ModifiedCentenePolicy CP.PHAR.629

Clinical Policy: Retifanlimab-dlwr (Zynyz)

Defines Centene's 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 gastrointestinal MSI-H/dMMR/POLE/POLD1 tumors; applies to members under Centene lines of business including Commercial, HIM/ICHRA, and Medicaid.

Policy Summary

PayerCentene

PolicyRetifanlimab-dlwr (Zynyz) coverage criteria

Policy CodePolicy CP.PHAR.629

Change TypeMaterial updates — added SCAC FDA indication, MCC full approval, NCCN off-label uses, HCPCS code J9345, and extended Medicaid/HIM approval durations

Effective DateJun 1, 2023

Next Review Date

Key ActionSubmit prior authorization with supporting clinical documentation demonstrating the member meets the indication‑specific criteria and dosing limits.

SourceLink

POLICY UPDATE CHANGES

Added new FDA-approved indication for SCAC (squamous cell carcinoma of the anus).

Updated FDA approval status for MCC (Merkel cell carcinoma) from accelerated approval to full approval per prescribing information.

Added off-label criteria for appendiceal neoplasms and other cancers per NCCN and simplified NCCN off-label uses.

Added Zynyz HCPCS code J9345 and removed inactive codes.

Extended Medicaid and HIM initial approval durations from 6 months to 12 months for maintenance medication for a chronic condition.

500 mgMaximum dose

q4wDosing interval

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Coverage Criteria for Retifanlimab-dlwr (Zynyz)

Continuation Therapy

Covered when ALL of the following are met:

Continuation: 1. Member is currently receiving Zynyz via Centene benefit or documentation supports the member has been receiving Zynyz for a covered indication for at least 30 days. 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; OR (b) 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.

Updated Indications and Prescribing Constraints

Policy updates and prescribing constraints:

Indications updated: Includes FDA-approved SCAC; MCC approval updated per prescribing information; NCCN off-label uses for select GI tumors (appendiceal, colon, rectal, small bowel) added per NCCN recommendations.

Refer to per-indication sections for full criteria.

Prescribing format: For certain indications Zynyz must be prescribed as a single agent; for anal carcinoma combination with carboplatin and paclitaxel is an option per 2Q 2025 update.

See individual indication criteria for single-agent vs combination requirements.

Non‑FDA approved indications that are not specifically addressed in this policy are not authorized unless the provider submits sufficient documentation demonstrating efficacy and safety in accordance with the applicable off‑label use policies: CP.CPA.09 (Commercial), HIM.PA.154 (Health Insurance Marketplace/ICHRA), or CP.PMN.53 (Medicaid), or unless coverage is otherwise supported by the member’s evidence of coverage.

The prior policy requirement that disease be “not amenable to surgery or radiation therapy” for certain metastatic or recurrent locally advanced Merkel cell carcinoma has been removed per prescribing information and policy updates; the MCC criteria now reflect the revised FDA and NCCN‑aligned indications (including expanded pathways such as in‑transit regional disease and primary regional disease).

Providers should refer to the MCC section of this policy for the current per‑indication clinical criteria when requesting authorization.

Uses of retifanlimab‑dlwr that are non‑FDA approved and are not included in the specific indications of this policy require supporting clinical evidence per the referenced off‑label/no coverage policies. Requests for such off‑label use should include documentation (peer‑reviewed literature, practice guidelines, or other evidence) demonstrating efficacy and safety consistent with the applicable off‑label policy.

Coding lists in this clinical policy are provided for informational purposes only. Coding alone does not establish medical necessity, and the inclusion or exclusion of any codes in this document does not guarantee coverage. Providers must reference current professional coding guidance and ensure that submitted codes accurately reflect the services rendered to avoid claim denials.

Covered Regimens and Dosing

Regimen	Indication	Coverage status	Notes
Retifanlimab-dlwr 500 mg IV every 4 weeks plus carboplatin and paclitaxel
First-line treatment of adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC)
Covered
FDA‑approved first‑line regimen per prescribing information; maximum single administration 500 mg q4w

Regimen	Indication(s)	Coverage status	Notes
Retifanlimab-dlwr 500 mg IV every 4 weeks (single agent)
1) Metastatic or recurrent locally advanced Merkel cell carcinoma (MCC); 2) Locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum‑based chemotherapy
Covered
Single‑agent use is FDA‑labeled for MCC and for SCAC after progression/intolerance to platinum; dose not to exceed 500 mg q4w

Regimen	Indication	Coverage status	Notes / Biomarker requirement
Retifanlimab-dlwr 500 mg IV every 4 weeks (single agent)
NCCN‑recommended off‑label use for appendiceal neoplasm, colon cancer, rectal cancer, or small bowel adenocarcinoma that are MSI‑H, dMMR, or POLE/POLD1 ultra‑hypermutated (e.g., TMB > 50 mut/Mb)
Covered
Coverage requires oncologist prescription and biomarker documentation (MSI‑H, dMMR, or POLE/POLD1 ultra‑hypermutated); dose not to exceed 500 mg q4w or supported by guidelines

Regimen	Indication	Coverage status	Notes / Policy update
Zynyz (retifanlimab-dlwr) as single agent or in combination with carboplatin and paclitaxel
Anal carcinoma (squamous cell carcinoma of the anal canal) — single‑agent use and, per 2Q 2025 update, combination with carboplatin and paclitaxel
Covered
Policy updated (2Q 2025) to add combination option with carboplatin/paclitaxel for anal carcinoma; FDA‑approved first‑line combination and single‑agent second‑line indications referenced

Coding and Billing

HCPCS CodesHCPCS

J9345

Injection, retifalimab-dlwr, 1 mg

Relevant HCPCS CodesHCPCSCovered

J9345

Injection, retifanlimab-dlwr, 1 mg

Maximum single administration dose

Maximum single administration dose500 mg per IV infusion (maximum 500 mg every 4 weeks)

Dosing intervalEvery 4 weeks (q4w)

Applies toMerkel cell carcinoma and squamous cell carcinoma of the anal canal dosing regimens specified in policy

Initial approval duration (Medicaid/HIM)

Initial approval duration (Medicaid/HIM)12 months (extended from 6 months for maintenance medication)

Commercial initial approval duration6 months (per policy summary)

Provider Actions and Requirements

Prior Authorization

Prior Authorization Required

Prior authorization required — Prior authorization is required per this clinical policy. Provider must submit documentation (such as office chart notes, lab results, or other clinical information) supporting that the member has met all approval criteria. Failure to submit required documentation or requests for non‑FDA indications without sufficient evidence may result in denial.

Prior authorization required for all indications listed in this policy per indication-specific criteria (MCC, SCAC, or NCCN-recommended off-label).
Provider must submit clinical documentation (office notes, labs, imaging, pathology, treatment history) demonstrating the member meets the approval criteria.
Non‑covered or insufficiently supported off‑label indications may be denied per off‑label use policies (CP.CPA.09, HIM.PA.154, CP.PMN.53) and evidence of coverage documents.

Step Therapy

Therapy Sequencing and Regimen Requirements

Therapy sequencing and regimen requirements — Providers must follow the policy's indication-specific sequencing rules. For anal carcinoma (SCAC) the policy allows single‑agent use or combination with carboplatin and paclitaxel per NCCN; for MCC and NCCN off‑label uses the agent must be prescribed as a single agent unless otherwise specified by FDA or NCCN recommendations.

Line of Therapy Specifications

first-line | second-line

First-line | second-line: First-line combination with carboplatin and paclitaxel for inoperable locally recurrent or metastatic SCAC; single-agent use for SCAC after progression on or intolerance to platinum-based chemotherapy.

first-line | salvage

First-line | salvage: Treatment of metastatic or recurrent locally advanced Merkel cell carcinoma as single-agent therapy.

mixed

Mixed line of therapy: Policy includes FDA-approved indications and NCCN 2A recommended uses across multiple lines; specific line (first-line, second-line, salvage) is determined per indication in the main policy text.

Biomarker Requirements for Off-Label Use

MSI-H

Biomarker requirement (MSI-H)Tumor must be microsatellite instability-high (MSI-H) to meet NCCN-recommended off-label GI tumor criteria

Indications using MSI-HAppendiceal neoplasm, colon cancer, rectal cancer, or small bowel adenocarcinoma (per NCCN off-label section)

DocumentationPrescribed by or in consultation with an oncologist and age ≥ 18 years

dMMR

Biomarker requirement (dMMR)Tumor must be deficient in mismatch repair (dMMR) to meet NCCN-recommended off-label GI tumor criteria

Indications using dMMRAppendiceal neoplasm, colon cancer, rectal cancer, or small bowel adenocarcinoma (per NCCN off-label section)

Definitions and Key Terms

Retifanlimab-dlwr (Zynyz)

Agent classProgrammed death receptor-1 (PD-1) blocking antibody

Proprietary nameZynyz (retifanlimab-dlwr)

Use in policyReferenced as the covered agent for MCC, SCAC, and certain NCCN-recommended off-label GI tumors

MSI-H / dMMR / POLE/POLD1 (ultra-hypermutated)

DefinitionTumors with high microsatellite instability (MSI-H), deficient mismatch repair (dMMR), or POLE/POLD1 ultra-hypermutated phenotype

Example thresholdPOLE/POLD1 ultra-hypermutated phenotype example: TMB > 50 mut/Mb

Relevant indications

Background

Retifanlimab‑dlwr (Zynyz) is a programmed death receptor‑1 (PD‑1) blocking antibody with FDA‑approved indications that include: first‑line use in combination with carboplatin and paclitaxel for adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal, single‑agent use for SCAC after progression on or intolerance to platinum‑based chemotherapy, and treatment of metastatic or recurrent locally advanced Merkel cell carcinoma. The policy incorporates these FDA‑approved indications and aligns coverage pathways with current prescribing information and NCCN recommendations; see the clinical criteria sections for indication‑specific authorization requirements.

Revision History and Policy Changes

2026-03-31annual_reviewLatest

2Q 2026 annual review added off-label criteria for appendiceal neoplasms and other cancers per NCCN, simplified NCCN off-label uses, and added ICHRA line of business.

2025-12-26regulatory_update

RT4 update: updated MCC approval from accelerated to full approval per prescribing information, added pathways for in-transit and primary regional disease, and removed requirement that disease be 'not amenable to surgery or radiation' for certain MCC populations.

2025-05-21

Policy Summary

PayerCentene

PolicyRetifanlimab-dlwr (Zynyz) coverage criteria

Policy CodePolicy CP.PHAR.629

Change TypeMaterial updates — added SCAC FDA indication, MCC full approval, NCCN off-label uses, HCPCS code J9345, and extended Medicaid/HIM approval durations

Effective DateJun 1, 2023

Next Review Date

Key ActionSubmit prior authorization with supporting clinical documentation demonstrating the member meets the indication‑specific criteria and dosing limits.

SourceLink

On This Page

Documentation Required

Required documentation — Provider must submit supporting documentation that the member meets all approval criteria. Examples include office chart notes, laboratory results, pathology reports, imaging, and prior treatment records.

Documentation should clearly show diagnosis, staging/mutation status when applicable (e.g., MSI‑H, dMMR, POLE/POLD1/TMB), prescriber consultation with oncology, age, and dosing rationale.
Missing or incomplete documentation may result in delay or denial of the prior authorization request.

Billing Rule

Billing and Coding Guidance

Billing and coding guidance — Use the current HCPCS code for retifanlimab when billing and verify coding against the most up‑to‑date professional coding guidance. Inclusion or exclusion of any codes in this policy does not guarantee coverage.

HCPCS: J9345 — Injection, retifanlimab-dlwr, 1 mg.
Inclusion or exclusion of any codes does not guarantee coverage; providers should reference current coding guidance prior to claim submission.

Note

Policy Revisions and Pathway Updates

Policy revisions and clinical pathway changes — Policy updates have added NCCN‑recommended pathways and indication-specific prescribing requirements (for example, single‑agent prescribing for certain indications and the option to combine with carboplatin/paclitaxel for SCAC). Providers must follow the current indication-specific sequencing and documentation rules when submitting requests.

Recent updates added NCCN‑recommended off‑label pathways (colon, rectal, small bowel, appendiceal cancers with MSI‑H/dMMR/POLE-associated ultra‑hypermutated phenotype) and clarified single‑agent requirements for MCC; consult the policy for specific criteria.
Changes to approval durations and added/removed codes may affect prior authorization determinations — confirm requirements at time of request.