Clinical Pharmacology Corner: FDA Approves IMFINZI (Durvalumab)

FDA Approves IMFINZI™ (Durvalumab) 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 Treatment with Platinum-Containing Chemotherapy

On May 1, 2017, the U.S. Food and Drug Administration granted accelerated approval to IMFINZI (durvalumab) 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 treatment with platinum-containing chemotherapy. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The approved recommended dose of IMFINZI is 10 mg/kg, administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

IMFINZI can result in severe and life-threatening immune-mediated adverse reactions, including pneumonitis, hepatitis, colitis, and endocrinopathies. Fatal immune-mediated pneumonitis and hepatitis were reported in clinical trials. IMFINZI should be withheld for moderate, or permanently discontinued for severe or life-threatening immune-mediated adverse reactions. Detailed clinical and laboratory monitoring guidelines for early detection of adverse reactions of IMFINZI and recommended management are described in the full prescribing information (link below).

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)

• MOA: Durvalumab is a programmed death-ligand 1 (PD-L1) blocking monoclonal antibody. 
• Dose Proportionality: Durvalumab demonstrated dose-proportional increases in exposure at doses ≥ 3 mg/kg (0.3 times the approved recommended dosage). 
• Distribution: The geometric mean (% coefficient of variation [CV%]) steady-state volume of distribution was 5.6 L (17%).
• Half-Life: The geometric mean (CV%) half-life was approximately 17 days (23.2%). Time to reach steady-state concentrations was 16 weeks.
• Elimination: Durvalumab steady state clearance decreased over time in patients who received varied dosing regimens that included the approved recommended dosage; the decrease was not considered clinically significant.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Of evaluable patients, 3.3% (37 of 1124) tested positive for anti-drug antibodies (ADA). The presence of ADAs did not have a clinically important effect on PK, but their impact on safety or efficacy is unknown.

Use in Specific Populations

The following factors have no clinically significant effect on durvalumab PK: body weight (34-149 kg), serum albumin, sex, ECOG performance status, soluble PD-L1 level, tumor type, age (19-96 years), race, mild to moderate renal impairment (CLcr ≥ 30 mL/min to 89 mL/min), and mild hepatic impairment (bilirubin ≤ upper limit of normal (ULN) and aspartate transaminase (AST) > ULN or bilirubin > 1.0 to 1.5 times ULN and any AST). The effect of severe renal impairment (CLcr 15 to 29 mL/min) or moderate to severe hepatic impairment (bilirubin > 1.5 times ULN and any AST) on the PK of durvalumab is unknown.

Efficacy and Safety

Approval was based on one single-arm trial of 182 patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after prior platinum-containing chemotherapy. Durvalumab, 10 mg/kg intravenously, was administered every 2 weeks. Confirmed objective response rate (ORR) as assessed by blinded independent central review per RECIST 1.1, was 17.0% (95% CI: 11.9, 23.3). At the data cutoff for the ORR analysis, median response duration was not reached (range: 0.9+ to 19.9+ months). ORR was also analyzed by PD-L1 expression status as measured by the VENTANA PD-L1 (SP263) Assay. In the 182 patients, the confirmed ORR was 26.3% (95% CI: 17.8, 36.4) in 95 patients with a high PD-L1 score and 4.1% (95% CI: 0.9, 11.5) in 73 patients with a low or negative PD-L1 score. The most common adverse reactions in at least 15% of patients were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. The most frequent serious (Grade 3 or 4) adverse reactions (> 2%) were acute kidney injury, urinary tract infection, musculoskeletal pain, liver injury, general physical health deterioration, sepsis, abdominal pain, and pyrexia/tumor associated fever.

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Full prescribing information is available at https://go.usa.gov/x5pwe.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

We always welcome your thoughts regarding the format, content, and utility of the communication. Comments may be sent via email to ocp@fda.hhs.gov.

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov