Zynyz Drug Information

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.

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

Recommended Dosage

The recommended dosages of ZYNYZ are provided in Table 1. Administer ZYNYZ as an intravenous infusion after dilution, over 30 minutes, as recommended. Table 1: s No dose reduction of ZYNYZ is recommended.

In general, withhold ZYNYZ for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue ZYNYZ for life‑threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating steroids. Dosage modifications for ZYNYZ for adverse reactions that require management different from these general guidelines are summarized in Table 2.

Table 2: Recommended Dosage Modifications for

Preparation and Administration

Visually inspect the vial for particulate matter and discoloration prior to administration. ZYNYZ is a clear to slightly opalescent, colorless to pale yellow solution and is free of particles. Discard the vial if the solution is cloudy, discolored, or contains particulate matter.

Do not shake the vial. Each vial is for one-time use in only one patient. Use polyvinylchloride (PVC) and di-2-ethylhexyl phthalate (DEHP), polyolefin copolymer, polyolefin with polyamide, or ethylene vinyl acetate infusion bags.

Mix diluted solution by gentle inversion. Do not shake. Storage of diluted ZYNYZ solution Protect the diluted ZYNYZ solution from light during storage.

Store diluted ZYNYZ solution: At room temperature for no more than 8 hours from the time of preparation to the end of the infusion. OR Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of preparation to the end of the infusion. If refrigerated, allow the diluted solution to come to room temperature prior to administration.

The diluted solution must be administered within 4 hours (including infusion time) once it is removed from the refrigerator. Do not freeze or shake diluted solution. Administration Administer diluted ZYNYZ solution by intravenous infusion over 30 minutes through a polyethylene, polyurethane, or PVC with DEHP intravenous line containing a sterile, non‑pyrogenic, low-protein binding polyethersulfone, polyvinylidene fluoride, or cellulose acetate 0.2 micron to 5 micron in-line or add-on filter or 15 micron mesh in-line or add-on filter.

Do NOT administer ZYNYZ as an intravenous push or bolus injection. Do not co‑administer other drugs through the same infusion line.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in Warnings and Precautions reflects exposure to ZYNYZ 500 mg as an intravenous infusion every 4 weeks in combination with carboplatin and paclitaxel in 154 patients with SCAC enrolled in the POD1UM-303 trial, and as a single agent in 94 patients with SCAC in the POD1UM-202 trial, 107 patients with MCC in the POD1UM-201 trial, and 251 patients with other solid tumors. All patients received ZYNYZ until disease progression or unacceptable toxicity; those in the POD1UM-202 and POD1UM-201 trials received ZYNYZ for up to 24 months and those in the POD1UM-303 trial received ZYNYZ for up to 12 months.

The median duration of exposure of the pooled monotherapy population was 5.4 months (range: 1 day to 27 months). Squamous Cell Carcinoma of the Anal Canal (SCAC) Inoperable Locally Recurrent or Metastatic SCAC: ZYNYZ in Combination with Carboplatin and Paclitaxel The safety of ZYNYZ in patients with inoperable locally recurrent or metastatic SCAC was evaluated in 154 patients enrolled in the POD1UM-303 trial. Among patients who received ZYNYZ, the median duration of exposure was 7.4 months (range: 1 day to 14.6 months).

Serious adverse reactions occurred in 47% of patients receiving ZYNYZ in combination with carboplatin and paclitaxel. In patients receiving ZYNYZ in combination with carboplatin and paclitaxel, ZYNYZ was permanently discontinued due to an adverse reaction in 11% of patients. Adverse reactions that resulted in permanent discontinuation of ZYNYZ included immune-mediated enterocolitis (2 patients), warm autoimmune hemolytic anemia, hepatitis, adrenal insufficiency, blood bilirubin increased, AST increased, blood alkaline phosphatase increased, arthritis, encephalopathy, peripheral sensorimotor neuropathy, hypothyroidism, immune‑mediated cholangitis, pruritus, malaise, and rash (1 patient each).

Dosage interruptions due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 55% of patients who received ZYNYZ in combination with carboplatin and paclitaxel. Adverse reactions that resulted in dosage interruptions in ≥ 2% of patients were neutropenia, anemia, thrombocytopenia, leukopenia, fatigue, COVID-19, and urinary tract infection. The most common (≥ 20%) adverse reactions were fatigue, peripheral neuropathy, nausea, alopecia, diarrhea, musculoskeletal pain, constipation, hemorrhage, rash, vomiting, decreased appetite, pruritus, and abdominal pain.

Table 3 and Table 4 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in POD1UM-303. Table 3: Adverse Reactions in ≥ 10% of Patients with Inoperable Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in Combination with Carboplatin and Paclitaxel with a Difference Between Arms of ≥ 5% for All Grades or ≥ 2% for Grades 3 or 4 vs Table 4: Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥ 1% of Patients with Inoperable Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in Combination with Carboplatin and Paclitaxel in POD1UM-303 Platinum-refractory Intolerant Locally Recurrent or Metastatic SCAC: ZYNYZ as a Single Agent The safety of ZYNYZ in patients with platinum-refractory intolerant locally recurrent or metastatic SCAC was evaluated in 94 patients in the POD1UM‑202 trial. Patients received ZYNYZ 500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months.

The median duration of exposure was 2.8 months (range: 1 day to 27.1 months). 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. Permanent discontinuation of ZYNYZ due to an adverse reaction occurred in 4.3% of patients.

These adverse reactions included diarrhea, non-urinary tract infection, perineal pain, and rash. Adverse reactions that resulted in dose delay in ≥ 2% of patients who received ZYNYZ were non-urinary tract infection, rash, diarrhea, abdominal pain, hemorrhage, musculoskeletal pain, pyrexia, and urinary tract infection. The most common (≥ 10%) adverse reactions that occurred in patients receiving ZYNYZ were fatigue, musculoskeletal pain, diarrhea, non-urinary tract infections, perineal pain, hemorrhage, urinary tract infection, rash, nausea, decreased appetite, constipation, abdominal pain, dyspnea, pyrexia, vomiting, cough, pruritus, hypothyroidism, headache, and decreased weight.

Table 5 and Table 6 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in POD1UM-202. Table 5: Adverse Reactions in ≥ 10% of Patients with Platinum-Refractory Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in POD1UM- Table 6: Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥ 1% of Patients with Platinum-Refractory Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in POD1UM- Merkel Cell Carcinoma (MCC) Metastatic or Recurrent Locally Advanced MCC: ZYNYZ as a Single Agent The safety of ZYNYZ was evaluated in 107 patients enrolled in the POD1UM-201 trial with metastatic or recurrent locally advanced MCC. The median duration of exposure was 10.3 months (range: 1 day to 25 months).

The most frequent serious adverse reactions (≥ 2% of patients) were fatigue, arrhythmia, and pneumonitis. These included asthenia, colitis, demyelinating polyneuropathy, diarrhea, drug hypersensitivity, eosinophilic fasciitis, hepatitis, hypophysitis, increased transaminases, infusion-related reaction, pancreatitis, polyarthritis, radiculopathy, toxic epidermal necrolysis, and tubulointerstitial nephritis (1 patient each). Adverse reactions or laboratory abnormalities that required dosage interruption in > 2% of patients who received ZYNYZ were increased transaminases, increased lipase, increased amylase, and pyrexia.

Table 7 and Table 8 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in POD1UM-201.

Pregnancy Risk Summary Based on its mechanism of action, ZYNYZ can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ZYNYZ in pregnant women. Animal studies have demonstrated that inhibition of the PD‑1/PD‑L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death ( see Data ).

Human IgG4 immunoglobulins (IgG4) are known to cross the placenta; therefore, retifanlimab-dlwr has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Data Animal Data Animal reproduction studies have not been conducted with ZYNYZ to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering ZYNYZ during pregnancy include increased rates of abortion or stillbirth.

As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to retifanlimab-dlwr may increase the risk of developing immune-mediated disorders or altering the normal immune response.

Pediatric Use The safety and effectiveness of ZYNYZ have not been established in pediatric patients.