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|
Date |
FDA Approval Type |
Drug Name |
Brand Name |
Indication |
|
March 22, 2023 |
Accelerated Approval |
retifanlimab-dlwr |
Zynyz |
Treatment of metastatic or recurrent locally advanced Merkel cell carcinoma (MCC) in adult patients |
On March 22, 2023, the FDA granted accelerated approval to Zynyz (Retifanlimab-dlwr) for the treatment of metastatic or recurrent locally advanced Merkel cell carcinoma (MCC) in adult patients.
Retifanlimab-dlwr is a monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which can inhibit the immune response to cancer cells.
By blocking PD-1, retifanlimab-dlwr may help to restore the immune response against cancer cells. MCC is a rare and aggressive type of skin cancer that affects Merkel cells, making it difficult to treat.
Zynyz provides a new treatment option for patients with metastatic or recurrent locally advanced MCC. However, patients should discuss the potential benefits and risks of treatment with their healthcare provider before starting Zynyz, as there may be associated risks and side effects.
Zynyz (Retifanlimab-dlwr) Indication and Usage:
Retifanlimab-dlwr has been approved by the FDA for the treatment of adult patients with MCC.
The approval is based on tumor response rate and duration of response, and further confirmatory trials are required to verify clinical benefit.
Retifanlimab-dlwr targets the PD-1 receptor on immune cells, blocking its interaction with PD-L1 and PD-L2, potentially restoring immune response against cancer cells.
Patients should discuss potential benefits and risks with their healthcare provider and be monitored for adverse reactions during treatment.
Zynyz (Retifanlimab-dlwr) Dosage Recommendation:
The recommended dosage is 500 mg, administered as an intravenous infusion over 30 minutes every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months.
Zynyz should be administered as an intravenous infusion after dilution with a sterile 0.9% sodium chloride injection or sterile 5% dextrose injection, and the final concentration should be between 1 mg/mL and 10 mg/mL.
The infusion rate should be monitored closely, and infusion-related reactions should be managed appropriately.
Dose Modification for Adverse Reactions:
No recommended dose reduction for Zynyz.
Zynyz should be withheld if severe immune-mediated adverse reactions occur, or permanently discontinued for life-threatening reactions or recurring severe reactions requiring systemic immunosuppressive treatment.
Dosage modifications summarized in Table 1 should be followed for adverse reactions such as pneumonitis, colitis, endocrinopathies, neurological toxicities, and infusion-related reactions.
Guidelines for administering ZYNYZ intravenously are summarized in the following table:
|
Administration |
Guidelines |
|
Infusion set |
Do not use a polyurethane infusion set |
|
Vial inspection |
Visually inspect the vial for any particulate matter or discoloration. Discard if the solution appears cloudy, discolored, or contains particulate matter |
|
Shaking |
Do not shake the vial |
|
Dilution |
Dilute ZYNYZ and administer via intravenous infusion over 30 minutes using a polyethylene or PVC with DEHP intravenous line with a sterile, non-pyrogenic, low protein binding filter |
|
Other drugs |
Do not administer other drugs through the same infusion line |
|
Preparation |
Take 20 mL of ZYNYZ, dilute it with 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP to a final concentration between 1.4 mg/mL to 10 mg/mL, and gently invert the solution to mix it |
|
Storage |
Store diluted solution protected from light at room temperature not exceeding 25°C (77°F) for a maximum of 8 hours or under refrigeration between 2°C to 8°C (36°F to 46°F) for a maximum of 24 hours. Do not freeze or shake the solution. Use within 4 hours, including infusion time, once removed from the refrigerator. |
Zynyz (Retifanlimab-dlwr) Contraindications and Precautions:
Type of Reaction |
Incidence (n=440) |
Grades |
Management |
Outcome |
|
Contraindications |
None |
- |
- |
- |
|
Immune-Mediated Adverse Reactions |
- |
- |
Monitor patients closely for symptoms and signs, evaluate liver enzymes, creatinine, and thyroid function periodically |
May require discontinuation of ZYNYZ, systemic corticosteroid therapy is necessary |
|
Immune-Mediated Pneumonitis |
3% |
The fatality rate of 0.2% |
Systemic corticosteroids |
Pneumonitis resolved in 10 out of 13 patients, 1 experienced recurrence after reinitiating ZYNYZ |
|
Immune-Mediated Colitis |
1.6% |
Grade 2 to Grade 4 |
Corticosteroid-refractory colitis may be associated with cytomegalovirus infection/reactivation, repeating infectious workup recommended |
Colitis resolved in 4 patients, ZYNYZ was withheld in 1 patient and reinitiated without recurrence of colitis |
|
Immune-Mediated Hepatitis |
3% |
Varying severity |
Majority of patients required systemic corticosteroids |
Hepatitis resolved in most patients, some experienced recurrence after reinitiating ZYNYZ |
|
Immune-Mediated Endocrinopathies |
- |
- |
Hormone replacement and withhold or discontinue ZYNYZ |
Varies depending on type, but most resolved with hormone replacement therapy |
|
Immune-Mediated Nephritis with Renal Dysfunction |
1.6% |
Grade 4, Grade 3, and Grade 2 |
Systemic corticosteroids |
Nephritis resolved in 3 of 7 patients, the patient who had ZYNYZ withheld did not experience recurrence after reinitiating ZYNYZ. |
Side effects of Zynyz (Retifanlimab-dlwr:
|
System/organ affected |
Potential side effects |
|
Cardiac/vascular |
Myocarditis, pericarditis, vasculitis |
|
Gastrointestinal |
Pancreatitis, increased serum amylase and lipase levels, gastritis, duodenitis |
|
Musculoskeletal |
Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis, polymyalgia rheumatica |
|
Neurological |
Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy |
|
Ocular |
Uveitis, iritis, and other ocular inflammatory toxicities. Some cases can be associated with retinal detachment. Various grades of visual impairment including blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. |
|
Endocrine |
Hypoparathyroidism |
|
Hematologic/Immune |
Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection |
|
Infusion-related |
Infusion-related reactions, including severe reactions requiring intervention and monitoring |
Zynyz (Retifanlimab-dlwr) Moa:
Retifanlimab-dlwr works by blocking the interaction between the PD-1 receptor and its ligands, PD-L1 and PD-L2, found on T cells.
This binding inhibition results in increased T-cell activity, which ultimately enhances the immune system's ability to target and eliminate cancerous cells.
The drug achieves this by overcoming the inhibition of T-cell activity in the tumor microenvironment, leading to an enhanced anti-tumor immune response.
In terms of pharmacokinetics, Retifanlimab-dlwr is administered intravenously and has 100% bioavailability when given by this route.
The drug is highly bound to proteins, with approximately 95% bound. Metabolism primarily occurs in the liver, through proteolytic degradation, and the drug has a half-life of around 23 days.
Retifanlimab-dlwr is primarily excreted through feces, with a small amount excreted in the urine. At the recommended dose of 500 mg every 4 weeks, steady-state concentration is achieved after 4-8 weeks of dosing, with a mean concentration of 35 μg/mL.
Patient Counseling Information:
Inform the patient to review the Medication Guide Immune-Mediated Adverse Reactions.
Inform the patient that ZYNYZ may cause immune-mediated adverse reactions, such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic adverse reactions, and other immune-mediated adverse reactions.
Instruct the patient to promptly contact their healthcare provider if they experience any new or worsening signs or symptoms Infusion-Related Reactions.
Advise the patient to immediately notify their healthcare provider of any signs or symptoms of infusion-related reactions or Complications of Allogeneic HSCT or Solid Organ Transplant Rejection.
Advise the patient to immediately contact their healthcare provider if they experience signs or symptoms of post-allogeneic HSCT complications or solid organ transplant rejection Embryo-Fetal Toxicity.
Inform females of reproductive potential that ZYNYZ may cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
Instruct females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of ZYNYZ.
Lactation: Advise female patients not to breastfeed while taking ZYNYZ and for 4 months after the last dose
