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.

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

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)material_revision