Last Review Date: 06/01/2021

Date of Origin:  06/24/2014

Dates Reviewed:  09/2014, 01/2015, 05/2015, 11/2015, 04/2016, 08/2016, 11/2016, 05/2017, 08/2017, 11/2017, 02/2018, 05/2018, 09/2018, 12/2018, 03/2019, 06/2019, 09/2019, 12/2019, 03/2020, 06/2020, 09/2020, 12/2020, 03/2021, 06/2021

I. Length of Authorization

Coverage will be provided for 6 months and may be renewed.

II. Dosing Limits

1. Quantity Limit (max daily dose) [NDC Unit]:

• Cyramza 100 mg/10 mL: 4 vials per 14 days
• Cyramza 500 mg/50 mL: 2 vials per 14 days

2. Max Units (per dose and over time) [HCPCS Unit]:

Gastric, Gastroesophageal, HCC, and Colorectal Cancer:

• 180 billable units every 14 days

NSCLC:

• 240 billable units every 14 days

III. Initial Approval Criteria ¹

Coverage is provided in the following conditions:

• Patient is at least 18 years of age; AND

Universal Criteria ¹

• Patient does not have uncontrolled severe hypertension; AND
• Patient must not have had a surgical procedure within the preceding 28 days or have a surgical wound that has not fully healed; AND

Gastric, Esophageal, and Gastro-esophageal Junction Adenocarcinoma † Ф ^{1-3,5-7,14,15}

• Used as subsequent therapy; AND
• Used as a single agent OR in combination with paclitaxel OR in combination with an irinotecan based regimen; AND
  • Patient has unresectable locally advanced, recurrent, or metastatic disease; OR
  • Used as palliative therapy for locoregional disease in patients who are not surgical candidates

Non-Small Cell Lung Cancer † ^1,3,8,12,13

• Patient has recurrent, advanced, or metastatic disease; AND
  • Used as subsequent therapy following progression on a first-line cytotoxic regimen; AND
    • Used in combination with docetaxel; AND
    • Patient has not previously been treated with docetaxel or ramucirumab; OR

• • Used in combination with erlotinib for EGFR mutation-positive disease (excluding locoregional recurrence or symptomatic local disease without evidence of disseminated disease, except for mediastinal lymph node recurrence with prior radiation therapy) ‡; AND
    • Used as first-line therapy; OR
    • Used for continuation of therapy following disease progression on combination erlotinib and ramucirumab therapy for asymptomatic disease, symptomatic brain lesions, or symptomatic systemic limited metastases

Colorectal Adenocarcinoma † ^{1,3,9-11,17,18}

• Used in combination with FOLFIRI (irinotecan, folinic acid/leucovorin, and 5-fluorouracil) for metastatic disease that progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine †; OR
• Used in combination with irinotecan or FOLFIRI; AND
  • Used as first-line therapy for metastatic disease after adjuvant therapy with FOLFOX (fluorouracil, folinic acid/leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the previous 12 months ‡; OR
  • Used as subsequent therapy for advanced or metastatic disease ‡; AND
    • Patient has not previously been treated with irinotecan-based therapy

Hepatocellular Carcinoma (HCC) † Ф ^1,3,4,16

• Used as single agent therapy; AND
• Used as subsequent therapy for progressive disease; AND
• Patient has an alfa-fetoprotein (AFP) level of ≥ 400 ng/mL; AND
  • Patient was previously treated with sorafenib †; OR
  • Patient has unresectable disease and is not a transplant candidate ‡; OR
  • Patient has local disease (i.e., liver confined disease),  inoperable by performance status, comorbidity or with minimal or uncertain extrahepatic disease ‡; OR
  • Patient has metastatic disease or extensive liver tumor burden ‡

† FDA Approved Indication(s); ‡ Compendia recommended indication(s); Ф Orphan Drug

IV. Renewal Criteria^1,3,13

Authorizations can be renewed based on the following criteria:

• Patient continues to meet universal and other indication-specific relevant criteria such as concomitant therapy requirements (not including prerequisite therapy), performance status, etc. identified in section III; AND
• Disease response with treatment as defined by stabilization of disease or decrease in size of tumor or tumor spread; AND
• Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: hemorrhage, arterial thromboembolic events, uncontrolled hypertension, infusion-related reactions, severe proteinuria (> 3g/24h)/nephrotic syndrome, gastrointestinal perforations, impaired wound healing, posterior reversible encephalopathy syndrome (PRES), thyroid dysfunction, worsening of pre-existing hepatic impairment, etc.; AND

Non-Small Cell Lung Cancer (continuation of therapy in combination with erlotinib following disease progression):

• Refer to Section III for criteria

V. Dosage/Administration^1,12

VI. Billing Code/Availability Information

HCPCS code:

• J9308 − Injection, ramucirumab, 5 mg: 1 billable unit = 5 mg

NDC:

• Cyramza 100 mg/10 mL solution, single dose vial: 00002-7669-xx
• Cyramza 500 mg/50 mL solution, single dose vial: 00002-7678-xx

VII. References

1. Cyramza [package insert]. Indianapolis, IN; Eli Lilly and Company; July 2020. Accessed April  2021.
2. Fuchs CS, Tomasek J, Yong CJ, et al.  Ramucirumab monotherapy for previously treated advanced gastric or gastro-esophageal 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.
3. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium^®) for ramucirumab. National Comprehensive Cancer Network, 2021. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES^® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed April 2021.
4. Zhu AX, Kang YK, Yen CJ, et al. REACH-2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. J Clin Oncol 2018;36:4003.
5. De Vita F, Borg C, Farina G, et al. Ramucirumab and paclitaxel in patients with gastric cancer and prior trastuzumab: subgroup analysis from RAINBOW study. Future Oncol. 2019 Aug;15(23):2723-2731. doi: 10.2217/fon-2019-0243. Epub 2019 Jun 25.
6. Shitara K, Muro K, Shimada Y, et al. Subgroup analyses of the safety and efficacy of ramucirumab in Japanese and Western patients in RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer. Gastric Cancer. 2016 Jul;19(3):927-38. doi: 10.1007/s10120-015-0559-z. Epub 2015 Oct 28.
7. 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 Oct;15(11):1224-35. doi: 10.1016/S1470-2045(14)70420-6. Epub 2014 Sep 17.
8. 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 Aug 23;384(9944):665-73. doi: 10.1016/S0140-6736(14)60845-X. Epub 2014 Jun 2.
9. Yoshino T, Portnoy DC, Obermannová R, et al. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. Ann Oncol. 2019 Jan 1;30(1):124-131. doi: 10.1093/annonc/mdy461.
10. Obermannová R, Van Cutsem E, Yoshino T, et al. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. Epub 2016 Aug 29.
11. 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 May;16(5):499-508. doi: 10.1016/S1470-2045(15)70127-0. Epub 2015 Apr 12.
12. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Dec;20(12):1655-1669. doi: 10.1016/S1470-2045(19)30634-5. Epub 2019 Oct 4.
13. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium^®) for Non-Small Cell Lung Cancer Version 4.2021. National Comprehensive Cancer Network, 2021. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES^® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed April 2021.
14. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium^®) for Gastric Cancer Version 2.2021. National Comprehensive Cancer Network, 2021. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES^® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed April 2021.
15. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium^®) for Esophageal and Esophagogastric Junction Cancers Version 2.2021. National Comprehensive Cancer Network, 2021. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES^® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed April 2021.
16. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium^®) for Hepatobiliary Cancers Version 2.2021. National Comprehensive Cancer Network, 2021. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES^® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed April 2021.
17. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium^®) for Colon Cancer Version 2.2021. National Comprehensive Cancer Network, 2021. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES^® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed April 2021.
18. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium^®) for Rectal Cancer Version 1.2021. National Comprehensive Cancer Network, 2021. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES^® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed April 2021.

19. Palmetto GBA. Local Coverage Article (LCA): Billing and Coding for Chemotherapy (A56141). Centers for Medicare & Medicaid Services, Inc. Updated on 11/12/2020 with effective date 11/19/2020. Accessed April 2021.

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Determinations (LCDs), and Local Coverage Articles (LCAs) may exist and compliance with these policies is required where applicable. They can be found at: http://www.cms.gov/medicare-coverage-database/search/advanced-search.aspx. Additional indications may be covered at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD/LCA):