Medicare Advantage

Medical Policy

Title:

Retifanlimab-dlwr (Zynyz®)

Policy #:

MA08.161d

Policy

In the absence of coverage criteria from applicable Medicare statutes, regulations, NCDs, LCDs, CMS manuals, or other Medicare coverage documents, this policy uses internal coverage criteria developed by the Company in consideration of peer-reviewed medical literature, clinical practice guidelines, and/or regulatory status.

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member's medical needs and condition.

MEDICALLY NECESSARY

ANAL CARCINOMA

First-line treatment

Retifanlimab-dlwr (Zynyz^®) is considered medically necessary and, therefore, covered as a first-line treatment, as an intravenous infusion, in combination with carboplatin and paclitaxel, for the treatment of individuals 18 years of age or older with squamous carcinoma of the anal canal who meet ANY of the following:

Inoperable locally recurrent or metastatic disease
Primary treatment of metastatic disease (National Comprehensive Cancer Network [NCCN] preferred)
Persistent metastatic or progressive locoregional disease (NCCN preferred)

Second-line and subsequent therapy

Retifanlimab-dlwr (Zynyz) is considered medically necessary and, therefore, covered as a single agent intravenous infusion for the treatment of individuals 18 years of age or older with squamous carcinoma of the anal canal (NCCN preferred) who meet ALL of the following:

Disease is metastatic or locally recurrent
Disease progression on or intolerance to platinum-based chemotherapy
Second-line and subsequent therapy
No prior immunotherapy received

APPENDICEAL NEOPLASMS
Retifanlimab-dlwr (Zynyz) is considered medically necessary and, therefore, covered as a single agent intravenous infusion for the treatment of individuals 18 years of age or older with an appendiceal neoplasm that is deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or polymerase epsilon/delta (POLE/POLD1) mutation positive with ultra-hypermutated phenotype (e.g., tumor mutational burden [TMB] >50 mutations/megabase [mut/Mb]) (if no previous treatment with a checkpoint inhibitor) for ONE of the following scenarios:

As neoadjuvant systemic therapy for ONE of the following:

Biopsy-proven recurrence of high-risk disease and not previous cytoreductive surgery
Metastatic disease in peritoneal-only disease

Recurrence with serial tumor marker elevation or radiographic progression and progressive or positive findings
Biopsy-proven recurrence of high-risk disease if cytoreductive surgery was previously received or not possible
Progressive disease or inadequate response after neoadjuvant systemic therapy for metastatic perineal-only disease
Extraperitoneal disease

COLON CANCER

Retifanlimab-dlwr (Zynyz) is considered medically necessary and, therefore, covered as an intravenous infusion for the treatment of individuals 18 years of age or older with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) or polymerase epsilon/delta (POLE/POLD1) mutation with ultrahypermutated phenotype (e.g., tumor mutational burden [TMB] >50 mutations/megabase [mut/Mb]) colon cancer as a single-agent treatment for ONE of the following:

Individual is a candidate for immunotherapy and no prior immunotherapy received in ONE of the following scenarios:

For locally unresectable or medically inoperable disease (NCCN preferred)
As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
For synchronous unresectable metastases
As treatment for unresectable metachronous metastases

As neoadjuvant therapy in clinical T4b or bulky nodal disease (NCCN preferred)
As neoadjuvant therapy for resectable synchronous liver and/or lung metastases (if no previous treatment with a checkpoint inhibitor [NCCN preferred])
As initial treatment for resectable metachronous metastases if no previous immunotherapy

MERKEL CELL CARCINOMA

Retifanlimab-dlwr (Zynyz) is considered medically necessary and, therefore, covered as an intravenous infusion for the treatment of individuals 18 years of age or older with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC) as single-agent treatment for ONE of the following:

For primary clinical N0 locally advanced disease if curative surgery and curative radiation therapy (RT) are not feasible
For recurrent N0 locally advanced disease if curative surgery and curative RT are not feasible or for progression on neoadjuvant nivolumab (NCCN preferred)
For primary N+, M0 regional disease with biopsy-positive draining nodal basin if curative surgery and curative RT are not feasible (NCCN preferred)
For recurrent N+ regional disease if curative surgery and curative RT are not feasible (NCCN preferred)
For in-transit N+ regional disease (NCCN preferred)
For M1 disseminated disease (NCCN preferred)

RECTAL CANCER

Retifanlimab-dlwr (Zynyz) is considered medically necessary and, therefore, covered as an intravenous infusion for the treatment of individuals 18 years of age or older with dMMR/MSI-H or POLE/POLD1 mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb) rectal cancer as a single-agent treatment for ONE of the following:

Individual is a candidate for immunotherapy and no immunotherapy received in ONE of the following scenarios:

As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
As primary treatment for synchronous unresectable metastases
As primary treatment for potentially resectable or unresectable isolated pelvic/anastomotic recurrence
As primary treatment for unresectable metachronous metastases

As neoadjuvant treatment for resectable synchronous liver only and/or lung only metastases (no previous treatment with a checkpoint inhibitor [NCCN preferred])
As initial treatment for resectable metachronous metastases and no previous immunotherapy

SMALL BOWEL ADENOCARCINOMA
Retifanlimab-dlwr (Zynyz) is considered medically necessary and, therefore, covered as an intravenous infusion for the treatment of individuals 18 years of age or older with dMMR/MSI-H or POLE/POLD1 mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb) small bowel adenocarcinoma as a single-agent treatment for ONE of the following:

As primary treatment for locally unresectable or medically inoperable disease
For advanced or metastatic disease, if no previous treatment with a checkpoint inhibitor, for any line of therapy

EXPERIMENTAL/INVESTIGATIONAL

All other uses of retifanlimab-dlwr (Zynyz) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

There is no Medicare coverage determination addressing retifanlimab-dlwr (Zynyz) for intravenous use; therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, retifanlimab-dlwr (Zynyz) is covered under the medical benefits of the Company's Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION STATUS

The US Food and Drug Administration (FDA) approved retifanlimab-dlwr (Zynyz) on March 22, 2023, for the treatment of metastatic or recurrent locally advanced Merkel cell carcinoma in adults. This indication was initially approved under accelerated approval based on tumor response rate and duration of response, but received traditional approval on December 17, 2025, based on the final clinical trial results. Supplemental approvals for retifanlimab-dlwr (Zynyz) have since been issued by the FDA.

PEDIATRIC USE

The safety and effectiveness of retifanlimab-dlwr (Zynyz) in pediatric individuals have not been evaluated.

Description

Retifanlimab-dlwr (Zynyz) is a programmed death receptor-1 (PD-1)-blocking monoclonal antibody. Programmed death receptors are present on T cells, part of the body's immune system. If they bind to the PD ligands, PD-L1 and PD-L2, that are found on tumor cells, they prevent the T cells from surveilling and killing tumor cells. Blocking the binding of the ligands to the programmed death receptors allows the T cells to remain active and perform their surveillance and killing of tumors.

ANAL CARCINOMA

Anal carcinoma is a rare type of cancer that begins in the tissues of the anus, the opening at the end of the digestive tract. Most cases are a specific subtype called squamous cell carcinoma of the anal canal (SCAC), which makes up about 80 percent of all anal cancers. A major cause of anal carcinoma is long‑term infection with human papillomavirus (HPV). About 90 percent of anal squamous cell tumors are HPV‑positive. Anal carcinoma can often be treated successfully when found early, but advanced disease can be more difficult to treat.

CLINICAL TRIALS
First-line treatment

The safety and efficacy of retifanlimab-dlwr (Zynyz), in combination with carboplatin and paclitaxel, were evaluated in a multicenter, randomized, double‑blind, phase III clinical trial (POD1UM‑303; NCT04472429) in individuals with inoperable, locally recurrent or metastatic squamous cell carcinoma of the anal canal, who were chemotherapy naive. A total of 308 participants were enrolled and randomly assigned 1:1 into two cohorts. The first cohort of 154 individuals received intravenous (IV) retifanlimab-dlwr (Zynyz) plus carboplatin and paclitaxel. The second cohort of 154 individuals received placebo plus carboplatin and paclitaxel. Individuals in cohort 1 continued to receive treatment, for up to 1 year, or until there was disease progression, unacceptable toxicity, withdrawal of consent, or death. Individuals in cohort 2 could receive single-agent retifanlimab-dlwr (Zynyz) upon disease progression, if desired. The primary endpoint was progression‑free survival (PFS). Key secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), and safety.

The median PFS in the retifanlimab-dlwr (Zynyz) cohort was 9.3 months (95 percent confidence interval [CI], 7.5–11.3 months) compared with 7.4 months (95 percent CI, 7.1–7.7 months) in the placebo cohort (hazard ratio [HR] 0.63 [95 percent CI, 0.47–0.84]; P=0.0006). Median OS was 29.2 months (95 percent CI, 24.2 months to not estimable [NE]) for the retifanlimab-dlwr (Zynyz) cohort versus 23.0 months (95 percent CI, 15.1–27.9 months) for placebo (HR 0.70; P=0.027). ORR was 55.8 percent (95 percent CI, 47.6–63.8 percent) with retifanlimab-dlwr (Zynyz) compared with 44.2 percent (95 percent CI, 36.2–52.4 percent) with placebo (nominal P=0.013). Median DOR was 14.0 months (95 percent CI, 8.6–22.2 months) in the retifanlimab-dlwr (Zynyz) cohort versus 7.2 months (95 percent CI, 5.6–9.3 months) in the placebo cohort. There were four fatal adverse events in the retifanlimab-dlwr (Zynyz) cohort, but only one was considered to be treatment related. There was one fatal adverse event in the placebo cohort that was not considered to be treatment related. Although there was a higher rate of grade 3 or worse adverse events in the retifanlimab-dlwr (Zynyz) cohort versus the placebo cohort, the toxicities were manageable with standard care.

Second-line and subsequent therapy

The safety and efficacy of retifanlimab-dlwr (Zynyz) was studied in a phase II, open-label, multicenter clinical trial (POD1UM-202; NCT03597295). Study participants included 94 individuals with locally advanced or metastatic squamous cell anal cancer whose disease had progressed on or after platinum‑based chemotherapy, or were ineligible for or intolerant to platinum-based chemotherapy. Participants received retifanlimab-dlwr (Zynyz) 500 mg IV every 4 weeks, for a maximum of 2 years, or until there was disease progression, unacceptable toxicity, or discontinuation. The primary endpoint was ORR. Key secondary endpoints included DOR, PFS, and OS.

The ORR was 13.8 percent (95 percent CI, 7.6–22.5 percent), including one complete and twelve partial responses. The median DOR was 9.5 months (95 percent CI, 5.6 months to NE). The median PFS was 2.3 months (95 percent CI, 1.9–3.6 months). The median OS was 10.1 months (95 percent CI, 7.9 to NE). Side effects were common but generally manageable, with the safety profile consistent with other PD‑1 inhibitors.

MERKEL CELL CARCINOMA

Merkel cell carcinoma (MCC) is a rare, highly aggressive form of skin cancer that usually develops on sun-exposed areas of the body. It often affects older adults, and usually those with light skin coloration. Individuals with immune deficiency are at a higher risk of developing MCC. MCC is prone to locoregional recurrence and distant metastasis. Recurrence of MCC is associated with a poor prognosis. The 5-year survival of individuals with metastatic disease is 13.5 percent.

CLINICAL TRIAL
The safety and efficacy of retifanlimab-dlwr (Zynyz) was studied in a phase II, nonrandomized, open-label, multicenter clinical trial (POD1UM-201; NCT03599713). Study participants included 101 individuals with treatment-naïve MCC that was metastatic or advanced locally recurrent. The participants received retifanlimab-dlwr (Zynyz) 500 mg as an IV infusion every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. The primary outcome measure was ORR. Key secondary outcome measures were DOR, PFS, OS, and safety.

The ORR was 55 percent (95 percent CI, 44–64 percent) with 18 (18 percent) complete responses and 37 (37 percent) partial responses. The median DOR was not reached (95 percent CI, 14.0 months to NE) for individuals achieving a complete response and was 25.3 months (95 percent CI, 14.2 months to NE) for individuals with a partial response. At the time of data cutoff, the median PFS was 54 percent (95 percent CI, 43–63 percent). At the time of data cutoff, the median OS was not yet reached, but 63 percent of participants were still alive at 3 years. The safety profile was consistent with other PD-1 inhibitors.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American Hospital Formulary Service (AHFS). Retifanlimab-dlwr (Zynyz^®). AHFS Drug Information. [UpToDate Lexidrug Web site]. 01/07/2026 Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed January 16, 2026.

ClinicalTrials.gov. A study of INCMGA00012 in metastatic Merkel cell carcinoma (POD1UM-201). ClinicalTrials.gov Identifier: NCT03599713. First Posted: July 26, 2018. Last Update Posted: August 5, 2025. Available at: https://clinicaltrials.gov/. Accessed January 16, 2026.

ClinicalTrials.gov. A study of INCMGA00012 in squamous carcinoma of the anal canal following platinum-based chemotherapy (POD1UM-202). ClinicalTrials.gov Identifier: NCT03597295. First Posted: June 4, 2021. Last Update Posted: August 21, 2025. Available at: https://clinicaltrials.gov/. Accessed January 16, 2026.

ClinicalTrials.gov. Carboplatin-paclitaxel with retifanlimab or placebo in participants with locally advanced or metastatic squamous cell anal carcinoma (POD1UM-303/InterAACT2). ClinicalTrials.gov Identifier: NCT04472429. First Posted: April 8, 2025. Last Update Posted: November 3, 2025. Available at: https://clinicaltrials.gov/. Accessed January 16, 2026.

Grignani G, Rutkowski P, Lebbe C, et al. Phase II study of retifanlimab in patients with recurrent locally advanced or metastatic Merkel cell carcinoma (POD1UM-201). J Immunother Cancer. 2025;13(8):e012478.

Elsevier's Clinical Pharmacology Compendium. Retifanlimab-dlwr (Zynyz^®). [Clinical Key Web site]. 12/26/2025. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed January 16, 2026.

Merative Micromedex^® DRUGDEX^® (electronic version). Retifanlimab-dlwr (Zynyz^®). [Micromedex Web site]. 01/14/2026. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed January 16, 2026.

National Cancer Institute. Immune checkpoint inhibitors. [National Institute of Health website]. 04/07/2022. Available at: https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors. Accessed January 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Anal carcinoma V5.2025. [NCCN Web site]. 10/31/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf [via subscription only]. Accessed January 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Appendiceal neoplasms and cancers V1.2026. [NCCN Web site]. 10/30/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/appendiceal.pdf [via subscription only]. Accessed January 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Colon cancer V5.2025. [NCCN Web site]. 10/30/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf [via subscription only]. Accessed January 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Merkel cell carcinoma V2.2026. [NCCN Web site]. 01/13/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf [via subscription only]. Accessed January 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Rectal cancer V4.2025. [NCCN Web site]. 10/31/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf [via subscription only]. Accessed January 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Small bowel adenocarcinoma V4.2025. [NCCN Web site]. 10/31/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/small_bowel.pdf [via subscription only]. Accessed January 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium^®. [NCCN Web site]. Retifanlimab-dlwr (Zynyz^®). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed January 16, 2026.

Park SY, Doolittle-Amieva C, Moshiri Y, et al. How we treat Merkel cell carcinoma: within and beyond current guidelines. Future Oncol. 2021;17(11):1363-1377.

Park SY, Nghiem PT, Tai P, Silk AW. Treatment of recurrent and metastatic Merkel cell carcinoma. [UpToDate Web site]. 10/29/2025. Available at: https://www.uptodate.com/contents/treatment-of-recurrent-and-metastatic-merkel-cell-carcinoma?search=Treatment of recurrent and metastatic Merkel cell carcinoma&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. [via subscription only]. Accessed January 16, 2026.

Rao S, Anandappa G, Capdevila J, et al. A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202). ESMO Open. 2022;7(4):100529.

Rao S, Samalin-Scalzi E, Evesque L, et al. Retifanlimab with carboplatin and paclitaxel for locally recurrent or metastatic squamous cell carcinoma of the anal canal (POD1UM-303/InterAACT-2): a global, phase 3 randomised controlled trial. Lancet. 2025;405(10495):2144-2152.

Stachyra K, Dudzisz-Sledz M, Bylina E, et al. Merkel cell carcinoma from molecular pathology to novel therapies. Int J Mol Sci. 2021;22(12):6305.

UpToDate^® Lexidrug^TM. Retifanlimab-dlwr (Zynyz^®). [UpToDate Lexidrug Web site]. 01/14/2026. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed January 16, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Retifanlimab-dlwr (Zynyz^®). Prescribing information. [FDA Web site]. 12/17/2025. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed January 16, 2026.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

HCPCS Level II Code Number(s)

J9345 Injection, retifanlimab-dlwr, 1 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From MA08.161d:

05/04/2026

The policy will become effective 05/04/2026.

The following indication has been added to this policy as medically necessary in accordance with National Comprehensive Cancer Network (NCCN) compendium and guideline:

Appendiceal Neoplasms

The following policy criteria have been revised in accordance with NCCN compendium and guidelines:

Anal carcinoma
Colon cancer
Merkel cell carcinoma

Revisions From MA08.161c:

07/01/2025

This policy will become effective 07/01/2025.

The following indications have been added to this policy in accordance with National Comprehensive Cancer Network (NCCN) compendium and guidelines:
Colon cancer V2.2025 (03/31/2025)
Rectal cancer V2.2025 (03/31/2025)
Small bowel adenocarcinoma V3.2025 (03/31/2025)

The following policy criteria have been revised in accordance with NCCN compendium and guideline:
Merkel cell carcinoma

All ICD-10 codes have been removed from the policy, since they are informational.
Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy

Revisions From MA08.161b:

09/09/2024

This version of the policy will become effective 09/09/2024

The following indication has been added to this policy in accordance with National Comprehensive Cancer Network (NCCN) compendium and guideline:
Anal Carcinoma V1.2024 (12/20/2023)

The following policy criteria have been revised in accordance with NCCN compendium and guideline:
Merkel Cell Carcinoma V1.2024 (11/22/2023)

The following ICD-10 codes have been added to this policy:
C21.0 Malignant neoplasm of anus, unspecified
C21.1 Malignant neoplasm of anal canal
C21.2 Malignant neoplasm of cloacogenic zone
C21.8 Malignant neoplasm of overlapping sites of rectum, anus and anal canal

The following unspecified ICD-10 codes have been removed from this policy:
C4A.10   Merkel cell carcinoma of unspecified eyelid, including canthus
C4A.20   Merkel cell carcinoma of unspecified ear and external auricular canal
C4A.60   Merkel cell carcinoma of unspecified upper limb, including shoulder

C4A.70 Merkel cell carcinoma of unspecified lower limb, including hip

Revisions From MA08.161a:

01/01/2024	Effective 01/01/2024 this policy applies to New Jersey Medicare Advantage (MA) lines of business.
10/01/2023	The policy will become effective 10/01/2023. Inclusion of a policy in a Code Update memo does not imply that a full review of the policy was completed at this time. The following HCPCS code has been added to this policy: J9345 Injection, retifanlimab-dlwr, 1 mg The following HCPCS codes have been deleted from this policy: C9399 Unclassified drugs or biologicals J3590 Unclassified biologics

Revisions From MA08.161:

06/05/2023

The policy will become effective 06/05/2023.

The following new policy has been developed to communicate the Company's coverage criteria for retifanlimab-dlwr (Zynyz^TM).

Version Effective Date:

5/4/2026

Version Issued Date: