Early in 2018, durvalumab (Imfinzi) was approved for the treatment of unresectable stage III non–small cell lung cancer (NSCLC) that has not progressed following concurrent platinum-based chemotherapy and radiation therapy.^1,2

Supporting Efficacy Data

Approval was based on a planned interim analysis of progression-free survival from the double-blind phase III PACIFIC trial, in which 713 patients with unresectable stage III disease who had completed concurrent platinum-based chemotherapy and radiation therapy within 42 days prior to study drug initiation were randomized 2:1 to receive intravenous (IV) durvalumab at 10 mg/kg (n = 476) or IV placebo (n = 237) every 2 weeks for up to 12 months or until disease progression or unacceptable toxicity.^2,3 Randomization was stratified by sex, age, and smoking history.

Patients had to have a World Health Organization performance status of 0 or 1 (51%). Patients had a median age of 64 years; 70% were male; 69% were white and 27% were Asian; 16% were current smokers, 75% were former smokers, and 9% were never smokers; 53% had stage IIIA disease and 45% had stage IIIB disease; and 46% had squamous histology and 54% had nonsquamous histology.

At interim analysis (approximately 81% of planned events for final analysis), median progression-free survival was 16.8 months in the durvalumab group vs 5.6 months in the placebo group (hazard ratio = 0.52, P < .00010). Overall survival data were immature at the time of analysis. Overall response rates were 26% vs 14%.

How It Works

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (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, 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. PD-L1 blockade with durvalumab increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.

How It Is Used

The recommended dose of durvalumab in the NSCLC indication is 10 mg/kg via infusion over 60 minutes every 2 weeks until disease progression, unacceptable toxicity, or a maximum of 12 months. No dose reductions are recommended.

Durvalumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and discontinued for grade 3 or 4 reactions. Guidelines for dose modification for other adverse reactions follow:

• The dose should be withheld until the reaction decreases to grade 1 or resolves and the corticosteroid dose is ≤ prednisone at 10 mg/d (or equivalent) for the following conditions: grade 2 pneumonitis; hepatitis with alanine transaminase (ALT) or aspartate transaminase (AST) > 3 but ≤ 8 times the upper limit of normal (ULN) or total bilirubin > 1.5 but ≤ 5 times ULN; grade 2 colitis or diarrhea; nephritis with creatinine > 1.5 to 3 times ULN; rash or dermatitis of grade 2 for > 1 week or of grade 3; or other grade 3 immune-related adverse reactions.
• The dose should be withheld until clinical stability is achieved for the following conditions: grade 2 to 4 hyperthyroidism; grade 2 to 4 adrenal insufficiency or hypophysitis/hypopituitarism; grade 2 to 4 type 1 diabetes mellitus; and grade 3 or 4 infection.
• The dose should be permanently discontinued for the following conditions: grade 3 or 4 pneumonitis; hepatitis with ALT or AST > 8 times ULN or total bilirubin > 5 times ULN or concurrent ALT or AST > 3 times ULN and total bilirubin > 2 times ULN with no other cause; grade 3 or 4 colitis or diarrhea; nephritis with creatinine > 3 times ULN; grade 4 rash or dermatitis; other grade 4 immune-related adverse events; persistent grade 2 or 3 adverse reactions (excluding endocrinopathies); inability to taper corticosteroids; and recurrent grade 3 or 4 adverse reactions.

Safety Profile

The most common adverse events of any grade in the durvalumab group in the PACIFIC trial were cough (40% vs 30% in placebo group), fatigue (34% vs 32%), pneumonitis/radiation pneumonitis (34% vs 25%), upper respiratory tract infections (26% vs 19%), dyspnea (25% vs 25%), and rash (23% vs 12%). The most common grade 3 or 4 adverse events in the durvalumab group were pneumonia and pneumonitis/radiation pneumonitis. Serious adverse events occurred in 29% of the durvalumab group, with the most common being pneumonitis/radiation pneumonitis

and pneumonia. Adverse events led to discontinuation of durvalumab in 15% of patients, with the most common cause being pneumonitis/radiation pneumonitis (6%). Fatal pneumonitis/radiation pneumonitis and fatal pneumonia occurred in < 2% of patients, with the incidence being similar in both groups.

Durvalumab carries warnings/precautions for immune-mediated pneumonitis, hepatitis, colitis, endocrinopathies, nephritis, and dermatologic reactions; infection; infusion-related reactions; and embryofetal toxicity. Patients should be monitored for changes in liver and renal function. Patients should be advised not to breastfeed while receiving durvalumab. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm597248.htm. Accessed July 23, 2018.

2. Imfinzi (durvalumab) injection prescribing information, AstraZeneca, February 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761069s002lbl.pdf. July 23, 2018.

3. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919-1929, 2017.