Retifanlimab-dlwr (Zynyz)

Number: 1030

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses retifanlimab-dlwr (Zynyz) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of retifanlimab-dlwr (Zynyz) is required of all Aetna participating providers and members in applicable plan designs. For precertification of retifanlimab-dlwr (Zynyz), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.  

Note: Site of Care Utilization Management Policy applies. For information on site of service for retifanlimab-dlwr (Zynyz), see Utilization Management Policy on Site of Care for Specialty Drug Infusions. 

1. Exclusions

   Aetna considers members not eligible for Zynyz when they have experienced disease progression while on PD-1 or PD-L1 inhibitor therapy.

2. Criteria for Initial Approval

   Aetna considers retifanlimab-dlwr (Zynyz) medically necessary for the following indications:

   1. Merkel Cell Carcinoma (MCC)

      As a single agent for treatment of locally advanced, regional, or metastatic MCC; or

   2. Squamous Cell Carcinoma of the Anal Canal (SCAC)

      For treatment of SCAC when either of the following criteria is met:

      1. The requested medication will be used in combination with carboplatin and paclitaxel for one of the following:

         1. Primary treatment of metastatic disease; or
         2. Treatment of recurrent disease; or

      2. The requested medication will be used as a single agent for subsequent therapy for locally recurrent or metastatic disease if the member has progressed on or is intolerant to platinum-based chemotherapy; or
         

   3. Colorectal Cancer

      As a single agent for treatment of locally unresectable, medically inoperable, advanced, recurrent, or metastatic 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] greater than 50 mut/Mb) colorectal cancer (including appendiceal adenocarcinoma); or

   4. Small Bowel Adenocarcinoma

      As a single agent for treatment of 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] greater than 50 mut/Mb) small bowel adenocarcinoma when either of the following criteria is met:

      1. The requested medication will be used as primary treatment for locally unresectable or medically inoperable disease; or
      2. The requested medication will be used for advanced or metastatic disease; or

   5. Appendiceal Neoplasms and Cancers

      As a single agent for treatment of recurrent, progressive, or metastatic 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] greater than 50 mut/Mb) appendiceal neoplasms and cancers.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   Aetna considers continuation of retifanlimab-dlwr (Zynyz) therapy medically necessary for the following indications:

   1. Squamous Cell Carcinoma of the Anal Canal (SCAC)

      1. For continued treatment (up to 12 months total) in combination with carboplatin and paclitaxel in members requesting reauthorization for SCAC when there is no evidence of unacceptable toxicity or disease progression while on the current regimen; or
      2. For continued treatment (up to 24 months total) as a single agent in members requesting reauthorization for SCAC when there is no evidence of unacceptable toxicity or disease progression while on the current regimen; or

   2. All other indications

      For continued treatment (up to 24 months total) in members requesting reauthorization for an indication listed in the Criteria for Initial Approval section when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.
      

Dosage and Administration

Retifanlimab-dlwr is supplied as Zynyz 500 mg/20 mL (25 mg/mL) solution in a single-dose vial for intravenous infusion.

Merkel Cell Carcinoma

The recommended dosage of Zynyz is 500 mg administered as an intravenous infusion over 30 minutes every 4 weeks. Administer Zynyz as an intravenous infusion after dilution.

• Monotherapy:

  • Adult individuals 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.
  • Adult individuals with metastatic or recurrent locally advanced MCC: 500 mg every 4 weeks; until disease progression, unacceptable toxicity, or up to 24 months.
    
    

• Combination therapy:

  • Adult individuals with inoperable locally recurrent or metastatic SCAC in combination with carboplatin and paclitaxel: 500 mg every 4 weeks; until disease progression, unacceptable toxicity, or up to 12 months.

Refer to the full prescribing information for Zynyz for dosage modifications for adverse reactions and preparation and administration instructions.

Source: Incyte, 2025

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
0161U	PMS2 (PMS1 homolog 2, mismatch repair system component) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) mRNA sequence analysis
81301	Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed
81405	Molecular pathology procedure, Level 6
81445	Solid organ neoplasm, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants and copy number variants or rearrangements, if performed; DNA analysis or combined DNA and RNA analysis
81450	Hematolymphoid neoplasm or disorder, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and RNA analysis
81455	Solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and RNA analysis
88341	Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure
88342	initial single antibody stain procedure
96413 - 96415	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9345	Injection, retifanlimab-dlwr, 1 mg
Other HCPCS codes related to the CPB:
C9308	Injection, carboplatin (avyxa), 1 mg
J9022	Injection, atezolizumab, 10 mg
J9023	Injection, avelumab, 10 mg
J9045	Injection, carboplatin, 50 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9119	Injection, cemiplimab-rwlc, 1 mg
J9173	Injection, durvalumab, 10 mg
J9263	Injection, oxaliplatin, 0.5 mg
J9264	Injection, paclitaxel protein-bound particles, 1 mg
J9267	Injection, paclitaxel, 1 mg
J9271	Injection, pembrolizumab, 1 mg
J9299	Injection, nivolumab, 1 mg
ICD-10 codes covered if selection criteria are met:
C17.0 – C17.9	Malignant neoplasm of small intestine
C18.0 – C18.9	Malignant neoplasm of colon
C19	Malignant neoplasm of rectosigmoid junction
C20	Malignant neoplasm of rectum
C21.0 - C21.8	Malignant neoplasm of anus and anal canal
C4A.0 – C4A.9	Merkel cell carcinoma
C7A.020	Malignant carcinoid tumor of the appendix
D37.3	Neoplasm of uncertain behavior of appendix

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Merkel Cell Carcinoma

  Zynyz is indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC).

• Squamous Cell Carcinoma of the Anal Canal

  Zynyz, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC).

  Zynyz, as a single agent, is indicated for the treatment of adult patients with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy.

Compendial Uses

• Appendiceal neoplasms and cancers
• Merkel cell carcinoma
• Squamous cell carcinoma of the anal canal
• Colorectal cancer
• Small bowel adenocarcinoma

Retifanlimab-dlwr is available as Zynyz (Incyte Corporation) and is a programmed death receptor-1 (PD-1)-blocking antibody. Retifanlimab-dlwr binds to the PD-1 receptor and blocks PD-L1 and PD-L2 interaction which potentiates T-cell activity with resultant inhibition of T-cell proliferation and cytokine production. Additionally, upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors (Incyte, 2025).

According to the prescribing information, Zynyz carries the following warnings and precautions:

• Immune-mediated adverse reactions

  • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, and immune-mediated dermatologic adverse reactions, and solid organ transplant rejection.
  • Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.
  • Withhold or permanently discontinue Zynyz and administer corticosteroids based on the severity of reaction.
    
    
• Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue Zynyz based on severity of reaction.
• Complications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1–blocking antibody.
• Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception.

Per the prescribing information for Zynyz, the most common (≥10%) adverse reactions in MCC as a single agent are fatigue, musculoskeletal pain, pruritis, diarrhea, rash, pyrexia, nausea, and constipation. The most common (≥10%) adverse reactions in SCAC as a single agent are fatigue, musculoskeletal pain, pruritis, diarrhea, non-urinary tract infections, perineal pain, hemorrhage, urinary tract infection, rash, pyrexia, nausea, decreased appetite, constipation, abdominal pain, dyspnea, vomiting, cough, hypothyroidism, headache, and decreased weight. The most common (≥20%) adverse reactions in SCAC in combination with carboplatin and paclitaxel are fatigue, peripheral neuropathy, nausea, alopecia, diarrhea, musculoskeletal pain, constipation, hemorrhage, rash, vomiting, decreased appetite, pruritus, and abdominal pain.

Gastro-Esophageal Adenocarcinoma

Catenacci et al. (2022) stated that human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastro-esophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize effectiveness, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb), was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the 1st-line HER2-positive/PD-L1-positive GEA. MAHOGANY cohort A part 1 is a single-arm study to examine margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score of 1% or greater), and non-microsatellite instability (MSI)-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed ORR.

As of August 3, 2021, a total of 43 patients were enrolled and received margetuximab/retifanlimab; 9 grade-3 treatment-related adverse events (TRAEs) were reported in 8 (18.6%) patients and 8 serious TRAEs in 7 (16.3%) patients; there were no grade-4/5 TRAEs; 3 patients discontinued margetuximab/retifanlimab because of immune-related AEs. The ORR by independent assessment was 53% (21/40 (95% CI: 36.1% to 68.5%), with a median DOR of 10.3 months (95% CI: 4.6 months to not evaluable); the disease control rate (DCR) was 73% [29/40 (95% CI: 56.1% to 85.4%)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. The authors concluded that the chemotherapy-free regimen of combined margetuximab/retifanlimab as 1st-line treatment in double biomarker-selected patients showed a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compared favorably with the ORR observed with other chemotherapy-free approaches. These researchers stated that the sponsor decided to discontinue enrollment in cohort A part 2 for business reasons, including that chemotherapy continues to make significant contributions in the treatment of patients with GEA, while chemotherapy-free immunotherapy of this type is less effective than hoped.

Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare form of skin cancer that is aggressive and can metastasize to other areas of the body. An estimated 60% of MCC tumors are found in men. As of 2015, an estimated 2,500 individuals per year are diagnosed with this cancer in the United States. The incidence of MCC is approximately 0.7 people per 100,000 people in the general United States population. It dramatically increases to an estimated 9.8 people per 100,000 in individuals more than 85 years of age (NORD, 2023).

On March 22, 2023, the U.S. Food and Drug Administration granted accelerated approval to retifanlimab-dlwr (Zynyz) for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). The FDA approval was based on data from the POD1UM-201 trial (FDA, 2023). 

The POD1UM-201 trial, an open-label, multiregional, single-arm study, evaluated the safety and efficacy of Zynyz for 65 patients with metastatic or recurrent locally advanced MCC who had not received prior systemic therapy for their advanced disease. Patients received Zynyz 500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. Tumor response assessments were performed every 8 weeks for the first year of therapy and 12 weeks thereafter. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) assessed by an independent central review committee according to RECISTv1.1. The ORR was 52% (95% confidence interval [CI]: 40, 65) with complete response rate of 18%. Twenty-six patients (76%) had a DOR ≥ 6 months and 21 (62%) had a DOR ≥ 12 months. Safety was evaluated for 105 patients with MCC and the most common (≥ 10%) adverse reactions were fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea. Serious adverse reactions occurred in 22% of patients receiving Zynyz (FDA, 2023; Incyte, 2023).

Squamous Cell Carcinoma of the Anal Canal

Rao et al. (2022a) noted that locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has a poor prognosis following platinum-based chemotherapy. Retifanlimab showed clinical activity across a range of solid tumors in clinical trials. These investigators presented findings from POD1UM-202, an open-label, single-arm, multi-center, phase-II clinical trial examining retifanlimab in patients with previously treated advanced or metastatic SCAC. Subjects included patients 18 years of age or older who had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was given intravenously every 4 weeks. The primary endpoint was ORR by independent central review. Secondary endpoints were DOR, DCR, progression-free survival (PFS), overall survival (OS), and safety. A total of 94 patients were enrolled. At a median follow-up of 7.1 months (range of 0.9 to 19.4 months), ORR was 13.8% [95% CI: 7.6% to 22.5%], with 1 complete response (CR; 1.1%) and 12 partial responses (PRs; 12.8%). Responses were observed regardless of human immunodeficiency virus (HIV) or human papillomavirus (HPV) status, PD-L1 expression, or liver metastases. Stable disease (SD) was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI: 38.5% to 59.5%). Median DOR was 9.5 months (range of 5.6 months to not estimable). Median (95% CI) PFS and OS were 2.3 (1.9 to 3.6) and 10.1 (7.9 to not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. The authors concluded that retifanlimab showed clinically meaningful and durable anti-tumor activity and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.

Rao et al. (2022b) stated that SCAC is an HPV-driven cancer with poor prognosis in locally advanced or recurrent settings. Carboplatin-paclitaxel is the preferred 1st-line treatment for unresectable locally advanced or metastatic SCAC, with the reported median PFS and OS of 8.1 and 20.0 months, respectively. Immune checkpoint blockade (ICB) showed improved survival in HPV-driven cervical and head and neck cancers. Retifanlimab is an investigational humanized, hinge-stabilized, immunoglobulin G4κ monoclonal antibody targeting PD-1, with characteristics common to the ICB class. In POD1UM-202, retifanlimab demonstrated substantial clinical activity and an expected safety profile in patients with advanced SCAC who progressed on platinum-based chemotherapy. Based on these encouraging results, POD1UM-303/InterAACT 2, a randomized, double-blind, multi-regional, phase-III clinical trial, examined the addition of retifanlimab to the standard of care (SOC) carboplatin-paclitaxel in patients with inoperable locally recurrent or metastatic SCAC not previously treated with systemic chemotherapy. Patients 18 years of age or older with inoperable locally recurrent or metastatic SCAC, measurable disease per RECIST v1.1, and no prior systemic chemotherapy or PD-(L)1-directed therapy will be enrolled and stratified by PD-L1 expression, region, and extent of disease. Patients with well-controlled HIV infection are eligible. Planned enrollment is approximately 300 patients worldwide, with a 1:1 randomization to retifanlimab or placebo. Subjects will receive up to 6 induction cycles (24 weeks) of carboplatin (area-under-the-curve [AUC] 5 on day 1) and paclitaxel (80 mg/m² on days 1, 8, and 15) every 28 days per SOC. Concurrently, retifanlimab 500 mg or placebo will be administered intravenously in a blinded fashion on day 1 of each 28-day cycle for up to 13 cycles (1 year) in the absence of unacceptable toxicity, disease progression, withdrawal of consent, loss to follow-up, or premature discontinuation. Cross-over to open-label retifanlimab will be allowed for subjects assigned to placebo upon verification of progression by blinded independent central radiographic review (BICR). The primary study endpoint is PFS per RECIST v1.1 by BICR. Secondary endpoints are OS, ORR, DOR, DCR, safety, and retifanlimab pharmacokinetics. This clinical trial was recruiting at the time.

On May 15, 2025, the Food and Drug Administration approved retifanlimab-dlwr (Zynyz) with carboplatin and paclitaxel for the first-line treatment of adults with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC). The FDA also approved retifanlimab-dlwr, as a single agent, for adults with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy. The FDA approval was based on the POD1UM-303/InterAACT 2 and POD1UM-202 trials (FDA, 2025).

The POD1UM-303/InterAACT 2 trial, which evaluated retifanlimab-dlwr in combination with carboplatin and paclitaxel for the treatment of inoperable locally recurrent or metastatic SCAC in 308 patients (154 patients in each group), the study results revealed Median progression-free survival (PFS) was 9.3 months (95% CI: 7.5, 11.3) in the retifanlimab-dlwr arm and 7.4 months (95% CI: 7.1, 7.7) in the placebo arm (hazard ratio 0.63 [95% CI: 0.47, 0.84] p-value 0.0006). Interim overall survival (OS) results were not statistically significant: median OS was 29.2 months (95% CI: 24.2, not estimable [NE]) and 23 months (95% CI: 15.1, 27.9) in the respective arms (hazard ratio 0.70 [95% CI: 0.49, 1.01]). Forty-five percent of patients who received placebo received retifanlimab-dlwr after disease progression. Objective response rate (ORR) was 56% (95% CI: 48, 64) and 44% (95% CI: 36, 52) in the respective arms. Safety assessment in the trial showed the most frequent serious adverse reactions (≥ 2% of patients) were sepsis (3.2%), pulmonary embolism (3.2%), diarrhea (2.6%), and vomiting (2.6%) in patients receiving Zynyz in combination with carboplatin and paclitaxel. Serious adverse reactions occurred in 47% of patients (FDA, 2025; Incyte, 2025).

The POD1UM-202 trial evaluated the efficacy of retifanlimab-dlwr as a singe agent for locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy in an open-label, multicenter, single-arm trial. The 94 patients enrolled received retifanlimab-dlwr 500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. Tumor response assessments were performed every 8 weeks throughout the treatment period. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as assessed by an independent review committee (IRC) according to RECIST v1.1. ORR was 14% (95% CI: 8, 23) and median DOR was 9.5 months (95% CI: 4.4, not estimable [NE]). Safety was assessed in the patients in the study. Serious adverse reactions occurred in 40% of patients receiving Zynyz. 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 (FDA, 2025; Incyte, 2025).

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References