CAM 117

Ramucirumab (Cyramza®)

Category:Prescription Drug   Last Reviewed:December 2019
Department(s):Medical Affairs   Next Review:December 2020
Original Date:December 2015    

Description
Ramucirumab is a fully human monoclonal antibody and angiogenesis inhibitor, also described as a VEGF receptor-2 antagonist that targets the VEGF-receptors to inhibit blood vessel structure, growth, and migration, thereby impeding sufficient blood flow necessary for tumor growth and survival.

Esophageal, Gastric, and Gastroesophageal Junction Adenocarcinoma
Gastric and esophageal cancers are rare. The National Cancer Institute (NCI) estimates 24,590 new cases and 10,720 deaths from gastric cancer in the United States in 2015. About 29% to 35% of gastric cancer cases have regional spread to lymph nodes or metastasis to distant sites. For esophageal cancer, the NCI estimates 16,980 new cases and 15,590 deaths will occur in 2015. Gastroesophageal junction adenocarcinoma, a form of cancer that is located in the region where the esophagus joins the stomach, is also rare, but equally lethal. Five-year survival rates for both cancers are relatively low; 17% for esophageal cancer and 28% for gastric cancer (Buas and Vaughan, 2013; Howlader, 2014). Treatments are aimed at extending OS, while also providing palliative and supportive care.

NSCLC
Lung cancer is the leading cause of death from cancer in the United States and worldwide, with advanced NSCLC representing the majority of these cases (Garon, 2014). The NCI estimates 224,210 new cases and 159,260 deaths from lung cancer (NSCLC and SCLC combined) in the United States in 2014. It has been estimated that only 16% of all individuals with lung cancer will survive 5 years or more following diagnosis.

Adverse Events and Warnings
A Black Box warning on the FDA Product Information (PI) Label for ramucirumab (Cyramza, 2015) states the following:

Warning: Hemorrhage, Gastrointestinal Perforation, and Impaired Wound Healing

  • Hemorrhage: Cyramza increased the risk of hemorrhage, and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue Cyramza in patients who experience severe bleeding.
  • Gastrointestinal Perforation: Permanently discontinue Cyramza in patients who experience a gastrointestinal perforation.
  • Impaired Wound Healing: Withhold Cyramza prior to surgery and discontinue Cyramza if a patient develops wound healing complications.

Additional Warnings from the FDA PI Label for ramucirumab (Cyramza, 2015) include:

  • Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in the clinical trials of Cyramza.
    • Permanently discontinue Cyramza in an individual who experiences a severe ATE.
  • Control hypertension prior to initiating treatment with Cyramza.
    • Monitor blood pressure every 2 weeks or more frequently as indicated during treatment.
    • Temporarily suspend Cyramza for severe hypertension and discontinue for hypertension that cannot be controlled with antihypertensive therapy or in individuals with hypertensive crisis or hypertensive encephalopathy.
  • Premedicate prior to each Cyramza infusion with an IV histamine H1 antagonist.
    • Monitor for signs and symptoms of infusion-related reactions.
    • For individuals who have experienced a Grade 1 or 2 infusion reaction, premedicate with dexamethasone and acetaminophen prior to each Cyramza infusion.
  • Cyramza may increase the risk of gastrointestinal perforation, a potentially fatal event.
    • Permanently discontinue Cyramza in an individual who experiences a gastrointestinal perforation.
  • Withhold Cyramza prior to surgery as it has the potential to adversely affect wound healing.
  • New onset or worsening encephalopathy, ascites, or hepatorenal syndrome can occur in an individual with Child-Pugh B or C cirrhosis.
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in the clinical trials of Cyramza.
    • Confirm the diagnosis of RPLS with an MRI.
    • Discontinue Cyramza in individuals who develop RPLS..

Policy 
Medically Necessary:

I.   Esophageal, Gastric, and Gastroesophageal Junction Adenocarcinoma

Ramucirumab is considered MEDICALLY NECESSARY as a single agent or in combination with paclitaxel for the treatment of individuals with advanced (non-resectable) or metastatic esophageal, gastric, or gastroesophageal junction adenocarcinoma with disease progression that occurs during or after fluoropyrimidine- or platinum-containing chemotherapy.

II.   Non-Small Cell Lung Cancer (NSCLC)

Ramucirumab is considered MEDICALLY NECESSARY in combination with docetaxel for the treatment of individuals with metastatic NSCLC when 1 of the following criteria is met:

  1. Individual does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberration, and the disease has progressed on or after platinum-containing chemotherapy; OR
  2. Individual has an EGFR or ALK genomic tumor aberration and both of the following criteria are met:
    1. Disease has progressed on a U.S. Food & Drug Administration (FDA)-approved therapy for these aberrations prior to receiving ramucirumab; and
    2. Disease has progressed on or after platinum-containing chemotherapy.

III.   Colorectal Cancer

Ramucirumab is considered MEDICALLY NECESSARY in combination with irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) for the treatment of individuals with metastatic colorectal cancer (mCRC) with disease progression that occurs during or after bevacizumab-, oxaliplatin-, and fluoropyrimidine-containing chemotherapy.

IV.  Hepatocellular Carcinoma

As a single agent, for the treatment of hepatocellular carcinoma in patients who have an alpha fetoprotein of ≥400 ng/mL and have been treated with sorafenib.

Investigational

Ramucirumab is considered INVESTIGATIONAL when the criteria are not met and for all other indications, including but not limited to:

  • Breast cancer
  • Genitourinary cancer
  • Metastatic melanoma
  • Ovarian, fallopian tube or primary peritoneal cancer
  • Renal cell cancer

Rationale
Gastric and Gastroesophageal Junction Adenocarcinoma
On April 14, 2014, ramucirumab was approved by the FDA as a single agent therapy for individuals with unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression during or after treatment with fluoropyrimidine- or platinum-containing chemotherapy. On November 5, 2014, ramucirumab was approved by the FDA for use in combination with paclitaxel for the treatment of individuals with unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression during or after treatment with fluoropyrimidine- or platinum-containing chemotherapy. 

The first pivotal trial (Fuchs, 2014) consisted of a multicenter, double-blind, randomized clinical study (phase III) (n=355) of individuals who had locally advanced or metastatic gastric (75%) or gastroesophageal junction adenocarcinoma (25%) and were previously treated with fluoropyrimidine- or platinum-containing chemotherapy. Subjects were required to have disease progression that occurred during treatment or within 4 months after the last dose of chemotherapy, or within 6 months after the last dose of adjuvant therapy. All subjects were randomized (2:1) to receive either single agent ramucirumab (n=238) (8 mg/kg over a 60-minute infusion occurring every 2 weeks) and best supportive care (BSC) or placebo (n=117) and BSC (placebo infusion administered every 2 weeks). The primary outcome measure was overall survival (OS). The median OS for the ramucirumab group was 5.2 months compared with 3.8 months for the placebo group (hazard ratio [HR]=0.78; 95% confidence interval [CI], 0.60-0.998; p=0.047). These results indicate that the risk of death was significantly reduced by 22% in the treatment group compared with placebo. Since quality of life (QOL) outcomes were not measured, the clinical significance of this magnitude of treatment effect is not known. However, based on the OS data, the study authors concluded that ramucirumab had significant and positive treatment effects in individuals previously treated with fluoropyrimidine- or platinum-containing chemotherapy.

The second pivotal trial (Wilke, 2014) consisted of a multicenter, double-blind, randomized clinical study (phase III) (n=656) in which subjects were randomized to receive either ramucirumab (8 mg/kg) plus paclitaxel (80 mg/m2) (n=330) orplacebo plus paclitaxel (80 mg/m2) (n=335). Subjects were adults with advanced gastric or gastroesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy. The primary outcome measure was OS, and secondary outcomes were progression-free survival (PFS) and the objective response rate. The median OS for the treatment group was 9.6 months (95% CI, 8.5-10.8) compared with 7.4 months for the placebo group (95% CI, 6.3-8.4) (HR=0.81; 95% CI, 0.68-0.96; p=0.017). The median PFS for the treatment group was 4.4 months (95% CI, 4.2-5.3) compared with 2.9 months for the placebo group (95% CI, 2.8-3.0) (HR=0.64; 95% CI, 0.54-0.75; p<0.001). Finally, the objective response rate for the treatment group was 28% (95% CI, 23-33) compared with 16% for the placebo group (95% CI, 13-22). The most commonly observed adverse events (Grade 3 or higher) for those treated with ramucirumab combined with paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. Since quality of life (QOL) outcomes were not measured, the clinical significance of the magnitude of treatment effects is not known. However, based on the OS data, the study authors concluded that ramucirumab combined with paclitaxel had significant and positive treatment effects in individuals previously treated with fluoropyrimidine- or platinum-containing chemotherapy, and may be considered as a new second-line treatment for individuals with advanced gastric cancer.

According to the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines (CPGs) for esophageal and esophagogastric junction cancer (2015) and for gastric cancer (2015), intravenous (IV) ramucirumab is a preferred option for second-line therapy as a single agent or in combination with paclitaxel (category 1) for individuals with unresectable locally advanced or metastatic esophagogastric junction (EGJ) or gastric adenocarcinoma.

Esophageal Adenocarcinoma
Esophageal cancer is the sixth most common cause of cancer deaths worldwide with adenocarcinoma more common in North America and Western European countries. Esophageal adenocarcinoma originates most often in the lower third of the esophagus, and may involve the EGJ. In January 2015, the NCCN Drugs and Biologics Compendium for ramucirumab and the NCCN CPG for esophageal and esophagogastric junction cancers updated their recommendations to include the off-FDA label use of ramucirumab as a single agent or in combination with paclitaxel as preferred second-line therapy for metastatic or locally advanced esophageal adenocarcinoma. The NCCN based this category 2A recommendation on uniform consensus and consideration of the recent FDA approvals of ramucirumab for EGJ and gastric adenocarcinoma. The peer-reviewed published literature for EGJ and gastric adenocarcinoma consists of the two pivotal clinical trials that included participants with EGJ adenocarcinoma, randomized to receive ramucirumab (Fuchs, 2014; n=60) or ramucirumab plus paclitaxel (Wilke, 2014; n=66). To date, there are no randomized controlled trials published that evaluate the use of ramucirumab specifically for esophageal adenocarcinoma.

NSCLC
On December 11, 2014, the FDA approved the use of ramucirumab in combination with docetaxel for the treatment of individuals with metastatic NSCLC who experience disease progression on or after platinum-based chemotherapy. The FDA also approved ramucirumab for the treatment of individuals with EGFR or ALK genomic tumor aberrations, who experience disease progression on FDA-approved therapy specific for these aberrations, before they receive treatment with ramucirumab.

The pivotal trial was a randomized, double-blind study (phase III) (n=1253) evaluating individuals with squamous or non-squamous NSCLC, who progressed during or after first-line platinum-based therapy for locally advanced or metastatic disease (Garon, 2014). Individuals were randomized to either ramucirumab (10 mg/kg) plus docetaxel (75 mg/m2) every 21 days, orplacebo plus docetaxel (75 mg/m2) every 21 days. Individuals received a median of 4.5 doses of ramucirumab with a median duration of 3.5 months. A total of 195 of 627 individuals (31%) received ramucirumab for at least 6 months. The primary outcome measure was OS and the secondary outcomes included PFS and the objective response rate. Study authors reported that OS was significantly improved in the ramucirumab treatment group compared with placebo. The median OS was 10.5 months for the treatment group compared with 9.1 months for the placebo group (HR=0.86; 95% CI, 0.75-0.98; p=0.024). Similarly, PFS was significantly improved in the treatment group compared with placebo. The median PFS was 4.5 months for the treatment group compared with 3.0 months for placebo (HR=0.76; 95% CI, 0.68-0.86; p<0.001).

The most commonly observed serious adverse events observed with ramucirumab plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). In individuals older than 65 years, there were 18 (8%) deaths during treatment or within 30 days of ending treatment compared with 9 (4%) deaths for placebo plus docetaxel. In individuals younger than age 65, there were 13 (3%) deaths during treatment or within 30 days of ending treatment with ramucirumab plus docetaxel compared with 26 (6%) deaths for placebo plus docetaxel. Treatment with ramucirumab resulted in significantly greater number of participants who discontinued treatment (9%) compared with the placebo group (5%).

Based on the results of this randomized controlled trial, study authors concluded that ramucirumab plus docetaxel offers a significant survival benefit as second-line treatment of individuals with advanced stage NSCLC.

Colorectal Cancer
On April 24, 2015, the FDA approved ramucirumab for use in combination with irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) for the treatment of an individual with metastatic colorectal cancer whose disease has progressed during or after bevacizumab-, oxaliplatin-, and fluoropyrimidine-containing chemotherapy. The safety and efficacy of ramucirumab for this use was based on the results of a randomised, double-blind, multinational trial of individuals with metastatic colorectal cancer that progressed during or within 6 months of discontinuation of bevacizumab-, oxaliplatin-, and fluoropyrimidine-based combination chemotherapy (Tabernero, 2015).

A total of 1072 participants were randomized to receive FOLFIRI plus placebo or FOLFIRI plus ramucirumab. The median age of the study population was 62 years, 57% were men, and 99% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Both study groups repeated treatment every 2 weeks; the treatment arm received 8 mg/kg of IV infused ramucirumab every 2 weeks until disease progression or unacceptable toxicity. The primary efficacy endpoint was reported as a statistically significant improvement observed in OS in those participants who received FOLFIRI plus ramucirumab compared to those who received FOLFIRI plus placebo (HR 0.85; 95% CI: 0.73, 0.98; p=0.023, stratified log-rank test). The median OS was 13.3 and 11.7 months for participants in the FOLFIRI plus ramucirumab compared to those in the FOLFIRI plus placebo arms, respectively. The median PFS was 5.7 months in participants in the FOLFIRI plus ramucirumab arm versus 4.5 months in those in the FOLFIRI  plus placebo arm (HR 0.79; 95% CI: 0.70, 0.90; p<0.001). Thyroid dysfunction (hypothyroidism) was reported in 2.6% of participants; however, the safety data was consistent with the known safety profile in the studies of previously approved FDA indications for ramucirumab.

Hepatocellular Carinoma
The efficacy of CYRAMZA was evaluated in REACH-2 (NCT02435433), a multinational, randomized, double-blind, placebo-controlled, multicenter study in patients with advanced HCC with AFP ≥400 ng/mL who had disease progression on or after prior sorafenib therapy or who were intolerant to sorafenib. Patients in REACH-2 were required to have ECOG PS of 0 or 1, Child-Pugh A, BCLC stage B and no longer amenable to locoregional therapy, or BCLC stage C. Patients were randomized (2:1) to receive CYRAMZA 8 mg/kg or placebo every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity. Randomization was stratified by geographic region, macrovascular invasion (yes versus no), and ECOG PS (0 versus 1). The major efficacy outcome measure was OS. Additional efficacy outcome measures included PFS and ORR based on investigator assessment.

A total of 292 patients were randomized, 197 to the CYRAMZA-treatment group and 95 to the placebo-treatment group. Baseline demographics and disease characteristics were similar between the arms. The median age was 64 years (range 26-88); 80% were men; 50% were Asian; 58% had ECOG PS 0; 35% had macrovascular invasion; 72% had extrahepatic spread; 17% were sorafenib intolerant, 37% had hepatitis B, 26% had hepatitis C, 24% had significant prior alcohol use, and 64% had prior locoregional therapy.

Efficacy results are shown in Table 12 and Figure 5.

Table 12: Efficacy Results in REACH-2

 

CYRAMZA + BSC
N=197

Placebo + BSC
N=95

Overall Survival

Number of deaths (%) 

147 (75%) 

74 (78%) 

Median – months (95% CI) 

8.5 (7.0, 10.6)

7.3 (5.4, 9.1)

Hazard Ratio (95% CI)

0.71 (0.53, 0.95) 

Stratified Log-rank p-value

0.020  

Progression-free Survival

Number of events (%)a 

172 (87%) 

86 (91%)

Median – months (95% CI)

2.8 (2.8, 4.1)

1.6 (1.5, 2.7)

Hazard Ratio (95% CI)

0.45 (0.34, 0.60)

Stratified Log-rank p-value 

<0.0001  

Overall Response Rate

Rate – percent (95% CI)

4.6% (1.7, 7.5)

1.1% (0, 3.1)

Abbreviations: BSC = best supportive care; CI = confidence interval
a  26 of 172 events in CYRAMZA-treated patients and 9 of 86 events in placebo-treated patients were deaths.
b  all responses were partial

Ramucirumab has been studied as second-line therapy in a phase II, single-arm trial of individuals (n=39) with metastatic renal cell cancer with disease progression on or intolerance to tyrosine kinase inhibitor (TKI) therapy (Garcia, 2014). Ramucirumab was associated with evidence of antitumor activity; however, the study did not meet the primary endpoint of ≥ 15% best "objective response rate" (ORR 5.1%; 95% CI, 0.6%-17.3%). In another phase II trial, individuals (n=60) with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer following ≥ 1 platinum-based chemotherapeutic regimen received ramucirumab at 2-week intervals. Antitumor activity was observed; however, the predetermined efficacy endpoints were not met, as the best overall response was reported as "partial" in 5% (3 of 60 participants), 56.7% (34 of 60 participants) had stable disease, and 33.3% (20 of 60 participants) had progressive disease (Penson, 2014).

Mackey and colleagues (2015) recently published the results of a randomized, placebo-controlled, phase III trial (ROSE/TRIO-12) evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in the treatment of individuals with unresectable, locally recurrent or metastatic breast cancer. A total of 1144 participants 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 plus ramucirumab or docetaxel plus placebo once every 3 weeks. Participants received treatment until disease progression, unacceptable toxicity, or other withdrawal criteria. The primary endpoint was investigator-assessed PFS. The median PFS in the ramucirumab plus docetaxel group was 9.5 months, compared with 8.2 months in participants who received placebo plus docetaxel (HR, 0.88; p=0.077). The median OS was 27.3 months in ramucirumab plus docetaxel group, compared with 27.2 months in participants who received placebo plus docetaxel (HR, 1.01; p=0.915). Significantly higher rates of toxicities were observed in participants receiving ramucirumab, including fatigue, febrile neutropenia, hypertension, palmar-plantar erythrodysesthesia syndrome, and stomatitis. The investigators concluded that the addition of ramucirumab to docetaxel in individuals with HER2-negative advanced breast cancer did not significantly improve important clinical outcomes.

In summary, the evidence in the peer-reviewed literature is insufficient to draw reasonable conclusions regarding the clinical safety and effectiveness of ramucirumab to improve net health outcomes for any of these non-FDA approved indications.

References 

  1. Buas MF, Vaughan TL. Epidemiology and risk factors for gastroesophageal junction tumors: understanding the rising incidence of this disease. Semin Radiat Oncol. 2013; 23(1):3-9.
  2. Carvajal RD, Wong MK, Thompson JA, et al. A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma. Eur J Cancer. 2014; 50(12):2099-2107.
  3. Chiorean EG, Hurwitz HI, Cohen RB, et al. Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors. Ann Oncol. 2015 Mar 18. [Epub ahead of print].
  4. Fuchs CS, Tomasek J, Yong CJ, et al.  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.
  5. 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.
  6. 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.
  7. 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 multicenter, double-blind, randomized phase 3 trial. Lancet. 2014; 384(9944): 665-673.
  8. 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.
  9. 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.
  10. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 Apr 10. [Epub ahead of print].
  11. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15(11):1224-1235.
  12. 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. 
  13. Cyramza [Product Information]. Indianapolis, IN. Eli Lilly and Company; July 2019. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125477s011lbl.pdf. Accessed on October 2019.
  14. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2011. Updated December 17, 2014. Available at: http://seer.cancer.gov/csr/1975_2011/. Accessed on April 27, 2015.
  15. National Comprehensive Cancer Network®. NCCN® Drugs & Biologic Compendium® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on April 27, 2015.
  16. NCCN Clinical Practice Guidelines in Oncology®. © 2015 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on April 27, 2015.
    • Esophageal and Esophagogastric Junction Cancers (V.1.2015). January 8, 2015.
    • Gastric Cancer (V.1.2015). January 8, 2015.
    • Non-Small Cell Lung Cancer (V.4.2015). January 30, 2015.
  17. Ramucirumab. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Accessed on November 2019.
  18. U.S. National Institutes of Health (NIH). ClinicalTrials.gov. Search: ramucirumab. Available at: https://www.clinicaltrials.gov/ct2/results?term=ramucirumab&Search=Search. Accessed on April 27, 2015.
  19.  National Cancer Institute (NCI). A to Z List of Cancers. Available at: http://www.cancer.gov/cancertopics/types/alphalist. Accessed on April 27, 2015.
    • Esophageal Cancer Treatment (PDQ®). Last modified February 18, 2015.
    • Gastric Cancer Treatment (PDQ). Last modified February 6, 2015.
    • Non-Small Lung Cancer Treatment (PDQ). Last modified August 6, 2014.

Coding Section 

Codes Number Description
HCPCS  J9308 Injection, ramucirumab, 5 mg
  150.0-150.9 Malignant neoplasm of esophagus
  151.0-151.9 Malignant neoplasm of stomach
  153.0-154.1 Malignant neoplasm of colon, rectosigmoid junction, rectum
  162.2-162.9 Malignant neoplasm of bronchus and lung
  197.0 Secondary malignant neoplasm of lung
  197.5 Secondary malignant neoplasm of large intestine and rectum
  197.8 Secondary malignant neoplasm of other digestive organs and spleen
  V10.03 Personal history of malignant neoplasm of esophagus
  V10.04 Personal history of malignant neoplasm of stomach
  V10.11 Personal history of malignant neoplasm of bronchus and lung
ICD-10-CM (effective 10/01/15) C15.3-C15.9 Malignant neoplasm of esophagus
  C16.0-C16.9 Malignant neoplasm of stomach
  C18.0-C20 Malignant neoplasm of colon, rectosigmoid junction, rectum
  C34.00-C34.92 Malignant neoplasm of bronchus and lung
  C78.00-C78.02 Secondary malignant neoplasm of lung
  C78.5 Secondary malignant neoplasm of large intestine and rectum
  C78.89 Secondary malignant neoplasm of other digestive organs
  Z85.01 Personal history of malignant neoplasm of esophagus
  Z85.028 Personal history of other malignant neoplasm of stomach
  Z85.118 Personal history of other malignant neoplasm of bronchus and lung

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

Dosage Information 
CYRAMZA® is a human vascular endothelial growth factor receptor 2 antagonist indicated

  • as a single agent or in combination with paclitaxel, for treatment of advanced gastric or gastro-esophageal junction adenocarcinoma, with disease proression on or after prior fluropyrimidine- or plastinum-containing chemotherapy.
  • in combination with docetaxel, for treatment of metastic non-small cell lung cancer 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.
  • in combination with FOLFIRI, for the treatment of metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and fluoropyrimidine.

Dosage and Administration
For intravenouse infusion only. Do not administer as an intravenous push or bolus. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2015 Forward     

12/02/2019 

Annual review, updating policy to allow medical necessity for use with hepatobiliary cancer. Also updating rationale and references. 

12/04/2018 

Annual review, no change to policy intent. 

12/7/2017 

Annual review, no change to policy intent.

12/01/2016 

Annual review, no change to policy. Updating coding.

12/14/2015

NEW POLICY


Go Back