Retifanlimab (Monograph)

Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; humanized anti-programmed death receptor-1 (anti-PD-1) monoclonal antibody.

Uses for Retifanlimab

Merkel Cell Carcinoma

Treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC).

Indication approved under accelerated approval based on tumor response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

Designated an orphan drug by FDA for this use.

Immunotherapy has emerged as a first-line treatment option in patients with locally advanced or metastatic MCC; this typically involves an anti-programmed death receptor-1 (PD-1) antibody or anti-programmed death ligand-1 (PD-L1) antibody. Specific place in therapy for retifanlimab not yet established.

Retifanlimab Dosage and Administration

General

Pretreatment Screening

Perform pregnancy testing in females of reproductive potential prior to initiating retifanlimab-dlwr.
Assess baseline liver enzymes, creatinine, and thyroid function prior to treatment.

Patient Monitoring

Assess liver enzymes, creatinine, and thyroid function periodically during treatment.
Monitor patients for signs and symptoms of infusion-related reactions.
Closely monitor patients for signs and symptoms of immune-mediated adverse reactions during treatment.
Monitor patients for hyperglycemia or other signs and symptoms of diabetes.
Closely monitor patients who undergo allogeneic hematopoietic stem cell transplantation for evidence of transplant-related complications.

Premedication and Prophylaxis

Consider premedication with an antipyretic, antihistamine, or both in patients who have had previous systemic reactions to infusions of therapeutic proteins.

Administration

IV Administration

Administer by IV infusion.

Dilute prior to administration.

Available as a single-dose vial containing retifanlimab-dlwr 500 mg/20 mL (25 mg/mL) solution.

Do not administer using a polyurethane infusion set.

Administer diluted solution through a polyvinylchloride (PVC) with di-2-ethylhexyl phthalate (DEHP) IV line containing a sterile, non-pyrogenic, low-protein binding polyethersulfone, polyvinylidene fluoride, or cellulose acetate 0.2–5 micron in-line or add-on filter, or 15 micron mesh in-line or add-on filter.

Do not coadminister other drugs through the same infusion line.

Dilution

Withdraw 20 mL (500 mg) of retifanlimab-dlwr from 1 vial; discard any unused portion.

Dilute with either 0.9% sodium chloride injection or 5% dextrose injection to a final concentration of 1.4–10 mg/mL.

Use infusion bags made of PVC with DEHP, polyolefin copolymer, polyolefin with polyamide, or ethylene vinyl acetate.

Mix diluted solution by gentle inversion; do not shake.

Rate of Administration

Administer diluted solution by IV infusion over 30 minutes.

Do not administer as an IV push or bolus injection.

Dosage

Adults

Merkel Cell Carcinoma

IV

500 mg via IV infusion over 30 minutes every 4 weeks; continue treatment for up to 24 months or until disease progression or unacceptable toxicity occurs.

<C> Dosage Modification for Adverse Reactions

Dosage reductions not recommended.

In general, withhold therapy for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue drug for life-threatening (grade 4) immune-mediated adverse reactions and recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or if unable to reduce corticosteroid dose to ≤10 mg of prednisone equivalent per day within 12 weeks of steroid initiation.

Table 1 outlines dosage modifications for adverse reactions that require different management from these general guidelines.

Resume in patients with complete or partial resolution (grade 0 to 1) after corticosteroid taper. Permanently discontinue if no resolution within 12 weeks of steroid initiation or inability to reduce prednisone to <10 mg/day (or equivalent) within 12 weeks of steroid initiation.

Table 1. Recommended Dosage Modifications for Adverse Reactions.1
Adverse Reaction	Dosage Modification Based on Severity
Pneumonitis	Grade 2: Withhold Grade 3 or 4: Permanently discontinue
Colitis	Grade 2 or 3: Withhold Grade 4: Permanently discontinue
Hepatitis without tumor involvement of the liver	AST or ALT >3 but ≤8 times ULN OR total bilirubin increases to >1.5 and ≤3 times ULN: Withhold AST or ALT increases to >8 times ULN OR total bilirubin >3 times ULN: Permanently discontinue
Hepatitis with tumor involvement of the liver	Baseline AST and ALT are ≤ULN: Withhold or permanently discontinue based on recommendations for hepatitis without tumor involvement of the liver Baseline AST or ALT is >1 and ≤3 times ULN and increases >5 and ≤10 times ULN OR baseline AST or ALT is >3 and ≤5 times ULN and increases >8 and ≤10 times ULN: Withhold AST or ALT increases to >10 times ULN OR total bilirubin increases to >3 times ULN: Permanently discontinue
Endocrinopathies	Grade 2: Depending on clinical severity, consider withholding until symptom improvement with hormone replacement; resume once acute symptoms have resolved Grade 3 or 4: Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with renal dysfunction	Grade 2 or 3 increased blood creatinine: Withhold Grade 4 increased blood creatinine: Permanently discontinue
Exfoliative dermatologic conditions	Grade 3 or suspected Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS: Withhold Grade 4 or confirmed Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS: Permanently discontinue
Myocarditis	Grade 2, 3, or 4: Permanently discontinue
Neurological toxicities	Grade 2: Withhold Grade 3 or 4: Permanently discontinue
Infusion-related reactions	Grade 1 or 2: Interrupt or slow the rate of infusion Grade 3 or 4: Permanently discontinue

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Use

No specific dosage recommendations at this time.

Cautions for Retifanlimab

Contraindications

None.

Warnings/Precautions

Immune-mediated Adverse Reactions

Severe and fatal immune-mediated adverse reactions may occur in any organ system or tissue. Reactions may occur at any time, generally during treatment but may also occur after drug is discontinued.

Early identification and management needed to ensure safe use.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Assess liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.

If suspected immune-mediated reactions occur, initiate appropriate workup to exclude alternative causes (including infection).

Medically manage immune-mediated adverse reactions promptly; refer for specialty consultation as appropriate.

Withhold or permanently discontinue depending on nature and severity of the reaction.

If treatment interruption or discontinuation required, administer systemic corticosteroids (1–2 mg/kg per day prednisone or equivalent) until improvement to grade 1 or less; upon improvement, initiate corticosteroid taper and continue to taper over ≥1 month. Consider administration of other systemic immunosuppressants if reaction not controlled with corticosteroid therapy.

Immune-mediated adverse reactions described in following sections may not be inclusive of all possible severe and fatal reactions.

Pneumonitis

Immune-mediated pneumonitis, sometimes fatal, reported.

In patients treated with other PD-1/PD-L1 blocking monoclonal antibodies, incidence of pneumonitis higher in patients with history of prior thoracic radiation.

Colitis

Immune-mediated colitis reported.

Cytomegalovirus infection/reactivation reported in patients with corticosteroid-refractory immune-mediated colitis treated with anti-PD-1/PD-L1 monoclonal antibodies. In patients with corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Hepatitis

Immune-mediated hepatitis reported.

Endocrinopathies

Immune-mediated endocrinopathies, including adrenal insufficiency, hypophysitis, thyroid dysfunction (i.e., hyperthyroidism, hypothyroidism, thyroiditis), and type 1 diabetes, reported.

Primary and secondary adrenal insufficiency reported. For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement therapy as clinically indicated. Withhold or permanently discontinue depending on severity.

Immune-mediated hypophysitis reported; may present with acute symptoms associated with mass effect (e.g., headache, photophobia, visual field cuts). May lead to hypopituitarism. If hypophysitis occurs, initiate hormone replacement therapy as clinically indicated. Withhold or permanently discontinue depending on severity.

Immune-mediated thyroid disorders, including thyroiditis, hyperthyroidism, and hypothyroidism, reported. Thyroiditis may present with or without endocrinopathy. Hypothyroidism may follow hyperthyroidism. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue depending on severity.

Type 1 diabetes reported. Monitor patients for hyperglycemia or other signs and symptoms of diabetes mellitus. Initiate insulin therapy as clinically indicated. Withhold retifanlimab depending on severity.

Nephritis with Renal Dysfunction

Immune-mediated nephritis reported.

Dermatologic Adverse Reactions

Immune-mediated rash or dermatitis reported. Bullous and exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), reported with anti-PD-1/PD-L1 monoclonal antibodies.

For treatment of mild to moderate non-exfoliative rashes, topical emollients and/or topical corticosteroids may be adequate. Withhold or permanently discontinue depending on severity.

Other Immune-mediated Adverse Reactions

Other immune-mediated adverse reactions reported rarely; in some instances, reactions were severe or fatal.

Specific reactions included cardiac/vascular disorders (myocarditis, pericarditis, vasculitis); GI disorders (pancreatitis, gastritis, duodenitis); musculoskeletal disorders (myositis/polymyositis, rhabdomyolysis and associated sequelae, arthritis, polymyalgia rheumatica); neurologic disorders (meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis [including exacerbation], Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy); hypoparathyroidism; ocular disorders (uveitis, iritis, other ocular inflammatory toxicities); and other hematologic/immune disorders (hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis [Kikuchi lymphadenitis], sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection).

Some cases of ocular toxicity may 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.

Infusion-related Reactions

Severe infusion-related reactions reported.

Monitor for signs and symptoms.

Slow infusion rate, interrupt infusion, or permanently discontinue based on severity.

Consider premedication with an antipyretic, antihistamine, or both in patients who have had previous systemic reactions to infusions of therapeutic proteins.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Serious or fatal complications can occur in patients who receive allogeneic HSCT before or after treatment with anti-PD-1/PD-L1 antibodies. Complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome without an identified infectious cause.

Closely monitor patients for evidence of transplant-related complications and intervene promptly. Weigh benefits versus risks of therapy prior to or after allogeneic HSCT.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on findings from animal studies and mechanism of action.

Perform pregnancy testing in females of reproductive potential prior to starting retifanlimab-dlwr.

Advise pregnant women of potential risk to fetus.

Advise females of reproductive potential to use effective contraception during treatment with retifanlimab and for 4 months after the last dose.

Immunogenicity

Potential for immunogenicity. Development of anti-drug antibodies and neutralizing antibodies to retifanlimab-dlwr reported. Effects of these antibodies on safety, efficacy, pharmacokinetics, and pharmacodynamics of retifanlimab unknown.

Effects of antibodies on safety, efficacy, pharmacokinetics, and pharmacodynamics of retifanlimab unknown.

Specific Populations

Pregnancy

May cause fetal harm based on findings from animal studies and mechanism of action.

No available human data.

Inhibition of PD-1/PD-L1 pathway may increase risk of immune-mediated rejection of the developing fetus.

Human IgG₄ known to cross placenta; thus, retifanlimab has potential to be transmitted from the mother to developing fetus.

Perform pregnancy testing in females of reproductive potential prior to starting retifanlimab.

Advise pregnant women of the potential risk to a fetus.

Lactation

Unknown whether retifanlimab distributes into human milk; effects on milk production or the breast-fed infant also unknown. Maternal IgG known to be distributed into human milk.

Effects of local GI exposure and limited systemic exposure to retifanlimab in the breast-fed infant are unknown.

Advise women to not breast-feed during treatment and for 4 months after the last dose.

Females and Males of Reproductive Potential

Perform pregnancy testing in females of reproductive potential prior to treatment initiation.

Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Studies did not include sufficient numbers of younger adults to determine whether geriatric patients (≥65 years of age) respond differently than younger adults.

No clinically important differences in pharmacokinetics observed based on age (18–94 years).

Hepatic Impairment

No clinically important differences in pharmacokinetics observed in patients with mild (Child-Pugh A) hepatic impairment.

Pharmacokinetics not studied in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

Renal Impairment

No clinically important effects on retifanlimab-dlwr pharmacokinetics observed based on renal function (eGFR ≥26 mL/minute per 1.73 m²).

Common Adverse Effects

Adverse effects (≥10%): fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, nausea.

Drug Interactions

No formal drug interaction studies to date.

Retifanlimab Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations and AUC increase proportionally over dose range of 375–750 mg.

Steady-state concentrations achieved at cycle 6 (approximately 6 months) following IV administration every 4 weeks; systemic accumulation was 1.3-fold.

Distribution

Extent

Not known whether distributed into human milk.

Elimination

Half-life

19 days.

Special Populations

No clinically important differences in pharmacokinetics based on age (18–94 years), sex, body weight (35–133 kg), race, albumin level, ECOG score (0 to 2), tumor burden), HIV status, renal function, or mild hepatic impairment.

Stability

Storage

Parenteral

Solution for injection

Store unopened vials at 2–8ºC; do not freeze or shake. Store in original carton to protect from light.

Store diluted solution at room temperature (up to 25ºC) for ≤8 hours from time of preparation to end of infusion, or refrigerated (2–8ºC) for ≤24 hours from time of preparation to end of infusion. Allow refrigerated diluted solution to come to room temperature prior to administration; administer diluted solution within 4 hours (including infusion time) after removal from refrigeration. Do not freeze or shake. Protect from light during storage.

Actions

Humanized immunoglobulin IgG₄ kappa monoclonal antibody that blocks programmed death receptor-1 (PD-1).
Binds to the PD-1 receptor, blocking interaction with programmed death ligand (PD-L) 1 and PD-L2, potentiating T-cell activity.
Binding of PD-L1 and PD-L2 to the PD-1 receptor on T cells inhibits T-cell proliferation and cytokine production.
Upregulation of PD-1 ligands occurs in some tumors; signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors.

Advice to Patients

Advise patients to contact their clinician immediately for signs or symptoms of immune-mediated pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath).
Advise patients to contact their clinician immediately for signs or symptoms of immune-mediated colitis (e.g., diarrhea, blood or mucus in stools, severe abdominal pain).
Advise patients to contact their clinician immediately for signs or symptoms of immune-mediated hepatitis (e.g., jaundice, severe nausea or vomiting, pain on the right side of the abdomen, dark urine).
Advise patients to contact their clinician immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, or type 1 diabetes.
Advise patients to contact their clinician immediately for signs or symptoms of immune-mediated nephritis (e.g., decreased urine output, hematuria, peripheral edema, lack of appetite).
Advise patients to contact their clinician immediately if they develop a new rash.
Advise patients that immune-mediated adverse reactions can occur during treatment and may involve any organ system, and to contact their clinician immediately for any new or worsening signs or symptoms.
Advise patients to contact their clinician immediately for signs or symptoms of infusion-related reactions (e.g., chills, fever, shortness of breath, wheezing, rash, itching, flushing).
Advise patients to contact their clinician immediately if they develop signs or symptoms of post-allogeneic hematopoietic stem cell transplantation complications or solid organ transplant rejection.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise females of reproductive potential that retifanlimab-dlwr may cause fetal harm. Advise such females to inform their clinician of a known or suspected pregnancy, and to use effective contraception during treatment with retifanlimab-dlwr and for 4 months after the last dose.
Advise women to inform their clinician if they are or plan to breast-feed. Advise women to not breast-feed during treatment with retifanlimab-dlwr and for 4 months after the last dose.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.