Commercial

Medical Policy

Title:

Retifanlimab-dlwr (Zynyz®)

Policy #:

08.02.05c

Policy

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

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 (National Comprehensive Cancer Network [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 M1 disseminated disease (NCCN preferred)

ANAL 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 squamous carcinoma of the anal canal as second-line and subsequent therapy as a single agent if no prior immunotherapy received (NCCN preferred).

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 ultra-hypermutated 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
Systemic therapy for advanced or metastatic disease if individual is a candidate for immunotherapy and no prior immunotherapy received

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 ultra-hypermutated 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 ultra-hypermutated 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.

MANDATES

PENNSYLVANIA MEMBERS
In accordance with the Commonwealth of Pennsylvania's Act 6 of 2020 or Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have Stage 4, advanced metastatic cancer, refer to the Medical Policy titled "Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive Agents" (08.01.08) for additional information regarding the applicable coverage of 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

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, retifanlimab-dlwr (Zynyz) is covered under the medical benefits of the Company's 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 is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

PEDIATRIC USE

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

Description

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.

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.

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 65 individuals with treatment-naïve MCC that was metastatic or advanced locally recurrent. The participants received retifanlimab-dlwr (Zynyz) 500 mg as an intravenous infusion every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. The primary outcome measure was objective response rate (ORR). One of the secondary outcome measures was duration of response (DOR). The ORR was 52 percent (95 percent confidence interval [CI], 40–65) with 12 (18 percent) complete responses and 22 (34 percent) partial responses. The DOR for the 34 individuals with a response ranged from 1.1 months to 24.9+ (ongoing) months. At 6 months, 26/34 (76 percent) individuals had an ongoing response. At 12 months, 21/34 (62 percent) had an ongoing response.

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 2025. [UpToDate Lexidrug Web site]. 02/17/2025 Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed April 9, 2025.

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: October 15, 2024. Available at: https://clinicaltrials.gov/. Accessed April 9, 2025.

Elsevier's Clinical Pharmacology Compendium. Retifanlimab-dlwr (Zynyz^®). [Clinical Key Web site]. 09/20/2024. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed April 9, 2025.

Merative Micromedex^® DRUGDEX^® (electronic version). Retifanlimab-dlwr (Zynyz^®). [Micromedex Web site]. 01/27/2025. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed April 9, 2025.

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 April 9, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Anal carcinoma V3.2025. [NCCN Web site]. 03/31/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf [via subscription only]. Accessed April 9, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Colon cancer V2.2025. [NCCN Web site]. 03/31/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf [via subscription only]. Accessed April 9, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Merkel cell carcinoma V1.2025. [NCCN Web site]. 01/13/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf [via subscription only]. Accessed April 9, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Rectal cancer V2.2025. [NCCN Web site]. 03/31/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf [via subscription only]. Accessed April 9, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Small bowel adenocarcinoma V3.2025. [NCCN Web site]. 03/31/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/small_bowel.pdf [via subscription only]. Accessed April 9, 2025.

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 April 9, 2025.

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]. 09/12/2023. 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 April 9, 2025.

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.

Retifanlimab (Zynyz^®) [prescribing information]. Wilmington, DE: Incyte Corporation. 04/2024. Available at: https://www.zynyz.com/. Accessed April 9, 2025.

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® LexidrugTM. Retifanlimab-dlwr (Zynyz^®). [UpToDate Lexidrug Web site]. 03/25/2025. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed April 9, 2025.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Retifanlimab-dlwr (Zynyz^®). Prescribing information. [FDA Web site]. 04/22/2024. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed April 9, 2025.

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 appropiate 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 08.02.05c:

07/01/2025

The policy will become effective 07/01/2025.

The following policy criteria have been added to this policy in accordance with National Comprehensive Cancer Network (NCCN) 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 accessed 04/07/2025:
Merkel cell carcinoma

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

Revisions From 08.02.05b:

09/09/2024

The policy will become effective 09/09/2024.

The following indication has been added to this policy in accordance with the National

Comprehensive Cancer Network (NCCN) compendium (accessed 07/29/2024) and guideline

(Anal Carcinoma V1.2024; 12/20/2023):

Anal carcinoma

The following policy criteria have been revised in accordance with the NCCN compendium

(accessed 07/29/2024) and guideline (Merkel Cell Carcinoma V1.2024; 11/22/2023):

Merkel cell carcinoma

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 08.02.05a:

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 08.02.05:

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:

7/1/2025

Version Issued Date: