Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. METHODS: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. FINDINGS: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. INTERPRETATION: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. FUNDING: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

Efficacy and safety of weekly nab-paclitaxel plus gemcitabine in Chinese patients with metastatic adenocarcinoma of the pancreas: a phase II study.

BACKGROUND: This phase II bridging study assessed the safety and efficacy of nab-paclitaxel/gemcitabine (Metastatic Pancreatic Adenocarcinoma Clinical Trial [MPACT] regimen) in Chinese patients with metastatic pancreatic cancer (MPC). METHODS: This 3-part sequential study evaluated nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. Part 1 evaluated safety. Part 2 evaluated efficacy using Simon's optimal 2-stage design: if >2 responses were observed in Stage 1 (n = 28), 54 additional patients would be enrolled in Stage 2. If >9 responses were observed, the study was complete. Otherwise, nab-paclitaxel/gemcitabine would be compared with gemcitabine alone in Part 3. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR), overall survival (OS), and safety. RESULTS: Eighty-three patients were treated. The prespecified primary endpoint was met: the independently assessed ORR in Stages 1 + 2 was 35% (95% CI, 24.8-46.2); therefore, Part 3 was not initiated. The median DOR was 8.9 months (95% CI, 6.01-8.94). The median OS and progression-free survival were 9.2 (95% CI, 7.6-11.1) and 5.5 (95% CI, 5.29-7.16) months, respectively. The 12-month OS rate was 30%. In an updated analysis, the median OS was 9.3 months and the 12-month OS rate was 32%. Longer OS was observed in patients with baseline neutrophil-to-lymphocyte ratio ≤ 5 vs > 5. The most common grade ≥ 3 adverse events were leukopenia (35%), neutropenia (34%), anemia (15%), thrombocytopenia (10%), and fatigue (13%). Grade 3 peripheral neuropathy occurred in 7% of patients (no grade 4 reported). CONCLUSIONS: The MPACT regimen of nab-paclitaxel/gemcitabine is efficacious in Chinese patients with MPC. No new safety signals were observed. TRIAL REGISTRATION: NCT02135822 , May 8, 2014.

Daptomycin pharmacodynamics against Staphylococcus aureus hemB mutants displaying the small colony variant phenotype.

OBJECTIVES: Staphylococcus aureus small colony variants (SCVs) are slow-growing morphological variants associated with persistent infections. While vancomycin activity has been shown to be attenuated against SCVs of S. aureus, few data exist regarding daptomycin. The objective was to evaluate the pharmacodynamics of daptomycin against defined S. aureus mutants displaying the SCV phenotype. METHODS: Two S. aureus hemB mutants (Ia48 and III33) displaying the SCV phenotype and their parental strains (COL and Newman) were evaluated. Time-kill experiments were performed using a starting inoculum of 10(6) cfu/mL at 0, 0.25, 0.5, 1, 2, 4, 8, 16, 32 and 64 times the MIC. Samples were obtained at 0, 1, 2, 4, 6, 8 and 24 h, plated and incubated to determine colony counts. A Hill-type pharmacodynamic mathematical model was fitted to the data to characterize the effect. RESULTS: Bactericidal activity for daptomycin was achieved and occurred in a concentration-dependent manner against both hemB mutants and their parental strains. Against strains with normal phenotype, bactericidal activity was achieved rapidly, within 2 h at concentrations > or =16 times the MIC, while against SCVs, bactericidal activity was achieved within 6 h at concentrations > or =16 times the MIC. Against both hemB mutants, daptomycin maintained bactericidal activity at 24 h, with similar profiles of killing activity when compared with their parental strains. CONCLUSIONS: Daptomycin achieved bactericidal activity against S. aureus hemB mutants and parenteral isolates. Daptomycin represents a potential therapeutic option for infections caused by S. aureus strains displaying the SCV phenotype and additional studies are warranted.