Retifanlimab is a PD-1 blocking antibody indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma. Immune-mediated adverse reactions including colitis, pneumonitis, hepatitis, endocrinopathies, exfoliative skin reactions, myocarditis, and nephritis have been reported with retifanlimab therapy in clinical trials; treatment with high-dose corticosteroids may be necessary for patients who develop immune-mediated toxicity.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Retifanlimab injection is a clear to slightly opalescent, colorless to pale yellow solution. Discard if the solution is cloudy, discolored, or contains particulate matter.
Intravenous Administration
-For intravenous (IV) infusion only. Do not give as an IV push or bolus injection.
-Dilution is required prior to administration.
-Consider premedication with an antipyretic and/or an antihistamine before administration if the patient has a history of infusion-related reactions to therapeutic proteins.
Preparation of IV Infusion:
-Withdraw 20 mL from the retifanlimab vial and dilute in 0.9 % Sodium Chloride Injection or 5% Dextrose Injection to a final concentration between 1.4 mg/mL and 10 mg/mL. Discard any unused portion of the vial.
-Mix diluted solution by gently inverting the bag; do not shake.
-Use infusion bags made of polyvinylchloride (PVC) and di-2-ethylhexyl phthalate (DEHP), polyolefin copolymer, polyolefin with polyamide, or ethylene vinyl acetate.
-Storage following dilution: Protect from light. Do not freeze or shake. Store at room temperature up to 25 degrees C (77 degrees F) for up to 8 hours from the time of preparation to the end of infusion or refrigerated at 2 to 8 degrees C (26 to 46 degrees F) for no more than 24 hours from the time of preparation to the end of infusion. If refrigerated, allow the solution to come to room temperature and administer within 4 hours of removal from the refrigerator (including infusion time).
Administration:
-Administer the prepared IV infusion over 30 minutes.
-Use a polyethylene or PVC with DEHP IV infusion set with 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 use a polyurethane infusion set.
-Do not co-administer other drugs through the same infusion line.
-During administration, monitor for infusion-related reactions. Interrupt or slow the rate of the infusion if the patient develops an infusion-related reaction of grade 1 to 2 severity. Permanently discontinue retifanlimab for infusion-related reactions of grade 3 or 4 severity.
Immune-mediated hepatitis occurred in 3% (grade 3 or 4, 2.5%) of patients with Merkel cell carcinoma or other solid tumors who received retifanlimab (n = 440). Eleven of 13 patients (85%) who experienced hepatitis received systemic corticosteroids; hepatitis resolved in 6 patients (46%). Monitor hepatic function at baseline and periodically during treatment. Retifanlimab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and if there is tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary. Elevated hepatic enzymes that worsened from baseline including increased AST (23%; grade 3 or 4, 2.2%), ALT (21%; grade 3 or 4, 3.3%), and alkaline phosphatase (20%; grade 3 or 4, 1.1%) levels occurred in patients with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 105) in a clinical trial.
Immune-mediated colitis occurred in 1.7% (grade 3 or 4, 0.4%) of patients with Merkel cell carcinoma or other solid tumors who received retifanlimab (n = 440). Five of 7 patients (71%) who experienced colitis received systemic corticosteroids; colitis resolved in 4 patients (57%). Monitor patients for symptoms of colitis. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating the infectious workup to exclude alternative etiologies. Other immune-mediated gastrointestinal toxicities reported with retifanlimab or other PD-1/PD-L1-blocking antibodies include gastritis and duodenitis (less than 1% each); these events may also require interruption or discontinuation of treatment and corticosteroid therapy. Diarrhea (15%) and nausea (10%) were reported in patients with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 105) in a clinical trial.
Immune-mediated hyperthyroidism occurred in 6% of patients with Merkel cell carcinoma or other solid tumors who received retifanlimab (n = 440). Systemic corticosteroids were required for 13% of patients and 46% of patients received endocrine therapy. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin medical management as clinically indicated. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary.
Immune-mediated hypothyroidism (10%) and thyroiditis (0.7%) occurred in patients with Merkel cell carcinoma or other solid tumors who received retifanlimab (n = 440). Systemic corticosteroids were required for 1 patient and 79% of patients received endocrine therapy. Evaluate thyroid function at baseline and monitor periodically during treatment. Thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism. Begin hormone replacement for hypothyroidism. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary.
Immune-mediated hypoparathyroidism was reported in less than 1% of patients who received retifanlimab or other PD-1/PD-L1-blocking antibodies. If hypothyroidism occurs, begin medical management as clinically indicated. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary.
Immune-mediated primary or secondary adrenocortical insufficiency (0.7%; grade 3, 0.5%) and immune-mediated hypophysitis (0.5%) occurred in patients with Merkel cell carcinoma or other solid tumors who received retifanlimab (n = 440). All patients who developed adrenal insufficiency and hypophysitis required systemic corticosteroids; resolution occurred in 1 of 3 patients with adrenal insufficiency and 1 of 2 patients with hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts, and this condition can cause hypopituitarism. Initiate symptomatic medical treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary.
Fatal and serious adverse events have occurred in patients who received an allogeneic hematopoietic stem-cell transplant (HSCT) prior to and after treatment with a PD-1/PD-L1-blocking antibody, such as retifanlimab. Monitor patients closely for evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause); treat adverse events promptly. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.
Grade 3 infusion-related reactions occurred in 1 patient (0.2%) with Merkel cell carcinoma or other solid tumors who received retifanlimab (n = 440). Monitor patients for signs and symptoms of infusion reactions. Consider premedication with antipyretics and/or antihistamines for patients who have had prior systemic reactions to infusions of therapeutic proteins. Interrupt or slow the rate of infusion for mild or moderate infusion related reactions (grade 1 or 2); stop the infusion and permanently discontinue retifanlimab for severe or life-threatening infusion-related reactions (grade 3 or 4).
Immune-mediated dermatologic/skin toxicity occurred in 8% (grade 3, 1.1%) of patients with Merkel cell carcinoma or other solid tumors who received retifanlimab (n = 440). Systemic corticosteroids were administered in 25% of patients who experienced skin toxicity; skin toxicity resolved in 75% of patients. Monitor patients for suspected severe skin reactions including bullous rash, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS); exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary. Rash (11%; grade 3 or 4, 1%) and pruritus (18%) were reported in patients with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 105) in a clinical trial. The term rash included maculopapular rash and bullous rash/dermatitis. Eosinophilic fasciitis that resulted in therapy discontinuation was also reported in 1 patient in this trial.
Immune-mediated interstitial nephritis occurred in 1.6% (grade 3 or 4, 1.2%) of patients with Merkel cell carcinoma or other solid tumors who received retifanlimab (n = 440). Four of 7 patients (57%) who experienced nephritis received systemic corticosteroids; nephritis resolved in 3 patients (43%). Nephritis with renal dysfunction led to permanent discontinuation of retifanlimab in 0.9% of patients and withholding of treatment in 1 patient. The 1 patient in whom retifanlimab was withheld for immune-mediated nephritis had treatment reinitiated after symptom improvement and did not have recurrence of immune-mediated nephritis. Monitor renal function at baseline and periodically during treatment. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary.
Immune-mediated endocrinopathies reported with retifanlimab include new onset diabetes mellitus. Type 1 diabetes mellitus (which may present with diabetic ketoacidosis) occurred in 1 patient (grade 3, 0.2%) with Merkel cell carcinoma or other solid tumors who received retifanlimab (n = 440); the patient was treated with insulin. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold retifanlimab therapy for cases of severe hyperglycemia until blood sugar control is achieved; administer insulin as clinically indicated.
Immune-mediated pneumonitis occurred in 3% (grade 3, 0.9%) of patients with Merkel cell carcinoma or other solid tumors who received retifanlimab (n = 440); 1 patient experienced fatal pneumonitis. Ten of 13 patients (77%) who experienced pneumonitis received systemic corticosteroids; pneumonitis resolved in 10 patients (71%). Monitor patients for signs and symptoms of pneumonitis. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary.
Fatigue including asthenia occurred in 28% (grade 3 or 4, 1%) of patients with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 105) in a clinical trial.
Fever occurred in 10% of patients with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 105) in a clinical trial.
Electrolyte abnormalities that worsened from baseline including decreased sodium level/hyponatremia (23%; grade 3 or 4, 3.3%), decreased potassium level/hypokalemia (9%; grade 3 or 4, 1.1%), and increased calcium level/hypercalcemia (8%; grade 3 or 4, 1.1%) occurred in patients with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 105) in a clinical trial.
Immune-mediated cardiac and vascular toxicity that was reported in less than 1% of patients who received retifanlimab or that occurred with the use of other PD-1/PD-L1-blocking antibodies include myocarditis, pericarditis, and vasculitis; some cases were severe or fatal. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary. Serious cardiac arrhythmias occurred in 2% or more of patients with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 105) in a clinical trial; 1 patient discontinued therapy due to atrial fibrillation.
Immune-mediated neurologic toxicity that was reported in less than 1% of patients who received retifanlimab or that occurred with the use of other PD-1/PD-L1-blocking antibodies include meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, and autoimmune peripheral neuropathy; some cases were severe or fatal. Retifanlimab therapy may need to be interrupted or discontinued depending on the toxicity severity; treatment with systemic corticosteroids may be necessary. Polyneuropathy and radiculopathy that resulted in therapy discontinuation were each reported in 1 patient with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 105) in a clinical trial.
Immune-mediated toxicity that was reported in less than 1% of patients who received retifanlimab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura (ITP), and solid organ transplant rejection; some cases were severe or fatal. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary.
Immune-mediated toxicity that was reported in less than 1% of patients who received retifanlimab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include hemolytic anemia and aplastic anemia; some cases were severe or fatal. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary. Hematological toxicity that worsened from baseline including decreased hemoglobin level/anemia (38%; grade 3 or 4, 1.1%), decreased lymphocyte count/lymphopenia (29%; grade 3 or 4, 10%), decreased neutrophil count/neutropenia (13%; grade 3 or 4, 3.3%), and decreased leukocyte count/leukopenia (12%; grade 3 or 4, 1.1%) occurred in patients with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 105) in a clinical trial.
Immune-mediated ocular toxicity that was reported in less than 1% of patients who received retifanlimab or that occurred with the use of other PD-1/PD-L1-blocking antibodies include uveitis, iritis, and other ocular inflammation toxicity; some cases were associated with retinal detachment. Visual impairment including vision loss/blindness may occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a diagnosis of Vogt-Koyanagi-Harada syndrome. Patients may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.
Immune-mediated toxicity that was reported in less than 1% of patients who received retifanlimab or that occurred with the use of other PD-1/PD-L1-blocking antibodies include pancreatitis and increases in serum amylase levels/hyperamylasemia and lipase levels; some cases were severe or fatal. Retifanlimab therapy may need to be interrupted or discontinued depending on toxicity severity; treatment with systemic corticosteroids may be necessary. Increased lipase (30%; grade 3 or 4, 3.4%) and amylase (19%; grade 3 or 4, 1.2%) levels that worsened from baseline occurred in patients with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 105) in a clinical trial.
Antibody formation occurred in 3 patients (2.9%) with metastatic or recurrent locally advanced Merkel cell carcinoma who received retifanlimab (n = 104) in a clinical trial. Of these, neutralizing antibodies were confirmed in 2 patients (0.5%). The effect of these antibodies on the safety or effectiveness of retifanlimab is unknown.
Severe infusion-related reactions have occurred with retifanlimab. Monitor patients for signs and symptoms of infusion reactions. Consider premedication with antipyretics and/or antihistamines for patients who have had prior systemic reactions to infusions of therapeutic proteins. Interrupt or slow the rate of infusion for mild or moderate infusion related reactions (grade 1 or 2); stop the infusion and permanently discontinue retifanlimab for severe or life-threatening infusion-related reactions (grade 3 or 4). Infusion-related reactions can include chills or shaking, itching or rash, flushing, shortness of breath or wheezing, dizziness or feeling faint, fever, or back pain.
Immune-mediated reactions, which may be severe or fatal, can occur in patients treated with drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), including retifanlimab, thus removing inhibition of the immune response. These immune-mediated reactions can occur in any organ system or tissue and can also affect more than one body system or tissue simultaneously. Immune-mediated reactions can occur at any time after starting therapy including during treatment or after discontinuation of therapy. Because early identification and management is critical to safe use of retifanlimab, closely monitor patients for signs and symptoms of underlying immune-mediated reactions. Examination and workup should exclude alternative etiologies including infection in cases of a suspected immune-mediated reaction. Begin medical management promptly, including specialty consultation as appropriate. An interruption or discontinuation of retifanlimab therapy may be necessary, depending on the severity of the reaction. In general, if an interruption or discontinuation of therapy is necessary due to an immune-mediated reaction, administer systemic corticosteroids (1 to 2 mg/kg/day of prednisone or equivalent); upon improvement to grade 1 or less, begin a steroid taper over at least 1 month. Consider additional systemic immunosuppression in patients whose symptoms are not controlled with corticosteroid therapy. Endocrinopathies and dermatologic reactions may not require systemic corticosteroids but may require specific medical management based on the type of event. Withhold treatment for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue retifanlimab 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 corticosteroids to 10 mg/day prednisone or less (or equivalent) within 12 weeks of initiating steroids.
Immune-mediated pneumonitis has been reported with retifanlimab therapy; some cases were fatal. The incidence of pneumonitis with other PD-1/PD-L1 -blocking antibodies is higher in patients who have received prior thoracic radiation therapy. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, retifanlimab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary.
Immune-mediated colitis has been reported with retifanlimab therapy. Additionally, cytomegalovirus (CMV) infection/reactivation has been reported in patients with steroid-refractory immune-mediated colitis. Monitor all patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Retifanlimab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Use retifanlimab with caution in patients with pre-existing inflammatory bowel disease such as ulcerative colitis or Crohn's disease.
Immune-mediated hepatitis has been reported with retifanlimab therapy. Monitor hepatic function at baseline and periodically during treatment. Retifanlimab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary. Retifanlimab has not been studied in patients with moderate or severe hepatic disease/impairment; use with caution in patients with pre-existing hepatic disease.
Immune-mediated primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with retifanlimab. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts; hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement therapy and/or systemic corticosteroids for adrenal insufficiency and for hypophysitis as clinically indicated. Retifanlimab therapy may need to be interrupted or discontinued depending on severity.
Retifanlimab can cause immune-mediated thyroid disease. Thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism or medical management as clinically indicated. Retifanlimab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, has been reported with retifanlimab therapy as an immune-mediated adverse reaction. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold retifanlimab therapy for cases of severe hyperglycemia until blood sugar control is achieved or depending on the severity of presentation; administer insulin as clinically indicated.
Immune-mediated nephritis/interstitial nephritis with increased serum creatinine has been reported with retifanlimab therapy. Monitor renal function at baseline and periodically during treatment. Retifanlimab therapy may need to be interrupted or discontinued depending on the severity of the nephritis and associated renal impairment; treatment with systemic corticosteroids may also be necessary. There are no data for retifanlimab use in patients with severe renal impairment or renal failure (eGFR less than 26 mL/minute/1.73 m2).
Immune-mediated serious rash, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred in patients treated with PD-1/PD-L1-blocking antibodies. Monitor patients for suspected severe skin reactions and exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Retifanlimab therapy may need to be interrupted or discontinued depending on the severity; treatment with systemic corticosteroids may also be necessary.
Fatal and other serious complications including hyperacute, acute, and chronic graft-versus-host-disease, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and a steroid-requiring febrile syndrome (without an identified infectious cause) have been reported in patients who receive an allogeneic stem cell transplant (SCT) before or after being treated with a PD-1/PD-L1-blocking antibody. Therefore, perform a risk/benefit analysis prior to starting treatment with retifanlimab, in patients who may receive or who have a history of undergoing an allogeneic SCT. Monitor patients closely for evidence of transplant-related complications and intervene promptly. Complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic SCT.
Use retifanlimab with caution in patients with a previous organ transplant. Immune-mediated organ transplant rejection has been reported with PD-1/PD-L1-blocking antibodies, such as retifanlimab.
Various grades of visual impairment to include blindness can occur during retifanlimab treatment; patients should report visual changes right away. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-ike syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
Given the possibility of immune-mediated side effects in virtually any organ system or tissue, use retifanlimab with caution in patients with various autoimmune disease processes, such as myocarditis, systemic lupus erythematosus (SLE), autoimmune arthritis conditions such as rheumatoid arthritis, myasthenia gravis, immune thrombocytopenic purpura (ITP), or Guillain-Barre syndrome. Retifanlimab may need to be interrupted or discontinued depending on the severity of the toxicity of the affected organs/tissues; treatment with systemic corticosteroids may also be necessary.
Retifanlimab may cause fetal harm if used during pregnancy; there are no data regarding use of this medication in human pregnancy. Human IgG4 immunoglobulins (IgG4) are known to cross the placenta in animals and retifanlimab has the potential to be transmitted to the developing fetus. Animal studies have demonstrated that PD-1/PD-L1 pathway inhibition can lead to increased risk of immune-mediated rejection of the developing fetus resulting in increased risks for fetal death, abortion, or stillbirth. Based on its mechanism of action, fetal exposure to retifanlimab may increase the risk of developing immune-mediated disorders or altering the normal immune response. PD1/PDL1-blocking antibodies, such as retifanlimab, may impair maternal immune tolerance resulting in spontaneous abortion, intrauterine growth restriction, or early-onset preeclampsia.
Counsel patients about the reproductive risk and contraception requirements during retifanlimab treatment. Retifanlimab can cause fetal harm if taken during pregnancy. Patients should avoid pregnancy and use effective contraception during and for 4 months after the last dose of retifanlimab. Patients of reproductive potential should undergo pregnancy testing prior to initiation of treatment. Patients who become pregnant while receiving retifanlimab should be apprised of the potential hazard to the fetus.
Due to the potential for serious adverse reactions in breastfed children, avoidance of breast-feeding during retifanlimab therapy and for 4 months after the final dose is recommended. There is no information regarding the presence of retifanlimab in human milk, or its effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure to retifanlimab in the breastfed child are unknown.
For the treatment of metastatic or recurrent locally advanced Merkel cell carcinoma (MCC):
NOTE: The FDA has designated retifanlimab as an orphan drug for this indication.
Intravenous dosage:
Adults: 500 mg IV infusion every 4 weeks until disease progression or for up to 24 months. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. The objective response rate was 52% in patients with metastatic or recurrent locally advanced MCC who received retifanlimab (n = 65; median age, 71 years; range, 44 to 90 years) in a nonrandomized, phase 2 (POD1UM-201) trial. The complete response rate was 18%. In responding patients, the duration of response (DOR) ranged from 1.1 to more than 24.9 months; the DOR was 6 months or more in 76% of patients and 12 months or more in 62% of patients. In this trial, 88% of patients had metastatic MCC and 98% of patients were HIV-negative. Additionally, no patient had received prior systemic therapy, 72% of patients had received prior surgery, and 38% of patients had received prior radiotherapy. Merkel cell polyomavirus (MCPyV) was confirmed in 71% of tumor samples.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Infusion-Related Reactions
Grade 1 or 2 toxicity: Slow the infusion rate or interrupt the infusion.
Grade 3 or 4 toxicity: Permanently discontinue retifanlimab.
Immune-Related Reactions
General Information
Withhold or permanently discontinue retifanlimab depending on severity and the specific toxicity as noted. In general, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to grade 1 or less. Upon improvement to grade 1 or less, initiate corticosteroid taper over at least 1 month. Permanently discontinue retifanlimab if there is no resolution of toxicity or if the corticosteroid cannot be reduced to less than 10 mg/day prednisone (or equivalent) within 12 weeks of initiation. Consider administration of other systemic immunosuppressants in these patients if appropriate. Discontinue the drug if recurrent severe (Grade 3) immune-mediated reactions occur that require systemic immunosuppressive treatment.
Toxicity management for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are noted where applicable.
Colitis
Grade 2 or 3 toxicity: Hold retifanlimab and administer corticosteroids. Resume therapy when resolved to grade 1 or less after the corticosteroid taper.
Grade 4 toxicity: Permanently discontinue retifanlimab.
Endocrinopathies (including Adrenal insufficiency, Hypophysitis, Hypothyroidism, Hyperthyroidism, Type 1 diabetes mellitus, and Hypoparathyroidism)
Grade 2: Consider holding retifanlimab therapy until symptomatic improvement with appropriate treatment (e.g., specific hormone replacement therapy as indicated for the condition); resume retifanlimab therapy once acute symptoms have resolved.
Grade 3 or 4: Hold until clinically stable or permanently discontinue depending on severity of the condition; administer appropriate treatment (e.g., specific hormone therapy) as indicated for the condition.
Skin Reactions
Grade 1 or 2: Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.
Grade 3 exfoliative dermatologic events or suspected Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS): Hold retifanlimab and administer corticosteroids as applicable.
Grade 4 exfoliative dermatologic events or confirmed SJS, TEN, or DRESS: Permanently discontinue retifanlimab.
Myocarditis
Grade 2, 3, or 4 toxicity: Permanently discontinue retifanlimab.
Neurological toxicities
Grade 2: Hold retifanlimab and administer corticosteroids. Resume therapy when resolved to grade 1 or less after the corticosteroid taper.
Grade 3 or 4: Permanently discontinue retifanlimab.
Pneumonitis
Grade 2: Hold retifanlimab and administer corticosteroids. Resume therapy when resolved to grade 1 or less after the corticosteroid taper.
Grade 3 or 4: Permanently discontinue retifanlimab.
Other Immune-Mediated Adverse Reactions
Grade 3: Hold retifanlimab and administer corticosteroids. Resume therapy when resolved to grade 1 or less after the corticosteroid taper.
Recurrent grade 3 that requires treatment with other systemic immunosuppressants: Permanently discontinue retifanlimab.
Grade 4: Permanently discontinue retifanlimab and administer corticosteroids.
Maximum Dosage Limits:
-Adults
500 mg IV every 4 weeks.
-Geriatric
500 mg IV every 4 weeks.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Treatment-Related Immune-Mediated Hepatitis
No Tumor Involvement of the Liver
AST or ALT level of more than 3 and up to 8 times the ULN or total bilirubin level increases to more than 1.5 and up to 3 times the ULN: Hold retifanlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg/day or equivalent, followed by a 1-month taper). Resume therapy when resolved to grade 1 or less after the corticosteroid taper. Permanently discontinue retifanlimab if there is no resolution of toxicity or if corticosteroid dose cannot be reduced to less than 10 mg/day prednisone (or equivalent) within 12 weeks of initiating steroids.
AST or ALT level increases to more than 8 times the ULN or total bilirubin level more than 3 times the ULN: Permanently discontinue retifanlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg/day or equivalent, followed by a 1-month taper starting when toxicity resolves to grade 1 or less).
Tumor Involvement of the Liver
Baseline AST or ALT level at the ULN or less: Hold or permanently discontinue retifanlimab based on recommendations for hepatitis with no tumor involvement of the liver.
Baseline AST or ALT level of more than 1 and up to 3 times the ULN and increases to more than 5 and up to 10 times ULN or baseline AST or ALT was more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN: Hold retifanlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg/day or equivalent, followed by a 1-month taper). Resume therapy when resolved to grade 1 or less after the corticosteroid taper. Permanently discontinue retifanlimab if there is no resolution of toxicity or if corticosteroid dose cannot be reduced to less than 10 mg/day prednisone (or equivalent) within 12 weeks of initiating steroids.
AST or ALT level of more than 10 times the ULN or total bilirubin level more than 3 times the ULN: Permanently discontinue retifanlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg/day or equivalent, followed by a 1-month taper starting when toxicity resolves to grade 1 or less).
Patients with Renal Impairment Dosing
Treatment-Related Immune-Mediated Nephritis With Renal Dysfunction
Grade 2 or 3 increased serum creatinine (SCr) level: Hold retifanlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg/day or equivalent, followed by a 1-month taper). Resume therapy when resolved to grade 1 or less after the corticosteroid taper. Permanently discontinue retifanlimab if there is no resolution of toxicity or if corticosteroid dose cannot be reduced to less than 10 mg/day prednisone (or equivalent) within 12 weeks of initiating steroids.
Grade 4 increased SCr level: Permanently discontinue retifanlimab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg/day or equivalent, followed by a 1-month taper starting when toxicity resolves to grade 1 or less).
*non-FDA-approved indication
There are no drug interactions associated with Retifanlimab products.
In the body, the binding of the PD-1 ligands (PD-L1 and PD-L2) to the programmed death-1 receptor (PD-1 receptor) on T cells inhibits T-cell proliferation and cytokine production. Some tumors upregulate PD-1 ligands, and signaling through this pathway can reduce the active T-cell immune surveillance of tumors. Retifanlimab is a humanized IgG4 kappa monoclonal antibody that binds to the PD-1 receptor on T cells, blocks interaction with its ligands (PD-L1 and PD-L2), and potentiates T-cell anti-tumor activity.
Retifanlimab is administered intravenously. At steady-state, retifanlimab has a geometric mean volume of distribution of 6 L (coefficient of variation (CV), 20%), elimination half-life of 19 days (CV, 29%), and clearance of 0.24 L/day.
Affected cytochrome P450 isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Intravenous Route
Steady-state concentrations were achieved after 6 cycles of therapy when retifanlimab was administered at the recommended dose in patients with various solid tumors, including Merkel cell carcinoma. The systemic accumulation was 1.3-fold. The retifanlimab Cmax and AUC values increased proportionally over a dose range of 375 mg to 750 mg.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin level of less than or equal to the ULN and AST level greater than the ULN OR total bilirubin level of 1 to 1.5 times the ULN and any AST level) had no clinically significant impact on the pharmacokinetic (PK) parameters of retifanlimab. The PK parameters of retifanlimab have not been studied sufficiently in patients with moderate or severe hepatic impairment.
Renal Impairment
Renal impairment (estimated glomerular filtration rate of 26 mL/min/1.73 m2 or more) had no clinically significant impact the pharmacokinetic parameters of retifanlimab.
Geriatric
Age (range, 18 to 94 years) had no clinically significant impact on the pharmacokinetic parameters of retifanlimab.
Gender Differences
Sex had no clinically significant impact on the pharmacokinetic parameters of retifanlimab.
Ethnic Differences
Race (White, Black, or Asian) had no clinically significant impact on the pharmacokinetic parameters of retifanlimab.
Obesity
Body weight (range, 35 to 133 kg) had no clinically significant impact on the pharmacokinetic parameters of retifanlimab.
Other
Albumin level (range, 21 to 54 g/L), Eastern Cooperative Oncology Group score (range, 0 to 2), tumor burden (sum of the target lesion diameters, 10 to 360 mm), and HIV status had no clinically significant impact on the pharmacokinetic parameters of retifanlimab.