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      Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials

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          <p class="first" id="d3638556e428">This cohort study assesses the speed with which inhibitors of programmed cell death 1 protein reached eligible patients in practice and compares the ages of patients treated in clinical practice with the ages of those treated in pivotal clinical trials. </p><div class="section"> <a class="named-anchor" id="ab-coi180021-1"> <!-- named anchor --> </a> <h5 class="section-title" id="d3638556e434">Question</h5> <p id="d3638556e436">How quickly have immune checkpoint inhibitors changed clinical practice?</p> </div><div class="section"> <a class="named-anchor" id="ab-coi180021-2"> <!-- named anchor --> </a> <h5 class="section-title" id="d3638556e439">Findings</h5> <p id="d3638556e441">In this cohort study of 3089 patients, most eligible patients were being treated with inhibitors of programmed cell death 1 protein within 4 months after US Food and Drug Administration approval, with treated patients being significantly older than those studied in the pivotal clinical trials that supported US Food and Drug Administration–approved use. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180021-3"> <!-- named anchor --> </a> <h5 class="section-title" id="d3638556e444">Meaning</h5> <p id="d3638556e446">Immune checkpoint inhibitors may have rapidly changed clinical practice among populations of patients who differ substantially from those studied in pivotal clinical trials. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180021-4"> <!-- named anchor --> </a> <h5 class="section-title" id="d3638556e450">Importance</h5> <p id="d3638556e452">The US Food and Drug Administration (FDA) is increasing its pace of approvals for novel cancer therapeutics, including for immune checkpoint inhibitors of programmed cell death 1 protein (anti–PD-1 agents). However, little is known about how quickly anti–PD-1 agents agents reach eligible patients in practice or whether such patients differ from those studied in clinical trials that lead to FDA approval (pivotal clinical trials). </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180021-5"> <!-- named anchor --> </a> <h5 class="section-title" id="d3638556e455">Objectives</h5> <p id="d3638556e457">To assess the speed with which anti–PD-1 agents agents reached eligible patients in practice and to compare the ages of patients treated in clinical practice with the ages of those treated in pivotal clinical trials. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180021-6"> <!-- named anchor --> </a> <h5 class="section-title" id="d3638556e460">Design, Setting, and Participants</h5> <p id="d3638556e462">This retrospective cohort study, performed from January 1, 2011, through August 31, 2016, included patients from the Flatiron Health Network who were eligible for anti–PD-1 agents treatment of selected cancer types, which included melanoma, non–small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180021-7"> <!-- named anchor --> </a> <h5 class="section-title" id="d3638556e465">Main Outcomes and Measures</h5> <p id="d3638556e467">Cumulative proportions of eligible patients receiving anti–PD-1 agents treatment and their age distributions. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180021-8"> <!-- named anchor --> </a> <h5 class="section-title" id="d3638556e470">Results</h5> <p id="d3638556e472">The study identified 3089 patients who were eligible for anti–PD-1 agents treatment (median age, 66 [interquartile range, 56-75] years for patients with melanoma, 66 [interquartile range, 58-72] years for patients with RCC, and 67 [interquartile range, 59-74] years for patients with NSCLC; 1742 male [56.4%] and 1347 [43.6%] female; 2066 [66.9%] white). Of these patients, 2123 (68.7%) received anti–PD-1 agents treatment, including 439 eligible patients with melanoma (79.1%), 1417 eligible patients with NSCLC (65.6%), and 267 eligible patients with RCC (71.2%). Within 4 months after FDA approval, greater than 60% of eligible patients in each cohort had received anti–PD-1 agents treatment. Overall, similar proportions of older and younger patients received anti–PD-1 agents treatment during the first 9 months after FDA approval. However, there were significant differences in age between clinical trial participants and patients receiving anti–PD-1 agents treatment in clinical practice, with more patients being older than 65 years in clinical practice (range, 327 of 1365 [60.6%] to 46 of 72 [63.9%]) than in pivotal clinical trials (range, 38 of 120 [31.7%] to 223 of 544 [41.0%]; all <i>P</i> &lt; .001). </p> </div><div class="section"> <a class="named-anchor" id="ab-coi180021-9"> <!-- named anchor --> </a> <h5 class="section-title" id="d3638556e478">Conclusions and Relevance</h5> <p id="d3638556e480">Anti-PD-1 agents rapidly reached patients in clinical practice, and patients treated in clinical practice differed significantly from patients treated in pivotal clinical trials. Future actions are needed to ensure that rapid adoption occurs on the basis of representative trial evidence. </p> </div>

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          Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma.
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            The usual search for explanations and solutions for the research-practice gap tends to analyze ways to communicate evidence-based practice guidelines to practitioners more efficiently and effectively from the end of a scientific pipeline. This examination of the pipeline looks upstream for ways in which the research itself is rendered increasingly irrelevant to the circumstances of practice by the process of vetting the research before it can qualify for inclusion in systematic reviews and the practice guidelines derived from them. It suggests a 'fallacy of the pipeline' implicit in one-way conceptualizations of translation, dissemination and delivery of research to practitioners. Secondly, it identifies a 'fallacy of the empty vessel' implicit in the assumptions underlying common characterizations of the practitioner as a recipient of evidence-based guidelines. Remedies are proposed that put emphasis on participatory approaches and more practice-based production of the research and more attention to external validity in the peer review, funding, publication and systematic reviews of research in producing evidence-based guidelines.
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                Author and article information

                JAMA Oncology
                JAMA Oncol
                American Medical Association (AMA)
                August 01 2018
                August 09 2018
                : 4
                : 8
                : e180798
                [1 ]Section of General Internal Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
                [2 ]National Clinician Scholars Program, Yale University School of Medicine, New Haven, Connecticut
                [3 ]Flatiron Health Inc, New York, New York
                [4 ]Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut
                [5 ]The Ohio State University Comprehensive Cancer Center, Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus
                © 2018


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