Medical Policies - Prescription Drugs
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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb strength of recommendation or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.
When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.
Ramucirumab (Cyramza) may be considered medically necessary as a second line treatment (single agent, or in combination with paclitaxel) of unresectable locally advanced, recurrent or metastatic gastric adenocarcinoma, in patients with disease progression on or after prior fluoropyrimidine-or platinum-containing chemotherapy.
Ramucirumab (Cyramza) may be considered medically necessary as a second line treatment (single agent, or in combination with paclitaxel) of advanced or metastatic esophageal or gastro-esophageal junction (GEJ) adenocarcinoma, in patients with disease progression on or after prior fluoropyrimidine-or platinum-containing chemotherapy.
Ramucirumab (Cyramza) may be considered medically necessary (in combination with docetaxel), for treatment of metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy.
NOTE: Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Cyramza (e.g., Afatinib, Erlotinib, or Gefitinib for EGFR; Crizotinib or Ceritinib for ALK).
Ramucirumab (Cyramza) may be considered medically necessary in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) for the treatment of metastatic colorectal cancer in patients with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
Ramucirumab (Cyramza) is considered experimental, investigational and/or unproven
• As a first-line therapy for the gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma, or
• For the treatment of any other cancers or tumors, including, but not limited to:
Gastric (or stomach) cancer arises from the stomach lining. Histologically, adenocarcinoma constitutes 90% to 95% of all gastric malignancies. Though the incidence of gastric cancer in the U.S. has declined in the past few decades, survival rates are low because the majority of cases are diagnosed at a late stage. The incidence of gastric cancer increases with age. Median age at diagnosis is 69 years, with 50% of cases occurring between 65 and 85 years. An estimated 22,220 new cases and 10,990 deaths due to gastric cancer will occur in 2014. (1) Surgical resection is the standard of care for localized cancers of the upper gastrointestinal tract. However, the majority of patients are diagnosed with locally advanced tumors, regional lymph node involvement, or metastatic disease. (1)
On April 21, 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for the treatment of advanced gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma, as a single-agent after prior fluoropyrimidine- or platinum-containing chemotherapy. (4) Ramucirumab (brand name Cyramza) is a human, receptor-targeted antibody that blocks the VEGFR-2 (vascular endothelial growth factor receptor 2) and inhibits downstream signaling involved in the formation and maintenance of aberrant blood vessels that supply blood to tumors. (1)
Non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancer cases, and includes 2 major types: 1) non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma, and other cell types); and 2) squamous cell (epidermoid) carcinoma. Adenocarcinoma is the most common type of lung cancer seen in the U.S., and is also the most frequently occurring cell type in nonsmokers. Certain prognostic factors are predictive of survival in patients with NSCLC. Good prognostic indicators include early-stage disease at diagnosis, good performance status, no significant weight loss (not more than 5%) and female gender.
Generally, surgery provides the best chance of cure for patients with stage I or II disease. However, thoracic surgical oncology consultation should be part of the evaluation of the patient considered for curative local therapy. Treatment of NSCLC often involves some combination of surgical excision, radiation therapy, and chemotherapy. Specific targeted therapies have been developed for the treatment of advanced NSCLC, including:
• Bevacizumab (unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC and performance status (PS) 0 to 1, negative for either EGFR mutations or ALK gene rearrangements);
• Erlotinib (locally advanced or metastatic NSCLS after failure of at least one prior chemotherapy regimen);
• Atafinib (metastatic adenocarcinoma with sensitizing EGFR mutations);
• Crizotinib (locally advanced or metastatic NSCLC, positive for the ALK gene rearrangement);
• Certinib (ALK-positive metastatic NSCLC, progressed on or intolerant to crizotinib);
• Cetuximab (advanced NSCLC without EGFR mutations or ALK rearrangements).
On December 12, 2014, the FDA approved Cyramza in combination with docetaxel, for treatment of metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Cyramza. (4)
On April 24, 2015, the US FDA approved Cyramza for use in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) for the treatment of metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
This medical policy was originally developed in 2014 and has been updated with searches of scientific literature through August 2017. The following is a summary of the key literature to date.
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 NSCLI clinical trials have shown safety across a wide range of ramucirumab doses with impressive, evidence of both stable disease and partial responses in a variety of tumor types (2).
The evidence base for the proposed indication for ramucirumab consists of 2 pivotal trials: REGARD and RAINBOW.
Gastric, Esophageal and Esophagogastric Junction Cancer
In an international, randomized, multi-center, placebo-controlled, phase III clinical trial (the REGARD trial), Fuchs et al. (3) 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 junction (GEJ) 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 GEJ adenocarcinoma progressing after first-line chemotherapy. They stated that these findings validated V-2 signaling as an important therapeutic target in advanced gastric cancer.
In 2014, Wilke et al. (5) reported the results of the RAINBOW study in an abstract presented at the 2014 Gastrointestinal Cancers Symposium. In the RAINBOW trial, the authors conducted a global, placebo-controlled, double-blind, phase III trial to evaluate the efficacy and safety of paclitaxel (PTX) +/- ramucirumab (RAM) in patients with metastatic GEJ or gastric adenocarcinoma who had disease progression on or within 4 months after first-line platinum- and fluoropyrimidine-based combination therapy. Patients received ramucirumab (8 mg/kg IV q2wk) or placebo (PL), plus PTX (80 mg/m2 day 1, 8, 15 of a 4-week cycle) until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), time to progression (TTP), and safety. From Dec 2010 to Sep 2012, 665 patients were randomized (RAM+PTX: 330; PTX: 335). Baseline characteristics were generally balanced between arms. The OS hazard ratio (HR) was 0.807 (95% CI 0.678, 0.962; p=0.0169). Median OS was 9.63 months for RAM+PTX and 7.36 months for PTX. The HR for PFS was 0.635 (95% CI 0.536, 0.752; p <0.0001). Median PFS was 4.40 months and 2.86 months. Median TTP was 5.5 months RAM+PTX; 3.0 months PTX (p <0.0001). ORR was 28% RAM+PTX; 16% PTX (p=0.0001). Grade 3 adverse events (AEs) occurring in >5% of patients on RAM+PTX were: neutropenia (40.7% RAM+PTX; 18.8% PTX), leukopenia (17.4% vs 6.7%), hypertension (14.1% vs 2.4%), anemia (9.2% vs 10.3%), fatigue (7.0% vs 4.0%), abdominal pain (5.5% vs 3.3%), and asthenia (5.5% vs 3.3%). Febrile neutropenia was reported in 3.1% RAM+PTX; 2.4% PTX. The authors concluded the primary endpoint of improved OS was met. A statistically significant and clinically meaningful OS benefit of > 2 months was observed for RAM+PTX vs. PTX in gastric and GEJ cancer after progression on 1st-line therapy, as were significant benefits in PFS and ORR. Neutropenia was more frequently reported in the RAM+PTX arm but incidence of febrile neutropenia was comparable between arms. (NCT01170663).
National Comprehensive Cancer Network (NCCN)
The National Comprehensive Cancer Network (NCCN) Gastric Cancer Guideline 3.2017 (6) was revised to list ramucirumab single agent or in combination with paclitaxel as options for second line therapy in patients with unresectable locally advanced, recurrent, or metastatic gastric cancer
The NCCN Esophageal and Esophagogastric Junction Cancer Guideline 2.2017 (7) was revised to list ramucirumab single agent or in combination with paclitaxel as options for second line therapy in patients with advanced or metastatic esophageal or esophagogastric (EGJ) adenocarcinoma (category 1 for EGJ adenocarcinoma and category 2A for esophageal adenocarcinoma).
Non-Small Cell Lung Cancer (NSCLC)
The FDA approval of Cyramza plus docetaxel for metastatic NSCLC was based on the randomized, REVEL trial (15) of 1,253 participants with previously treated and progressive lung cancer. The trial was designed to measure overall survival, the length of time a participant lived before death. Treatment with ramucirumab plus docetaxel compared with placebo plus docetaxel in patients with squamous or nonsquamous non-small cell lung cancer who had progressed during or after first-line platinum-based chemotherapy, resulted in significantly better median overall survival (10.5 vs 9.1 months), median progression-free survival (4.5 vs 3 months), and overall response rate (23% vs 14%) (N=1253). Additionally, the addition of ramucirumab did not significantly adversely affect patient self-reported symptoms and quality of life according to the total Lung Cancer Symptom Scale (LCSS) score from baseline to 30 days after treatment completion compared with docetaxel monotherapy (27.3 to 32 mm vs 29.6 to 32.5 mm) or the clinician-reported patient functioning evaluated with the Average Symptom Burden Index (24.6 to 27.6 mm vs 26.8 to 28.4 mm). An improved or stable total LCSS score was achieved in 94.9% with combination therapy and 93.9% with docetaxel monotherapy.
National Comprehensive Cancer Network (NCCN)
In version 7.2017 of the NCCN guideline on NSCLC (13), the NCCN recommends ramucirumab in combination with docetaxel as an option for subsequent therapy for metastatic NSCLC that has progressed after first line chemotherapy (2A recommendation).
Colorectal Cancer (CRC)
The FDA label describes the study for CRC as multinational, randomized, double-blind, study of Cyramza plus FOLFIRI versus placebo plus FOLFIRI, in patients with metastatic CRC, who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. The randomized RAISE study (N=1072) involved patients with metastatic colorectal cancer that had progressed during or within 6 months after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 and along with having disease progression within 6 months of the last dose of first-line therapy. The 1072 patients were randomized (1:1) to receive either Cyramza (n=536) at 8 mg/kg as an intravenous infusion or placebo (n=536), in combination with FOLFIRI: irinotecan 180 mg/m2 administered intravenously over 90 minutes and folinic acid 400 mg/m2 administered intravenously simultaneously over 120 minutes; followed by 5-fluorouracil 400 mg/m2 intravenous bolus over 2 to 4 minutes; followed by 5-fluorouracil 2400 mg/m2 administered intravenously by continuous infusion over 46 to 48 hours. Treatment cycles on both arms were repeated every 2 weeks. Patients who discontinued one or more components of treatment because of an adverse event were permitted to continue therapy with the other treatment component(s) until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression free survival. Randomization was stratified by geographic region, tumor KRAS status, and time to disease progression after beginning first-line treatment (<6 months versus ≥6 months). Demographic and baseline characteristics were similar between treatment arms. Median age was 62 years; 57% of patients were men; 76% were White and 20% Asian; 49% had ECOG PS 0; 49% of patients had KRAS mutant tumors; and 24% of patients had <6 months from time to disease progression after beginning first-line treatment.
Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive Cyramza plus FOLFIRI compared to patients randomized to receive placebo plus FOLFIRI. The treatment effect was consistent across the pre-specified stratification factors.
National Comprehensive Cancer Network (NCCN)
In version 2.2017 of the NCCN Guideline on Colon Cancer (14), the NCCN recommends ramucirumab as a second line treatment option in combination with FOLFIRI or irinotecan following progression on therapy not containing irinotecan (2A recommendation).
Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.
Disclaimer for coding information on Medical Policies
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.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.
The following codes may be applicable to this Medical policy and may not be all inclusive.
ICD-9 Diagnosis Codes
Refer to the ICD-9-CM manual
ICD-9 Procedure Codes
Refer to the ICD-9-CM manual
ICD-10 Diagnosis Codes
Refer to the ICD-10-CM manual
ICD-10 Procedure Codes
Refer to the ICD-10-CM manual
The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
1. Ramucirumab. TEC Specialty Pharmacy Report. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (March 2014) :1-28.
2. Spratlin JL, Mulder KE, Mackey JR. Ramucirumab (IMC-1121B): A novel attack on angiogenesis. Future Oncol. 2010; 6(7):1085-1094. PMID: 20624120
3. Fuchs CS, Tomasek J, Yong CJ. REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-esophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014; 383(9911):31-39. PMID: 24094768
4. U.S. Food and Drug Administration. Cyranza product label. Approval April 24, 2014. Available at: http://www.fda.gov (accessed August 7, 2017).
5. Wilke H, Van Cutsem E, et al. RAINBOW: A global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (14T-IE-JVBE). 2014 Gastrointestinal Cancers Symposium January 16-18, 2014. J Clin Oncol 2014; 32(suppl 3; abstr LBA7). ©American Society of Clinical Oncology.
6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), National Comprehensive Cancer Network. Gastric Cancer Version 3.2017. Available at <www.NCCN.org> (accessed September 8, 2017).
7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), National Comprehensive Cancer Network. Esophageal and Esophagogastric Junction Cancers Version 2.2017. Available at <www.NCCN.org> (accessed September 8, 2017).
8. 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. PMID: 24674871
9. Wadhwa R, Elimova E, Shiozaki H, et al. Anti-angiogenic agent ramucirumab: Meaningful or marginal? Expert Rev Anticancer Ther. 2014; 14(4):367-379. PMID: 24605771
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 Feb 27. PMID: 24577874
11. 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. PMID: 22853980
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. PMID: 24088738
13. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), National Comprehensive Cancer Network. Non-Small Cell Lung Cancer Version 8.2017. in Oncology (NCCN Guidelines®), National Comprehensive Cancer Network. Available at <http://www.nccn.org> (accessed September 8, 2017).
14. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), National Comprehensive Cancer Network. Colon Cancer Version 2.2017. Available at <www.NCCN.org> (accessed September 8, 2017).
15. Garon EB, Ciuleanu TE, Arrieta O, et al: Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384(9944):665-673. PMID: 24933332
|10/15/2018||Reviewed. No changes.|
|11/1/2017||Document updated with literature review. Coverage statement reformatted to add a new indication for advanced or metastatic esophageal cancer and the criteria wording “locally advanced” and “recurrent” added to the existing coverage statement for gastric cancer. For colorectal cancer, FOLFIRI was further defined by adding the wording “irinotecan, folinic acid, and 5-fluorouracil”.|
|11/1/2016||Reviewed. No changes.|
|7/15/2015||Document updated with literature review. The following was added to Coverage: Ramucirumab (Cyramza) may be considered medically necessary 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.|
|3/15/2015||Document updated with literature review. The following was added to Coverage: Ramucirumab (Cyramza) may be considered medically necessary, in combination with docetaxel, for treatment of metastatic nonsmall cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. NOTE: Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Cyramza (e.g., Afatinib, Erlotinib, or Gefitinib for EGFR; Crizotinib or Ceritinib for ALK).|
|10/1/2014||New medical document. Coverage states the following: 1) Ramucirumab (Cyramza) may be considered medically necessary for the treatment of unresectable or metastatic gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma with disease progression when the following criteria are met: a) It is given as second-line therapy on or after fluoropyrimidine- or platinum-containing chemotherapy; AND b) It is given as a single agent or as a dual-agent with paclitaxel. 2) Ramucirumab (Cyramza) is considered experimental, investigational and/or unproven a) As a first-line therapy for the gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma; or b) For the treatment of any other cancers or tumors, including, but not limited to breast cancer, colorectal cancer, genitourinary tumor, hepatocellular cancer, lung carcinoma (including non-small-cell lung cancer), melanoma, ovarian cancer, prostate cancer, or renal cell carcinoma.|