Background Talimogene laherparepvec is an oncolytic immunotherapy approved in the US, Europe, Australia and Switzerland. We report the final planned analysis of OPTiM, a randomized open-label phase III trial in patients with unresectable stage IIIB–IVM1c melanoma. Methods Patients were randomized 2:1 to receive intratumoral talimogene laherparepvec or subcutaneous recombinant GM-CSF. In addition to overall survival (OS), durable response rate (DRR), objective response rate (ORR), complete responses (CR), and safety are also reported. All final analyses are considered to be descriptive and treatment responses were assessed by the investigators. Results Of 436 patients in the intent-to-treat population, 295 were allocated to talimogene laherparepvec and 141 to GM-CSF. Median follow-up in the final OS analysis was 49 months. Median OS was 23.3 months (95% confidence interval [CI], 19.5–29.6) and 18.9 months (95% CI, 16.0–23.7) in the talimogene laherparepvec and GM-CSF arms, respectively (unstratified hazard ratio, 0.79; 95% CI, 0.62–1.00; p = 0.0494 [descriptive]). DRR was 19.0 and 1.4% (unadjusted odds ratio, 16.6; 95% CI, 4.0–69.2; p < 0.0001); ORR was 31.5 and 6.4%. Fifty (16.9%) and 1 (0.7%) patient in the talimogene laherparepvec and GM-CSF arms, respectively, achieved CR. In talimogene laherparepvec-treated patients, median time to CR was 8.6 months; median CR duration was not reached. Among patients with a CR, 88.5% were estimated to survive at a 5-year landmark analysis. Talimogene laherparepvec efficacy was more pronounced in stage IIIB–IVM1a melanoma as already described in the primary analysis. The safety reporting was consistent with the primary OPTiM analysis. Conclusions In this final planned OPTiM analysis, talimogene laherparepvec continued to result in improved longer-term efficacy versus GM-CSF and remained well tolerated. The final analysis also confirms that talimogene laherparepvec was associated with durable CRs that were associated with prolonged survival. Trial registration ClinicalTrials.gov identifier: NCT00769704 . Electronic supplementary material The online version of this article (10.1186/s40425-019-0623-z) contains supplementary material, which is available to authorized users.

Background: Primary and recurrent giant cell tumor of bone is typically benign; however, rarely giant cell tumor of bone can undergo malignant transformation. Malignancy in giant cell tumor of bone may be primary (adjacent to benign giant cell tumor of bone at first diagnosis) or secondary (at the site of previously treated giant cell tumor of bone). Malignant giant cell tumor of bone has a poor prognosis; it is important to distinguish malignant from benign lesions to facilitate appropriate management. The true incidence of malignant giant cell tumor of bone is not known, probably owing to inaccurate diagnosis and inconsistent nomenclature. We have analyzed current data to provide a robust estimate of the incidence of malignancy in giant cell tumor of bone. Methods: A literature search was performed to source published reports of primary and secondary cases of malignant giant cell tumor of bone. Studies that reported a denominator were used to estimate the incidence of malignancy. Results: We identified 4 large series of patients with malignant giant cell tumor of bone that provided data on 2315 patients with giant cell tumor of bone. Across these studies, the cumulative incidence of malignancy was 4.0%; the cumulative incidence of primary malignancy was 1.6% compared with 2.4% for secondary malignancy. Our analyses confirmed that most malignant giant cell tumor of bone is secondary and occurs following radiation. In addition, data from 8 small series showed that 4.8% of patients with giant cell tumor of bone who received radiation therapy developed secondary malignancy. Conclusions: Malignant giant cell tumor of bone is rare, and its identification is hindered by a lack of clear diagnostic criteria. For optimal care of patients with giant cell tumor of bone, we recommend: comprehensive histologic sampling to ensure accurate diagnoses; watchful follow-up, particularly for patients treated with radiation; and timely treatment of local recurrence.

ObjectivesTalimogene laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial (NCT00769704), talimogene laherparepvec significantly improved durable response rate (DRR) versus granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 patients with unresectable stage IIIB–IVM1c melanoma. The median overall survival (OS) was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB–IVM1a). Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB–IVM1a disease.Patients and methodsThe patients were randomized (2:1 ratio) to intralesional talimogene laherparepvec or subcutaneous GM-CSF and were evaluated for DRR, overall response rate (ORR), OS, safety, benefit–risk and numbers needed to treat. Descriptive statistics were used for subgroup comparisons.ResultsAmong 249 evaluated patients with stage IIIB–IVM1a melanoma, DRR was higher with talimogene laherparepvec compared with GM-CSF (25.2% versus 1.2%; P<0.0001). ORR was also higher in the talimogene laherparepvec arm (40.5% versus 2.3%; P<0.0001), and 27 patients in the talimogene laherparepvec arm had a complete response, compared with none in GM-CSF-treated patients. The incidence rates of exposure-adjusted adverse events (AE) and serious AEs were similar with both treatments.ConclusionThe subgroup of patients with stage IIIB, IIIC and IVM1a melanoma (57.1% of the OPTiM intent-to-treat population) derived greater benefit in DRR and ORR from talimogene laherparepvec compared with GM-CSF. Talimogene laherparepvec was well tolerated.

SummarySynthetic repellents based on di-ethyl 3-methyl benzamide (DEET) are a popular method of obtaining protection from mosquitoes and yet clear evidence for a protective effect against malaria has hitherto never been convincingly demonstrated. A household randomized trial was undertaken among a study population of 127 families (25%) in an Afghan refugee village in Pakistan to compare the efficacy of repellent soap (Mosbar TM containing 20% DEET and 0.5% permethrin) vs. a placebo lotion. Cases of falciparum and vivax malaria were detected by passive case detection at the camp's clinic. At the end of the 6 month trial 3.7% (23 of 618) of individuals in the Mosbar group had presented with one or more episodes of falciparum malaria compared with 8.9% (47 of 530) of the placebo group (odds ratio 0.44, 95% CI 0.25-0.76). 16.7% of the Mosbar group (103 of 618) presented with vivax malaria compared with 11.7% (62 of 530) of the placebo group, and thus no effect was shown against vivax malaria (odds ratio 1.29, 95% CI 0.86-1.94). A considerable proportion of individuals (22%) had presented with vivax malaria during the 7 months leading up to the trial and thus any intervention effect would be partially masked by relapsed infections. The distribution of mosquitoes among households was broadly similar between Mosbar and placebo groups. The repellent was popularly received and very few side-effects were reported. There is a case for giving repellents more prominence in public health as a preventive measure in regions where vectors bite in the early evening or in emergency situations such as epidemics or newly established refugee camps.

Summary Background Effective treatment for metachromatic leukodystrophy (MLD) remains a substantial unmet medical need. In this study we investigated the safety and efficacy of atidarsagene autotemcel (arsa-cel) in patients with MLD. Methods This study is an integrated analysis of results from a prospective, non-randomised, phase 1/2 clinical study and expanded-access frameworks. 29 paediatric patients with pre-symptomatic or early-symptomatic early-onset MLD with biochemical and molecular confirmation of diagnosis were treated with arsa-cel, a gene therapy containing an autologous haematopoietic stem and progenitor cell (HSPC) population transduced ex vivo with a lentiviral vector encoding human arylsulfatase A (ARSA) cDNA, and compared with an untreated natural history (NHx) cohort of 31 patients with early-onset MLD, matched by age and disease subtype. Patients were treated and followed up at Ospedale San Raffaele, Milan, Italy. The coprimary efficacy endpoints were an improvement of more than 10% in total gross motor function measure score at 2 years after treatment in treated patients compared with controls, and change from baseline of total peripheral blood mononuclear cell (PBMC) ARSA activity at 2 years after treatment compared with values before treatment. This phase 1/2 study is registered with ClinicalTrials.gov , NCT01560182 . Findings At the time of analyses, 26 patients treated with arsa-cel were alive with median follow-up of 3·16 years (range 0·64–7·51). Two patients died due to disease progression and one due to a sudden event deemed unlikely to be related to treatment. After busulfan conditioning, all arsa-cel treated patients showed sustained multilineage engraftment of genetically modified HSPCs. ARSA activity in PBMCs was significantly increased above baseline 2 years after treatment by a mean 18·7-fold (95% CI 8·3–42·2; p<0·0001) in patients with the late-infantile variant and 5·7-fold (2·6–12·4; p<0·0001) in patients with the early-juvenile variant. Mean differences in total scores for gross motor function measure between treated patients and age-matched and disease subtype-matched NHx patients 2 years after treatment were significant for both patients with late-infantile MLD (66% [95% CI 48·9–82·3]) and early-juvenile MLD (42% [12·3–71·8]). Most treated patients progressively acquired motor skills within the predicted range of healthy children or had stabilised motor performance (maintaining the ability to walk). Further, most displayed normal cognitive development and prevention or delay of central and peripheral demyelination and brain atrophy throughout follow-up; treatment benefits were particularly apparent in patients treated before symptom onset. The infusion was well tolerated and there was no evidence of abnormal clonal proliferation or replication-competent lentivirus. All patients had at least one grade 3 or higher adverse event; most were...

Word count: 3,668 without Acknowledgements or 4,089 with Acknowledgements Key messages Formal and transparent discussion of multiple viewpoints, interests and priorities facilitates mutual understanding of complex decision problems  Benefit-risk assessments of treatments should be undertaken in a structured way so that it is clear how a decision on the overall balance of a treatment's effects has been reached  Various structured approaches and singular methodologies/visual representations are available to support benefit-risk assessment of medicines, but so far universal agreement as to the most suitable method for structured benefit-risk assessment has been lacking  A team combining expertise from public and private institutions carried out a review of benefit-risk methods and visual representations, including application of the tools to case studies based on real regulatory scenarios  The project produced a clear set of practical recommendations for undertaking benefit-risk assessments, organised around a generic, five stage benefit-risk assessment roadmap /2007-2013) and EFPIA companies' in kind contribution.The processes described and conclusions drawn from the work presented herein relate solely to the testing of methodologies and representations for the evaluation of benefit and risk of medicines. This report neither replaces nor is intended to replace or comment on any regulatory decisions made by national regulatory agencies, nor the European Medicines Agency.The authors declare the following conflicts of interest: Dr Hughes has been employed by Pfizer Inc. for the duration of the project. Mr Downey reports that he is an employee of Amgen, a participant in the Innovative Medicines Initiative, which is a public-private partnership. The manuscript describes testing benefit-risk methodologies and visualizations using case studies of marketed products. No Amgen treatments were used in the work associated with this publication. Dr Juhaeri is an employee of Sanofi, the producer of rimonabant and telithromycin, which were used in the PROTECT project as case studies. Dr Juhaeri declares that he is an employee or Sanofi, the manufacturer of rimonabant which was studied in this project. Mr Lieftucht reports that he is an employee of GlaxoSmithKline, a participant in the Innovative Medicines Initiative, which is a public-private partnership. One of the case studies described in the manuscript is a GSK product but Mr Lieftucht did not work on that case study. Dr Metcalf reports that she is an employee of GlaxoSmithKline, a participant in the Innovative Medicines Initiative, which is a publicprivate partnership. One of the case studies described in the manuscript is a GSK product but Dr Metcalf did not work on that case study. To draw on the practical experience from the PROTECT BR case studies and make recommendations regarding the application of a number of methodologies and visual representations for benefit-risk assessment. MethodsEight case studies based on the benefit-risk balance of real medicines were ...

APV and LPV exposures are significantly reduced using LPV/RTV/fosamprenavir, possibly increasing the risk of virologic failure. Consequently, A5143 was closed to enrollment.

SummaryDEET (Diethyl-3-methylbenzamide), the widely used mosquito repellent, has the potential to prevent malarial infection but hitherto there has been no study demonstrating this possibility during normal everyday use. Mosbar TM , a repellent soap containing DEET, was promoted through social marketing in villages in eastern Afghanistan. This was followed up with a case-control study of effectiveness against malarial infection conducted through local clinics. Mosbar was purchased by 43% of households. Reported use of insecticide-treated nets (ITNs) was 65% among the control group. There was a strong association between Mosbar use and ITN use, as 81% of Mosbar users also possessed ITN. The use of Mosbar was associated with a 45% reduction in the odds of malaria (95% CI: )11% to 72%, P ¼ 0.08) after adjusting for ITN and other unmatched factors. Ownership of ITNs was associated with a 46% reduction in the odds of malaria (95% CI: 12% to 67%, P ¼ 0.013) after adjusting for Mosbar and other unmatched factors. The greatest reduction in the odds of malaria was associated with combined use of Mosbar and ITN (69% reduction, 95% CI: 28% to 87%, P ¼ 0.007). The association between recalled use of Mosbar 10 days ago (nearer the time of infection) and reduction in malarial infections (adjusted odds ratio 0.08, 95% CI: 0.01-0.61, P ¼ 0.001) was significantly stronger than that shown by current use of Mosbar. Most purchasers of Mosbar were satisfied with the product (74%), although a minority said they preferred to use only ITN (8%). The local mosquito vectors, Anopheles stephensi and A. nigerrimus, started biting shortly after dusk and continued biting until early morning. It was shown that Mosbar prevented biting throughout this period. In regions where mosquito vectors bite during evening and night, repellents could have a useful supplementary role to ITN and their use should be more widely encouraged.