BAVENCIO

Avelumab is a human

IgG1 lambda monoclonal antibody that binds programmed cell death ligand-1 (PD-L1) to block its interaction with its receptors found on T cells and antigen-presenting cells.

Avelumab was first approved by the FDA on March 23, 2017.

On September and

December of the same year, it was also granted approval by EMA and Health Canada, 9 respectively.

It is used in the treatment of Merkel cell carcinoma, metastatic urothelial carcinoma, or renal cell carcinoma.

Avelumab is indicated for the treatment of adults with metastatic Merkel cell carcinoma (MCC). 8, 9 In the US, it is also used in patients 12 years and older.

It is also indicated as the maintenance treatment in patients with locally advanced or metastatic urothelial carcinoma (UC), which has not progressed with first-line platinum-containing chemotherapy. 6, 8, 9 In the US, avelumab is also indicated to treat locally advanced or metastatic UC with disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Avelumab is indicated, in combination with axitinib, for the first-line treatment of advanced renal cell carcinoma (RCC).

Avelumab is an immunotherapeutic and antineoplastic agent belonging to the immune checkpoint blockade cancer therapies group.

It induces antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro; 1, 3, 7 however it is unclear whether ADCC contributes to the therapeutic actions of avelumab.

Avelumab decreased tumour growth in syngeneic mouse tumour models. 3, 7.

In patients who received doses ranging from 1-20 mg/kg every two weeks, avelumab exposure increased dose proportionally in the dose range of 10-20 mg/kg. Steady-state concentrations of avelumab were reached after approximately four to six weeks (two to three cycles) of repeated dosing, and the systemic accumulation was approximately 1.25-fold.

The geometric mean volume of distribution at steady state for a subject receiving 10 mg/kg is 4.72 L.

Avelumab is expected to be distributed in the systemic circulation and, to a lesser extent, in the extracellular space.

The terminal half-life is approximately 6.1 days in patients with solid tumours receiving 10 mg/kg.

The total systemic clearance is approximately 0.59 L/day in patients with solid tumours receiving 10 mg/kg.

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There is limited information regarding the

LD of avelumab.

Three patients who received a dose of avelumab that was 5% to 10% above the recommended dose experienced an overdose: the patients reported no symptoms and continued on avelumab therapy without requiring any treatment for the overdose.

In the case of an overdose, patients should be closely monitored for signs or symptoms of adverse reactions.

The treatment is directed to the management of symptoms.

Premedicate for the first 4 infusions and subsequently as needed.

Carcinoma: 800 mg every 2 weeks.

Carcinoma; 800 mg every 2 weeks.

Carcinoma: 800 mg every 2 weeks in combination with axitinib 5 mg orally twice daily.

BAVENCIO as an intravenous infusion over 60 minutes. 2.1 Premedication Premedicate patients with an antihistamine and with acetaminophen prior to the first 4 infusions of BAVENCIO.

Premedication should be administered for subsequent

BAVENCIO doses based upon clinical judgment and presence/severity of prior infusion reactions. 2.2 Recommended Dosage for MCC The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for UC The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.4 Recommended Dosage for RCC The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks in combination with axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity.

When axitinib is used in combination with BAVENCIO, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of two weeks or longer.

Information for axitinib prior to initiation. 2.5 Dose Modifications No dose reduction for BAVENCIO is recommended.

In general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions.

Permanently discontinue

BAVENCIO 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 corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.

Dosage modifications for

BAVENCIO for adverse reactions that require management different from these general guidelines are summarized in Table 1.

Table 1: Recommended Monotherapy Dosage Modifications for Adverse Reactions Adverse Reaction Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 Dosage Modification ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, SJS = Stevens-Johnson syndrome, TEN = toxic epidermal necrosis, DRESS = drug rash with eosinophilia and systemic symptoms Immune-Mediated Adverse Reactions Pneumonitis Grade 2 Withhold Resume in patients with complete or partial resolution (Grade to 1) after corticosteroid taper.

Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating corticosteroids.

Grade 3 or 4 Permanently discontinue Colitis Grade 2 or 3 Withhold Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy, see Table 2 AST or ALT increases to more than and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue BAVENCIO based on recommendations for hepatitis where there is no tumor involvement of the liver.

Baseline AST or

ALT is more than and up to 3 times ULN and increases to more than and up to 10 times ULN or Baseline AST or ALT is more than and up to 5 times ULN and increases to more than and up to 10 times ULN Withhold AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Endocrinopathies 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 Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3 or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold Grade 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-related reactions Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue Table 2 presents dosage modifications that are different from those described above in Table for BAVENCIO used as monotherapy or in the Full Prescribing Information for the drug administered in combination.

Table 2: Recommended Specific Dosage Modifications for Adverse Reactions for Combination Therapy Treatment Adverse Reaction Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 Dosage Modification BAVENCIO in combination with axitinib Liver enzyme elevations ALT or AST at least 3 times ULN but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN Withhold both BAVENCIO and axitinib until adverse reactions recover to Grades 0-1 Consider corticosteroid therapy Consider rechallenge with BAVENCIO or axitinib or sequential rechallenge with both BAVENCIO and axitinib after recovery Dose reduction according to the axitinib Full Prescribing Information should be considered if rechallenging with axitinib.

ALT or

AST at least 10 times ULN or more than 3 times ULN with concurrent total bilirubin at least 2 times ULN Permanently discontinue both BAVENCIO and axitinib 2.6 Preparation and Administration Preparation Visually inspect vial for particulate matter and discoloration.

BAVENCIO is a clear, colorless to slightly yellow solution.

Discard vial if the solution is cloudy, discolored, or contains particulate matter.

Withdraw the required volume of

BAVENCIO from the vial(s) and inject it into a 250 mL infusion bag containing either 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection.

Gently invert the bag to mix the diluted solution and avoid foaming or excessive shearing.

Inspect the solution to ensure it is clear, colorless, and free of visible particles.

Discard any partially used or empty vials.

Storage of diluted BAVENCIO solution

Protect from light.

Store diluted BAVENCIO solution

At room temperature up to 77°F (25°C) for no more than 4 hours from the time of dilution.

Or Under refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution.

If refrigerated, allow the diluted solution to come to room temperature prior to administration.

Do not freeze or shake diluted solution.

Administer the diluted solution over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron).

Do not co-administer other drugs through the same intravenous line.

(avelumab) Injection is a sterile, preservative-free, and clear, colorless to slightly yellow solution for intravenous infusion supplied as a single-dose vial of 200 mg/10 mL (20 mg/mL), individually packed into a carton (NDC 44087-3535-1).

Store refrigerated at 36°F to 46°F (2°C to 8°C) in original package to protect from light.

Do not freeze or shake the vial.

The vial stopper is not made with natural rubber latex.

Store refrigerated at 36°F to 46°F (2°C to 8°C) in original package to protect from light.

Do not freeze or shake the vial.

The vial stopper is not made with natural rubber latex.

Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman.

There are no available data on the use of BAVENCIO in pregnant women.

Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death.

IgG1 immunoglobulins (IgG1) are known to cross the placenta.

Therefore, BAVENCIO has the potential to be transmitted from the mother to the developing fetus.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Animal reproduction studies have not been conducted with BAVENCIO to evaluate its effect on reproduction and fetal development.

A central function of the

PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus.

In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering BAVENCIO during pregnancy include increased rates of abortion or stillbirth.

As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice.

Based on its mechanism of action, fetal exposure to BAVENCIO may increase the risk of developing immune-mediated disorders or altering the normal immune response.

The safety and effectiveness of

BAVENCIO have been established in pediatric patients aged 12 years and older for metastatic MCC.

Use of

BAVENCIO in this is supported by evidence from adequate and well-controlled studies of BAVENCIO in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady state exposure of avelumab, that drug exposure is generally similar between adults and pediatric patients age 12 years and older for monoclonal antibodies, and that the course of MCC is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients.

The recommended dose in pediatric patients 12 years of age or greater is the same as that in adults.

Safety and effectiveness of

BAVENCIO have not been established in pediatric patients less than 12 years of age.

Of the 204 patients with MCC who received BAVENCIO in the JAVELIN Merkel 200 trial, 78% were 65 years or older and 43% were 75 years or older.

No overall differences in safety or efficacy were observed between elderly patients and younger patients.

Locally Advanced or Metastatic Urothelial Carcinoma

Of the 344 patients randomized to BAVENCIO 10 mg/kg plus BSC in the JAVELIN Bladder 100 trial, 63% were 65 years or older and 24% were 75 years or older.

No overall differences in safety or efficacy were reported between elderly patients and younger patients.

Of the 434 patients randomized to BAVENCIO 10 mg/kg administered in combination with axitinib 5 mg twice daily in the JAVELIN Renal 101 trial, 38% were 65 years or older and 8% were 75 years or older.

No overall difference in safety or efficacy were reported between elderly patients and younger patients.