Outcomes and endpoints in trials of cancer treatment: the past, present, and future

Wilson, Michelle; Karakasis, Katherine; Oza, Amit M.

doi:10.1016/s1470-2045(14)70375-4

Cited by 161 publications

(160 citation statements)

References 111 publications

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“…Furthermore, OS as a measure of therapeutic success becomes less useful as the course and duration of diseases such as cancer move from being acute to more chronic; longitudinal effects of chronic disease such as comorbidities and additional ongoing treatments add further limitations to OS as an outcome. 90,91 As a solution, there has recently been a steady move (by regulatory bodies) away from OS as a clinical end point measure and towards more short-term surrogate measures.…”

Section: Definition and Examples Of Surrogate Outcomesmentioning

confidence: 99%

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

Hettle

Corbett

Hinde

et al. 2017

Health Technol Assess

101

143

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BackgroundThe National Institute for Health and Care Excellence (NICE) commissioned a ‘mock technology appraisal’ to assess whether changes to its methods and processes are needed. This report presents the findings of independent research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to evaluate the mock appraisal.MethodsOur research included reviews to identify issues, analysis methods and conceptual differences and the relevance of alternative decision frameworks, alongside the development of an exemplar case study of chimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia.ResultsAn assessment of previous evaluations of regenerative medicines found that, although there were a number of evidential challenges, none was unique to regenerative medicines or was beyond the scope of existing methods used to conceptualise decision uncertainty. Regarding the clinical evidence for regenerative medicines, the issues were those associated with a limited evidence base but were not unique to regenerative medicines: small non-randomised studies, high variation in response and the intervention subject to continuing development. The relative treatment effects generated from single-arm trials are likely to be optimistic unless it is certain that the historical data have accurately estimated the efficacy of the control agent. Pivotal trials may use surrogate end points, which, on average, overestimate treatment effects. To reduce overall uncertainty, multivariate meta-analysis of all available data should be considered. Incorporating indirectly relevant but more reliable (more mature) data into the analysis can also be considered; such data may become available as a result of the evolving regulatory pathways being developed by the European Medicines Agency. For the exemplar case of CAR T-cell therapy, target product profiles (TPPs) were developed, which considered the ‘curative’ and ‘bridging to stem-cell transplantation’ treatment approaches separately. Within each TPP, three ‘hypothetical’ evidence sets (minimum, intermediate and mature) were generated to simulate the impact of alternative levels of precision and maturity in the clinical evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing NICE reference case alongside additional analyses suggested within alternative frameworks. The additional exploratory analyses were undertaken to demonstrate how assessments of cost-effectiveness and uncertainty could be impacted by alternative managed entry agreements (MEAs), including price discounts, performance-related schemes and technology leasing. The panel deliberated on the range of TPPs, evidence sets and MEAs, commenting on the likely recommendations for each scenario. The panel discussed the challenges associated with the exemplar and regenerative medicines more broadly, focusing on the need for a robust quantification of the level of uncertainty in the cost-effective estimates and the potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated with a wrong decision.ConclusionsIt is to be expected that there will be a significant level of uncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs and benefits, but the existing methods available to estimate the implications of this uncertainty are sufficient. The use of risk sharing and MEAs between the NHS and manufacturers of regenerative medicines should be investigated further.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Section: Definition and Examples Of Surrogate Outcomesmentioning

confidence: 99%

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

Hettle

Corbett

Hinde

et al. 2017

Health Technol Assess

101

143

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“…Improvements in median OS associated with ICBs versus other therapies have been reported in several cancer types (Table 2), including RCC treated with nivolumab versus the targeted agent everolimus [28], NSCLC treated with either pembrolizumab or atezolizumab versus the chemotherapeutic agent docetaxel [42,57], and UC treated with pembrolizumab versus chemotherapy [46]. However, as novel agents extend patient survival times, it becomes increasingly difficult to conduct long clinical trials in order to measure OS [75,76]. Although the use of ICBs has improved survival in melanoma over standard chemotherapy, with some patients experiencing OS of 3 to 5 years [77,78], when the follow-up is less than 1 year, median OS is usually not reached [22,23,39,43].…”

Section: Endpoints To Assess Clinical Outcomes Associated With Icbsmentioning

confidence: 99%

“…The correlation between objective response rate (ORR), time to progression, disease-free survival, or progressionfree survival (PFS) and OS is poorly understood [76,79]. Some studies investigating ICBs in NSCLC, RCC, HNSCC, and UC have demonstrated increased OS in the absence of a PFS benefit [27,28,31,42,47,57], whereas other trials in melanoma and NSCLC have demonstrated increased OS, as well as ORR and PFS, compared with standard of care (Table 2) [23,43].…”

Section: Endpoints To Assess Clinical Outcomes Associated With Icbsmentioning

confidence: 99%

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

et al. 2018

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Immune checkpoint blockers have revolutionized cancer treatment in recent years. These agents are now approved for the treatment of several malignancies, including melanoma, squamous and non-squamous non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck squamous cell carcinoma. Studies have demonstrated the significant impact of immunotherapy versus standard of care on patient outcomes, including durable response and extended survival. The use of immunotherapy-based combination therapy has been shown to further extend duration of response and survival. Immunotherapies function through modulation of the immune system, which can lead to immune-mediated adverse events (imAEs). These include a range of dermatologic, gastrointestinal, endocrine, and hepatic toxicities, as well as other less common inflammatory events. ImAEs are typically low grade and manageable when identified early and treated with appropriate measures. Identifying the right patient for the right therapy will become more important as new immunotherapies and immunotherapy-based combinations are approved and costs of cancer care continue to rise.

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“…Surrogate cancer endpoints include Progression-free survival (PFS), Overall survival rate (OSR), Complete response, Objective response rate (ORR), and Disease-free survival (DFS), Clinical benefit rate, among others [5]. Among all these endpoints, OSR is regarded as the most practical endpoint to measure the effectiveness of the oncology treatment including combined cancer therapies.…”

Section: Review Rationalementioning

confidence: 99%

Evaluation of Docetaxel vs. Tamoxifen in Combined Therapies Based on Overall Survival Rate (OSR) Endpoint among Female Breast Cancer Patients

Olawuyi¹,

Tidman²

2017

Adv Cancer Prev

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In this review, overall survival rate (OSR) result and safety data were evaluated based on data from four clinical trials on combined therapies of Docetaxel and Tamoxifen among breast cancer patients, which were published in peer-reviewed journals. Data was extracted from single treatment trials of Docetaxel plus Cisplatin, and Tamoxifen plus Vorinostat, and randomized trials of Docetaxel plus Capecitabine, and Tamoxifen plus Buserelin. Docetaxel was found to have slightly longer OSR than Tamoxifen in combined therapies, and it has better individual strength in combined therapies based on OSR comparison in the trials' treatment arms. However, a considerable number of toxicities caused by combined therapies of both drugs negates the superiority of the efficacy of combined therapies of one of the drugs over the other. Although other combined cancer drugs boost efficacy of Docetaxel and Tamoxifen in the combined therapies, they should be selected to minimize the toxicities in combined therapies of both drugs.

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Outcomes and endpoints in trials of cancer treatment: the past, present, and future

Cited by 161 publications

References 111 publications

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

Evaluation of Docetaxel vs. Tamoxifen in Combined Therapies Based on Overall Survival Rate (OSR) Endpoint among Female Breast Cancer Patients

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