Durvalumab Intravenous

Urothelial Carcinoma

Durvalumab is used for the treatment of locally advanced or metastatic urothelial carcinoma that has progressed following therapy with platinum-containing chemotherapy or has progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.^[1][5][6] The accelerated approval of durvalumab for this indication is based on overall tumor response rate and duration of response; there currently are no controlled trials demonstrating a clinical benefit (e.g., improvement in disease-related symptoms, increased survival).^[1] Continued approval for this indication may be contingent on verification and description of clinical benefit of durvalumab in confirmatory studies.^[1]

The current indication for durvalumab in the treatment of locally advanced or metastatic urothelial carcinoma is based principally on the results for a cohort of previously treated patients in an open-label, multicenter, noncomparative, multi-cohort, phase 1/2 study; the cohort of previously treated patients included 182 adults with locally advanced or metastatic urothelial carcinoma that had progressed during or following platinum-containing therapy for advanced disease or within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting.^[1][5][6] The primary measure of efficacy was objective response rate as assessed by an independent review facility according to Response Evaluation Criteria in Solid Tumors (RECIST).^[1][5][6]

In this study, the median age of patients in the previously treated cohort was 67 years; 64% were Caucasian; 72% were male; 66% had visceral metastases; 66% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 1; and 41% had a baseline creatinine clearance less than 60 mL/minute.^[1] Approximately one-third (35%) of patients enrolled in this cohort had received at least 2 prior therapies for metastatic disease and 20% had disease progression following platinum-containing therapy in the neoadjuvant or adjuvant setting; 70 or 30% of patients had received prior treatment with cisplatin- or carboplatin-based regimens, respectively.^[1] Most patients (52%) had high expression of programmed-death ligand-1 (PD-L1), 40% of patients had low PD-L1 expression, and samples from 8% of patients were not evaluable.^[1][2] High PD-L1 expression was defined as 25% or more of tumor cells or immune cells expressing PD-L1 if immune cells involve more than 1% of the tumor area or defined as 25% or more of tumor cells or 100% of immune cells if the immune cells involve 1% or less of the tumor area, as detected by an immunohistochemistry assay (Ventana PD-L1 [SP263]).^[1] Patients received durvalumab 10 mg/kg administered as an IV infusion every 2 weeks for up to 12 months or until disease progression or unacceptable toxicity occurred.^[1][5][6] This study excluded patients with a history of immunodeficiency or severe autoimmune disease; those with medical conditions requiring systemic immunosuppression; those with untreated brain metastases; and those with human immunodeficiency virus (HIV) infection, active tuberculosis, or hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.^[1]

The overall response rate for patients in the previously treated cohort of this study was 17%; complete response was achieved in 2.7% of patients in this cohort.^[1] At a median follow-up of 5.6 months, the median duration of response had not been reached.^[1] A subgroup analysis indicated that patients with high levels of PD-L1 expression had higher objective response rates compared with those having low levels of PD-L1 expression (26.3 versus 4.1%).^[1]

Non-small Cell Lung Cancer

Durvalumab is used for the treatment of unresectable stage III non-small cell lung cancer (NSCLC) that has not progressed following platinum-based chemotherapy combined with radiation therapy.^[1][11][12]

The current indication for durvalumab in the treatment of unresectable NSCLC that has not progressed following platinum-based chemotherapy combined with radiation therapy is based principally on the results of a multicenter, double-blind, randomized, placebo-controlled, phase 3 trial (PACIFIC).^[1][11][12] In this study, 713 patients with unresectable stage III NSCLC that had not progressed following at least 2 cycles of platinum-based chemotherapy and concurrent radiation therapy within 42 days of study initiation, were randomized (stratified by gender, age, and smoking history) in a 2:1 ratio to receive either durvalumab (10 mg/kg by IV infusion every 2 weeks) or placebo.^[1][11][12] Treatment was continued for up to 12 months or until disease progression or unacceptable toxicity occurred.^[1][11][12] The median age of patients in this study was 64 years; 69% were Caucasian; 27% were Asian; 70% were male; 75% were former smokers and 16% were current smokers; and 51% had a baseline ECOG performance status of 1.^[1] All patients had received radiation therapy and 99% of patients had received concomitant platinum-based chemotherapy; 55 or 42% of patients had received prior treatment with cisplatin- or carboplatin-based regimens, respectively, and 2% switched between cisplatin and carboplatin.^[1] This study excluded patients whose disease progressed during platinum-containing chemotherapy and radiation therapy, those with autoimmune disease within the previous 2 years, and those receiving immunosuppressive agents.^[1] The primary measures of efficacy were progression-free survival and overall survival (as evaluated by a blinded independent central review committee according to RECIST); an additional outcome measure was overall response rate.^[1][11]

In the PACIFIC study, patients receiving durvalumab had a longer median progression-free survival compared with patients receiving placebo (16.8 months versus 5.6 months; hazard ratio of 0.52).^[1][11] Median overall survival had not been reached at the time of the interim analysis (at a median follow-up of 14.5 months).^[11] At the time of the interim analysis, patients receiving durvalumab had higher overall response rates compared with those receiving placebo (26 versus 14%);^[1] complete responses were achieved in 1 or 0% of patients receiving durvalumab or placebo, respectively.^[1]

General

Restricted Distribution

Durvalumab can only be obtained through a limited network of specialty distributors.^[3] Clinicians may contact the manufacturer (AstraZeneca) by telephone at 844-275-2360 or consult the Imfinzi^® website for specific availability information (https://www.imfinzihcp.com/imfinzi-durvalumab-resources.html#how-to-order).^[3]

Administration

Durvalumab is administered by IV infusion over 60 minutes.^[1]

For IV infusion, the appropriate dose (10 mg/kg) of durvalumab injection concentrate (containing 50 mg/mL) should be diluted with an appropriate volume of 0.9% sodium chloride or 5% dextrose injection to a final concentration of 1-15 mg/mL.^[1] Prior to dilution, the injection should be inspected visually for particulate matter and discoloration.^[1] The solution should be clear to opalescent and colorless to slightly yellow; the solution should not be used if it is cloudy or discolored or if foreign particles are present.^[1] The diluted solution should be mixed by gentle inversion and should not be shaken.^[1] Durvalumab should be administered through a sterile, low-protein-binding 0.2- or 0.22-µm inline filter.^[1]

Diluted solutions of durvalumab should be administered immediately after preparation.^[1] If the diluted solution is not administered immediately, it may be stored for up to 4 hours at room temperature or up to 24 hours at 2-8°C (total storage time from initial vial entry for preparation of the dilution until start of the IV infusion.)^[1] Diluted solutions of the drug should not be frozen.^[1]

Any unused portion in the vial or infusion bag should be discarded since durvalumab injection contains no preservative.^[1]

Durvalumab should not be administered simultaneously through the same IV line with any other drug.^[1]

Dosage

Urothelial Carcinoma

For the treatment of locally advanced or metastatic urothelial carcinoma that has progressed following therapy with platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy, the recommended adult dosage of durvalumab is 10 mg/kg administered as a 60-minute IV infusion once every 2 weeks.^[1] Therapy should be continued until disease progression or unacceptable toxicity occurs.^[1]

Non-small Cell Lung Cancer

For the treatment of unresectable non-small cell lung cancer (NSCLC) that has not progressed following platinum-based chemotherapy combined with radiation therapy, the recommended adult dosage of durvalumab is 10 mg/kg administered as a 60-minute IV infusion once every 2 weeks.^[1] Therapy should be continued until disease progression or unacceptable toxicity occurs, or for up to 12 months.^[1]

Therapy Interruption for Toxicity

If immune-mediated adverse effects or certain other adverse effects occur, temporary or permanent discontinuance of durvalumab may be required based on severity of the reaction.^[1] Dosage reductions of durvalumab are not recommended.^[1]

Durvalumab should be permanently discontinued in patients experiencing persistent grade 2 or 3 adverse effects (except for endocrinopathies) that do not recover to grade 0 or 1 within 12 weeks of the last dose of durvalumab.^[1] Therapy with the drug also should be permanently discontinued in patients unable to reduce corticosteroid dosage to 10 mg or less of prednisone daily (or equivalent) within 12 weeks of the last dose of durvalumab.^[1]

Durvalumab should be permanently discontinued in patients experiencing recurrent grade 3 or 4 (severe or life-threatening) adverse effects.^[1]

Immune-mediated Pneumonitis

If grade 2 immune-mediated pneumonitis occurs, durvalumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the patient is receiving 10 mg or less of prednisone daily (or equivalent).^[1] (See Immune-mediated Pneumonitis under Cautions: Warnings/Precautions.)

If grade 3 or 4 immune-mediated pneumonitis occurs, durvalumab therapy should be permanently discontinued.^[1]

Immune-mediated Hepatic Effects

For serum aminotransferase (ALT or AST) elevations exceeding 3 times but not more than 8 times the upper limit of normal (ULN) or total bilirubin concentrations exceeding 1.5 times but not more than 5 times the ULN, durvalumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the patient is receiving 10 mg or less of prednisone daily (or equivalent).^[1] (See Immune-mediated Hepatic Effects under Cautions: Warnings/Precautions.)

For ALT or AST elevations exceeding 8 times the ULN or total bilirubin concentrations exceeding 5 times the ULN, durvalumab therapy should be permanently discontinued.^[1]

For ALT or AST elevations exceeding 3 times the ULN and total bilirubin concentrations exceeding 2 times the ULN with no other cause, durvalumab therapy should be permanently discontinued.^[1]

Immune-mediated GI Effects

If grade 2 immune-mediated colitis or diarrhea occurs, durvalumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the patient is receiving 10 mg or less of prednisone daily (or equivalent).^[1] (See Immune-mediated GI Effects under Cautions: Warnings/Precautions.)

If grade 3 or 4 immune-mediated colitis or diarrhea occurs, durvalumab therapy should be permanently discontinued.^[1]

Immune-mediated Endocrine Effects

If grade 2-4 immune-mediated adrenal insufficiency, hyperthyroidism, hypophysitis, hypopituitarism, or type 1 diabetes mellitus occurs, durvalumab should be interrupted until the patient is clinically stable.^[1] (See Immune-mediated Endocrine Effects under Cautions: Warnings/Precautions.)

Immune-mediated Renal Effects

For serum creatinine elevations exceeding 1.5 times but not more than 3 times the ULN (i.e., grade 2 toxicity), durvalumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the patient is receiving 10 mg or less of prednisone daily (or equivalent).^[1] (See Immune-mediated Renal Effects under Cautions: Warnings/Precautions.)

For serum creatinine concentrations exceeding 3 times the ULN (i.e., grade 3 or 4 toxicity), durvalumab therapy should be permanently discontinued.^[1]

Immune-mediated Dermatologic Effects

If grade 2 immune-mediated rash or dermatitis occurs and persists for more than 1 week or if grade 3 immune-mediated rash or dermatitis occurs, durvalumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the patient is receiving 10 mg or less of prednisone daily (or equivalent).^[1] (See Immune-mediated Dermatologic Effects under Cautions: Warnings/Precautions.)

If grade 4 immune-mediated rash or dermatitis occurs, durvalumab therapy should be permanently discontinued.^[1]

Other Immune-mediated Adverse Effects

If any other grade 3 immune-mediated adverse effects occur, durvalumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the patient is receiving 10 mg or less of prednisone daily (or equivalent).^[1] (See Other Immune-mediated Effects under Cautions: Warnings/Precautions.)

If any other grade 4 immune-mediated adverse effects occur, durvalumab therapy should be permanently discontinued.^[1]

Infectious Complications

If grade 3 or 4 infection occurs, durvalumab therapy should be interrupted until the patient is clinically stable.^[1] (See Infectious Complications under Cautions: Warnings/Precautions.)

Infusion-related Reactions

If grade 1 or 2 infusion-related reactions occur, the infusion rate of durvalumab should be decreased or durvalumab therapy should be interrupted.^[1] (See Infusion-related Reactions under Cautions: Warnings/Precautions.)

If grade 3 or 4 infusion-related reactions occur, durvalumab therapy should be permanently discontinued.^[1]

Special Populations

No dosage adjustment of durvalumab is necessary in patients with mild preexisting hepatic impairment.^[2] Durvalumab has not been studied in patients with moderate or severe preexisting hepatic impairment, and the manufacturer provides no specific dosage recommendations for such patients.^[1] (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment of durvalumab is necessary in patients with mild or moderate preexisting renal impairment.^[2] Durvalumab has not been studied in patients with severe preexisting renal impairment, and the manufacturer provides no specific dosage recommendations for such patients.^[1] (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustments of durvalumab based on age, race, gender, or weight are not necessary.^[2]

Contraindications

The manufacturer states there are no known contraindications to the use of durvalumab.^[1]

Warnings/Precautions

Immune-mediated Pneumonitis

Pneumonitis, including interstitial lung disease and immune-mediated pneumonitis (requiring corticosteroid therapy), sometimes fatal, has occurred in patients receiving durvalumab therapy.^{[1][6][11][12]}

In a combined safety database that included 1889 clinical study patients with urothelial carcinoma, non-small cell lung cancer (NSCLC), or other cancers who were receiving durvalumab 10 mg/kg every 2 weeks, pneumonitis (not specific to immune-mediated pneumonitis) occurred in 5% of patients; grade 3, 4, or 5 immune-mediated pneumonitis was reported in 0.8, less than 0.1, or 0.3% of patients, respectively.^[1][13] The median time to onset and the median time to resolution of pneumonitis were 1.8 months (range: 1 day to 13.9 months) and 4.9 months (range: 0 days to 13.7 months), respectively.^[1] Overall, 3.5% of patients required systemic corticosteroid therapy and 2.5 or 0.1% of these patients required high-dose corticosteroid therapy (40 mg or more of prednisone daily [or equivalent]) or infliximab, respectively.^[1] Pneumonitis led to discontinuance of durvalumab in 1.5% of patients in the combined safety database.^[1] Resolution of pneumonitis occurred in 54% of patients.^[1]

In the PACIFIC study evaluating durvalumab in 475 patients with NSCLC, pneumonitis of any grade, including radiation pneumonitis, was reported in 34% of patients who received radiation therapy within 42 days prior to initiation of durvalumab therapy compared with 2.3% of patients in other clinical studies who did not receive radiation therapy immediately prior to initiation of the drug.^[1][11] Grade 3 or 5 pneumonitis was reported in 3.4 or 1.1% of patients, respectively.^[1][11] The median time to onset and the median duration of pneumonitis in this study were 1.8 and 2.1 months, respectively.^[1] In addition, 21% of patients with pneumonitis required systemic corticosteroids with 12 or 0.1% of these patients requiring high-dose corticosteroids or infliximab, respectively.^[1] In this study, durvalumab was discontinued in 6.3% of patients because of pneumonitis.^[1] Resolution of pneumonitis occurred in 47% of patients experiencing this adverse effect.^[1]

Patients receiving durvalumab should be monitored for pulmonary symptoms indicative of pneumonitis, and those with suspected pneumonitis, should be evaluated with radiographic imaging.^[1] Temporary interruption or discontinuance of durvalumab may be necessary if immune-mediated pneumonitis occurs during therapy with the drug.^[1] In patients who develop grade 2 immune-mediated pneumonitis, durvalumab should be temporarily interrupted and systemic corticosteroid therapy should be initiated (1-2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.^[1] For toxicity not resulting in permanent discontinuance of the drug, durvalumab therapy may be resumed when the toxicity resolves to grade 0 or 1 and the corticosteroid dosage is reduced to less than 10 mg of prednisone daily (or equivalent).^[1] In patients who develop grade 3 or 4 immune-mediated pneumonitis, durvalumab therapy should be permanently discontinued and systemic corticosteroid therapy should be initiated (1-4 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.^[1]

Immune-mediated Hepatic Effects

Immune-mediated hepatitis (requiring corticosteroid therapy) and hepatotoxicity (i.e., elevations in serum ALT or AST, alkaline phosphatase, or total bilirubin concentrations), sometimes fatal, have occurred in patients receiving durvalumab therapy.^[1][6]

In the combined safety database, immune-mediated hepatitis occurred in 12% of 1889 patients; grade 3, 4, or 5 hepatitis was reported in 4.4, 0.4, or 0.2% of patients, respectively.^[1] The median time to onset was 1.2 months (range: 1 day to 13.6 months).^[1] Overall, 2.7% of patients required systemic corticosteroid therapy; 1.7 or 0.1% of these patients required high-dose corticosteroid therapy (40 mg or more of prednisone daily [or equivalent]) or mycophenolate treatment, respectively.^[1] Hepatitis resulted in discontinuance of durvalumab therapy in 0.7% of patients in the combined safety database.^[1] Resolution of immune-mediated hepatitis occurred in 49% of patients.^[1]

Patients receiving durvalumab should be monitored for signs and symptoms of hepatitis; liver function tests should be performed during and following discontinuation of durvalumab therapy.^[1] In patients who develop immune-mediated hepatitis, temporary interruption of therapy or drug discontinuance may be required.^[1] If ALT or AST concentrations exceed 3 times but not more than 8 times the ULN or total bilirubin concentrations exceed 1.5 times but not more than 5 times the ULN, durvalumab should be temporarily interrupted and systemic corticosteroid therapy at a dosage of 1-2 mg/kg of prednisone daily (or equivalent) should be initiated followed by tapering of the corticosteroid dosage.^[1] For toxicity not resulting in permanent discontinuance of the drug, durvalumab therapy may be resumed when the toxicity resolves to grade 0 or 1 and the corticosteroid dosage is reduced to less than 10 mg of prednisone daily (or equivalent).^[1] If ALT or AST elevations exceeding 8 times the ULN or total bilirubin concentrations exceeding 5 times the ULN occur or if AST or ALT concentrations exceeding 3 times the ULN occur with total bilirubin concentrations exceeding 2 times the ULN, durvalumab should be permanently discontinued and systemic corticosteroid therapy at a dosage of 1-2 mg/kg of prednisone daily (or equivalent) should be initiated followed by tapering of the corticosteroid dosage.^[1]

Immune-mediated GI Effects

Diarrhea or colitis, including immune-mediated colitis (requiring corticosteroid therapy), has occurred in patients receiving durvalumab therapy.^[1]

In the combined safety database, immune-mediated colitis or diarrhea occurred in 18% of 1889 patients; grade 3 and 4 immune-mediated colitis was reported in 1 and 0.1% of patients, respectively.^[1] The median time to onset was 1.4 months (range: 1 day to 14 months).^[1] In addition, 1.9% of patients required systemic corticosteroid therapy; 1 or 0.1% of patients required high-dose corticosteroid therapy (40 mg or more of prednisone daily [or equivalent]) or nonsteroidal immunosuppressants (e.g., infliximab, mycophenolate), respectively.^[1] Diarrhea or colitis resulted in discontinuance of durvalumab therapy in 0.4% of patients in the combined safety database.^[1] Resolution of immune-mediated GI effects occurred in 78% of patients.^[1]

Patients receiving durvalumab should be monitored for manifestations of colitis or diarrhea.^[1] Temporary interruption or discontinuance of durvalumab may be necessary if immune-mediated colitis occurs during therapy with the drug.^[1] In patients who develop grade 2 immune-mediated colitis or diarrhea, durvalumab should be temporarily interrupted and systemic corticosteroid therapy (1-2 mg/kg of prednisone daily [or equivalent]) should be initiated followed by tapering of the corticosteroid dosage.^[1] For toxicity not resulting in permanent discontinuance of the drug, durvalumab therapy may be resumed when the toxicity resolves to grade 0 or 1 and the corticosteroid dosage is reduced to less than 10 mg of prednisone daily (or equivalent).^[1] In patients who develop grade 3 or 4 immune-mediated colitis or diarrhea, durvalumab should be permanently discontinued and systemic corticosteroid therapy at a dosage of 1-2 mg/kg of prednisone daily (or equivalent) should be initiated followed by tapering of the corticosteroid dosage.^[1]

Immune-mediated Endocrine Effects

Immune-mediated endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, hypophysitis, and hypopituitarism, have occurred in patients receiving durvalumab therapy.^[1]

Thyroid Dysfunction

In the combined safety database, hypothyroidism or hyperthyroidism occurred in 11 or 7% of 1889 patients, respectively.^[1] Thyroiditis occurred in 0.9% of patients; grade 3 thyroiditis was reported in 0.1% of these patients.^[1] Thyroiditis or hyperthyroidism preceded hypothyroidism in 25% of patients.^[1]

Thyroid function should be evaluated prior to initiation of durvalumab therapy and periodically during therapy.^[1] In patients who develop immune-mediated hypothyroidism, durvalumab therapy may be continued and thyroid hormone replacement therapy should be initiated as clinically indicated.^[1] If immune-mediated hyperthyroidism occurs, appropriate medical therapy should be initiated and durvalumab therapy should be interrupted until the patient is clinically stable.^[1]

Adrenal Insufficiency, Hypophysitis, and Hypopituitarism

In the combined safety database, adrenal insufficiency occurred in 0.7% of 1889 patients; grade 3 adrenal insufficiency was reported in less than 0.1% of these patients.^[1] In addition, 0.4% of patients required systemic corticosteroids and 0.1% of patients required high-dose corticosteroid therapy.^[1]

In the combined safety database, hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in less than 0.1% of 1889 patients.^[1]

Patients should be monitored for signs and symptoms of adrenal insufficiency, hypophysitis, and hypopituitarism.^[1] If grade 2 or greater adrenal insufficiency, hypophysitis, or hypopituitarism occurs, systemic corticosteroid therapy at a dosage of 1-2 mg/kg of prednisone daily (or equivalent) should be initiated followed by tapering of the corticosteroid dosage; hormone replacement therapy should be initiated as clinically indicated.^[1] Durvalumab therapy should be interrupted until the patient is clinically stable.^[1]

Diabetes Mellitus

In the combined safety database, new-onset type 1 diabetes mellitus occurred in less than 0.1% of 1889 patients.^[1] The median time to onset of type 1 diabetes mellitus was 1.4 months.^[1]

Patients should be monitored for hyperglycemia or other signs and symptoms of diabetes.^[1] If grade 2 or greater type 1 diabetes mellitus occurs, insulin should be initiated as clinically indicated and durvalumab therapy should be interrupted until the patient is clinically stable.^[1]

Immune-mediated Renal Effects

Immune-mediated nephritis (evidence of renal dysfunction and requiring corticosteroid therapy), including elevations in serum creatinine or urea concentrations, decreased creatinine clearance, acute kidney injury, renal failure, decreased glomerular filtration rate, tubulointerstitial nephritis, or glomerulonephritis, sometimes fatal, have occurred in patients receiving durvalumab therapy.^[1][5]

In the combined safety database, nephritis occurred in 6.3% of 1889 patients; grade 3, 4, or 5 nephritis was reported in 1.1, 0.2, or 0.1% of patients, respectively.^[1] The median time to onset of nephritis was 2 months (range: 1 day to 14.2 months).^[1] In addition, 0.6% of patients required systemic corticosteroid therapy; 0.4% of patients received high-dose corticosteroid therapy (40 mg or more of prednisone daily [or equivalent]).^[1] Nephritis resulted in discontinuance of durvalumab therapy in 0.3% of patients in the combined safety database.^[1] Resolution of nephritis occurred in 50% of patients.^[1]

Renal function should be evaluated prior to initiation of durvalumab therapy and periodically during therapy.^[1] In patients who experience grade 2 elevations in serum creatinine concentrations (elevations exceeding 1.5 times but not more than 3 times the ULN), durvalumab should be temporarily interrupted and systemic corticosteroid therapy should be initiated at a dosage of 1-2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.^[1] In patients who develop grade 3 or 4 elevations in serum creatinine concentrations (elevations exceeding 3 times the ULN), durvalumab should be permanently discontinued and systemic corticosteroid therapy at a dosage of 1-2 mg/kg of prednisone daily (or equivalent) should be initiated followed by tapering of the corticosteroid dosage.^[1] For toxicity not resulting in permanent discontinuance of the drug, durvalumab therapy may be resumed when the adverse reaction resolves to grade 0 or 1 and the corticosteroid dosage is reduced to less than 10 mg of prednisone daily (or equivalent).^[1]

Immune-mediated Dermatologic Effects

Immune-mediated rash (e.g., bullous dermatitis, Stevens-Johnson syndrome/toxic epidermal necrolysis) has occurred in patients receiving durvalumab therapy.^[1]

In the combined safety database, rash or dermatitis occurred in 26% of 1889 patients and 0.4% of patients developed vitiligo.^[1] In addition, 2% of patients required systemic corticosteroid therapy; 1% of patients received high-dose corticosteroid therapy (40 mg or more of prednisone daily [or equivalent]).^[1] Rash or dermatitis resulted in discontinuance of durvalumab therapy in 0.1% of patients in the combined safety database.^[1] Resolution of immune-mediated rash occurred in 62% of patients.^[1]

Patients should be monitored for signs and symptoms of rash.^[1] Temporary interruption or discontinuance of durvalumab may be necessary if immune-mediated dermatologic effects occur during therapy with the drug.^[1] If grade 2 rash that persists more than 1 week or any grade 3 rash occurs, durvalumab should be temporarily interrupted and systemic corticosteroid therapy should be initiated at a dosage of 1-2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.^[1] For toxicity not resulting in permanent discontinuance of the drug, durvalumab therapy may be resumed when the toxicity resolves to grade 0 or 1 and the corticosteroid dosage is reduced to less than 10 mg of prednisone daily (or equivalent).^[1] If grade 4 rash or dermatitis occurs, durvalumab therapy should be permanently discontinued and systemic corticosteroid therapy at a dosage of 1-2 mg/kg of prednisone daily (or equivalent) should be initiated followed by tapering of the corticosteroid dosage.^[1]

Other Immune-mediated Effects

Other immune-mediated adverse effects, including aseptic meningitis, hemolytic anemia, thrombocytopenic purpura, myocarditis, myositis, and ocular inflammatory toxicity (e.g., uveitis, keratitis), have occurred in less than 1% of patients in the combined safety database receiving durvalumab therapy.^[1] Immune-mediated adverse effects may be severe and result in death.^[1] Immune-mediated adverse effects may occur in any organ system and may occur following discontinuance of durvalumab therapy.^[1]

If a grade 2 immune-mediated adverse effect is suspected, adequate evaluation should be performed to exclude other causes and corticosteroid therapy should be initiated as clinically indicated.^[1] In patients who experience such grade 3 immune-mediated toxicity, durvalumab should be temporarily interrupted and initiation of systemic corticosteroid therapy at a dosage of 1-4 mg/kg of prednisone daily (or equivalent) should be considered followed by tapering of the corticosteroid dosage.^[1] For toxicity not resulting in permanent discontinuance of the drug, durvalumab therapy may be resumed when the toxicity resolves to grade 0 or 1 and the corticosteroid dosage is reduced to less than 10 mg of prednisone daily (or equivalent).^[1] In patients who develop grade 4 immune-mediated toxicity, durvalumab should be permanently discontinued and initiation of systemic corticosteroid therapy at a dosage of 1-4 mg/kg of prednisone daily (or equivalent) should be considered followed by tapering of the corticosteroid dosage.^[1]

If uveitis occurs in conjunction with other immune-mediated adverse effects, Vogt-Koyanagi-Harada syndrome should be considered.^[1] Systemic corticosteroid therapy may be required to reduce the risk of permanent vision loss.^[1]

Infectious Complications

Severe infections, sometimes fatal, including sepsis and pneumonia, have occurred in patients receiving durvalumab therapy.^[1]

In the combined safety database, infections occurred in 43% of 1889 patients; grade 3, 4, or 5 infections were reported in 8, 1.9, or 1% of patients, respectively.^[1] In the study evaluating durvalumab in patients with urothelial carcinoma, urinary tract infections were the most common cause of grade 3 or higher infection, occurring in 4% of patients.^[1] In the study evaluating durvalumab in patients with NSCLC, pneumonia was the most common cause of grade 3 or higher infection, occurring in 5% of patients.^[1]

Patients should be monitored for signs and symptoms of infection.^[1] In patients experiencing grade 3 or higher infection, durvalumab should be temporarily interrupted until the patient is clinically stable.^[1]

Infusion-related Reactions

Severe or life-threatening infusion-related reactions have been reported in patients receiving durvalumab therapy.^[1]

In the combined safety database, infusion-related reactions occurred in 2.2% of 1889 patients; grade 3 reactions were reported in 0.3% of patients.^[1]

Patients should be monitored for signs and symptoms of infusion-related reactions.^[1] In patients with grade 1 or 2 infusion-related reactions, durvalumab therapy should be interrupted or the rate of infusion should be decreased; the manufacturer states that use of appropriate premedications (e.g., corticosteroids) should be considered with subsequent infusions.^[1] In patients experiencing grade 3 or 4 infusion-related reactions, durvalumab therapy should be permanently discontinued.^[1]

Fetal/Neonatal Morbidity and Mortality

Durvalumab may cause fetal harm if administered to pregnant women.^[1] Blockade of signaling of the programmed-death receptor-1 (PD-1) and programmed-death ligand-1 (PD-L1) pathway in animals has been shown to disrupt maternal immune tolerance to the fetus and has been associated with increased fetal loss and immune-mediated disorders.^[1] Therefore, inhibition of this pathway by durvalumab may increase the risk of fetal loss (e.g., abortion, stillbirth) or neonatal death.^[1] In cynomolgus monkeys receiving durvalumab (at exposure levels of 6-20 times the human exposure at the recommended dosage), increased premature delivery, fetal loss, and premature neonatal death occurred.^[1] Human immunoglobulin G₁ (IgG₁) has been shown to cross the placenta;^[1] therefore, fetal exposure to durvalumab may occur.^[1]

Pregnancy should be avoided during durvalumab therapy.^[1] Women of childbearing potential should be advised to use an effective method of contraception while receiving durvalumab and for at least 3 months after discontinuance of therapy.^[1] If durvalumab is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.^[1]

Immunogenicity

There is a potential for immunogenicity with durvalumab therapy.^[1] Development of anti-durvalumab antibodies was detected in 45 of 1570 patients (2.9%) receiving durvalumab.^[1] The presence of anti-durvalumab antibodies does not appear to have clinically important effects on the pharmacokinetic profile of the drug.^[1] However, the number of patients with anti-durvalumab antibodies is insufficient to determine whether such antibodies affect efficacy or safety of the drug.^[1]

Specific Populations

Pregnancy

Durvalumab may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.^[1] (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Lactation

It is not known whether durvalumab is distributed into human milk.^[1] Human IgG₁ is distributed into human milk.^[1] Because of the potential for serious adverse reactions to durvalumab in nursing infants, women should be advised to discontinue nursing during durvalumab therapy and for at least 3 months after discontinuance of therapy.^[1]

Pediatric Use

Safety and efficacy of durvalumab have not been established in pediatric patients.^[1]

Geriatric Use

In the study evaluating durvalumab in patients with urothelial carcinoma, 112 of 182 patients (61.5%) were 65 years of age or older and 34 patients (18.7%) were 75 years of age or older.^[1] In these respective age groups, the overall response rates were 15 and 12%.^[1] Grade 3 or 4 adverse reactions occurred in 38% of patients 65 years of age or older and 35% of patients 75 years of age or older.^[1]

In the study evaluating durvalumab in patients with NSCLC, 214 of 476 patients (45%) were 65 years of age or older and 36 patients (7.6%) were 75 years of age or older.^[1] In this study, the number of patients 75 years of age or older was insufficient to determine whether they respond differently than younger adults.^[1]

No overall differences in safety and efficacy were observed between geriatric patients 65 years of age or older and younger adults.^[1]

Hepatic Impairment

Analysis of population pharmacokinetic data indicates that durvalumab clearance in patients with mild hepatic impairment (total bilirubin concentrations not exceeding the ULN with AST concentrations exceeding the ULN, or total bilirubin concentrations greater than 1 to 1.5 times the ULN with any AST concentrations) is similar to that in patients with normal hepatic function.^[1][2] Data are not available for patients with moderate or severe hepatic impairment (total bilirubin concentrations exceeding 1.5 times the ULN with any AST concentrations).^[1]

Renal Impairment

Analysis of population pharmacokinetic data indicates that durvalumab clearance in patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/minute per 1.73 m²) is similar to that in patients with normal renal function.^[1][2] Data are not available for patients with severe renal impairment (creatinine clearance 15-29 mL/minute per 1.73 m²).^[1]

Common Adverse Effects

Adverse effects reported in 10% or more of patients receiving durvalumab for the treatment of urothelial carcinoma include fatigue,^[1][5][6] musculoskeletal pain,^[1] constipation,^[1] decreased appetite/hypophagia,^[1] nausea,^[1] peripheral edema,^[1] urinary tract infection,^[1] abdominal pain,^[1] pyrexia/tumor-associated fever,^[1] diarrhea/colitis,^[1] dyspnea/exertional dyspnea,^[1] rash,^[1] and cough/productive cough.^[1] Grade 3 or 4 laboratory abnormalities reported in 10% or more of patients receiving durvalumab for the treatment of urothelial carcinoma include hyponatremia^[1] and lymphopenia.^[1]

Adverse effects reported in 10% or more of patients receiving durvalumab for the treatment of NSCLC include cough/productive cough,^[1][11] pneumonitis/radiation pneumonitis,^[1][11] fatigue,^[1][11] upper respiratory infections,^[1][11] dyspnea,^[1][11] rash,^[1][11] diarrhea,^[1][11] pneumonia,^[1][11] pyrexia,^[1][11] hypothyroidism,^[1][11] pruritus,^[1][11] and abdominal pain.^[1] Laboratory abnormalities reported in 20% or more of patients receiving durvalumab for the treatment of NSCLC include hyperglycemia,^[1] hypocalcemia,^[1] lymphopenia,^[1] elevated ALT and AST concentrations,^[1] hyponatremia,^[1] hyperkalemia,^[1] and elevated concentrations of γ-glutamyltransferase (GGT).^[1]

No formal drug interaction studies have been performed to date.^[1]

Durvalumab, a recombinant fully human anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody, is an antineoplastic agent.^[1] The drug is an IgG₁ kappa immunoglobulin that binds to PD-L1.^[1]

The immune-checkpoint receptor programmed-death receptor-1 (PD-1) is expressed on activated T cells, B cells, macrophages, and dendritic cells.^[7][8][9] Overexpression of PD-1 ligands on the surface of tumor cells results in activation of PD-1 and CD80 (i.e., B7.1) and suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production.^[1][8] Durvalumab blocks the interaction between PD-L1 and the receptors PD-1 and CD80, resulting in activation of the antitumor immune response without inducing antibody-dependent cell-mediated cytotoxicity (ADCC).^[1][8][10] The drug also has been shown to reduce tumor growth in mouse tumor models.^[1][9]

Systemic exposure of durvalumab is dose proportional over the dosage range of 3-20 mg/kg.^[1] Following repeated doses of durvalumab every 2, 3, or 4 weeks, steady-state concentrations are reached by approximately 16 weeks.^[1] The mean terminal half-life of durvalumab is approximately 18 days.^[1]

Pharmacokinetics of durvalumab do not appear to be affected by age (range of 19-96 years), body weight (34-149 kg), gender, race, albumin concentrations, LDH concentrations, creatinine concentrations, PD-L1 expression, or ECOG performance status.^[1]

Importance of advising patients to read the manufacturer's medication guide.^[1]

Risk of immune-mediated pneumonitis.^[1] Importance of informing clinician immediately if new or worsening cough, chest pain, or shortness of breath occurs.^[1]

Risk of immune-mediated hepatitis.^[1] Importance of informing clinician immediately if signs and symptoms of liver damage (e.g., jaundice, severe nausea or vomiting, abdominal pain [particularly in the right upper quadrant], lethargy, easy bruising or bleeding) occur.^[1]

Risk of immune-mediated colitis.^[1] Importance of informing clinician immediately if diarrhea, severe abdominal pain, or changes in stool occur.^[1]

Risk of immune-mediated endocrine effects.^[1] Importance of informing clinician immediately if manifestations of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or type 1 diabetes mellitus occur.^[1]

Risk of immune-mediated nephritis.^[1] Importance of informing clinician immediately if signs or symptoms of nephritis occur.^[1]

Risk of immune-mediated dermatologic effects.^[1] Importance of informing clinician immediately if signs or symptoms of severe dermatologic reactions occur.^[1]

Risk of other immune-mediated adverse effects.^[1] Importance of informing clinician immediately if manifestations of aseptic meningitis, thrombocytopenic purpura, myocarditis, hemolytic anemia, myositis, uveitis, or keratitis occur.^[1]

Risk of infections.^[1] Importance of informing clinician if fever, flu-like symptoms, cough, or painful or frequent urination occurs.^[1]

Risk of infusion-related reactions.^[1] Importance of informing clinician if signs and symptoms of such reactions, including dizziness, chills, fever, breathing difficulty (e.g., shortness of breath, wheezing), pruritus, flushing, feeling of faintness, back or neck pain, and angioedema, occur.^[1]

Risk of fetal harm.^[1] Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving the drug and for at least 3 months after discontinuance of therapy.^[1] Importance of women informing clinicians if they are or plan to become pregnant.^[1] If pregnancy occurs, advise pregnant women of potential risk to the fetus.^[1]

Importance of advising women to avoid breast-feeding while receiving the drug and for at least 3 months after discontinuance of therapy.^[1]

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., autoimmune disorders, history of organ transplantation, liver damage, pulmonary disorders).^[1]

Importance of informing patients of other important precautionary information.^[1] (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of durvalumab is restricted.^[3] (See Restricted Distribution under Dosage and Administration: General.)

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