Retifanlimab

Retifanlimab is a humanised immunoglobulin G4 (IgG4) monoclonal antibody against the immune checkpoint receptor PD-1, produced in Chinese hamster ovary cells by recombinant DNA technology. It is classed with the PD-1/PD-L1 inhibitors among antineoplastic agents. For squamous cell carcinoma of the anal canal, the supporting evidence is the randomised, double-blind, phase III POD1UM-303/InterAACT-2 study of retifanlimab with carboplatin and paclitaxel in patients who had not yet received chemotherapy.

Mechanism of Action

• Target: PD-1 is a receptor on T cells. Its ligands PD-L1 and PD-L2 are expressed by antigen-presenting cells and may also be expressed by tumour cells and other cells in the tumour microenvironment.
• Blockade: retifanlimab binds PD-1 and blocks its interaction with PD-L1 and PD-L2. That interaction normally inhibits T-cell proliferation, cytokine secretion and cytotoxic activity.
• Effect: lifting this inhibitory signal potentiates T-cell activity against the tumour.
• Immune-related reactions: acting on the PD-1 pathway can also trigger immune-mediated reactions in many organs, such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and skin reactions (see Special Instructions).
• Immunogenicity: anti-drug antibodies were detected uncommonly, with no evidence of an effect on pharmacokinetics, efficacy or safety.

Pharmacokinetics

• Exposure: in a population analysis of 788 patients with various cancers, exposure (AUC) rose in proportion to dose. At the recommended 500 mg every 4 weeks, the geometric mean steady-state Cmax was 197 mg/L and the AUC 2,270 day·mg/L.
• Distribution: volume of distribution at steady state about 6 L.
• Metabolism: the metabolic route has not been characterised. As an antibody, retifanlimab is expected to be broken down by general protein degradation.
• Elimination: clearance was 0.301 L/day after the first dose and fell by 22.9% over time to 0.232 L/day at steady state. Half-life was 15.6 days after the first dose and 19.8 days at steady state.
• Special populations: age (18–94 years), weight (33–133 kg), sex, race and tumour burden have no clinically important effect. Mild or moderate renal impairment and mild hepatic impairment did not change clearance in a clinically important way. Data are limited in severe renal impairment (4 patients) and moderate hepatic impairment (1 patient), and retifanlimab has not been studied in end-stage renal disease.

• Squamous cell carcinoma of the anal canal (SCAC): in combination with carboplatin and paclitaxel, for the first-line treatment of adult patients with metastatic or inoperable locally recurrent SCAC.
• Merkel cell carcinoma (MCC): as monotherapy, for the first-line treatment of adult patients with metastatic or recurrent locally advanced MCC that is not amenable to curative surgery or radiation therapy.

• Hypersensitivity to retifanlimab or to any of the excipients (sodium acetate trihydrate, glacial acetic acid, sucrose, polysorbate 80).

Immune-related adverse reactions occur with retifanlimab; most of them, including severe ones, resolved after appropriate medical treatment or withdrawal of retifanlimab. The safety data come from 452 patients given retifanlimab alone (107 of them with Merkel cell carcinoma) and 154 patients given it with carboplatin and paclitaxel for anal canal cancer. On monotherapy the most common reactions were fatigue (35.4%), rash (18.8%), diarrhoea (18.6%), anaemia (16.2%), pruritus (15.9%), arthralgia, constipation and nausea (13.3% each), pyrexia (13.1%) and decreased appetite (12.6%). With chemotherapy they were neutropenia (70.1%), pruritus (24%), rash (23.4%), lymphopenia (14.3%), hypothyroidism (14.3%) and increased alanine aminotransferase (10.4%). Reactions were serious in 11.7% (monotherapy) and 13.6% (combination) of patients, mostly immune-related ones, and led to permanent discontinuation in 8% and 5.8%.

Very common (≥1/10): on monotherapy, anaemia, decreased appetite, diarrhoea, nausea, constipation, rash, pruritus, arthralgia, fatigue and pyrexia; with carboplatin and paclitaxel, neutropenia, lymphopenia, hypothyroidism, peripheral sensory neuropathy, colitis, rash, pruritus, asthenia and increased alanine aminotransferase.

Common (≥1/100 to <1/10): on monotherapy, hypothyroidism, hyperthyroidism, paraesthesia, pneumonitis, colitis, hepatitis, hepatocellular injury, acute kidney injury, renal failure, infusion-related reaction, and increased transaminases, creatinine, amylase, lipase, bilirubin and thyroid-stimulating hormone; with carboplatin and paclitaxel, adrenal insufficiency, hyperthyroidism, hypophysitis, hyperglycaemia, hyponatraemia, peripheral motor and sensorimotor neuropathy, stomatitis, hepatitis, arthritis, infusion-related reaction, and increased aspartate aminotransferase, lipase, creatinine and amylase.

Uncommon (≥1/1,000 to <1/100): on monotherapy, adrenal insufficiency, thyroiditis (including autoimmune thyroiditis), hypophysitis, type 1 diabetes mellitus (including diabetic ketoacidosis), polyneuropathy, radiculopathy, vocal cord paralysis, uveitis, keratitis, pericarditis, myocarditis, pancreatitis, hyperbilirubinaemia, cholangitis, arthritis, myositis, eosinophilic fasciitis, polymyalgia rheumatica, tubulointerstitial nephritis and decreased thyroid-stimulating hormone; with carboplatin and paclitaxel, autoimmune thyroiditis, secondary adrenocortical insufficiency and immune-mediated cholangitis.

The SmPC table lists no reactions as rare or of unknown frequency.

Immune-related reactions in more detail, as percentages of patients on monotherapy (with carboplatin and paclitaxel in brackets where the SmPC gives them):

• Lung, gut, liver and kidney: pneumonitis 3.1% (including 0.2% fatal, Grade 5); colitis 2.7% (10.4%); hepatitis 3.5% (1.3%); nephritis 2%.
• Endocrine: hypothyroidism 10.2% (14.3%); hyperthyroidism 5.8% (8.4%); hypophysitis 0.7% (1.3%); adrenal insufficiency 0.9% (5.8%); type 1 diabetes mellitus presenting as diabetic ketoacidosis 0.2%.
• Skin: immune-related skin reactions 9.5% (11.7%).
• Infusion-related reactions: 6.2% (9.7%); they led to discontinuation in 0.4% of patients on monotherapy and in none on the combination.

• No formal studies: no formal pharmacokinetic interaction studies have been conducted. Retifanlimab is cleared by catabolism, so no metabolic drug–drug interactions are expected, and it is not expected to be a victim or perpetrator of interactions involving drug transporters or CYP enzymes.
• Corticosteroids and immunosuppressants before treatment: systemic corticosteroids or immunosuppressants should be avoided before starting retifanlimab, except physiological doses of systemic corticosteroids (up to 10 mg/day prednisone or equivalent), because they may interfere with its pharmacodynamic activity and efficacy.
• Corticosteroids and immunosuppressants after starting: they can be used after starting retifanlimab to treat immune-related adverse reactions.
• Carboplatin and paclitaxel: retifanlimab given with them increased the risk and severity of neutropenia (see Special Instructions). Their own dosing and patient management follow their SmPCs.

Treatment should be initiated and supervised by a physician experienced in the treatment of cancer. Retifanlimab is for intravenous use only; the concentrate must be diluted before it is infused.

Recommended Dose

• Squamous cell carcinoma of the anal canal: 500 mg every 4 weeks as an intravenous infusion over 30 minutes, together with carboplatin and paclitaxel for 6 cycles, then 500 mg as monotherapy every 4 weeks for all cycles thereafter. Treatment continues until disease progression or unacceptable toxicity, for up to 1 year.
• Merkel cell carcinoma: 500 mg every 4 weeks as an intravenous infusion over 30 minutes, until disease progression or unacceptable toxicity, for up to 2 years.

Dose Modifications

Dose escalation or reduction is not indicated. Immune-related reactions are managed by withholding or permanently discontinuing the dose, according to the grade (SmPC Table 1, NCI CTCAE v5):

• Pneumonitis: withhold at Grade 2 until Grade 0–1; discontinue permanently at Grade 3 or 4.
• Colitis: withhold at Grade 2 or 3 until Grade 0–1; discontinue permanently for recurrent Grade 3 or for Grade 4.
• Hepatitis: withhold for Grade 3 until Grade 0–1 (the AST, ALT and bilirubin thresholds differ depending on whether the tumour involves the liver); discontinue permanently for Grade 4, or when Grade 3 does not resolve within 12 weeks of starting steroids or prednisone cannot be reduced below 10 mg/day (or equivalent) within 12 weeks.
• Endocrinopathies: for Grade 2 adrenal insufficiency, and for Grade 3 or 4 hypothyroidism, hyperthyroidism and type 1 diabetes mellitus (or hyperglycaemia), withhold until Grade 0–1 or until otherwise clinically stable. For Grade 2 hypophysitis, withhold until Grade 0–1 and restart once it is controlled by hormone replacement (and, if symptomatic, once the steroid taper is complete). For Grade 3 or 4 adrenal insufficiency and symptomatic Grade 3 or 4 hypophysitis, withhold until Grade 0–1 and discontinue permanently if there is no resolution within 12 weeks of starting steroids or prednisone cannot be reduced below 10 mg/day (or equivalent) within 12 weeks.
• Nephritis with renal dysfunction: withhold for Grade 2 raised creatinine until Grade 0–1; discontinue permanently for Grade 3 or 4, but only if retifanlimab is directly implicated in the renal toxicity.
• Skin reactions: withhold for Grade 3, suspected Stevens-Johnson syndrome or toxic epidermal necrolysis, or persistent Grade 2 (2 weeks or more) until Grade 0–1; discontinue permanently for Grade 4 or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis.
• Myocarditis: discontinue permanently for confirmed Grade 2, 3 or 4.
• Other immune-related reactions (including myositis, encephalitis, demyelinating neuropathy, Guillain-Barré syndrome, sarcoidosis, autoimmune haemolytic anaemia, pancreatitis, uveitis, diabetic ketoacidosis, arthralgia): withhold for Grade 3 until Grade 0–1; discontinue permanently for Grade 4. Persistent Grade 2 or 3 reactions (excluding endocrinopathies) 12 weeks or more after the last dose, recurrent Grade 3 or 4 reactions and recurrent Grade 2 pneumonitis also require permanent discontinuation.
• Infusion-related reactions: Grade 1, interrupt or slow the infusion; Grade 2, interrupt and, if symptoms resolve within 1 hour, resume at 50% of the original rate, and discontinue permanently at later occurrences after the recommended prophylaxis; Grade 3 or 4, discontinue permanently (a Grade 3 reaction that responds rapidly to symptomatic management or a brief interruption does not require permanent discontinuation).

Special Populations

• Elderly: no dose adjustment at 65 years or over.
• Renal impairment: no adjustment in mild or moderate impairment. Data are insufficient in severe impairment (creatinine clearance below 30 mL/min) and absent in end-stage renal disease, so no dosing recommendation can be made.
• Hepatic impairment: no adjustment in mild impairment. Data are insufficient in moderate impairment and absent in severe impairment, so no dosing recommendation can be made.
• Children and adolescents: there is no relevant use of retifanlimab below 18 years of age in squamous cell carcinoma of the anal canal or Merkel cell carcinoma.

Method of Administration

• The diluted solution is infused over 30 minutes. It must not be given as an intravenous push or bolus injection.
• It can only be given through an intravenous line with a sterile, non-pyrogenic, low-protein-binding in-line or add-on filter of polyethersulfone, polyvinylidene fluoride or cellulose acetate (0.2 to 5 micron), or a 15 micron mesh filter. Other medicinal products must not be given through the same infusion line.
• Dilution instructions are in section 6.6 of the SmPC.

Immune-related Adverse Reactions

These reactions may be severe or fatal, can occur in any organ or tissue and in several body systems at once, and can appear after treatment has stopped. Patients are monitored for symptoms and signs, and liver tests and thyroid function tests are checked at the start of treatment and periodically. A suspected reaction needs adequate evaluation, including specialist consultation, to confirm the cause or exclude others. Depending on severity, retifanlimab is withheld or permanently discontinued and corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) or other suitable therapy are given; once the reaction improves to Grade 1 or less, the corticosteroid taper starts and continues for at least 1 month. In patients with pre-existing autoimmune disease, observational data suggest a higher risk of immune-mediated reactions with checkpoint inhibitors, and flares of the underlying disease were frequent but mostly mild and manageable; data specific to retifanlimab are scarce.

• Pneumonitis: monitor for signs and symptoms; confirm suspected pneumonitis by radiographic imaging and exclude other causes; manage with treatment modification and corticosteroids.
• Colitis: monitor for signs and symptoms; manage with treatment modification, anti-diarrhoeal agents and corticosteroids.
• Hepatitis: check liver tests before and periodically during treatment; for Grade 1 hepatitis, monitor liver chemistry twice per week until it returns to baseline.
• Endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, type 1 diabetes mellitus including diabetic ketoacidosis): check thyroid function before and periodically during treatment, and cortisol as indicated by symptoms or falling thyroid-stimulating hormone. Treatment modification, corticosteroids, hormone replacement, oral anti-hyperglycaemics or insulin are used as clinically indicated.
• Nephritis: monitor renal function; manage with treatment modification and corticosteroids.
• Skin reactions: toxic epidermal necrolysis has been reported with retifanlimab and Stevens-Johnson syndrome with PD-1 inhibitors. Use caution in a patient who has had a severe or life-threatening skin reaction on another checkpoint inhibitor.
• Other reactions: clinically significant immune-related reactions in studies included uveitis, arthritis, myositis, demyelinating polyneuropathy (for example Guillain-Barré syndrome), pancreatitis, myocarditis, cholangitis and stomatitis.

Infusion-related Reactions

As with any therapeutic protein, retifanlimab can cause infusion-related reactions, some of them severe. Patients are monitored; the infusion is interrupted or slowed, or treatment is stopped permanently, depending on severity. Premedication with an antipyretic and/or an antihistamine should be considered for patients who have had clinically significant reactions to infusions of therapeutic proteins.

Neutropenia With Chemotherapy

Given with carboplatin and paclitaxel, retifanlimab increased the risk and severity of neutropenia. Frequent haematological monitoring is recommended, and treatment guidelines for neutropenia should be followed.

Transplant-related Reactions

• Solid organ transplant rejection: rejection has been reported after market launch in patients treated with PD-1 inhibitors, and retifanlimab may increase the risk in transplant recipients. The benefit of treatment is weighed against the risk of organ rejection.
• Allogeneic haematopoietic stem cell transplantation: fatal and other serious complications can occur in patients transplanted before or after a PD-1/PD-L1-blocking antibody. They include hyperacute, acute and chronic graft-versus-host disease, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome. Patients need close follow-up, and the benefit and risk of the antibody are weighed before or after transplantation.

Patients Excluded From Clinical Studies

The clinical programme excluded patients with an ECOG performance score of 2 or more, symptomatic central nervous system metastases, prior immunotherapy or autoimmune disease needing systemic immunosuppressants, another malignancy within the last 3 years, an organ transplant, active hepatitis infection, or uncontrolled HIV infection.

Traceability and Patient Card

The name and batch number of the administered product must be clearly recorded. Prescribers should inform patients about the patient card, which explains what to do if they notice a symptom of an immune-related reaction; each patient treated receives one.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 4 months after the last dose.
• Pregnancy: there are no data in pregnant women and animal reproduction studies have not been conducted. Inhibiting the PD-1/PD-L1 pathway can increase immune-mediated rejection of the developing foetus and cause foetal death, and human IgG4 antibodies cross the placenta, so retifanlimab can cause foetal harm. It is not recommended during pregnancy or in women of childbearing potential not using effective contraception.
• Breastfeeding: it is unknown whether retifanlimab is excreted in human milk. Human IgG is excreted in milk during the first few days after birth, then falls to low concentrations, so a risk to the infant cannot be excluded in that short period. During it, a decision should be made whether to stop or abstain from therapy, weighing the benefit of breastfeeding against the benefit of therapy. Afterwards retifanlimab can be used during breastfeeding if clinically needed.
• Fertility: no clinical data are available.

Sodium

Each dose contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Retifanlimab has a minor influence on the ability to drive and use machines. Because of possible reactions such as fatigue, patients should take care when driving or operating machinery until they are sure it does not affect them.

Store the vials in a refrigerator at 2–8 °C, in the original carton to protect them from light. Do not freeze. Each carton holds one 20 mL vial. Because the product is refrigerated, the cold chain should be kept unbroken from dispatch until use.

After dilution, chemical and physical stability in use has been shown for 24 hours at 2–8 °C and for 8 hours at room temperature (20–25 °C). From a microbiological point of view the diluted product should be used immediately. If it is not, in-use storage times and conditions are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

2 years for the unopened vial. After dilution, see Storage Conditions (24 hours at 2–8 °C or 8 hours at room temperature).

Prescription only (Rx), on restricted medical prescription (Annex II B of the marketing authorisation), with treatment started and supervised by a physician experienced in the treatment of cancer. Retifanlimab is given by intravenous infusion, so it is supplied to the hospital or clinic that administers it, delivered cold-chain at 2–8 °C.