miércoles, 29 de marzo de 2017

FDA Approves BAVENCIO® (Avelumab) for Treatment of Adults and Pediatric Patients 12 Years and Older with Metastatic Merkel Cell Carcinoma (MCC)

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FDA Approves BAVENCIO® (Avelumab) for Treatment of Adults and Pediatric Patients 12 Years and Older with Metastatic Merkel Cell Carcinoma (MCC)

On March 23, 2017, the U.S. Food and Drug Administration (FDA) approved BAVENCIO (avelumab) for treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The approved recommended dosage of BAVENCIO is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Because BAVENCIO can cause severe or life-threatening infusion-related reactions, premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions of BAVENCIO and subsequently as needed based upon clinical judgment and presence/severity of prior infusion reactions. 
BAVENCIO can result in severe immune-mediated adverse reactions, including but not limited to pneumonitis including fatal cases, hepatitis including fatal cases, colitis, endocrinopathies, nephritis and renal dysfunction. BAVENCIO should be withheld for moderate or permanently discontinued for severe or life-threatening immune-mediated adverse events. Detailed information regarding clinical and laboratory monitoring guidelines for early detection of adverse reactions of BAVENCIO and recommended management are described in the full prescribing information (link below).
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
MOA:  BAVENCIO is a programmed death ligand 1 (PD-L1) blocking antibody.
Dose Proportionality:  Exposure of avelumab increased dose-proportionally in the dose range of 10 mg/kg to 20 mg/kg (2 times the approved recommended dosage) every 2 weeks.
Terminal Half-Life:  6.1 days in patients receiving 10 mg/kg.
Elimination:  The primary elimination mechanism of avelumab is proteolytic degradation. Avelumab clearance was found to decrease over time in patients with MCC, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline value of approximately 41.7% (40%).
Use in Specific Populations
Body weight was positively correlated with the total systemic clearance of avelumab.
No clinically meaningful differences in the clearance of avelumab were observed in patients with MCC based on age, sex, race, PD-L1 status, tumor burden, mild (calculated creatinine clearance (CLcr) 60-89 mL/min, as estimated by the Cockcroft-Gault (C-G) formula), moderate (CLcr 30 to 59 mL/min, C-G); or severe (15 to 29 ml/min, C-G) renal impairment and mild (bilirubin ≤ upper limit of normal (ULN) and AST > ULN or bilirubin between 1 and 1.5 times ULN) or moderate (bilirubin between 1.5 and 3 times ULN) hepatic impairment.
There are limited data from patients with severe hepatic impairment (bilirubin > 3 times ULN), and the effect of severe hepatic impairment on the pharmacokinetics of avelumab is unknown.
Safety and Efficacy
BAVENCIO was studied in an open-label, single arm, multi-center study (n=88) conducted in patients with histologically confirmed metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease. Patients received BAVENCIO 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. The major efficacy outcome measures were confirmed objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as measured by blinded independent central review and duration of response (DOR). The ORR, n (%), was 29 (33.0%) (95% CI: 23.3, 43.8) and DOR ≥ 12 months, n (%), was 13 (45%).
Serious adverse reactions that occurred in more than one patient were acute kidney injury, anemia, abdominal pain, ileus, asthenia, and cellulitis. The most common adverse reactions (≥ 20%) were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema.

Full prescribing information is available at https://go.usa.gov/xX9BH.
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).
The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the website http://go.usa.gov/cMsjT.
We always welcome your thoughts regarding the format, content, and utility of the information you receive via this Burst email initiative. Comments may be sent via email to ocp@fda.hhs.gov.
This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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

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