ModifiedmhnPolicy CP.PHAR.629

Retifanlimab-dlwr (Zynyz) coverage

Clinical policy governing medical necessity and authorization criteria for retifanlimab-dlwr (Zynyz) for adults with Merkel cell carcinoma, squamous cell carcinoma of the anal canal, and certain NCCN-recommended off-label GI MSI-H/dMMR/ultra-hypermutated tumors. Applies to members under Centene-affiliated health plans including Commercial, HIM/ICHRA, and Medicaid.

Policy Summary

Payermhn

PolicyRetifanlimab-dlwr (Zynyz) coverage

Policy CodePolicy CP.PHAR.629

Change TypeMaterial coverage and coding updatesNCCN expansions

Effective DateJun 1, 2023

Next Review Date

Key ActionSubmit prior authorization with documentation proving diagnosis, oncologist involvement, age ≥18, and dosing ≤500 mg every 4 weeks (or supporting literature for higher dose).

SourceLink

POLICY UPDATE CHANGES

Added ICHRA line of business.

Updated FDA Approved Indication(s) section for MCC from accelerated approval to full approval per PI; extended Medicaid and HIM initial approval durations from 6 months to 12 months for maintenance medication.

Added off-label criteria for appendiceal neoplasms and cancers per NCCN and simplified NCCN off-label uses under 'NCCN Recommended Uses (off-label)'.

Added criteria for small bowel adenocarcinoma, colon cancer, and rectal cancer per NCCN 2A recommendation; for anal carcinoma, added option to be prescribed in combination with carboplatin and paclitaxel.

Added Zynyz HCPCS code J9345 and removed inactive codes.

3FDA-approved indications listed

12 moTypical Medicaid/HIM approval length

500 mg q4w

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Coverage Criteria

Initial Therapy — Merkel Cell Carcinoma

Covered when ALL of the following are met for Merkel Cell Carcinoma (MCC):

MCC Initial Approval: 1. Diagnosis of Merkel cell carcinoma (MCC); 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Disease meets one of the following: a) metastatic, recurrent locally advanced, or in‑transit regional disease; b) both i) primary locally advanced, primary regional, or recurrent regional disease and ii) disease is not amenable to surgery or radiation therapy; 5. Prescribed as a single agent; 6. Request meets one of the following: a) dose does not exceed 500 mg (1 vial) every four weeks; b) dose is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence).

Prescribed regimen must be FDA‑approved or recommended by NCCN

Initial Therapy — Anal Carcinoma (SCAC)

Covered when ALL of the following are met for Squamous Cell Carcinoma of the Anal Canal (SCAC):

SCAC Initial Approval: 1. Diagnosis of locally recurrent, progressive, or metastatic squamous cell carcinoma of the anal canal (SCAC); 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Prescribed as one of the following: a) single agent; b) in combination with carboplatin and paclitaxel (per NCCN 2A); 5. Request meets one of the following: a) dose does not exceed 500 mg (1 vial) every four weeks; b) dose is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence).

Prescribed regimen must be FDA‑approved or recommended by NCCN

NCCN Recommended Off-Label Uses

Covered when ALL of the following are met for NCCN-recommended off-label gastrointestinal tumor uses:

NCCN Off-label GI Tumors: 1. Diagnosis of one of the following: a) appendiceal neoplasm or cancer; b) colon cancer; c) rectal cancer; d) small bowel adenocarcinoma; 2. Tumor has one of the following biomarkers: a) microsatellite instability‑high (MSI‑H); b) deficient mismatch repair (dMMR); c) POLE/POLD1 with ultra‑hypermutated phenotype (e.g., tumor mutation burden > 50 mut/Mb); 3. Prescribed by or in consultation with an oncologist; 4. Age ≥ 18 years; 5. Prescribed as a single agent; 6. Request meets one of the following: a) dose does not exceed 500 mg (1 vial) every four weeks; b) dose is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence).

Prescribed regimen must be FDA‑approved or recommended by NCCN

Continuation Therapy

Covered for continuation/renewal when ALL of the following are met:

Continuation: 1. Member is currently receiving Zynyz via a Centene benefit or documentation supports the member has received Zynyz for at least 30 days for a covered indication; 2. Member is responding positively to therapy; 3. If request is for a dose increase, request meets one of the following: a) new dose does not exceed 500 mg (1 vial) every four weeks; b) new dose is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence).

Prescribed regimen must be FDA‑approved or recommended by NCCN

Coverage updates and NCCN-based expansions

Policy updates and NCCN-based coverage expansions

MCC FDA status update: FDA approval for Merkel cell carcinoma (MCC) was updated from accelerated approval to full approval per prescribing information.

Supports coverage under FDA‑approved indication.

NCCN 2A indicated uses: Coverage criteria were expanded to include NCCN 2A recommended uses such as primary locally advanced MCC pathways, recurrent regional disease, small bowel adenocarcinoma, colon cancer, rectal cancer, anal carcinoma, and appendiceal neoplasms per the NCCN compendium.

Some off‑label uses added per NCCN compendium.

Combination therapy option for anal carcinoma: For anal carcinoma, Zynyz may be prescribed as a single agent or in combination with carboplatin and paclitaxel per updated NCCN 2A recommendation.

Reflects treatment pathway expansion.

Non–FDA approved indications that are not specifically addressed in this policy are not authorized unless the provider submits sufficient documentation of efficacy and safety consistent with the applicable off‑label use policies or evidence of coverage documents. See the off‑label use policies CP.CPA.09 (Commercial), HIM.PA.154 (HIM/ICHRA), and CP.PMN.53 (Medicaid) for the required evidence standards and review pathways.

Per the most recent policy revision, the prior requirement that the disease be “not amenable to surgery or radiation therapy” for metastatic or recurrent locally advanced disease has been removed. This change aligns the criteria with updated prescribing information and NCCN guidance permitting coverage without that specific exclusion when other coverage criteria are met.

If the requested use is not specifically listed in the Diagnoses/Indications section and there has been a recent label change that is not yet reflected in this policy, or criterion for recent label change does not apply, refer the request to the applicable off‑label or formulary/no‑coverage policies for the line of business. Relevant policies include CP.CPA.190, HIM.PA.33, CP.PMN.255 (no coverage criteria) and CP.CPA.09, HIM.PA.154, CP.PMN.53 (off‑label use) as appropriate.

Codes listed in this clinical policy are provided for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage, and the absence of a code in this document should not be interpreted as assurance that a service or drug is covered. Providers must consult current professional coding guidance and plan‑specific billing requirements when submitting claims.

Coding and Billing

HCPCS CodesHCPCS

J9345

Injection, retifalimab-dlwr, 1 mg

HCPCS code referencedHCPCS

J9345

Injection, retifalimab-dlwr, 1 mg

Tumor mutation burden threshold example — POLE/POLD1 ultra-hypermutated

ThresholdTMB > 50 mut/Mb for POLE/POLD1 ultra-hypermutated phenotype (example)

ContextUsed to identify POLE/POLD1 ultra-hypermutated tumors within NCCN-recommended off-label GI tumor criteria

Applicable tumor typesAppendiceal neoplasm, colon cancer, rectal cancer, small bowel adenocarcinoma (per NCCN off-label criteria)

Initial approval duration (Medicaid/HIM)

Initial approval duration (Medicaid/HIM)12 months

ScopeApplies to maintenance medication for a chronic condition per policy updates

Provider Actions and Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for Zynyz (retifanlimab‑dlwr). Approval is contingent on meeting the specific indication criteria in this policy (MCC, SCAC, or NCCN‑recommended uses) and any applicable dosing limits.

HCPCS: J9345 — Injection, retifanlimab‑dlwr, 1 mg (informational; inclusion does not guarantee coverage).
Failure to submit required supporting documentation (e.g., office chart notes, lab results, pathology reports, or other clinical information) demonstrating that the member meets all approval criteria may result in denial of the request.
Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions, and limitations of the applicable coverage documents (e.g., evidence of coverage, certificate of coverage, policy/contract) and to state and federal laws and Health Plan administrative policies and procedures.
No explicit step‑therapy sequence is specified in this policy; coverage is based on meeting the indication‑specific criteria and any prior therapy requirements noted within those criteria.

Background

Retifanlimab‑dlwr (Zynyz) is a programmed cell death‑1 (PD‑1) blocking monoclonal antibody indicated for select advanced or metastatic malignancies. The policy specifies dosing of 500 mg IV every 4 weeks and includes coverage pathways for FDA‑approved indications such as Merkel cell carcinoma and squamous cell carcinoma of the anal canal, as well as selected NCCN‑recommended off‑label tumor types when biomarker criteria are met. Recent updates reflect MCC’s conversion from accelerated to full FDA approval, addition of in‑transit and primary regional disease pathways per NCCN, and expansion of certain off‑label gastrointestinal tumor indications per the NCCN compendium.

Definitions and Biomarker Criteria

MSI-H / dMMR — tumor biomarker for NCCN off-label GI uses

BiomarkerMicrosatellite instability-high (MSI-H)

Equivalent biomarkerDeficient mismatch repair (dMMR)

Use caseRequired biomarker for NCCN-recommended off-label gastrointestinal tumor uses (appendiceal, colon, rectal, small bowel adenocarcinoma)

NCCN 2A — definition and policy application

DefinitionNCCN 2A indicates uniform NCCN consensus based on lower-level evidence or non-randomized data supporting the use.

ApplicationUsed to justify coverage expansions and recommended uses in the policy (e.g., MCC pathways, anal carcinoma regimens)

Line of Therapy

first-line | second-line

Line of therapy considerations: First‑line use: Zynyz in combination with carboplatin and paclitaxel for inoperable locally recurrent or metastatic SCAC. Subsequent‑line use: single‑agent Zynyz for SCAC with disease progression on or intolerance to platinum‑based chemotherapy. For MCC and NCCN off‑label GI tumor uses, line of therapy is per clinician judgment and guideline recommendations.

mixed

Mixed line‑of‑therapy scenarios: Policy allows mixed scenarios per NCCN 2A compendium: for anal carcinoma, Zynyz may be used in combination with carboplatin and paclitaxel (often first‑line) or as single agent after platinum progression/intolerance; line designation should follow NCCN guidance and the main policy body for specifics.

Biomarker Requirements

MSI-H / dMMR / POLE/POLD1 ultra-hypermutated — biomarker threshold

ThresholdTMB > 50 mut/Mb for POLE/POLD1 ultra-hypermutated phenotype

Associated biomarkersMSI-H and dMMR are alternative biomarkers considered alongside POLE/POLD1 ultra-hypermutation

Relevant indicationsRequired for NCCN-recommended off-label GI tumor uses (appendiceal, colon, rectal, small bowel adenocarcinoma)

Covered Regimens and Dosing

Regimen	Indication	Coverage
Zynyz 500 mg IV every 4 weeks as a single agent
Merkel cell carcinoma (metastatic or recurrent locally advanced); NCCN-recommended off-label GI tumor uses (MSI-H/dMMR/POLE‑ultra‑hypermutated)
Covered when all policy criteria for the specific indication are met (see coverage criteria).

Regimen	Indication	Coverage
Retifanlimab‑dlwr (Zynyz) 500 mg IV every 4 weeks as a single agent or in combination with carboplatin and paclitaxel
Squamous cell carcinoma of the anal canal (SCAC): first‑line in combination with carboplatin + paclitaxel for inoperable locally recurrent or metastatic disease; single‑agent for disease progression on or intolerance to platinum
Covered per FDA indication and/or NCCN 2A recommendation when all policy criteria are met (see coverage criteria).

Revision History

2023-04-13policy_created

Policy created and initial coding implications documented; P&T approval noted May 2023.

2024-02-13annual_review_2Q2024

Added MCC pathways for primary locally advanced and recurrent regional disease per NCCN 2A and required Zynyz be prescribed as a single agent; added criteria for anal carcinoma and added Zynyz HCPCS code while removing inactive codes.

2025-03-06annual_review_2Q2025