Coverage Policy Manual
Policy #: 2023033
Category: Pharmacy
Initiated: July 2023
Last Review: July 2025
  Retifanlimab-dlwr (e.g., Zynyz)
Description:
Retifanlimab-dlwr (e.g., Zynyz) is a humanized IgG4 monoclonal antibody which is a programmed death receptor-1 (PD-1) blocking antibody. Retifanlimab-dlwr binds to the PD-1 receptor, blocking interaction with its ligands, PD-L1 and PD-L2, and potentiating T-cell activity. PD-L1 and PD-L2 binding to the PD-1 receptor on T-cells inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors; therefore, signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors.
 
Merkel cell carcinoma (MCC) is an uncommon and aggressive cutaneous malignancy that predominantly affects older adults with light skin types, with an incidence of less than one per 100,000 individuals. Inidividuals with MCC have a high propensity to develop recurrent or metastatic disease. Individuals with locoregional MCC who have completed initial therapy have a 20 to 75 percent chance of recurrent or metastatic disease depending on stage at diagnosis, with a majority occurring within three years of diagnosis. The overall 5-year survival rate of individuals diagnosed with distant metastasis of MCC is estimated at 14%.
 
Retifanlimab-dlwr is the fifth PD-1 inhibitor approved by the FDA, and 11th checkpoint inhibitor approved overall.
 
Regulatory Status
 
Retifanlimab-dlwr (e.g., Zynyz) was granted accelerated approval by the U.S. Food and Drug. Administration (FDA) on March 22, 2023, for the treatment of adult individuals with metastatic or recurrent locally advanced Merkel cell carcinoma. This indication was 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.
 
Retifanlimab-dlwr (e.g., Zynyz) was approved by the U.S. Food and Drug Administration (FDA) on May 15, 2025, for the treatment of squamous cell carcinoma of the anal canal (SCAC):
    •  In combination with carboplatin and paclitaxel for the first-line treatment of adult individuals with metastatic or with inoperable locally recurrent SCAC.
    •  As a single agent  for the treatment of adult individuals with locally recurrent or with metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy.
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
The initial use of this drug requires documentation of direct physician involvement (MD/DO) in the ordering and evaluation, as well as signature, in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
 
For members of plans that utilize an oncology benefits management program, Prior Approval is required for this service when rendered for oncologic indications and is managed through the oncology benefits management program.
 
Approval timeframes may differ for members/participants of Self-Insured plans.
 
Effective July 23, 2025
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Retifanlimab-dlwr (e.g., Zynyz) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
For FDA labeled indications, Retifanlimab-dlwr (e.g., Zynyz) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified in the dosage and administration section.
 
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication in the dosage and administration section.
 
FDA Labeled Indications:
 
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication below with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”).
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
MERKEL CELL CARCINOMA (MCC)
 
1. Individual must be 18 years of age or older; AND
2. Individual must have a diagnosis of recurrent locally advanced (N0) or recurrent regional (N+) or M1 disseminated disease, not amenable to surgery or radiation (NCCN 2A); AND
3. Must be used as a single agent treatment (NCCN 2A); AND
4. Individual must not have received prior PD-1 or PD-L1 directed therapy for locally advanced or metastatic MCC; AND
5. Individual must have an *ECOG performance status of 0 or 1.
 
CONTINUED APPROVAL for up to 1 year:   
 
1. Individual has met all the initial requirements; AND
2. Individual experiences objective benefit from continued treatment as defined by stabilization of disease or decrease in size of tumor or tumor spread; AND
3. Individual does not have unacceptable toxicity resulting from the treatment or infusion reactions (e.g., immune-medicated adverse reactions, infusion-related reactions, complications of allogeneic HSCT) (Zynyz, 2025); AND
4. May be given for up to 24 months.
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
SQUAMOUS CELL CARCINOMA OF THE ANAL CANAL (SCAC)
 
1. Individual must be 18 years of age or older; AND
2. Individual has a diagnosis of anal carcinoma with squamous cell histology; AND
3. Retifanlimab-dlwr (e.g., Zynyz) will be used:
a. In combination with carboplatin and paclitaxel for the first-line treatment of inoperable locally recurrent metastatic SCAC (Zynyz, 2025; NCCN 2A); OR
b. As a single agent for the treatment of locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy (NCCN 2A); AND
4. Individual has not received prior treatment with an anti-PD-1 or PD-L1 agent; AND
5. Retifanlimab-dlwr (e.g., Zynyz) will not be used for locally recurrent progressive anal carcinoma before abdominoperineal resection (NCCN 2B); AND
6. Individual has an *ECOG performance status of 0 to 1 (Rao, 2022).
 
CONTINUED APPROVAL for up to 1 year:   
 
1. Individual has met all the initial requirements; AND
2. Individual experiences objective benefit from continued treatment as defined by stabilization of disease or decrease in size of tumor or tumor spread; AND
3. Individual does not have unacceptable toxicity resulting from the treatment or infusion reactions (e.g., immune-medicated adverse reactions, infusion-related reactions, complications of allogeneic HSCT) (Zynyz, 2025); AND
4. May be given for up to 24 months.
 
Off-label Indications:
 
The use of this drug for off-label indications not listed below is subject to policy 2000030.
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. Merkel Cell Carcinoma (NCCN 2A); OR
2. Small Bowel Adenocarcinoma (NCCN 2A); OR
3. Anal Carcinoma (NCCN 2A); OR
4. Rectal Cancer (NCCN 2A); OR
5. Colon Cancer:
a. Colon Cancer (NCCN 2A); OR
b. Appendiceal Adenocarcinoma (NCCN 2A).
 
CONTINUED APPROVAL for up to 1 year:   
 
1. Individual has met all the initial requirements; AND
2. Individual experiences objective benefit from continued treatment as defined by stabilization of disease or decrease in size of tumor or tumor spread; AND
3. Individual does not have unacceptable toxicity resulting from the treatment or infusion reactions (e.g., immune-medicated adverse reactions, infusion-related reactions, complications of allogeneic HSCT) (Zynyz, 2025); AND
4. May be given for up to 24 months.
 
Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications. To view the most recent and complete version of the guideline or Compendium, go online to NCCN.org. Please note, NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
 
Policy Guidelines
 
ECOG Performance Status Scale (ACRIN, 2024)
0     Fully active, able to carry on all pre-disease performance without restriction
1     Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g.,  light housework, office work
2     Ambulatory and capable of all selfcare but unable to carry out any work activities; up  and about more than 50% of waking hours
3     Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4     Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5     Dead
 
Prescriber is responsible for verification that Individual does not have latent tuberculosis, hepatitis B infection, significantly compromised immune function (e.g., leukemia, lymphoma, AIDS, organ transplantation) or other serious active infection before starting the treatment.
 
Dosage and Administration
Dosing per FDA Guidelines unless otherwise specified below.
 
The recommended dose of retifanlimab-dlwr:
    •  Combination Therapy:
      •  Inoperable locally recurrent or metastatic SCA in combination with carboplatin and paclitaxel: 500 mg every 4 weeks until disease progression, unacceptable toxicity, or up to 12 months
    •  Monotherapy:
      •  Locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy: 500 mg every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months
      •  Metastatic or recurrent locally advanced MCC: 500 mg every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months
 
Retifanlimab-dlwr is available as a 500 mg/20 mL (25 mg/mL) solution in a single-dose vial. See FDA label for dosing modifications for adverse reactions.
 
Retifanlimab-dlwr should be administered as an in intravenous infusion by a healthcare professional.
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Retifanlimab-dlwr (e.g., Zynyz) for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, retifanlimab-dlwr (e.g., Zynyz), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Date July 17, 2024 to July 22, 2025
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Retifanlimab-dlwr meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
FDA Labeled Indications:
 
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Merkel Cell Carcinoma
 
1. Individual must be 18 years of age or older; AND
2. Individual must have a diagnosis of recurrent locally advanced (N0) or recurrent regional (N+) or M1 disseminated disease, not amenable to surgery or radiation (NCCN 2A); AND
3. Must be used as a single agent treatment (NCCN 2A); AND
4. Individual must not have received prior PD-1 or PD-L1 directed therapy for locally advanced or metastatic MCC; AND
5. Individual must have an ECOG performance status of 0 or 1.
 
CONTINUED APPROVAL for up to 1 year:   
 
1. Individual has met all the initial requirements; AND
2. No evidence of disease progression or unacceptable toxicity; AND
3. May be given up to 24 months (FDA label 2023).
 
Off-label Indications:
 
For off-label indications, authorizations will not exceed 500 mg intravenous infusion every 28 days until disease progression, unacceptable toxicity, or 24 months unless medical literature supports a higher dose.
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Anal Carcinoma
 
1. Individual must be 18 years of age or older; AND
2. Individual has a diagnosis of anal carcinoma with squamous cell histology (NCCN 2A); AND
3. Must be used as a single agent for metastatic disease if no prior immunotherapy received (NCCN 2A); AND
4. Will be used as second-line and subsequent therapy; AND
5. Will not be used for locally recurrent progressive anal carcinoma before abdominoperineal resection (NCCN 2B).
 
CONTINUED APPROVAL for up to 1 year:   
 
1. Individual has met all the initial requirements; AND
2. No evidence of unacceptable toxicity; AND
3. May be given for up to 24 months.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030). I
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of retifanlimab-dlwr is 500 mg intravenous infusion every 28 days until disease progression, unacceptable toxicity, or 24 months.
 
Retifanlimab-dlwr is available as a 500 mg/20 mL (25 mg/mL) solution in a single-dose vial.  See FDA label for dosing modifications for adverse reactions.
 
Retifanlimab-dlwr should be administered as an in intravenous infusion by a healthcare professional.  
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Retifanlimab-dlwr for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, retifanlimab-dlwr, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Date July 26, 2023 to July 16, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Retifanlimab-dlwr meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
    1. Individual must be >18 years of age.
    2. Individual must have a diagnosis of recurrent locally advanced (N0) or recurrent regional (N+) or M1 disseminated disease, not amenable to surgery or radiation (NCCN 2A).
    3. Must be used as a single agent treatment (NCCN 2A).
    4. Individual must not have received prior PD-1 or PD-L1 directed therapy for locally advanced or metastatic MCC.
    5. Individual must have an ECOG performance status of 0 or 1.  
    6. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for up to 1 year:  
 
    1. Individual has met all the initial requirements.
    2. No evidence of disease progression or unacceptable toxicity.  
    3. May be given up to 24 months (FDA label 2023).
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030). I
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of retifanlimab-dlwr is 500 mg IV every 28 days until disease progression, unacceptable toxicity, or 24 months.
 
Retifanlimab-dlwr is available as a 500 mg/20 mL (25 mg/mL) solution in a single-dose vial.  See FDA label for dosing modifications for adverse reactions.
 
Retifanlimab-dlwr should be administered as an in intravenous infusion by a healthcare professional.  
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Retifanlimab-dlwr for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, retifanlimab-dlwr, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
The accelerated approval of retifanlimab-dlwr was based on data from the Phase 2 POD1UM-201 (NCT03599713) clinical trial, an open-label, single-arm, multicenter study evaluating the safety and efficacy of retifanlimab-dlwr in 65 patients with metastatic or recurrent locally advanced MCC who had not received prior systemic therapy. Patients received retifanlimab-dlwr 500 mg through intravenous (IV) administration every 4 weeks for up to 2 years. As with all accelerated approvals, continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
 
In the efficacy population, which consisted of 65 patients, retifanlimab-dlwr monotherapy demonstrated an ORR of 52%. Complete responses were seen in 12 patients (18%), and 22 patients (34%) showed a partial response. Among the 34 responding patients, the duration of response (DOR) ranged from 1.1 to 24.9+ months. A total of 76% of patients (26/34) experienced a DOR of 6 months or longer, and 62% (21/34) experienced a DOR of 12 months or longer.
 
The safety population included 105 patients with MCC. The most common (≥10%) adverse reactions (ARs) were fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea. Serious ARs occurred in 22% of patients receiving retifanlimab-dlwr. The most frequent serious ARs (≥2% of patients) were fatigue, arrhythmia, and pneumonitis.
 
Permanent discontinuation of retifanlimab-dlwr due to an AR occurred in 11% of patients. The ARs leading to permanent discontinuation included asthenia, atrial fibrillation, concomitant disease progression of chronic lymphocytic leukemia, demyelinating polyneuropathy, eosinophilic fasciitis, increased transaminases, infusion-related reaction, lung disorder, pancreatitis, polyarthritis, and radiculopathy (one patient each). Dosage interruptions due to an AR occurred in 25% of patients who received retifanlimab-dlwr. ARs or laboratory abnormalities that required dosage interruption in ≥2% of patients who received retifanlimab-dlwr were increased transaminases, increased lipase, increased amylase, pneumonitis, and pyrexia.
 
It is also important to note that Bristol Myer’s Squibb’s (BMS’s) PD-1 inhibitor Opdivo has NCCN support (Category 2A) as a neoadjuvant treatment for MCC. Per the CheckMate 358 trial (NCT02488759), patients with resectable MCC received Opdivo 240 mg intravenously on Days 1 and 15 and underwent surgery on Day 29. Two doses of neoadjuvant Opdivo for resectable disease should not preclude a patient from using a PD-1/PD-L1 inhibitor for recurrent locally advanced or metastatic MCC.
 
Patients with MCC can be treated with one of three PD-1/PD-L1 inhibitors approved for MCC: Keytruda, Bavencio, or retifanlimab-dlwr.  Although there are no head-to-head trials for these three agents, cross-trial comparisons suggest similar efficacy among them.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2024.
 
2025 Update
On May 15 2025, U.S. Food and Drug Administration (FDA) has approved retifanlimab-dlwr, a humanized monoclonal antibody targeting programmed death receptor-1 (PD-1), in combination with carboplatin and paclitaxel (platinum-based chemotherapy) for the first-line treatment of adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC). In addition, the FDA granted approval for retifanlimab-dlwr as a single agent for the treatment of adult patients with locally recurrent or with metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy. The Priority Review and FDA approval of the supplemental Biologics License Application (sBLA) for retifanlimab-dlwr was based on data from two trials: the Phase 3 POD1UM-303/InterAACT2 trial evaluating retifanlimab-dlwr in combination with platinum-based chemotherapy (carboplatin-paclitaxel) in adult patients with metastatic or inoperable locally recurrent SCAC not previously treated with systemic chemotherapy, and the Phase 2 POD1UM-202 trial evaluating retifanlimab-dlwr monotherapy in previously treated patients with locally advanced or metastatic SCAC who have progressed on or were intolerant of platinum-based chemotherapy.
 
Results from POD1UM-303/InterAACT2, featured at a Presidential Symposium on Practice-Changing Trials at the European Society for Medical Oncology (ESMO) in 2024, showed a clinically meaningful and statistically significant 37% reduction in the risk of progression or death (P=0.0006). Patients in the retifanlimab-dlwr and chemotherapy combination group achieved a median progression-free survival (PFS) of 9.3 months compared to 7.4 months for patients in the placebo combination group. Additionally, a 6.2-month improvement in median overall survival (OS) was observed (P=0.0273) at an interim analysis; OS follow-up is ongoing. No new safety signals were observed. Serious adverse reactions occurred in 47% of patients receiving retifanlimab-dlwr in combination with chemotherapy. The most frequent serious adverse reactions (≥ 2% of patients) were sepsis (3.2%), pulmonary embolism (3.2%), diarrhea (2.6%) and vomiting (2.6%).
 
The retifanlimab-dlwr monotherapy approval is based on results from the POD1UM-202 study which demonstrated that treatment with retifanlimab-dlwr monotherapy produced an objective response rate (ORR) of 14% and disease control rate of 49%. Retifanlimab-dlwr demonstrated a safety profile as expected of a PD-1 inhibitor with no loss of human immunodeficiency virus (HIV) infection control.2 Serious adverse reactions occurred in 40% of patients receiving retifanlimab-dlwr. The most frequent serious adverse reactions (≥ 2% of patients) were non-urinary tract infection, perineal pain, abdominal pain, anemia, hemorrhage, diarrhea, pyrexia, urinary tract infection, musculoskeletal pain and dyspnea.
CPT/HCPCS:
J9345Injection, retifanlimab-dlwr, 1 mg
J9999Not otherwise classified, antineoplastic drugs
References: ECOG Performance Status Scale. ECOG, 25 Nov. 2024, ecog-acrin.org/resources/ecog-performance-status/. Accessed July 14, 2025.

IPD Analytics.(2023) New Drug Review, Zynyz (retifanlimab-dlwr). April 2023. Accessed July 21, 2023. Subscription required.

McEvoy AM, Lachance K, Hippe DS, et al.(2022) Recurrence and Mortality Risk of Merkel Cell Carcinoma by Cancer Stage and Time From Diagnosis. JAMA Dermatol 2022; 158:382.

NCCN Clinical Practice Guidelines in Oncology™.(2023) (2023) Merkel Cell Carcinoma V1.2023 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on July 24, 2023.

NCCN Drugs & Biologics Compendium for Retifanlimab-dlwr (e.g., Zynyz), National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed [July 14, 2025]. To view the most recent and complete version of the Compendium, go online to NCCN.org.

NCCN Drugs & Biologics Compendium® .(2023) Retifanlimab-dlwr (Zynyz) 2023 National Comprehensive Cancer Network, Inc. Available at: NCCN.org. Accessed July 24,2023. Subscription required.

NCCN(2024) Drugs & Biologics Compendium for Retifanlimab-dlwr (e.g., Zynyz) Accessed [July 5, 2024]. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Rao S, Anandappa G, Capdevila J, et.al.,(2022) 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 Aug;7(4):100529. doi: 10.1016/j.esmoop.2022.100529. Epub 2022 Jul 8. PMID: 35816951; PMCID: PMC9463376.

Rao S, Jones M, Bowman J, et.al.,(2022) POD1UM-303/InterAACT 2: A phase III, global, randomized, double-blind study of retifanlimab or placebo plus carboplatin-paclitaxel in patients with locally advanced or metastatic squamous cell anal carcinoma. Front Oncol. 2022 Aug 24;12:935383. doi: 10.3389/fonc.2022.935383. PMID: 36091159; PMCID: PMC9449327.

Zynyz [package insert]. Wilmington, DE: Incyte Corporation; 2025.

Zynyz [package insert]. Wilmington, DE: Incyte Corporation; March 2023
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.
CPT Codes Copyright © 2025 American Medical Association.