In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On May 1, 2017, durvalumab (Imfinzi) was granted accelerated approval for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.^1,2 The VENTANA programmed cell death ligand 1 (PD-L1; SP263) assay was concurrently approved as a complementary diagnostic for assessing PD-L1 protein in formalin-fixed, paraffin-embedded urothelial carcinoma tissue.

Supporting Efficacy Data

Approval was based on durable responses in a single-arm trial in which 182 patients with locally advanced or metastatic disease received intravenous durvalumab at 10 mg/kg every 2 weeks for up to 12 months or until unacceptable toxicity or disease progression. The trial excluded patients with a history of immunodeficiency, medical conditions requiring systemic immunosuppression (≥ 10 mg/d of prednisone or equivalent), a history of severe autoimmune disease, and untreated central nervous system (CNS) metastases.

Patients had a median age of 67 years (range = 34–88 years); 72% were male; 64% were white; 66% had visceral metastasis including 34% with liver metastasis and 13% had lymph node–only metastasis; 41% had baseline creatinine clearance of < 60 mL/min; Bellmunt risk score was 0 in 23%, one in 38%, two in 29%, and three in 9% of patients. A total of 20% had disease progression following platinum-containing neoadjuvant or adjuvant chemotherapy as their only prior line of therapy, 70% had received prior cisplatin, 30% had received prior carboplatin, and 35% received at least two prior lines of systemic therapy.

Confirmed objective response on blinded independent central review using Response Evaluation Criteria in Solid Tumors (1.1) was observed in 31 patients (17.0%, 95% confidence interval [CI] = 11.9%–23.3%), with a complete response in 5. At data cutoff, the median response duration had not been reached (range = 0.9+ to 19.9+ months). Among 168 patients with available PD-L1 expression data, response rates were 26.3% (95% CI = 17.8%–36.4%) in 95 with a high PD-L1 score (if immune cells involved > 1% of tumor area, tumor cells ≥ 25% or immune cells ≥ 25%; if immune cells involved ≤ 1% of the tumor area, tumor cells ≥ 25% or immune cells = 100%) and 4.1% (95% CI = 0.9%–11.5%) in 73 with low/negative score (did not meet criteria for high PD-L1). The median duration of response was not reached in the PD-L1–high group and was 12.3 months in the PD-L1 –ow/negative group.

How It Works

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of PD-L1 with programmed cell death protein 1 (PD-1) and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases inhibition of immune responses, without inducing antibody-dependent cell-mediated cytotoxicity. Expression of PD-L1 can be induced by inflammatory signals (eg, interferon-gamma), with the ligand expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). Through binding to its receptors, PD-L1 reduces cytotoxic T-cell activity and proliferation and cytokine production.

How It Is Used

The recommended dose of durvalumab is 10 mg/kg via infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. No dose reductions are recommended.

Durvalumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions, with consideration of premedication for subsequent doses. Treatment should be discontinued for grade 3 or 4 reactions.

Management of other adverse events includes withholding doses or discontinuing treatment and initiation of corticosteroid treatment. Withholding of durvalumab and use of corticosteroid treatment is recommended for grade 2 pneumonitis, grade 2 alanine transaminase (ALT) or aspartate transaminase (AST) elevation to > 3 to 5 times the upper limit of normal (ULN) or total bilirubin > 1.5 to 3 times ULN or grade 3 ALT/AST elevation to ≤ 8 time ULN or total bilirubin ≤ 5 time ULN, grade 2 colitis or diarrhea, grade 2 creatinine elevation to > 1.5 to 3 times ULN, and grade 2 rash/dermatitis for > 1 weeks or grade 3 rash/dermatitis.

Withholding of doses until clinical stability is achieved is recommended for grades 2–4 hyperthyroidism, adrenal insufficiency or hypophysitis/hypopituitarism, and type 1 diabetes; and withholding of dose and symptomatic management is recommend for grade 3 adverse events of other types. For grade 2–4 hypothyroidism, thyroid hormone replacement is recommended as clinically indicated.

Permanent discontinuation of durvalumab and use of corticosteroid treatment is recommended for grade 3 or 4 pneumonitis, grade 3 ALT/AST > 8 times ULN or total bilirubin > 5 times ULN or concurrent ALT/AST > 3 times ULN and total bilirubin > 2 times ULN with no other cause, grade 3 or 4 diarrhea or colitis, grade 3 creatinine elevation > 3 to 6 times ULN, grade 4 rash/dermatitis, and grade 4 adverse events of other types.

Recommended initial doses of prednisone or equivalent are 1 to 4 mg/kg/d for grade 3 or 4 pneumonitis and for grade 4 adverse events of other types and 1 to 2 mg/kg/d for grade 2 pneumonitis, hepatitis, colitis or diarrhea, adrenal insufficiency or hypophysitis/hypopituitarism, nephritis, and rash dermatitis. Corticosteroid taper should be initiated when the adverse event improves to grade ≤ 1 and continued for 1 months. For adverse events that do not result in treatment discontinuation, treatment can be resumed when the adverse reaction returns to ≤ grade 1 and the corticosteroid dose has been reduced to < 10 mg prednisone or equivalent per day.

Safety Profile

The most common adverse events of any grade in the single-arm study were fatigue (39%), musculoskeletal pain (24%), and constipation (21%). Grade 3 or 4 adverse events were seen in 43% of patients, with the most common being fatigue (6%), musculoskeletal pain (4%), and urinary tract infection (4%). The most common grade 3 or 4 laboratory abnormalities were hyponatremia (12%), lymphopenia (11%), and anemia (8%).

Serious adverse events occurred in 46% of patients, with the most common being acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), and liver injury (3.3%). Immune-mediated adverse events requiring systemic corticosteroids (5.5%) or hormone replacement therapy (2.7%) occurred in 8.2% of patients. An oral prednisone dose equivalent to ≥ 40 mg daily was required in 3.8% of patients for an immune-mediated adverse reaction.

Adverse events led to treatment interruption or delay in 31%, with the most common causes being liver injury (4.9%), urinary tract infection (3.3%), and acute kidney injury (3.3%), and to treatment discontinuation in 3.3%. Adverse events led to death in eight patients (4.4%), due to cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis; three additional patients were experiencing infection and disease progression at the time of death.

Durvalumab carries warnings/precautions for immune-mediated pneumonitis, immune-mediated hepatitis, immune-mediated colitis, immune-mediated endocrinopathies (including adrenal insufficiency, hypophysitis, or type 1 diabetes), immune-mediated nephritis, infection, infusion-related reactions, and embryofetal toxicity. Patients receiving treatment with durvalumab should be monitored for liver function, renal function, thyroid function, adrenal insufficiency, and signs/symptoms of type 1 diabetes. ■

REFERENCES

1. U.S. Food and Drug Administration: Durvalumab (Imfinzi). Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555930.htm. Accessed September 18, 2017.

2. Imfinzi (durvalumab) injection prescribing information, AstraZeneca, May 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf. Accessed September 18. 2017.