In this randomized phase 3 trial, ceftazidime-avibactam plus metronidazole was noninferior to meropenem in treating complicated intra-abdominal infection, with similar efficacy against ceftazidime-resistant and ceftazidime-susceptible pathogens and no new safety concerns observed.

In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. Patients and methods: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo 12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (KaplaneMeier-estimated medians). Results: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n ¼ 473) or placebo (n ¼ 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC !25%, <25%, !1%, <1%, and 1%e24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC !25% (0.41, 0.26e0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43e0.82; 16.9 versus 6.9 months), !1% (0.46, 0.33e0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48e1.11; 10.7 versus 5.6 months), 1%e24% [0.49, 0.30e0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42 e0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ! 25% (0.50, 0.30e0.83; NR versus 21.1 months), <25% (0.89, 0.63e1.25; 39.7 versus 37.4 months), !1% (0.59, 0.41e0.83; NR versus 29.6 months), 1%e24% (0.67, 0.41e1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43e0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71e1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. Conclusions: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for AVYCAZ (ceftazidime-avibactam) Injection.

Ceftazidime/avibactam demonstrated similar clinical efficacy to predominantly carbapenem comparators against MDR Enterobacteriaceae and P. aeruginosa, and may be a suitable alternative to carbapenem-based therapies for cIAI, cUTI and NP/VAP caused by MDR Gram-negative pathogens.

Background: Ceftazidime-avibactam plus metronidazole is effective in the treatment of complicated intra-abdominal infection (cIAI) in adults. This single-blind, randomized, multicenter, phase 2 study (NCT02475733) evaluated the safety, efficacy and pharmacokinetics of ceftazidime-avibactam plus metronidazole in children with cIAI. Methods: Hospitalized children (≥3 months to <18 years) with cIAI were randomized 3:1 to receive intravenous ceftazidime-avibactam plus metronidazole, or meropenem, for a minimum of 72 hours (9 doses), with optional switch to oral therapy thereafter for a total treatment duration of 7–15 days. Safety and tolerability were assessed throughout the study, along with clinical and microbiologic outcomes, and pharmacokinetics. A blinded observer determined adverse event (AE) causality, and clinical outcomes up to the late follow-up visit. Results: Eighty-three children were randomized and received study drug (61 ceftazidime-avibactam plus metronidazole and 22 meropenem); most (90.4%) had a diagnosis of appendicitis. Predominant Gram-negative baseline pathogens were Escherichia coli (79.7%) and Pseudomonas aeruginosa (33.3%); 2 E. coli isolates were ceftazidime-non-susceptible. AEs occurred in 52.5% and 59.1% of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. Serious AEs occurred in 8.2% and 4.5% of patients, respectively; none was considered drug related. No deaths occurred. Favorable clinical/microbiologic responses were observed in ≥90% of patients in both treatment groups at end-of-intravenous treatment and test-of-cure visits. Conclusions: Ceftazidime-avibactam plus metronidazole was well tolerated, with a safety profile similar to ceftazidime alone, and appeared effective in pediatric patients with cIAI due to Gram-negative pathogens, including ceftazidime-non-susceptible strains.