035 Injection, bevacizumab, 10 mg
J9190 Injection, fluorouracil, 500 mg
J9263 Injection, oxaliplatin, 0.5 mg
J9400 Injection, ziv-alfibercept, 1mg
ICD-9 codes covered if selection criteria are met:
150.0 - 152.9, 153.0 - 154.1, 157.0 - 157.9 Malignant Neoplasm of esophagus, stomach, small intestine (including duodenum), colon, rectosigmoid junction, rectum, and pancreas [unresectable or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma with
162.2 – 162.9 Malignant neoplasm of bronchus, and lung [non-small cell lung cancer]
ICD-9 codes not covered for indications listed in the CPB (not all inclusive list):
154.0 - 154.8 Malignant neoplasm of rectum, rectosigmoid junction, and anus
155.0 - 155.2 Malignant neoplasm of liver and intrahepatic bile ducts
158.8 - 158.9 Malignant neoplasm of specified and unspecified parts of peritoneum
163.0 - 163.9 Malignant neoplasm of pleura
172.0 - 172.9 Malignant melanoma of skin
174.0 - 174.9 Malignant neoplasm of female breast
175.0 - 175.9 Malignant neoplasm of male breast
183.0 Malignant neoplasm of ovary
183.2 Malignant neoplasm of fallopian tube
185 Malignant neoplasm of prostate
188.0 - 188.9 Malignant neoplasm of bladder
189.0 - 189.9 Malignant neoplasm of kidney and other and unspecified urinary organs
CPT Codes / HCPCS Codes / ICD-9 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015:
Other CPT codes related to the CPB :
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:
C9025 Injection, ramucirumab, 5 mg
Other HCPCS codes related to the CPB:
J8520 Capecitabine, oral, 150 mg
J8521 Capecitabine, oral, 500 mg
J9035 Injection, bevacizumab, 10 mg
J9190 Injection, fluorouracil, 500 mg
J9263 Injection, oxaliplatin, 0.5 mg
J9400 Injection, ziv-alfibercept, 1mg
ICD-10 codes covered if selection criteria are met:
C15.3 - C20, C25.0 - C25.9 Malignant Neoplasm of esophagus, stomach, small intestine (including duodenum), colon, rectosigmoid junction, rectum, and pancreas [unresectable or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy]
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):
C21.0 - C21.8 Malignant neoplasm of anus
C22.0 - C22.9 Malignant neoplasm of liver and intrahepatic bile ducts
C38.4 Malignant neoplasm of pleura
C43.0 - C43.9 Malignant melanoma of skin
C48.1 - C48.2 Malignant neoplasm of specified and unspecified parts of peritoneum
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
D03.0 - D03.9 Melanoma in situ


The above policy is based on the following references:
    1. 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.
    2. Spratlin JL, Mulder KE, Mackey JR. Ramucirumab (IMC-1121B): A novel attack on angiogenesis. Future Oncol. 2010;6(7):1085-1094.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. U.S. Food and Drug Administration (FDA). FDA approves Cyramza for stomach cancer. Press Announcement. Silver Spring, MD: FDA; April 21, 2014. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm394107.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery. Accessed April 23, 2014.
    8. Wadhwa R, Elimova E, Shiozaki H, et al. Anti-angiogenic agent ramucirumab: Meaningful or marginal? Expert Rev Anticancer Ther. 2014;14(4):367-379.
    9. 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.
    10. 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.
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