Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial.

Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB-IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58-0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30-0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8+ density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB-IVM1a melanoma.

Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis.

UNLABELLED: Network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and mixed treatment comparison [MTC]) allow for treatment comparisons in the absence of head-to-head trials. In this study, conditional estimates of relative treatment efficacy derived through these techniques show important differences in the fracture risk reduction profiles of marketed pharmacologic therapies for postmenopausal osteoporosis. INTRODUCTION: This study illustrates how network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and MTC) can provide comparisons of the relative efficacy of postmenopausal osteoporosis therapies in the absence of comprehensive head-to-head trials. METHODS: Source articles were identified in MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL) via Wiley Interscience; and Cumulative Index to Nursing and Allied Health Literature (CINAHL) between April 28, 2009 and November 4, 2009. Two reviewers identified English-language articles reporting randomized controlled trials (RCTs) with on-label dosing of marketed osteoporosis agents and fracture endpoints. Trial design, population characteristics, intervention and comparator, fracture outcomes, and adverse events were abstracted for analysis. Primary analyses included data from RCTs with fracture endpoints. Sensitivity analyses also included studies with fractures reported through adverse event reports. Meta-analysis compared fracture outcomes for pharmacological therapies vs. placebo (fixed and random effects models); adjusted indirect comparisons and MTC assessed fracture risk in postmenopausal women treated with denosumab vs. other agents. RESULTS: Using data from 34 studies, random effects meta-analysis showed that all agents except etidronate significantly reduced the risk of new vertebral fractures compared with placebo; denosumab, risedronate, and zoledronic acid significantly reduced the risk for nonvertebral and hip fracture, while alendronate, strontium ranelate, and teriparatide significantly reduced the risk for nonvertebral fractures. MTC showed denosumab to be more effective than strontium ranelate, raloxifene, alendronate, and risedronate in preventing new vertebral fractures. CONCLUSIONS: The conditional estimates of relative treatment efficacy indicate that there are important differences in fracture risk reduction profiles for marketed pharmacological therapies for postmenopausal osteoporosis.