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Treatment Paradigms for Advanced Non-Small Cell Lung Cancer at Academic Medical Centers: Involvement in Clinical Trial Endpoint Design.

ABSTRACT: Based on the positive results of various clinical trials, treatment options for non-small cell lung cancer (NSCLC) have expanded greatly over the last 25 years. While regulatory approvals of chemotherapeutic agents for NSCLC have largely been based on improvements in overall survival, recent approvals of many targeted agents for NSCLC (afatinib, crizotinib, ceritinib, osimertinib) have been based on surrogate endpoints such as progression-free survival and objective response. As such, selection of appropriate clinical endpoints for examining the efficacy of investigational agents for NSCLC is of vital importance in clinical trial design. This review provides an overview of clinical trial endpoints previously utilized for approved agents for NSCLC and highlights the key efficacy results for these trials. Trends for more recent approvals in NSCLC, including those for the immunotherapeutic agents nivolumab and pembrolizumab, are also discussed. The results of a correlative analysis of endpoints from 18 clinical trials that supported approvals of investigational agents in clinical trials for NSCLC are also presented. IMPLICATIONS FOR PRACTICE:While improving survival remains the ultimate goal of oncology clinical trials, overall survival may not always be the most feasible or appropriate endpoint to assess patient response. Recently, several investigational agents, both targeted agents and immunotherapies, have gained U.S. Food and Drug Administration approval in non-small cell lung cancer based on alternate endpoints such as progression-free survival or response rate. An understanding of the assessment of response and trial endpoint choice is important for future oncology clinical trial design.

SUBMITTER: Aggarwal C

PROVIDER: S-EPMC5469580 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Treatment Paradigms for Advanced Non-Small Cell Lung Cancer at Academic Medical Centers: Involvement in Clinical Trial Endpoint Design.

Aggarwal Charu C Borghaei Hossein H

The oncologist 20170413 6

Based on the positive results of various clinical trials, treatment options for non-small cell lung cancer (NSCLC) have expanded greatly over the last 25 years. While regulatory approvals of chemotherapeutic agents for NSCLC have largely been based on improvements in overall survival, recent approvals of many targeted agents for NSCLC (afatinib, crizotinib, ceritinib, osimertinib) have been based on surrogate endpoints such as progression-free survival and objective response. As such, selection ...[more]

PMID: 28408617

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Project description:BackgroundAcademic Medical Centers (AMCs) must simultaneously serve different purposes: Delivery of high quality healthcare services to patients, as the main mission, supported by other core missions such as academic activities, i.e., researching, teaching and tutoring, while maintaining solvency. This study aims to develop a methodology for constructing models evaluating the academic value provided by AMCs and implementing it at the largest AMC in Israel.MethodsThirty five practiced educators and researchers, academic experts, faculty members and executives, all employed by a metropolitan 1500-bed AMC, were involved in developing academic quality indicators. First, an initial list of AMCs' academic quality indicators was drafted, using a literature review and consulting scholars. Afterwards, additional data and preferences were collected by conducting semi-structured interviews, complemented by a three-round Delphi Panel. Finally, the methodology for constructing a model evaluating the academic value provided by the AMC was developed.ResultsThe composite academic quality indicators methodology consists of nine indicators (relative weight in parentheses): 'Scientific Publications Value' (18.7%), 'Completed Studies' (13.5%), 'Authors Value' (13.0%), 'Residents Quality' (11.3%), 'Competitive Grants Budget' (10.2%), 'Academic Training' (8.7%), 'Academic Positions' (8.3%), 'Number of Studies' (8.3%) and 'Academic Supervision' (8.0%). These indicators were grouped into three core categories: 'Education', 'Research' and 'Publications', having almost the same importance on a scale from zero to one (0-1), i.e., 0.363, 0.320, and 0.317, respectively. The results demonstrated a high level of internal consistency (Cronbach-alpha range: 0.79-0.86).ConclusionsWe have found a gap in the ability to measure academic value provided by AMCs. The main contribution of this research is the development of methodology for constructing evaluation models for AMCs academic performance. Further studies are needed to further test the validity and reliability of the proposed methodology at other sites.

Project description:Background and purposePrior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity.Materials and methodsWe retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0-2; n = 66), CCI intermediate (3-4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution.ResultsMedian follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs < 10 Gy, DWP was higher (5-year rate, 16.9 % vs 6.7 %, p = 0.04) and OS worse (median, 22.9 vs 34.1 months, p < 0.001). Ventricle (left, right, and bilateral) and pericardial but not atrial substructure dose were associated with DWP, whereas all three were inversely associated with OS. Cutpoint analysis identified right ventricle mean dose ≥ 5.5 Gy as a predictor of DWP. In the external cohort, we confirmed an association of ventricle, but not atrial, dose with DWP.ConclusionCardiovascular substructure dose showed distinct associations with DWP. Future cardiotoxicity studies in NSCLC could consider DWP as an endpoint.

Dataset Information

Treatment Paradigms for Advanced Non-Small Cell Lung Cancer at Academic Medical Centers: Involvement in Clinical Trial Endpoint Design.

Publications

Treatment Paradigms for Advanced Non-Small Cell Lung Cancer at Academic Medical Centers: Involvement in Clinical Trial Endpoint Design.

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