CurrentmhnPolicy CP.PHAR.119

Clinical Policy: Ramucirumab (Cyramza)

Defines medical necessity criteria, dosing limits, approved and off-label covered indications, prior authorization documentation requirements, approval durations, and coding implications for ramucirumab (Cyramza) for commercial, HIM, and Medicaid lines of business.

Policy Summary

Payermhn

PolicyClinical Policy: Ramucirumab (Cyramza)

Policy CodePolicy CP.PHAR.119

Change TypeRevised (multiple annual reviews) / Clarified

Effective Date06.01.15

Next Review Date

Key ActionProvider must submit office chart notes, lab results or other clinical information supporting that member meets all approval criteria, including EGFR mutation status when required and AFP value for HCC.

SourceLink

POLICY UPDATE CHANGES

1Q 2025 annual review: for colorectal cancer, added criteria for off label use in appendiceal adenocarcinoma as second-line or subsequent therapy; for HCC, removed confirmation of Child-Pugh class A status; revised Appendix B to list only redirections; references reviewed and updated.

RT4: clarified FDA-Approved Indications section to specify use in adults per updated FDA labeling (04.23.25).

1Q 2024 annual review: added off-label indication criteria for mesothelioma per NCCN.

1Q 2022 annual review: revised criteria for advanced esophageal, EGJ or gastric cancer allowing combination with irinotecan with or without fluorouracil and added requirement for unresectable, locally advanced, recurrent, or metastatic disease per NCCN.

5Covered Indications (FDA and listed off-label)

1Off-label indications

2Required biomarkers/labs

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0.86Confidence score

Coverage Summary

Policy CP.PHAR.119 (Clinical Policy: Ramucirumab [Cyramza]) — coverage stance: covered_with_criteria. Ramucirumab (Cyramza) is covered when documentation demonstrates the member meets the medical necessity criteria in this policy, which align to FDA-approved indications and NCCN recommendations for relevant cancers.

Covered indications per the policy include: advanced or metastatic esophageal/EGJ/gastric adenocarcinoma (single agent or in combination with paclitaxel or irinotecan ± fluorouracil) ; non-small cell lung cancer (NSCLC) (in combination with docetaxel or with erlotinib for EGFR-sensitizing mutation–positive disease) ; colorectal cancer (CRC) including appendiceal adenocarcinoma (off-label) as second-line or subsequent therapy (in combination with irinotecan or FOLFIRI) ; hepatocellular carcinoma (HCC) (single-agent use after sorafenib with AFP threshold) ; and mesothelioma (off-label) in combination with gemcitabine as subsequent therapy.

Key required biomarker/laboratory thresholds and age requirement: Age ≥ 18 years for all indications; for HCC, AFP ≥ 400 ng/mL and progression on or after sorafenib are required. For NSCLC when used with erlotinib, a sensitizing EGFR mutation (e.g., exon 19 deletion or exon 21 L858R) is required. Dosing limits and regimen requirements are specified in the policy and must be met or justified by guidelines/literature for off‑label uses.

Scope: defines medical necessity criteria, dosing maxima, approved and specified off‑label indications, prior authorization documentation requirements (including labs and mutation status), approval durations, and coding implications for commercial, HIM, and Medicaid lines of business.

Thresholds / Dose limits

Age≥ 18 years

AFP≥ 400 ng/mL

Esophageal/EGJ/Gastric dose limit≤ 8 mg/kg every 2 weeks

CRC dose limit≤ 8 mg/kg every 2 weeks

HCC dose limit≤ 8 mg/kg every 2 weeks

NSCLC (docetaxel) dose limit≤ 10 mg/kg on day 1 of a 21-day cycle

NSCLC (erlotinib) dose limit≤ 10 mg/kg every 2 weeks

Minimum prior treatment duration for continuation≥ 30 days on therapy

Initial Therapy Criteria

Initial Approval Criteria

Provider must submit documentation supporting that member has met all approval criteria. Cyramza is medically necessary when the following criteria are met:

A. Esophageal, Esophagogastric Junction, and Gastric Cancer

Diagnosis of esophageal, EGJ or gastric cancer
Disease is unresectable, locally advanced, recurrent, or metastatic
Prescribed by or in consultation with an oncologist
Age ≥ 18 years≥ 18 years
Prescribed as subsequent therapy in one of the following ways

Continuation Therapy Criteria

Continued Therapy

All indications in Section I must meet all criteria:

Currently receiving medication via Centene benefit, or documentation supports that member has received Cyramza for at least 30 days≥ 30 days

Member is responding positively to therapy

Dose increase criteria

Esophageal/EGJ/gastric cancer, CRC, HCC: New dose does not exceed 8 mg/kg every 2 weeks≤ 8 mg/kg every 2 weeks
NSCLC in combination with docetaxel: New dose does not exceed 10 mg/kg on day 1 of a 21-day cycle

Diagnoses / Indications Not Authorized

Diagnoses/Indications NOT authorized

Non-FDA approved indications not addressed in this policy are not authorized unless criteria met per off-label use policy

Non-FDA approved indications which are not addressed in this policy are not authorized unless there is sufficient documentation of efficacy and safety according to the off-label use policy (CP.CPA.09, HIM.PA.154, CP.PMN.53) or evidence of coverage documents

Provider Actions

Documentation Required

Submit clinical documentation

Provider must submit clinical documentation to support that the member meets all approval criteria. Required documentation includes office chart notes and relevant laboratory results such as AFP for HCC, and EGFR mutation status when therapy is prescribed in combination with erlotinib, as well as any other clinical information necessary to demonstrate indication, prior therapies, and dosing rationale.

Prior Authorization

Prior authorization may be required for companion agents

Prior authorization may be required for companion agents depending on the regimen and line of business. Agents that may require PA include paclitaxel, fluorouracil, irinotecan, docetaxel, erlotinib, gemcitabine, and sorafenib.

Applicable Codes

HCPCS / J-code for ramucirumabHCPCS

J9308

Injection, ramucirumab, 5 mg

Clinical Evidence and Guidelines

Key evidence and guideline sources cited in the policy: the randomized controlled trial REACH-2 (ramucirumab after sorafenib in HCC with elevated AFP; Lancet Oncology 2019), the Cyramza Prescribing Information (Eli Lilly; April 2025), and NCCN guidelines/compendium entries (gastric, esophageal, NSCLC, colon/rectal, HCC, mesothelioma; 2024 versions).

These sources form the primary evidence base and guideline alignment used to define covered indications, biomarker thresholds (e.g., AFP ≥ 400 ng/mL for HCC), EGFR mutation requirements for erlotinib combinations, and dosing regimens referenced in the policy.

Key trials / References

REACH-2ramucirumab after sorafenib in HCC with elevated AFP (Lancet Oncol 2019)

Prescribing informationCyramza Prescribing Information, Eli Lilly; April 2025

Guidelines referencedNCCN guidelines (versions 2024) for relevant cancers

Background

Ramucirumab (Cyramza) is a human VEGFR2 antagonist approved for multiple advanced cancers either as monotherapy or in combination with other agents. The policy aligns coverage with FDA approvals and NCCN recommendations and specifies diagnosis, prior therapy requirements, dosing limits (e.g., ≤ 8 mg/kg every 2 weeks for several indications and ≤ 10 mg/kg regimens for certain NSCLC combinations), and biomarker requirements where applicable.

AFP: alpha fetoprotein — a serum tumor marker used to select HCC patients (policy threshold: AFP ≥ 400 ng/mL).

EGJ: esophagogastric junction — anatomical site referenced in gastric/EGJ cancer indications.

EGFR: epidermal growth factor receptor — genomic target; sensitizing EGFR mutations are required if ramucirumab is used with erlotinib in NSCLC.

FOLFIRI: fluorouracil, leucovorin, irinotecan — chemotherapy regimen with which ramucirumab is combined for CRC.

NCCN: National Comprehensive Cancer Network — practice guideline source referenced for recommended regimens and off‑label uses.

NSCLC: non-small cell lung cancer — one of the covered tumor types in the policy.

HCC: hepatocellular carcinoma — a covered indication with an AFP threshold and prior sorafenib requirement.

Revision History

1Q 2025 (P&T Approval Date 02.25)material_revisionLatest

1Q 2025 annual review: added off‑label CRC criteria for appendiceal adenocarcinoma as second‑line or subsequent therapy; removed confirmation of Child‑Pugh class A status for HCC; revised Appendix B to list only redirections; references reviewed and updated.

04.23.25clarification

RT4: clarified FDA‑Approved Indications section to specify use in adults per updated FDA labeling.

1Q 2024 (P&T Approval Date 02.24)

Policy Summary

Payermhn

PolicyClinical Policy: Ramucirumab (Cyramza)

Policy CodePolicy CP.PHAR.119

Change TypeRevised (multiple annual reviews) / Clarified

Effective Date06.01.15

Next Review Date

SourceLink

On This Page

ONE of: As a single agent
ONE of: In combination with paclitaxel
ONE of: In combination with irinotecan with or without fluorouracil

Dose requirement

Dose does not exceed 8 mg/kg every 2 weeks≤ 8 mg/kg every 2 weeks
Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)

Prescribed regimen must be FDA-approved or recommended by NCCN

B. Non-Small Cell Lung Cancer (NSCLC)

Diagnosis of metastatic, recurrent, or advanced NSCLC
Prescribed by or in consultation with an oncologist
Age ≥ 18 years≥ 18 years
ONE of
- Prescribed as subsequent therapy in combination with docetaxel
- Prescribed in combination with erlotinib (Tarceva®)
If prescribed in combination with erlotinib, disease is positive for a sensitizing EGFR mutation (e.g., EGFR exon 19 deletions or exon 21 [L858R] substitution mutation)
Dose requirement
- In combination with docetaxel: Dose does not exceed 10 mg/kg on day 1 of a 21-day cycle≤ 10 mg/kg on day 1 of a 21-day cycle
- In combination with erlotinib: Dose does not exceed 10 mg/kg on day 1 every 2 weeks≤ 10 mg/kg every 2 weeks
- Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)
Prescribed regimen must be FDA-approved or recommended by NCCN

C. Colorectal Cancer (CRC)

Diagnosis of advanced or metastatic CRC (including appendiceal adenocarcinoma [off label])
Prescribed by or in consultation with an oncologist
Age ≥ 18 years≥ 18 years
Prescribed in combination with irinotecan or FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil)
For appendiceal adenocarcinoma, prescribed as second-line or subsequent therapy (off label)
Dose requirement
- Dose does not exceed 8 mg/kg every 2 weeks≤ 8 mg/kg every 2 weeks
- Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)
Prescribed regimen must be FDA-approved or recommended by NCCN

D. Hepatocellular Carcinoma (HCC)

Diagnosis of HCC
Prescribed by or in consultation with an oncologist
Age ≥ 18 years≥ 18 years
AFP ≥ 400 ng/mLAFP ≥ 400 ng/mL
Disease has progressed on or after therapy with sorafenib
Prescribed as single-agent therapy
Dose requirement
- Dose does not exceed 8 mg/kg every 2 weeks≤ 8 mg/kg every 2 weeks
- Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)
Prescribed regimen must be FDA-approved or recommended by NCCN

E. Mesothelioma (off-label)

Diagnosis of mesothelioma classified as one of the following: Pleural; Pericardial; Tunica vaginalis testis
Prescribed by or in consultation with an oncologist
Age ≥ 18 years≥ 18 years
Prescribed in combination with gemcitabine
Prescribed as subsequent therapy
Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)
Prescribed regimen must be FDA-approved or recommended by NCCN

Other diagnoses/indications (Initial)

If use not listed in section I

If this drug has recently (within the last 6 months) undergone a label change that is not yet reflected in this policy, refer to no coverage or non-formulary policies depending on formulary status (CP.CPA.190, HIM.PA.33, CP.PMN.255, HIM.PA.103, CP.PMN.16)

If the requested use is not listed under section III and criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business (CP.CPA.09, HIM.PA.154, CP.PMN.53)

≤ 10 mg/kg on day 1 of a 21-day cycle

NSCLC in combination with erlotinib: New dose does not exceed 10 mg/kg every 2 weeks≤ 10 mg/kg every 2 weeks

New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence)

Prescribed regimen must be FDA-approved or recommended by NCCN

Billing Rule

J-code billing

Use HCPCS J9308 (Injection, ramucirumab, 5 mg) when submitting claims for ramucirumab.

Denial Risk

Non-authorized uses risk denial

Requests for non-FDA approved indications that are not addressed in this policy are not authorized and will be denied unless sufficient documentation of efficacy and safety is provided in accordance with the off-label use policy for the applicable line of business.

Documentation Required

Dose justification for off-label doses

If the requested dose exceeds the stated maximums in the policy, the prescriber must submit supporting evidence from practice guidelines or peer‑reviewed literature to justify the off‑label dose.

1Q 2024 annual review: added off‑label indication criteria for mesothelioma per NCCN; references reviewed and updated.

1Q 2022 (P&T Approval Date 02.22)material_revision

1Q 2022 annual review: revised criteria for advanced esophageal, EGJ or gastric cancer to allow combination with irinotecan with or without fluorouracil and added requirement for unresectable, locally advanced, recurrent, or metastatic disease per NCCN; Appendix B updated; references reviewed and updated.