Coverage Policy Manual
Policy #: 2017016
Category: Pharmacy
Initiated: May 2017
Last Review: May 2018
  Ramucirumab (Cyramza™)

Description:
Ramucirumab is a fully human monoclonal antibody, that binds to VEGFR2 on the extracellular domain of endothelial cells.  This inhibits activation of VEGFR2, which causes cell proliferation and migration of human endothelial cells to be inhibited.  (Clinical Pharmacology, 2017).  
 
Regulatory Status
Cyramza™ was initially approved by the FDA in April 2014 as monotherapy for advanced or metastatic gastric or gastro-esophageal junction (GEJ) adenocarcinoma; approval was expanded in late 2014 for the treatment of GEJ adenocarcinoma in combination with paclitaxel and for metastatic non-small cell lung cancer (NSCLC) in combination with docetaxel, and then again in April 2015 for the treatment of metastatic colorectal cancer (mCRC) in combination with FOLFIRI. (U.S. Food and Drug Administration 2014 & 2015).
 
In April 2014 the FDA included a “black box warning” in the labeling indicating that Cyramza increased the risk of hemorrhage and GI hemorrhage including severe, sometimes fatal events. In April 2015 they expanded “black box warning’ to include an increase of risk of GI perforation and impaired wound healing that was due to antibodies inhibiting the VEGF pathway.  

Policy/
Coverage:
Effective May 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Ramucirumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
 
FDA labeled
 
  1.  Gastric Cancer, for the treatment of advanced gastric or gastro-esophageal junction adenocarcinoma,  
      • with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy,
      • as a single agent or in combination with paclitaxel.
 
2. Non-Small Cell Lung Cancer, for the treatment of metastatic non-small cell lung cancer
      • with disease progression on or after platinum-based chemotherapy
      • in combination with docetaxel.
 
Note: Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab
 
3. Colorectal Cancer, for the treatment of metastatic colorectal cancer
      • with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine,
      • in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen.
 
Off – Label
    1. Colon Cancer
Primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (Capecitabine and oxaliplatin) within the past 12 months
        • in combination with irinotecan or
        • in combination with FOLFIRI (fluorouracil, leucovorin and irinotecan) regimen.
Subsequent therapy for progression of unresectable advanced or metastatic disease
        • in combination with irinotecan or
        • with FOLFIFI (fluorouracil, leucovorin and irinotecan) regimen in patient not previously treated with irinotecan-based therapy.  
 
2. Esophageal and Esophagogastric Junction Cancers
Palliative therapy for patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic adenocarcinoma and
        • a Karnofsky performance score >60% or ECOG performance score <2 or
        • as a preferred second-line or subsequent therapy as a single agent or in combination with paclitaxel.  
 
3. Gastric Cancer
Palliative therapy for patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and
        • a Karnofsky performance score >60% or ECOG performance score <2
        • as a preferred second-line or subsequent therapy as a single agent or in combination with paclitaxel.  
 
4. Non-Small Cell Lung Cancer
Subsequent therapy (if not already given) in combination with docetaxel for metastatic disease in patients with performance status 0-2 who have not previously received docetaxel
        • following progression on initial cytotoxic therapy.
        • for further progression on a systemic immune checkpoint inhibitor or other systemic therapy.
5. Rectal Cancer
As primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (Capecitabine and oxaliplatin) within the past 12 months
        • in combination with irinotecan.
        • in combination with FOLFIRI (fluorouracil, leucovorin and irinotecan) regimen.
 
            Subsequent therapy for progression of unresectable advanced or metastatic disease in
            combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan)
            regimen in patients not previously treated with irinotecan-based regimens.
 
Dosing:
Gastric Cancer
      • The recommended dose of Cyramza either as a single agent or in combination with weekly paclitaxel is 8mg/kg every 2 weeks administered as an IV infusion over 60 mins.  Continue Cyramza until disease progression or unacceptable toxicity.
      • When given in combination, administer Cyramza prior to administration of paclitaxel.
Non-Small Cell Lung Cancer
      • The recommended dose of Cyramza is 10mg/kg administered by IV infusion over 60 mins on day 1 of a 21-day cycle prior to docetaxel infusion.  Continue Cyramza until progression or unacceptable toxicity.
Colorectal Cancer
The recommended dose of Cyramza is 8 mg/kg every 2 weeks administered by IV over 60 mins prior to FOLFIRI administration.  Continue Cyramza until progression or unacceptable toxicity.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of Ramucirumab for the treatment of any other indications or any other circumstances than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Coverage Prior to May 2018
 Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
Ramucirumab meets primary coverage criteria and is covered for treatment for the following listed
indications:
 
FDA labeled (2017)
 
1. Gastric Cancer, for the treatment of advanced gastric or gastro-esophageal junction
     adenocarcinoma,
· with disease progression on or after prior fluoropyrimidine- or platinum-containing
               chemotherapy,
· as a single agent or in combination with paclitaxel.
 
2. Non-Small Cell Lung Cancer, for the treatment of metastatic non-small cell lung cancer
· with disease progression on or after platinum-based chemotherapy
· in combination with docetaxel.
 
Note: Patients with EGFR or ALK genomic tumor aberrations should have disease
progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab
 
3. Colorectal Cancer, for the treatment of metastatic colorectal cancer
· with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a
             fluoropyrimidine,
· in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen.
 
 
Off-label (2017)
 
  1. Colon cancer,
      • as primary treatment for patients with unresectable metachronous metastases
· previous adjuvant treatment with 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
         
      •  as subsequent therapy after first progression for unresectable advanced or metastatic
                    disease
· for disease not previously treated with irinotecan-based therapy
· in combination with irinotecan OR with FOLFIRI (fluorouracil, leucovorin, and
  rinotecan) regimen
2. Esophageal and Esophagogastric Junction Cancers
      •  as palliative therapy for patients with unresectable locally advanced, recurrent, or metastatic
              esophageal or esophagogastric junction (EGJ) adenocarcinoma and
      •  Karnofsky performance score •60% or ECOG performance score •2
      • as preferred second-line therapy as a single agent or in combination with paclitaxel
 
3. Gastric Cancer
      • as palliative therapy for patients who are not surgical candidates or have unresectable
             locally advanced, recurrent, or metastatic disease and
      • Karnofsky performance score •60% or ECOG performance score •2
      • as preferred second-line therapy as a single agent or in combination with paclitaxel
 
4. Rectal Cancer
      • As primary treatment for patients with unresectable metachronous metastases and previous
            adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and
            oxaliplatin) within the past 12 months
          • in combination with irinotecan
 
      • Subsequent therapy after first progression for unresectable advanced or metastatic disease
             for disease not previously treated with irinotecan-based regimens
          •  in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and
                           irinotecan) regimen
 
Dosing:
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of
less than 10mg/kg ever 2 weeks
 
Ramucirumab is given as an IV infusion over 60 minutes.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Ramucirumab for the treatment of any other indications or any other circumstances than
those outlined above does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of Ramucirumab for the
treatment of any other indications or any other circumstances than those outlined above is considered
investigational.  Investigational services are specific contract exclusions in most member benefit
certificates of coverage.
 

Rationale:
Gastric Cancer
Fuchs et al (2014) published the results of the phase III REGARD trial which was a multinational, randomized, double-blind, multicenter study of Ramucirumab plus best supportive care (BSC) versus placebo plus BSC. 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction [GEJ]) who previously received platinum- or fluoropyrimidine-containing chemotherapy were randomized 2:1 between the two treatment arms of those receiving Ramucirumab plus BSC (n=238) and those receiving Placebo plus BSC (n=117) intravenously every 2 weeks. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy or within 6 months after the last dose of adjuvant therapy. Patients were also required to have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.   Median overall survival was 5.2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3.8 months (1·7-7·1) in those in the placebo group (hazard ratio. The authors concluded that Ramucirumab has survival benefits in patients with advanced gastric or GEF adenocarcinoma progressing after first-line chemotherapy.  
 
Al-Batran et al (2016) published the results of a phase III RAINBOW trial that was a multinational, randomized, double-blind study of Ramucirumab plus paclitaxel versus placebo plus paclitaxel.  665 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction) who previously received platinum- and fluoropyrimidine-containing chemotherapy were randomized 1:1 between the two treatment arms of those receiving Ramucirumab plus paclitaxel (n=330) and those receiving Placebo plus paclitaxel (n=335) intravenously. Patients were required to have experienced disease progression during, or within 4 months after the last dose of first-line therapy. Patients were also required to have ECOG PS of 0 or 1. The major efficacy outcome measure was overall survival (OS) and the supportive efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). Median OS was 9.6 months in the Ramucirumab plus paclitaxel group versus 7.4 months in the Placebo plus paclitaxel group.  PFS in the Ramucirumab plus paclitaxel group was 4.4 months versus 2.9 months in the Placebo plus paclitaxel group. ORR in the Ramucirumab plus paclitaxel group was 28% months versus 16% in the Placebo plus paclitaxel group. The authors concluded that addition of ramucirumab to paclitaxel prolonged overall survival while maintaining patient quality-of-life with delayed symptom worsening and functional status deterioration in patients with previously treated advanced gastric/GEJ adenocarcinoma.  
 
Non-Small Cell Lung Cancer (NSCLC)
Garon et al (2014) published the results of the REVEL trial which was a multicentre, double-blind, randomized phase 3 trial of CYRAMZA plus docetaxel versus placebo plus docetaxel.   1253 patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease were randomized 1:1 between the two treatment arms of Ramucirumab plus docetaxel (N=628) and Placebo plus docetaxel (N=625). The major efficacy outcome measure was overall survival and the supportive efficacy outcome measures were progression-free survival and objective response rate. Patients were also required to have ECOG PS 0 or 1.  Median overall survival was 10.5 months for 628 patients allocated ramucirumab plus docetaxel and 9.1 months for 625 patients who received placebo plus docetaxel. Median progression-free survival was 4.5 months for the ramucirumab group compared with 3.0 months for the control group. The authors concluded that Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC.
 
Metastatic Colorectal Cancer (mCRC)
Tabernero et al (2015) published the results of the RAISE trial which was a  multinational, randomized, double-blind, study of Ramucirumab plus FOLFIRI versus placebo plus FOLFIRI, in patients with mCRC, who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.  1072 patients were 1:1 randomized to receive either Ramucirumab plus FOLFIRI (n=536) or Placebo plus FOLFIRI (n=536) intravenously every 2 weeks.  The major efficacy outcome measure was overall survival (OS) and the supportive efficacy outcome measure was progression-free survival (PFS).  Median OS was 13.3 months for patients in the ramucirumab group versus 11.7 months for the placebo group. PFS was 5.7 months in the ramucirumab group versus 4.5 months in the placebo group.  The authors concluded that Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma.

CPT/HCPCS:
J9308Injection, ramucirumab, 5 mg

References: Al-Batran SE, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov ON, Kim TY, Cunningham D, Rougier P, Muro K, Liepa AM, Chandrawansa K, Emig M, Ohtsu A, Wilke H.(2016) Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. 2016 Apr;27(4):673-9. doi: 10.1093/annonc/mdv625. Epub 2016 Jan 7.

Eli Lilly and Company(2017) Cyramza® [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017

Elsevier.(2018) Ramucirumab [Internet]. Tampa (FL): Elsevier. c2018- [cited 2018 May 01]. Available from: http://www.clinicalpharmacology.com

Fuchs CS, Tomasek J, Yong CJ et al, REGARD Trial Investigators.(2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. doi: 10.1016/S0140-6736(13)61719-5. Epub 2013 Oct 3.

Garon EB, Ciuleanu TE, Arrieta O, Prabhash K et al.(2014) 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 Aug 23;384(9944):665-73. doi: 10.1016/S0140-6736(14)60845-X. Epub 2014 Jun 2.

NCCN(2018) NCCN Compendia. https://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=5. Accessed March 31, 2017.

Tabernero J, Yoshino T, Cohn AL, RAISE Study Investigators.(2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with mCRC that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): Lancet Oncol. 2015 May;16(5):499-508. doi: 10.1016/S1470-2045(15)70127-0. Epub 2015 Apr 12.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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