Avelumab

Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmed death ligand 1 (PD-L1), produced in Chinese hamster ovary cells by recombinant DNA technology. PD-L1 is a checkpoint protein that tumours and the immune cells around them can display to dampen the activity of cytotoxic T cells; avelumab blocks that signal.

Mechanism of Action

• PD-L1 blockade: avelumab binds PD-L1 and prevents it from engaging its receptors PD-1 and B7.1, which are found on cytotoxic T cells and antigen-presenting cells.
• T-cell response: blocking this interaction removes the suppressive effect of PD-L1 on cytotoxic CD8+ T cells and restores anti-tumour T-cell responses.
• Natural killer cells: avelumab has also been shown to induce natural killer (NK) cell-mediated lysis of tumour cells through antibody-dependent cell-mediated cytotoxicity (ADCC); how far this contributes to its clinical effect is unclear.
• Preclinical effect: tumour growth was reduced in mouse tumour models.

Pharmacokinetics

• Distribution: expected to remain mainly in the circulation, with limited spread into the extracellular space; volume of distribution at steady state 4.72 L. As is usual for an antibody, it does not bind plasma proteins in a specific manner.
• Metabolism: cleared through catabolic pathways, by non-specific proteolytic degradation.
• Elimination: total systemic clearance about 0.59 L/day (population analysis of 1,629 patients), which falls over time (largest mean reduction about 32%). Elimination half-life 6.1 days at the recommended dose.
• Steady state: reached after about 4 to 6 weeks (2 to 3 cycles) of 10 mg/kg every 2 weeks, with about 1.25-fold accumulation. Exposure rises in proportion to dose between 10 and 20 mg/kg every 2 weeks, and no clinically meaningful difference in exposure is expected between 800 mg and 10 mg/kg every 2 weeks.
• With axitinib: exposure to avelumab (10 mg/kg) and to axitinib (5 mg) was unchanged compared with either medicine alone.
• Special populations: age, sex, race, PD-L1 status, tumour burden, renal impairment and mild or moderate hepatic impairment do not change clearance. Clearance rises with body weight, but steady-state exposure was roughly uniform from 30 to 204 kg with weight-normalised dosing.

• Merkel cell carcinoma: monotherapy for adults with metastatic Merkel cell carcinoma (MCC).
• Urothelial carcinoma: monotherapy for first-line maintenance treatment of adults with locally advanced or metastatic urothelial carcinoma (UC) who are progression-free after platinum-based chemotherapy.
• Renal cell carcinoma: in combination with axitinib, first-line treatment of adults with advanced renal cell carcinoma (RCC).

• Hypersensitivity to avelumab or to any of the excipients (mannitol, glacial acetic acid, polysorbate 20, sodium hydroxide, water for injections).

Avelumab is associated with infusion-related reactions and with immune-mediated reactions; most resolved after appropriate medical treatment or withdrawal of avelumab. The frequencies below are for monotherapy (2,082 patients with solid tumours, including Merkel cell and urothelial carcinoma, given 10 mg/kg every 2 weeks). The most common reactions were fatigue (30.0%), nausea (23.6%), diarrhoea (18.5%), constipation (18.1%), decreased appetite (17.6%), infusion-related reactions (15.9%), vomiting (15.6%) and weight decreased (14.5%). The most common grade 3 or higher reactions were anaemia (5.6%), hypertension (3.9%), hyponatraemia (3.6%), dyspnoea (3.5%) and abdominal pain (2.6%).

Very common (≥1/10): anaemia, infusion-related reaction, decreased appetite, cough, dyspnoea, nausea, diarrhoea, constipation, vomiting, abdominal pain, back pain, arthralgia, fatigue, pyrexia, peripheral oedema, weight decreased.

Common (≥1/100 to <1/10): lymphopenia, thrombocytopenia, hypothyroidism, hyperthyroidism, hyponatraemia, headache, dizziness, peripheral neuropathy, hypertension, pneumonitis, dry mouth, pruritus, rash (including maculo-papular), dry skin, myalgia, asthenia, chills, influenza-like illness, and raised blood creatinine, alkaline phosphatase, lipase, gamma-glutamyltransferase and amylase.

Uncommon (≥1/1,000 to <1/100): eosinophilia, hypersensitivity, cytokine release syndrome, adrenal insufficiency, thyroiditis (including autoimmune thyroiditis), autoimmune hypothyroidism, hyperglycaemia, myasthenia gravis and myasthenic syndrome, hypotension, flushing, ileus, colitis, autoimmune hepatitis, eczema, dermatitis, psoriasis, erythema and other forms of rash, myositis, rheumatoid arthritis, renal failure, nephritis, and raised alanine aminotransferase, aspartate aminotransferase and creatine phosphokinase.

Rare (≥1/10,000 to <1/1,000): anaphylactic reaction, type I hypersensitivity, sarcoidosis, acute adrenocortical insufficiency, hypopituitarism, diabetes mellitus (including type 1), Guillain-Barré syndrome, Miller Fisher syndrome, uveitis, myocarditis, interstitial lung disease, pancreatitis, autoimmune colitis, enterocolitis, enteritis, proctitis, acute hepatic failure, hepatic failure, hepatitis, hepatotoxicity, erythema multiforme, purpura, vitiligo, pemphigoid, lichen planus, drug eruption, arthritis, Sjögren’s syndrome, tubulo-interstitial nephritis, non-infective cystitis, systemic inflammatory response syndrome, raised transaminases, decreased free thyroxine and raised thyroid-stimulating hormone.

Not known: neutropenia, gastritis, sclerosing cholangitis, polymyalgia rheumatica.

Many of the less frequent reactions are immune-mediated (for example thyroiditis, colitis, hepatitis, nephritis, myocarditis, myositis). Important serious reactions:

• Infusion-related reactions: across all related terms, 24.6% of monotherapy patients (513 of 2,082) had one, and in 97.7% of them the first reaction came during the first four infusions.
• Immune-mediated reactions in monotherapy: pneumonitis 1.3%, hepatitis 1.0%, colitis 1.5%, thyroid disorders 6.7%, adrenal insufficiency 0.5%, type 1 diabetes mellitus 0.2% and nephritis 0.3%. Fatal cases have been reported for pneumonitis (one) and hepatitis (two), and, with axitinib, two fatal cases each of pancreatitis and myocarditis. They can begin after treatment has stopped.
• With axitinib: in 489 patients with advanced renal cell carcinoma (avelumab 10 mg/kg every 2 weeks plus axitinib 5 mg twice daily) the most common reactions were diarrhoea (62.8%), hypertension (49.3%), fatigue (42.9%), nausea (33.5%), dysphonia (32.7%), decreased appetite (26.0%), hypothyroidism (25.2%), cough (23.7%), headache (21.3%), dyspnoea (20.9%) and arthralgia (20.9%). Hypothyroidism, headache, dizziness, hypertension, dysphonia, rash, pruritus, myalgia, chills, asthenia and raised ALT and AST were very common with the combination. Grade 3 and 4 rises in ALT and AST occurred in 9% and 7% of patients, immune-mediated hepatitis in 6.3% and immune-mediated thyroid disorders in 24.7%.

• No interaction studies have been conducted with avelumab. As a monoclonal antibody it is cleared mainly through catabolic pathways, so pharmacokinetic interactions with other medicines are not expected.
• Axitinib: when avelumab 10 mg/kg was given with axitinib 5 mg, exposure to each medicine was unchanged compared with either alone.

Treatment must be started and supervised by a physician experienced in cancer treatment. Avelumab is given only as an intravenous infusion, after dilution, and must never be given as an intravenous push or bolus injection.

Recommended Dose

• Monotherapy (Merkel cell carcinoma, urothelial carcinoma maintenance): 800 mg by intravenous infusion over 60 minutes every 2 weeks, continued until disease progression or unacceptable toxicity.
• With axitinib (renal cell carcinoma): avelumab 800 mg every 2 weeks as above, together with axitinib 5 mg by mouth twice daily (12 hours apart), with or without food, until disease progression or unacceptable toxicity. The axitinib dose is set out in the axitinib product information.

Premedication

An antihistamine and paracetamol must be given before each of the first four infusions. If the fourth infusion is completed without an infusion-related reaction, premedication for later infusions is at the physician’s discretion.

Dose Adjustments for Side Effects

Dose escalation or reduction is not recommended. Instead, a dose may be delayed or treatment stopped, depending on the reaction:

• Infusion-related reactions: grade 1, slow the infusion rate by 50%; grade 2, withhold until grade 0–1 and restart at a 50% slower rate; grade 3 or 4, permanently discontinue.
• Pneumonitis: grade 2, withhold until grade 0–1; grade 3 or 4, or recurrent grade 2, permanently discontinue.
• Hepatitis: AST or ALT above 3 and up to 5 times the upper limit of normal (ULN), or total bilirubin above 1.5 and up to 3 times ULN, withhold until grade 0–1; AST or ALT above 5 times ULN, or bilirubin above 3 times ULN, permanently discontinue. With axitinib, grade 2 hepatotoxicity is withheld until it resolves and grade 3 or 4 means permanent discontinuation.
• Colitis or diarrhoea: grade 2 or 3, withhold until grade 0–1; grade 4, or recurrent grade 3 colitis, permanently discontinue.
• Pancreatitis and myocarditis: withhold if suspected, permanently discontinue if confirmed.
• Endocrinopathies and nephritis: withhold for grade 3 or 4 endocrinopathies until resolution; withhold for grade 2 or 3 nephritis until it improves to grade 1 or lower, and discontinue for grade 4.
• Other immune-mediated reactions: withhold and give corticosteroids; resume once the reaction is grade 1 or lower after the steroid taper; permanently discontinue for a recurring grade 3 reaction and for any grade 4 reaction.

The SmPC holds the full table of criteria.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment; too few data in severe impairment for a dosing recommendation.
• Hepatic impairment: no adjustment in mild impairment; too few data in moderate or severe impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Preparation

The concentrate is diluted with sodium chloride 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) solution for infusion and given over 60 minutes through a sterile, non-pyrogenic, low-protein-binding 0.2 micrometre in-line or add-on filter.

Traceability

Avelumab is a biological medicinal product, so the name and batch number of each administered product should be clearly recorded.

Infusion-Related Reactions

Reactions can be severe. Patients are monitored during the infusion for fever, chills, flushing, low blood pressure, breathlessness, wheezing, back pain, abdominal pain and urticaria. After a recurrent grade 1 or 2 reaction, treatment may continue under close monitoring with a slower infusion rate and paracetamol and antihistamine premedication.

Immune-Mediated Adverse Reactions

Immune-mediated reactions can be severe or fatal and may affect one or several organs at once. They usually occur during treatment but can appear after it has stopped, so patients are monitored for signs and symptoms, and prompt medical management, with specialist consultation as appropriate, is needed. Other causes are excluded first. Most reactions were reversible with interruption or discontinuation of avelumab, corticosteroids and supportive care. If corticosteroids are used, the taper lasts at least 1 month, and other systemic immunosuppressants may be considered if steroids do not control the reaction. In patients with pre-existing autoimmune disease, observational data suggest a higher risk of immune-mediated reactions; flares of the underlying disease were frequent but mostly mild and manageable.

• Pneumonitis: confirm with imaging; corticosteroids for grade 2 or higher (initial 1 to 2 mg/kg a day of prednisone or equivalent, then a taper). One fatal case has been reported.
• Hepatitis: liver function is monitored; corticosteroids for grade 2 or higher. Two fatal cases have been reported.
• Colitis: corticosteroids for grade 2 or higher.
• Pancreatitis and myocarditis: specialist input (gastroenterology or cardiology) and corticosteroids for symptomatic patients; for myocarditis, additional immunosuppression (for example mycophenolate, infliximab or anti-thymocyte globulin) if there is no improvement within 24 hours. Two fatal cases of each have been reported with axitinib.
• Endocrinopathies: thyroid function is checked at the start, periodically and as indicated, with replacement therapy for hypothyroidism and anti-thyroid medicine for hyperthyroidism as needed. Patients are monitored for adrenal insufficiency and for hyperglycaemia, because avelumab can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which is treated with insulin.
• Nephritis and renal dysfunction: serum creatinine is checked before and periodically during treatment; corticosteroids for grade 2 or higher.
• Other immune-mediated reactions reported: myositis, hypopituitarism, uveitis, myasthenia gravis, myasthenic syndrome, myocarditis-myositis-myasthenia gravis overlap syndrome (some fatal), non-infective cystitis, sarcoidosis, Guillain-Barré syndrome, sclerosing cholangitis, arthritis, polymyalgia rheumatica, Sjögren’s syndrome and gastritis.

Hepatotoxicity with Axitinib

When avelumab is combined with axitinib, grade 3 and 4 rises in ALT and AST were more frequent than with avelumab alone, so liver function and symptoms are monitored more often than during monotherapy.

Patients Excluded from Clinical Studies

Studies excluded patients with active central nervous system metastases, active or past autoimmune disease, another cancer within the last 5 years, an organ transplant, conditions needing immune suppression, or active HIV, hepatitis B or hepatitis C infection. Avelumab is used with caution in these groups, after weighing benefit and risk individually.

Patient Card

The prescriber must discuss the risks of treatment with the patient, who is given a Patient Card to carry at all times.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid pregnancy and use effective contraception during treatment and for at least 1 month after the last dose.
• Pregnancy: there are no or limited data. In mouse pregnancy models, blocking PD-L1 disrupted tolerance to the foetus and increased foetal loss, so harm to the foetus, including abortion or stillbirth, is possible; human IgG1 crosses the placenta. Avelumab is not recommended in pregnancy unless the woman’s condition requires it.
• Breastfeeding: it is unknown whether avelumab passes into milk, but antibodies can; breastfeeding is not advised during treatment and for at least 1 month after the last dose.
• Fertility: the effect on male and female fertility is unknown.

Polysorbate and Sodium

Each vial contains 5 mg of polysorbate 20, which may cause allergic reactions. A 200 mg dose contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free; the sodium chloride used for dilution should be considered for patients on a controlled sodium diet.

Effect on Driving

Avelumab has a negligible influence on the ability to drive and use machines. Fatigue has been reported, so patients should take care until they are sure it does not affect them.

Store vials in a refrigerator at 2–8 °C, in the original package to protect from light. Do not freeze. Avelumab stays in the cold chain from supply until it is prepared at the hospital or clinic. Storage after dilution is covered under Shelf Life.

3 years for the unopened vial. Once a vial is opened, the medicine should be diluted and infused immediately. The in-use stability of the diluted solution has been shown as follows:

• 0.9% sodium chloride: 96 hours at 2–8 °C protected from light, or 72 hours at 20–25 °C in room light.
• 0.45% sodium chloride: 24 hours at 2–8 °C protected from light, or 24 hours at 20–25 °C in room light.

From a microbiological point of view, the diluted solution should be infused immediately unless the method of dilution rules out the risk of microbial contamination.

Prescription only (Rx): a medicinal product subject to restricted medical prescription (Annex II B), started and supervised by a physician experienced in cancer treatment. Avelumab is given as an intravenous infusion, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.