Durvalumab (Imfinzi) is a human immunoglobulin G1 kappa monoclonal antibody that blocks programmed cell death ligand 1 (PD-L1) binding to PD-1 and CD80 (B7.1). It is used in the treatment of advanced urothelial and non-small-cell lung carcinoma.

Durvalumab (Imfinzi) Uses:

• Unresectable non-small-cell lung cancer:

  • Treatment of unresectable stage III non-small-cell lung cancer which has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

• Locally advanced or metastatic Urothelial carcinoma, :

  • Treatment of locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or after platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Adult dose:

Durvalumab (Imfinzi) Dose in the treatment of stage III, Unresectable Non-small cell lung cancer:

• 10 mg/kg IV once every 2 weeks;
• Continue until disease progression or unacceptable toxicity or a maximum of 1 year.
• In the clinical trial, durvalumab was started within 6 weeks after chemoradiotherapy; treatment was continued beyond 12 months if the disease was controlled at the end of 12 months but then progressed during follow-up..

Durvalumab (Imfinzi) Dose in the treatment of locally advanced or metastatic Urothelial carcinoma:

• 10 mg/kg IV once every 2 weeks until disease progression or unacceptable toxicity.

Use in Children:

Durvalumab Pregnancy Risk Category: X

• Side effects that can cause harm in animal reproduction studies.
• It is known that immunoglobulins can cross the placenta, and the fetus could be exposed to durvalumab.
• Effective contraception should be used by females with reproductive potential during treatment and for at most 3 months following the last durvalumab dosage.

Durvalumab is not recommended for use while breastfeeding

• Although durvalumab may not be present in breastmilk, it is known that endogenous immunoglobulins can be excreted from breastmilk.
• Due to the possible adverse effects on breastfed babies, the manufacturer does not recommend breastfeeding during therapy or for more than 3 months after the last dose of durvalumab.

Renal dose:

Durvalumab (Imfinzi) Dose in Kidney disease:

• Renal impairment prior to treatment initiation:

  • CrCl 30 to 89 mL/minute:
    • No dosage adjustment, clinically irrelevant
  • CrCl 15 to 29 mL/minute:
    • There are no dosage adjustments provided in the manufacturer's labeling (it has not been studied).

• Renal toxicity during treatment (nephritis):

  • Nephritis, creatinine >1.5 to 3 times ULN:
    • Withhold dose.
    • Administer systemic corticosteroids (prednisone initially 1 to 2 mg/kg daily or equivalent, tapered down later.
    • May restart durvalumab when nephritis has resolved or improved to grade 1 and corticosteroid dose is ≤10 mg/day prednisone or equivalent.
  • Nephritis, creatinine >3 times ULN:
    • Discontinue permanently.
    • Administer systemic corticosteroids (prednisone initially 1 to 2 mg/kg daily or equivalent, tapered down later.

Durvalumab (Imfinzi) Dose in Liver disease:

• Hepatic impairment prior to treatment initiation:

  • Mild impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1 to 1.5 times ULN and any AST):
    • There are no dosage adjustments provided in the manufacturer's labeling; however, there is no clinically relevant effect on pharmacokinetics.
  • Moderate impairment (bilirubin >1.5 to 3 times ULN and any AST) or severe (bilirubin >3 times ULN and any AST):
    • There are no dosage adjustments provided in the manufacturer's labeling (it has not been studied).

• Hepatotoxicity during treatment:

  • Hepatitis, ALT or AST >3 to ≤8 times ULN or total bilirubin >1.5 to ≤5 times ULN:
    • Hold dose. Administer systemic corticosteroids (prednisone initially 1 to 2 mg/kg daily or equivalent, tapered down later.
    • May resume durvalumab when hepatitis has improved to grade 1 or resolved and corticosteroid dose is ≤10 mg/day prednisone or equivalent.
  • Hepatitis, ALT or AST >8 times ULN or total bilirubin >5 times ULN:
    • Discontinue altogether.
    • Administer systemic corticosteroids (prednisone initially 1 to 2 mg/kg daily or equivalent, tapered down later.
  • Hepatitis, concurrent ALT or AST >3 times ULN and total bilirubin >2 times ULN with no other cause:
    • Discontinue permanently.
    • Administer systemic corticosteroids (prednisone initially 1 to 2 mg/kg daily or equivalent, tapered down later

Side effects:

Common Side Effects of Durvalumab (Imfinzi):

• Cardiovascular:

  • Peripheral Edema

• Central Nervous System:

  • Fatigue

• Dermatologic:

  • Dermatitis
  • Skin Rash
  • Pruritus

• Endocrine & Metabolic:

  • Hyperglycemia
  • Hypocalcemia
  • Hyponatremia
  • Hyperkalemia
  • Increased Gamma-Glutamyl Transferase
  • Hypothyroidism

• Gastrointestinal:

  • Constipation
  • Decreased Appetite
  • Colitis
  • Diarrhea
  • Nausea
  • Abdominal Pain

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Lymphocytopenia

• Hepatic:

  • Increased Serum ALT
  • Increased Serum AST
  • Hepatitis

• Infection:

  • Infection

• Neuromuscular & Skeletal:

  • Musculoskeletal Pain

• Respiratory:

  • Cough
  • Productive Cough
  • Pneumonitis
  • Radiation Pneumonitis
  • Upper Respiratory Tract Infection
  • Pneumonia
  • Dyspnea
  • Dyspnea On Exertion

• Miscellaneous:

  • Fever

Less Common Side Effects Of Durvalumab (Imfinzi):

• Central Nervous System:

  • Voice Disorder

• Dermatologic:

  • Night Sweats

• Endocrine & Metabolic:

  • Hyperthyroidism
  • Hypermagnesemia
  • Dehydration
  • Hypercalcemia
  • Hypoalbuminemia
  • Hypokalemia

• Genitourinary:

  • Dysuria

• Hematologic & Oncologic:

  • Anemia
  • Neutropenia

• Hepatic:

  • Increased Serum Alkaline Phosphatase
  • Hyperbilirubinemia

• Immunologic:

  • Antibody Development

• Infection:

  • Increased Susceptibility To Infection

• Renal:

  • Nephritis
  • Increased Serum Creatinine

• Miscellaneous:

  • Infusion-Related Reaction

Side effects of Durvalumab (frequency of side effects not defined):

• Endocrine & metabolic:

  • Hypophysitis

• Hepatic:

  • Hepatic injury

• Infection:

  • Sepsis

• Renal:

  • Acute renal failure

Contraindications to Durvalumab (Imfinzi):

The manufacturer's labeling does not list any contraindications. Canadian labeling: Additional contraindications not in the US labeling

• Hypersensitivity to durvalumab and any component of the formulation

Warnings and precautions

• Insufficiency of the adrenals:

  • Some reports have been made of immune-related adrenal deficiency. Therefore, be aware of signs and symptoms of adrenal insufficiency.
  • Grade 2 or greater adrenal insufficiency should be treated with systemic corticosteroids. Hormone replacement may also be administered as indicated.

• Dermatologic toxicities:

  • It has been reported that immune-mediated rash can be observed.
  • Other anti-PDL1 monoclonal antibody antibodies have also been shown to be effective in treating bullous dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis.
  • Be on the lookout for any signs or symptoms of dermatologic toxicities.
  • Systemic corticosteroids should be used for grade 2 rash or severe dermatitis that lasts more than one week.
  • You may need to interrupt or discontinue treatment depending on the severity.

• Diabetes mellitus

  • Patients who received durvalumab have developed immune-related type 1 diabetes mellitus.
  • The median time it took to get started was 1.4 months.
  • Monitor your glucose levels and look out for signs and symptoms of diabetes.
  • Start insulin therapy for type 1 diabetes mellitus. Keep durvalumab (based on severity) until you are clinically stable.

• Toxicities to the gastrointestinal tract:

  • Reports of immune-mediated colitis (grade 3 and 4)
  • The median time it took to get started was 1.4 months. (Range: 1 day to 14 month).
  • Monitor for colitis and diarrhea symptoms and take appropriate action with systemic steroids.
  • Clinical studies showed that systemic corticosteroids were used to manage some patients. Other immunosuppressants, such as mycophenolate or infliximab were only rarely used.
  • About three-fourths of patients with immune-mediated diarrhea/colitis experienced resolution.

• Hepatotoxicity

  • Patients who received durvalumab have developed immune-mediated hepatitis (some fatal).
  • Median time from onset was 1 Month (range: 1 Day to 14 Month).
  • Observe for signs/symptoms of hepatitis (including abnormal liver function tests) during and after durvalumab treatment.
  • Grade 2 or higher immune-mediated liver disease can be managed with systemic corticosteroids, treatment interruption or discontinuation.
  • Clinical studies showed that some patients with immune-mediated liver disease received high doses of corticosteroids. Mycophenolate was rarely required to treat immune-mediated liver disease.
  • About half of patients with immune-mediated liver disease were able to recover.
  • Reports of Grade 3-4 ALT, AST and/or Total Bilirubin Elevations have been made.

• Hypophysitis, hypopituitarism

  • Patients who have received durvalumab have developed immuno-related hypophysitis/hypopituitarism.
  • Monitor for hypophysitis and hypopituitarism.
  • Grade 2 and higher hypophysitis should be treated with corticosteroids or hormone replacement therapy. Withhold durvalumab, depending on severity.
  • Hypopituitarism has been linked to adrenal insufficiency, diabetes insipidus and hypopituitarism.

• Infection

  • Nearly half of patients who received durvalumab contracted an infection (some fatal).
  • Grade 3 and 4 infections were the most common.
  • Infection rates were higher in NSCLC patients than in patients in other studies, where radiation therapy was not usually administered immediately prior to durvalumab.
  • Monitor for symptoms and signs of infection. If the infection is confirmed or suspected, take appropriate anti-infectives.
  • Grade 3 and 4 infections should be treated with withhold.

• Infusion reactions

  • Durvalumab has been associated with infusion reactions, which can include life-threatening or severe reactions.
  • Watch out for infusion reactions symptoms.
  • For mild or moderate infusion reactions, interrupt or slow down the infusion rate (premedicate with subsequent injections).
  • Durvalumab should be stopped permanently for Grade 3 and 4 infusion reactions.

• Nephrotoxicity

  • Durvalumab can cause immune-mediated nephritis, including fatal cases.
  • Before starting treatment, monitor your renal function and continue to do so throughout durvalumab.
  • Systemic corticosteroids may be required for nephritis.
  • In 50% cases, nephritis is resolved.
  • The median time it took to get started was 2 months. This ranged from 1 day to 14 months.

• Toxicities to the lungs

  • Patients who have received durvalumab (including fatalities) have developed immune-mediated pneumonitis, or interstitial lung disease.
  • The median time it took to start was 2 month (range: 1 to 19months) and the median time it took to resolve was 2 to five months (range upto 19months).
  • A non-small cell lung carcinoma study found that patients who had completed their definitive chemoradiation within 42 day prior to initiating durvalumab showed a higher incidence of pneumonitis, including radiation pneumonitis, than patients in other studies, where radiation therapy was not usually administered immediately after durvalumab.
  • Monitor for symptoms of pneumonitis and evaluate the patient with radiographic imaging. If necessary, discontinue or interrupt treatment with durvalumab and systemic corticosteroids. Some patients were treated with infliximab.
  • Clinical studies showed that approximately half of patients with immune-mediated pneumonitis were cured.

• Thyroid disorders

  • Patients who received durvalumab have experienced immune-related thyroid disorders.
  • Monitoring thyroid function at baseline, and regularly during treatment. Also monitor for signs and symptoms of thyroid disorders.
  • Clinical trials have shown hypothyroidism and hyperthyroidism as well as thyroiditis (including grade 3-thyroiditis) to be common.
  • Thyroiditis, or hyperthyroidism in some cases, was the first sign of hypothyroidism.
  • Maintain durvalumab while managing hypothyroidism (if indicated).
  • Start appropriate medical management of hyperthyroidism. Withhold durvalumab (based upon severity).
  • Hyperthyroidism was treated with a beta blocker or thioamide in certain cases.

• Ocular toxicities:

  • There have been reports of ocular inflammatory toxicities, including keratitis and uveitis.
  • To minimize permanent vision loss, uveitis may be caused by other immune-mediated reactions.

• Other immune-mediated toxicities

  • Durvalumab can also cause immune-related adverse reactions (rarely), such as aseptic meningitis and hemolytic anemia.
  • These immune-mediated toxicities typically occur during treatment but may also develop after discontinuation.
  • If you suspect that there are other causes for grade 2 immune-mediated reactions then exclude them and begin systemic corticosteroids if clinically indicated.
  • Systemic corticosteroids should be administered for immune-mediated reactions of grade 3 and 4.
  • You may need to interrupt or discontinue treatment.
  • Other immune-mediated reactions with anti-PDL1 monoclonal antibody have been reported as well, including myasthenia gravis and pancreatitis.

Durvalumab: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Monitor the liver function during each cycle
• Tests of renal function (before and after treatment)
• Thyroid function tests (at baseline and periodically during treatment)
• Blood glucose
• Examine for signs and symptoms of adrenal insufficiency, colitis/diarrhea or diabetes/hyperglycemia. Hepatitis/hepatotoxicity. Hypophysitis, hypopituitarism, hypophysitis, hepatitis/hepatotoxicity. Immune thrombocytopenia purpura. Infection, pneumonitis. (Examine suspected pneumonitis using radiographic imaging). Ocular toxicity. Thyroid disorders
• Monitor for infusion reactions

How to administer Durvalumab (Imfinzi)?

IV:

• Infuse over 60 minutes through an IV line containing a sterile, low-protein binding 0.2 or 0.22-micron in-line filter.
• Do not administer other medications through the same IV line.
• Monitor for infusion reactions. Withhold or slow the infusion for grade 1 or 2 infusion-related reactions (consider premedications with subsequent infusions);
• Stop permanently for grade 3 or 4 reactions.

Mechanism of action of Durvalumab (Imfinzi):

Durvalumab, a human immunoglobulin kappa monoclonal anti-PD-1 (B7.1) antibody that blocks programmed cells death ligand 1 (PDL1) binding to PD-1 (B7.1), is a human immuneglobulin G1 kappa monoclonal antibodies. PD-L1 blockade increases Tcell activation and allows T-cells kill tumor cells. PD-L1 acts as an immune checkpoint protein on tumor cells and infiltrating cells. It also down-regulates antitumor t cell function by binding with PD-1 or B7.1. The antitumor t cell function can be restored by blocking PD-1 and B7.1 interactions.

Half-life, elimination:

• Terminal half-life: About 18 days

Excretion:

• Steady-state clearance: 8.2 mL/hour

International Brand Names of Durvalumab:

• Imfinzi

Durvalumab Brand Names in Pakistan:

No Brands Available in Pakistan.