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      Correlation Between Surrogate End Points and Overall Survival in a Multi-institutional Clinicogenomic Cohort of Patients With Non–Small Cell Lung or Colorectal Cancer

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          Key Points

          Question

          What surrogate end point for capturing worsening disease is most correlated with overall survival (OS) in large linked clinicogenomic data sets?

          Findings

          In this cohort study of patients with non–small cell lung cancer or colorectal cancer who initiated systemic therapy for advanced disease, progression-free survival based on both radiologist and medical oncologist assessment was more consistently correlated with OS than other candidate end points, including time to treatment discontinuation and time to next treatment.

          Meaning

          This study suggests that, based on its correlation with OS, progression-free survival based on both radiologist and medical oncologist assessment may be an optimal surrogate end point for analysis of observational clinicogenomic data in cancer research.

          Abstract

          Importance

          Contemporary observational cancer research requires associating genomic biomarkers with reproducible end points; overall survival (OS) is a key end point, but interpretation can be challenging when multiple lines of therapy and prolonged survival are common. Progression-free survival (PFS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) are alternative end points, but their utility as surrogates for OS in real-world clinicogenomic data sets has not been well characterized.

          Objective

          To measure correlations between candidate surrogate end points and OS in a multi-institutional clinicogenomic data set.

          Design, Setting, and Participants

          A retrospective cohort study was conducted of patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC) whose tumors were genotyped at 4 academic centers from January 1, 2014, to December 31, 2017, and who initiated systemic therapy for advanced disease. Patients were followed up through August 31, 2020 (NSCLC), and October 31, 2020 (CRC). Statistical analyses were conducted on January 5, 2021.

          Exposures

          Candidate surrogate end points included TTD; TTNT; PFS based on imaging reports only; PFS based on medical oncologist ascertainment only; PFS based on either imaging or medical oncologist ascertainment, whichever came first; and PFS defined by a requirement that both imaging and medical oncologist ascertainment have indicated progression.

          Main Outcomes and Measures

          The primary outcome was the correlation between candidate surrogate end points and OS.

          Results

          There were 1161 patients with NSCLC (648 women [55.8%]; mean [SD] age, 63 [11] years) and 1150 with CRC (647 men [56.3%]; mean [SD] age, 54 [12] years) identified for analysis. Progression-free survival based on both imaging and medical oncologist documentation was most correlated with OS (NSCLC: ρ = 0.76; 95% CI, 0.73-0.79; CRC: ρ = 0.73; 95% CI, 0.69-0.75). Time to treatment discontinuation was least associated with OS (NSCLC: ρ = 0.45; 95% CI, 0.40-0.50; CRC: ρ = 0.13; 95% CI, 0.06-0.19). Time to next treatment was modestly associated with OS (NSCLC: ρ = 0.60; 0.55-0.64; CRC: ρ = 0.39; 95% CI, 0.32-0.46).

          Conclusions and Relevance

          This cohort study suggests that PFS based on both a radiologist and a treating oncologist determining that a progression event has occurred was the surrogate end point most highly correlated with OS for analysis of observational clinicogenomic data.

          Abstract

          This cohort study measures associations between candidate surrogate end points and overall survival in a multi-institutional clinicogenomic data set of patients with non–small cell lung cancer (NSCLC) or colorectal cancer.

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          Most cited references27

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          New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

          Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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            The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.

            Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalisability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September, 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles.18 items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies.A detailed explanation and elaboration document is published separately and is freely available on the websites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE statement will contribute to improving the quality of reporting of observational studies
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              Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial

              First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.
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                Author and article information

                Journal
                JAMA Netw Open
                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                2574-3805
                26 July 2021
                July 2021
                26 July 2021
                : 4
                : 7
                : e2117547
                Affiliations
                [1 ]Department of Medical Oncology, Division of Population Sciences, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
                [2 ]Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
                [3 ]Department of Medicine, Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
                [4 ]Department of Biomedical Informatics, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
                [5 ]Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
                [6 ]American Association for Cancer Research, Philadelphia, Pennsylvania
                [7 ]Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada
                [8 ]Department of Medicine, University of Toronto, Toronto, Ontario, Canada
                [9 ]Associate Editor, JAMA
                Author notes
                Article Information
                Accepted for Publication: May 5, 2021.
                Published: July 26, 2021. doi:10.1001/jamanetworkopen.2021.17547
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Kehl KL et al. JAMA Network Open.
                Corresponding Author: Kenneth L. Kehl, MD, MPH, Department of Medical Oncology, Division of Population Sciences, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA 02215 ( kenneth_kehl@ 123456dfci.harvard.edu ).
                Author Contributions: Dr Kehl had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Kehl, Riely, Schrag, Panageas.
                Acquisition, analysis, or interpretation of data: All authors.
                Drafting of the manuscript: Kehl, Lepisto, Warner, Brown, Schrag.
                Critical revision of the manuscript for important intellectual content: Kehl, Riely, Lavery, Warner, LeNoue-Newton, Sweeney, Rudolph, Brown, Yu, Bedard, Schrag, Panageas.
                Statistical analysis: Kehl, Lavery, Brown, Schrag, Panageas.
                Obtained funding: Kehl, Riely, Sweeney.
                Administrative, technical, or material support: Riely, Lepisto, Rudolph, Bedard, Schrag.
                Supervision: Panageas.
                Conflict of Interest Disclosures: Dr Kehl reported receiving grants from Wong Family Foundation, American Association of Cancer Research (AACR), Simeon J. Fortin Foundation, Doris Duke Foundation, and the National Cancer Institute during the conduct of the study; grants from IBM; and personal fees from Aetion and Roche outside the submitted work. Dr Riely reported receiving grants from AACR during the conduct of the study; grants from Novartis, Pfizer, Merck, Mirati, Takeda, and Roche; and nonfinancial support from Pfizer and Merck outside the submitted work. Ms Lepisto reported receiving grants from AACR during the conduct of the study. Ms Lavery reported receiving grants from AACR during the conduct of the study. Dr Warner reported receiving grants from AACR during the conduct of the study; grants from the National Institutes of Health; consulting fees from Westat and IBM; and having equity in HemOnc.org LLC. Dr LeNoue-Newton reported receiving research funding from AACR during the conduct of the study; and research funding from GE Healthcare outside the submitted work. Dr Sweeney reported receiving grants from Amgen Inc, AstraZeneca UK Ltd, Bristol Myers Squibb, Bayer Healthcare Pharmaceuticals Inc, Boehringer Ingelheim, Genentech, Janssen Pharmaceuticals Inc, Merck Sharp & Dohme Corp, Novartis, and Pfizer Inc during the conduct of the study. Ms Brown reported receivng grants from AACR during the conduct of the study. Dr Bedard reported receiving grants from AACR during the conduct of the study; consulting fees from Seattle Genetics, Eli Lilly and Co, Amgen Inc, Merck Sharp & Dohme Corp, Bristol Myers Squibb, Sanofi, and Pizer; serving on the advisory boards for Bristol Myers Squibb, Eli Lilly and Co, Amgen, Seattle Genetics, Merck, Pfizer, and Gilead; and receiving research funding directed to his institution from Bristol Myers Squibb, Sanofi, AstraZeneca, Genentech, Servier, GlaxoSmithKline, Novartis, SignalChem, PTC Therapeutics, Nektar, Merck Sharp & Dohme Corp, Seattle Genetics, Mersana, Immunomedics, and Eli Lilly and Co. Dr Schrag reported receiving fees from JAMA for editorial services; speaking fees from Pfizer; research funding given directly to the institution from AACR, Patient-Centered Outcomes Research Institute, GRAIL, and the National Cancer Institute (NCI). Dr Panageas reported receiving grants from NCI Cancer Center Support Grant and research funding from AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) Consortium during the conduct of the study. AACR Project GENIE receives funding from Amgen Inc, Bristol Myers Squibb Co, Merck Sharp & Dohme Corp, AstraZeneca UK Ltd, Genentech, Novartis, Bayer Healthcare Pharmaceuticals Inc, H3 Biomedicine, Puma Biotechnology, Boehringer Ingelheim, and Janssen Pharmaceuticals Inc. No other disclosures were reported.
                Funding/Support: This study was supported by the AACR; Wong Family Foundation, Simeon J. Fortin Foundation, Doris Duke Foundation, and NCI grant K99CA245899-01 (Dr Kehl); and Cancer Center support grant P30 CA08748 and the NCI (Dr Riely, Mss Lavery, Rudolph, Brown, and Dr Panageas).
                Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Group Members: The AACR Project GENIE Consortium members are listed in Supplement 2.
                Disclaimer: Interpretations are the responsibility of study authors.
                Additional Contributions: The authors would like to acknowledge the AACR and its financial and material support in the development of the AACR Project GENIE registry as well as members of the AACR Project GENIE consortium for their commitment to data sharing.
                Article
                zoi210522
                10.1001/jamanetworkopen.2021.17547
                8314138
                34309669
                9c600562-81db-4f33-8299-c1b631229ffd
                Copyright 2021 Kehl KL et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 4 February 2021
                : 5 May 2021
                Categories
                Research
                Original Investigation
                Online Only
                Oncology

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