Retifanlimab

Retifanlimab-dlwr is a humanized monoclonal antibody targeting programmed cell death receptor-1 (PD-1). The antibody is approved in combination with carboplatin and paclitaxel (platinum-based chemotherapy) for the first-line treatment of adult patients with unresectable, locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) and as monotherapy for the treatment of adult patients with locally recurrent or metastatic SCAC with disease progression or intolerance to platinum-based chemotherapy in the US.

Retifanlimab-dlwr is also approved for the treatment of adult patients with metastatic or locally advanced, recurrent Merkel cell carcinoma (MCC) in the US and the EU. This indication is approved under an accelerated approval process based on tumor response rate and duration of response.

Embryo-fetal toxicity: Retifanlimab-dlwr may cause fetal harm in pregnant women. Animal studies have shown that inhibition of the PD-1/PD-L1 signaling pathway may increase the risk of immune-mediated rejection of the developing fetus and may result in fetal death. Women should be made aware of the potential risk to the fetus. Women of childbearing potential should be instructed to use an effective method of contraception during treatment and for up to four months after the last dose.

Breast-feeding: Because of the possibility of serious adverse reactions in breast-fed infants, women are advised not to breast-feed during treatment and for 4 months after the last dose.

Very common side effects of retifanlimab-dlwr (which may affect more than 1 in 10 people treated) are fatigue, rash, diarrhea, anemia (low red blood cell count), itching, joint pain, constipation, nausea, fever and decreased appetite. Most serious side effects are related to the drug's effect on the immune system, such as inflammation in various body organs and tissues and rash.

Specifically, the following immune disorders are important:

Immune-mediated pneumonitis: Retifanlimab-dlwr may cause immune-mediated pneumonitis.Immune-mediatedPneumonitis occurred in 3% (13/440) of patients, including fatal (0.2%), Grade 3 (0.9%) and Grade 2 (1.4%) reactions. Pneumonitis led to permanent discontinuation of RETIFANLIMAB-DLWR in 1 patient and discontinuation in 0.9%.

Systemic corticosteroids were required in 77% (10/13) of patients. Pneumonitis resolved in 10 of the 13 patients.

Immune-mediated colitis

The most common (≥ 10 %) adverse reactions in patients receiving retifanlimab-dlwr were fatigue, musculoskeletal pain, diarrhea, infections outside of the

Retifanlimab-dlwr may cause immune-mediated colitis. Cytomegalovirus infections/reactivations are common in patients with corticosteroid-refractory immune-mediated colitis treated withPD-1/PD-L1 blocking antibody. In cases of corticosteroid-refractory colitis: Consider repeating the infection test to rule out alternative causes.

Retifanlimab-dlwr as monotherapy: Immune-mediated colitis occurred in 1.6% (7/440) of patients, including Grade 4 (0.2%), Grade 3 (0.2%) and Grade 2 (0.7%). Colitis led to permanent discontinuation of RETIFANLIMAB-DLWR in 1 patient and discontinuation of treatment in 0.9%. 71% (5/7) of patients required systemic corticosteroids. Colitis resolved in 4/7 patients.

Retifanlimab-dlwr in combination with carboplatin and paclitaxel: Immune-mediated colitis occurred in 10% (16/154) of patients receiving retifanlimab-dlwr in combination with carboplatin and paclitaxel, including grade 4 (0.6%), grade 3 (2.6%) and grade 2 (3.2%). Colitis led to permanent discontinuation of RETIFANLIMAB-DLWR in 2 patients and discontinuation of RETIFANLIMAB-DLWR in 2 patients. 94% (15/16) of patients required systemic corticosteroids. Colitis resolved in 15 of the 16 patients.

Immune-mediated hepatitis: Retifanlimab-dlwr may cause immune-mediated hepatitis.Immune-mediatedHepatitis occurred in 3% (13/440) of patients, including Grade 4 (0.2%), Grade 3 (2.3%) and Grade 2 (0.5%). Hepatitis led to permanent discontinuation of RETIFANLIMAB-DLWR in 1.4% of patients and discontinuation of treatment in 0.9%. Systemic corticosteroids were required in 85% (11/13) of patients. Hepatitis resolved in 6/13 patients.

Immune-mediated endocrinopathies

Adrenal insufficiency: Retifanlimab-dlwr may cause primary or secondary adrenal insufficiency. For adrenal insufficiency ≥ Grade 2, initiate symptomatic treatment according to facility guidelines, including hormone replacement therapy if clinically indicated. Depending on the severity, treatment with retifanlimab-dlwr may be interrupted or permanently discontinued.

Hypophysitis: Retifanlimab-dlwr may cause immune-mediated hypophysitis. This may be associated with acute symptoms such as headache, photophobia or visual field loss.

Thyroid disorders: Retifanlimab-dlwr may cause immune-mediated thyroid disorders. Thyroiditis may be associated with or without endocrinopathy. Hyperthyroidism may be followed by hypothyroidism. If hyperthyroidism is clinically indicated, hormone replacement therapy or drug treatment should be initiated. Depending on the severity, treatment with RETIFANLIMAB-DLWR can be interrupted or permanently discontinued. Thyroiditis occurred in 0.7% (3/440, all grade 1) of patients. No patient discontinued or interrupted treatment with RETIFANLIMAB-DLWR due to thyroiditis. Thyroiditis resolved in one of the three patients.

Hypothyroidism: Hypothyroidism occurred in 10% (42/440) of patients treated with retifanlimab-dlwr, including Grade 2 hypothyroidism (4.8%). No patient discontinued treatment due to hypothyroidism. Retifanlimab-dlwr was discontinued in 0.5 % of patients.

Hyperthyroidism: Hyperthyroidism occurred in 6% (24/440) of patients receiving retifanlimab-dlwr, including one of grade 2 severity (2.5%). Treatment with retifanlimab-dlwr was not discontinued in any patient, and treatment was interrupted in one patient. 13% (3/24) of patients required systemic corticosteroids, and 46% (11/24) of patients received endocrine therapy.

Type 1 diabetes mellitus, which may be associated with diabetic ketoacidosis: Patients should be monitored for hyperglycemia or other signs and symptoms of diabetes. Treatment with insulin should be initiated as clinically indicated. Depending on severity, retifanlimab-dlwr may be discontinued.

Immune-mediated nephritis with renal dysfunction: Retifanlimab-dlwr may cause immune-mediated nephritis. Nephritis occurred in 1.6% (7/440) of patients receiving RETIFANLIMAB-DLWR, including Grade 4 (0.5%), Grade 3 (0.7%) and Grade 2 (0.5%). Nephritis led to permanent discontinuation of RETIFANLIMAB-DLWR in 0.9% of patients and discontinuation of treatment in 1 patient. Systemic corticosteroids were required in 57% (4/7) of patients. Nephritis resolved in 3/7 patients.

Immune-mediated dermatological side effects

Retifanlimab-dlwr may cause immune-mediated exanthema. Bullous and exfoliative dermatitis, including Stevens-Johnson syndrome, drug exanthema with eosinophilia and systemic symptoms, and toxic epidermal necrolysis occurred with PD-1/PD-L1 blocking antibodies. Immune-mediated skin reactions occurred in 8% (36/440) of patients, including grade 3 (1.1%) and grade 2 (7%).

Other immune-mediated adverse reactions that occurred with a frequency of < 1% in 440 patients included

Cardiovascular: myocarditis, pericarditis, vasculitis

Gastrointestinal: pancreatitis, including elevation of 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 palsy, autoimmune neuropathy

Ocular: Uveitis, iritis and other ocular inflammatory toxicities.

Endocrine: Hypoparathyroidism

Hematologic/immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, rejection of solid organ transplants, rejection of other transplants (including corneal transplants).

Retifanlimab-dlwr is administered once every 4 weeks as an intravenous drip infusion. Treatment should be continued for a maximum of 2 years or until the cancer worsens. The doctor may interrupt treatment if certain side effects occur or stop treatment altogether if the side effects are severe.

Retifanlimab-dlwr; Zinyz

Merkel cell carcinoma is rare; retifanlimab was designated as an "orphan drug" on January 13, 2023.

1. Cho SH et al. (2025) High-resolution crystal structure of PD-1 in complex with retifanlimab, the FDA-approved immune checkpoint blocking antibody for treating Merkel cell carcinoma. Biochem Biophys Res Commun 742:151106.
2. Grignani G et al. (2025) Phase II study of retifanlimab in patients with recurrent locally advanced or metastatic Merkel cell carcinoma (POD1UM-201). J Immunother Cancer 13:e012478.
3. Kang C (2023) Retifanlimab: First Approval Drugs. 83:731-737.