Efficacy of tucatinib for HER2-positive metastatic breast cancer after HER2-targeted therapy: a network meta-analysis.

Aim: A systematic literature review and network meta-analysis of randomized controlled trials in patients receiving therapy for HER2+ unresectable/metastatic breast cancer after ≥1 HER2-directed therapy was conducted to compare progression-free survival (PFS) and overall survival (OS). Methods: Hazard ratios (HRs) and relative differences from fractional polynomials (FPs) for PFS and OS were assessed by Bayesian network meta-analyses. Results: For PFS, surface under the cumulative rankogram (SUCRA) ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by T-DM1 monotherapy and neratinib plus capecitabine. For OS, SUCRA ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1 monotherapy, with similar scores. Conclusion: Tucatinib plus trastuzumab with capecitabine, and T-DM1 monotherapy, consistently showed improved PFS and OS versus lapatinib/trastuzumab plus capecitabine and non-targeted treatments.

Lay abstract Although several therapies are used in HER2-positive metastatic breast cancer, direct head-to-head comparisons of these therapies are lacking. We conducted a network meta-analysis, a way of indirectly comparing the results of different clinical trials, to compare how long patients receiving therapy had no disease progression, and also how long patients survived. In terms of avoiding disease progression, tucatinib plus trastuzumab with capecitabine ranked highest, followed by T-DM1 monotherapy and neratinib plus capecitabine. In terms of survival, tucatinib plus trastuzumab with capecitabine ranked highest, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1. Tucatinib in combination with trastuzumab plus capecitabine and also T-DM1 monotherapy consistently demonstrated improved progression-free and overall survival outcomes compared with other therapies.

An Evaluation of Survival Curve Extrapolation Techniques Using Long-Term Observational Cancer Data.

Objectives. Uncertainty in survival prediction beyond trial follow-up is highly influential in cost-effectiveness analyses of oncology products. This research provides an empirical evaluation of the accuracy of alternative methods and recommendations for their implementation. Methods. Mature (15-year) survival data were reconstructed from a published database study for "no treatment," radiotherapy, surgery plus radiotherapy, and surgery in early stage non-small cell lung cancer in an elderly patient population. Censored data sets were created from these data to simulate immature trial data (for 1- to 10-year follow-up). A second data set with mature (9-year) survival data for no treatment was used to extrapolate the predictions from models fitted to the first data set. Six methodological approaches were used to fit models to the simulated data and extrapolate beyond trial follow-up. Model performance was evaluated by comparing the relative difference in mean survival estimates and the absolute error in the difference in mean survival v. the control with those from the original mature survival data set. Results. Model performance depended on the treatment comparison scenario. All models performed reasonably well when there was a small short-term treatment effect, with the Bayesian model coping better with shorter follow-up times. However, in other scenarios, the most flexible Bayesian model that could be estimated in practice appeared to fit the data less well than the models that used the external data separately. Where there was a large treatment effect (hazard ratio = 0.4), models that used external data separately performed best. Conclusions. Models that directly use mature external data can improve the accuracy of survival predictions. Recommendations on modeling strategies are made for different treatment benefit scenarios.

Relative efficacy of interventions in the treatment of second-line non-small cell lung cancer: a systematic review and network meta-analysis.

BACKGROUND: Locally advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed after first-line treatment has a poor prognosis. Recent randomized clinical trials (RCTs) have demonstrated survival benefits of alternative treatments to docetaxel. However, information is lacking on which patients benefit the most and what drug or regimen is optimal. We report a systematic review and network meta-analysis (NMA) of second-line treatments in all subgroup combinations determined by histology, programmed death ligand 1 (PD-L1) expression, and epidermal growth factor receptor (EGFR) mutation. METHODS: MEDLINE, PubMed, EMBASE, Biosciences Information Service (using the Dialog Platform), Cochrane Library, and abstracts from scientific meetings were searched for RCTs published up to September 2015. Key outcomes were overall survival (OS) and progression-free survival (PFS). Bayesian hierarchical exchangeable NMAs were conducted to calculate mean survival times and relative differences for eight subgroups, using docetaxel as the reference comparator. For OS, the NMA was based on hazard ratios applied to a first-order fractional polynomial model fitted to the reference treatment. For PFS, a second-order fractional polynomial model was fitted to reconstructed patient-level data for the entire network of evidence. RESULTS: The search identified 30 studies containing 17 different treatment regimens. Docetaxel plus ramucirumab was associated with a significant improvement in OS and PFS, relative to docetaxel, regardless of patient type. Docetaxel plus nintedanib showed similar efficacy to docetaxel plus ramucirumab in the nonsquamous populations. EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib showed superior levels of efficacy in EGFR mutation-positive populations and the one PD-1 immunotherapy (nivolumab) studied showed superior efficacy in the populations exhibiting high PD-L1 expression. CONCLUSIONS: In the absence of head-to-head comparisons, we performed a mixed-treatment analysis to synthesize evidence of the efficacy of each treatment. Benefits are optimized by targeting specific treatments to individual patients guided by histology, PD-L1 expression, and EGFR mutation status. SYSTEMATIC REVIEW REGISTRATION: This review is registered in PROSPERO (registration number: CRD42014013780 available at www.crd.york.ac.uk/PROSPERO ).

Cost Effectiveness of Nusinersen in the Treatment of Patients with Infantile-Onset and Later-Onset Spinal Muscular Atrophy in Sweden.

BACKGROUND: Spinal muscular atrophy is a rare neuromuscular disorder with a spectrum of severity related to age at onset and the number of SMN2 gene copies. Infantile-onset (≤ 6 months of age) is the most severe spinal muscular atrophy and is the leading monogenetic cause of infant mortality; patients with later-onset (> 6 months of age) spinal muscular atrophy can survive into adulthood. Nusinersen is a new treatment for spinal muscular atrophy. OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of nusinersen for the treatment of patients with infantile-onset spinal muscular atrophy and later-onset spinal muscular atrophy in Sweden. METHODS: One Markov cohort health-state transition model was developed for each population. The infantile-onset and later-onset models were based on the efficacy results from the ENDEAR phase III trial and the CHERISH phase III trial, respectively. The cost effectiveness of nusinersen in both models was compared with standard of care in Sweden. RESULTS: For a time horizon of 40 years in the infantile-onset model and 80 years in the later-onset model, treatment with nusinersen resulted in 3.86 and 9.54 patient incremental quality-adjusted life-years and 0.02 and 2.39 caregiver incremental quality-adjusted life-years and an incremental cost of 21.9 and 38.0 million SEK (Swedish krona), respectively. These results translated into incremental cost-effectiveness ratios (including caregiver quality-adjusted life-years) of 5.64 million SEK (€551,300) and 3.19 million SEK (€311,800) per quality-adjusted life-year gained in the infantile-onset model and later-onset model, respectively. CONCLUSIONS: Treatment with nusinersen resulted in overall survival and quality-adjusted life-year benefits but with incremental costs above 21 million SEK (€2 million) [mainly associated with maintenance treatment with nusinersen over a patient's lifespan]. Nusinersen was not cost effective when using a willingness-to-pay threshold of 2 million SEK (€195,600), which has been considered in a recent discussion by the Dental and Pharmaceutical Benefits Agency as a reasonable threshold for rare disease. Nonetheless, nusinersen gained reimbursement in Sweden in 2017 for paediatric patients (below 18 years old) with spinal muscular atrophy type I-IIIa.

Cost-Effectiveness of Olaratumab in Combination with Doxorubicin for Patients with Soft Tissue Sarcoma in the United States.

BACKGROUND: Standard first-line treatments for advanced soft tissue sarcoma (STS) have changed little for 40 years, and outcomes have been poor. Recently, the United States (US) Food and Drug Administration conditionally approved olaratumab in combination with doxorubicin (Olara + Dox) based on a randomized phase II trial that reported a significant 11.8-month improvement in median survival versus single-agent doxorubicin (Dox). The present study investigated the cost-effectiveness of Olara + Dox compared with Dox and five other standard-of-care regimens from the US payer perspective. METHODS: An economic model was constructed to estimate costs and outcomes over patients' lifetimes from start of therapy. Progression-free and overall survival were based on survival analysis of patient-level data and a meta-analysis. Adverse-event rates were based on trials. Costs were from published sources. RESULTS: Olara + Dox resulted in an estimated additional 1.27 life-years (LYs) compared with Dox, with an increase in total expected lifetime costs of $133,653. The incremental cost-effectiveness ratio (ICER) was estimated at $105,408 per LY gained; in a fully incremental analysis, all other regimens were dominated (higher costs and lower LYs or a higher ICER). CONCLUSION: Olara + Dox is cost-effective for STS treatment compared with Dox and other standard-of-care regimens at willingness-to-pay thresholds of $150,000 per LY and above.

Systematic Review with Network Meta-Analysis: Comparative Efficacy of Biologics in the Treatment of Moderately to Severely Active Ulcerative Colitis.

BACKGROUND: Biological therapies are increasingly used to treat ulcerative colitis (UC). AIM: To compare the efficacy of biologics in adults with moderately-to-severely active UC, stratified by prior exposure to anti-tumour necrosis factor (anti-TNF) therapy. METHODS: A systematic literature review was undertaken to identify studies of biologics approved for UC. Network meta-analysis was conducted for endpoints at induction and maintenance. RESULTS: Seven studies were included in the meta-analysis of induction treatment for anti-TNF therapy-naïve patients. All biologics were more effective than placebo in inducing clinical response, clinical remission, and mucosal healing. Infliximab demonstrated a statistically significant improvement over adalimumab in clinical response (odds ratio [OR] [95% credible interval (CrI)]: 2.19 [1.35-3.55]), clinical remission (OR [95% CrI]: 2.81 [1.49-5.49]), and mucosal healing (OR [95% CrI]: 2.23 [1.21-4.14]); there were no other significant differences between biologics for induction efficacy. Five studies were included in the meta-analysis of maintenance treatment, two studies rerandomised responder patients at end of induction, and three followed the same patients 'straight through'. To account for design differences, the number of responders at end of induction was assumed to be equivalent to the number rerandomised. Vedolizumab showed significantly different durable clinical response from comparators (OR [95% CrI] infliximab 3.18 [1.14-9.20], golimumab 2.33 [1.04-5.41], and adalimumab 3.96 [1.67-9.84]). In anti-TNF therapy-experienced patients, only vedolizumab and adalimumab could be compared. At induction, no significant differences in efficacy were seen. During maintenance, vedolizumab showed significantly improved rates of mucosal healing versus adalimumab (OR [95% CrI]: 6.72 [1.36-41.0]). CONCLUSIONS: This study expands the understanding of comparative efficacies of biologic treatments for UC, encompassing outcomes and populations not previously studied. All biologic treatments were effective for UC during induction. Vedolizumab demonstrated possible clinical benefits in the maintenance setting versus all comparators, irrespective of prior anti-TNF exposure and after adjusting for differences in study design.

Where are the bodies: the haunting of Indonesia.

Controversies about the 1965-66 killings of communists in Indonesia have revolved around questions of "how many?" and "who was responsible?" While there is general agreement that at least 500,000 people were killed, public discourse in Indonesia plays down the significance of tile killings by placing the burden of responsibility on the victims. Attempts to create a national reconciliation process have been stalled. By examining the social and cultural problems surrounding the bodies of the victims, this paper demonstrates the complexity of issues of corporeality and haunting. Examples from Bali and Java show how hard it is to memorialize the killings, and thus the difficulties of incorporating the killings into national discourse.

Evaluation of quality of life and priorities of patients with glaucoma.

PURPOSE: To investigate the quality of life and priorities of patients with glaucoma. METHODS: Patients diagnosed with glaucoma and no other ocular comorbidity were consecutively recruited. Clinical information was collected. Participants were asked to complete three questionnaires: EuroQuol (EQ-5D), time tradeoff (TTO), and choice-based conjoint analysis. The latter used five-attribute outcomes: (1) reading and seeing detail, (2) peripheral vision, (3) darkness and glare, (4) household chores, and (5) outdoor mobility. Visual field loss was estimated by using binocular integrated visual fields (IVFs). RESULTS: Of 84 patients invited to participate, 72 were enrolled in the study. The conjoint utilities showed that the two main priorities were "reading and seeing detail" and "outdoor mobility." This rank order was stable across all segmentations of the data by demographic or visual state. However, the relative emphasis of these priorities changed with increasing visual field loss, with concerns for central vision increasing, whereas those for outdoor mobility decreased. Two subgroups of patients with differing priorities on the two main attributes were identified. Only 17% of patients (those with poorer visual acuity) were prepared to consider TTO. A principal component analysis revealed relatively independent components (i.e., low correlations) between the three different methodologies for assessing quality of life. CONCLUSIONS: Assessments of quality of life using different methodologies have been shown to produce different outcomes with low intercorrelations between them. Only a minority of patients were prepared to trade time for a return to normal vision. Conjoint analysis showed two subgroups with different priorities. Severity of glaucoma influenced the relative importance of priorities.