FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia.

On August 3, 2017, the FDA granted regular approval to Vyxeos (also known as CPX-351; Jazz Pharmaceuticals), a liposomal formulation of daunorubicin and cytarabine in a fixed combination, for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC). Approval was based on data from Study CLTR0310-301, a randomized, multicenter, open-label, active-controlled trial comparing Vyxeos with a standard combination of daunorubicin and cytarabine ("7+3") in 309 patients 60-75 years of age with newly diagnosed t-AML or AML-MRC. Because of elemental copper concerns with the Vyxeos formulation, patients with Wilson disease were excluded from the study. Vyxeos demonstrated an improvement in overall survival (HR 0.69; 95% confidence interval, 0.52-0.90; P = 0.005) with an estimated median overall survival of 9.6 months compared with 5.9 months for the "7+3" control arm. The toxicity profile of Vyxeos was similar to that seen with standard "7+3" with the exception of more prolonged neutropenia and thrombocytopenia on the Vyxeos arm. Because the pharmacology of Vyxeos differs from that of other formulations of daunorubicin and cytarabine, labeling includes a warning against interchanging formulations during treatment. This is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC.

FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib.

On December 11, 2015, the FDA granted accelerated approval to alectinib (Alecensa; Genentech) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by an independent review committee in these studies were 38% [95% confidence interval (CI), 28-49] and 44% (95% CI, 36-53); the median durations of response (DOR) were 7.5 months and 11.2 months. In a pooled analysis of 51 patients with measurable disease in the central nervous system (CNS) at baseline, the CNS ORR was 61% (95% CI, 46-74); the CNS DOR was 9.1 months. The primary safety analysis population included 253 patients. The most common adverse reactions were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common laboratory abnormalities were anemia (56%), increased aspartate aminotransferase (51%), increased alkaline phosphatase (47%), increased creatine phosphokinase (43%), hyperbilirubinemia (39%), hyperglycemia (36%), increased alanine aminotransferase (34%), and hypocalcemia (32%). Dose reductions due to adverse reactions occurred in 12% of patients, whereas 27% of patients had alectinib dosing interrupted for adverse reactions. Permanent discontinuation of alectinib due to adverse reactions occurred in only 6% of patients. With the clinically meaningful ORR and DOR as well as the safety profile observed in these trials, alectinib was determined to have a favorable benefit-risk profile for the treatment of the indicated population. Clin Cancer Res; 22(21); 5171-6. ©2016 AACR.

Improving pediatric dosing through pediatric initiatives: what we have learned.

OBJECTIVE: The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling. METHODS: We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing. RESULTS: The first 108 drugs with new or revised pediatric labeling changes had dosing changes or pharmacokinetic information (n = 23), new safety information (n = 34), information concerning lack of efficacy (n = 19), new pediatric formulations (n = 12), and extended age limits (n = 77). A product might have had > or = 1 labeling change. We selected specific examples (n = 16) that illustrate significant differences in pediatric pharmacokinetics. CONCLUSIONS: Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.