Blog
About

2
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The Molecular Analysis for Therapy Choice (NCI-MATCH) Trial: Lessons for Genomic Trial Design

      , MD 1 , , PhD 2 , , MD 3 , , PhD 2 , , MS 4 , , MD 5 , , PhD 6 , , MD 7 , , MD 8 , , MD, PhD 9 , , MD 3 , , PhD 3 , , PhD 3 , , BS 6 , , MD, PhD 5 , , MS, MBA 10 , , MS 6 , , MD 3 , , MD 3 , , BSMT 11 , , PharmD 11 , , BS 12 , , PhD 4 , , JD 3 , , PhD 3 , , MD 13 , , MD 14 , , MD 15 , , MD 5 , , PhD 6 , , MD 16 , , MD 17 , , MD 3 , , MD, PhD 6 , , MD 18 , , MD 3 , , MD 11 , , MD 19 , , MD 3 , for the NCI-MATCH Team

      JNCI Journal of the National Cancer Institute

      Oxford University Press

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology.

          Methods

          Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA–targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial.

          Results

          At interim analysis, accrual was robust, tumor biopsies were safe (<1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround).

          Conclusions

          The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.

          Related collections

          Most cited references 23

          • Record: found
          • Abstract: found
          • Article: not found

          EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

           W Pao,  V. Miller,  M Zakowski (2004)
          Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.

            Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              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.
                Bookmark

                Author and article information

                Journal
                J Natl Cancer Inst
                J Natl Cancer Inst
                jnci
                JNCI Journal of the National Cancer Institute
                Oxford University Press
                0027-8874
                1460-2105
                October 2020
                10 January 2020
                10 January 2020
                : 112
                : 10
                : 1021-1029
                Affiliations
                [1 ] Massachusetts General Hospital , Boston, MA, USA
                [2 ] Dana Farber Cancer Institute ECOG-ACRIN Biostatistics Center , Boston, MA, USA
                [3 ] Division of Cancer Treatment and Diagnosis , National Cancer Institute, NIH, Bethesda, MD, USA
                [4 ] Center for Biomedical Informatics and Information Technology , National Cancer Institute, NIH, Bethesda, MD, USA
                [5 ] University of Texas MD Anderson Cancer Center , Houston, TX, USA
                [6 ] Frederick National Laboratory for Cancer Research , Frederick, MD, USA
                [7 ] Thomas Jefferson University Hospital , Philadelphia, PA, USA
                [8 ] Massachusetts General Hospital , Harvard University, Boston, MA, USA
                [9 ] Yale University , New Haven, CT, USA
                [10 ] Center for Biomedical Informatics and Information Technology , Frederick National Laboratory for Cancer Research, Frederick, MD, USA
                [11 ] ECOG-ACRIN Cancer Research Group , Philadelphia, PA, USA
                [12 ] ECOG-ACRIN Cancer Research Group , Boston, MA, USA
                [13 ] Radiation Oncology , Dana Farber Cancer Institute, Boston, MA, USA
                [14 ] Mayo Clinic , Rochester, MN, USA
                [15 ] Herbert Irving Comprehensive Cancer Center , Columbia University, New York, NY, USA
                [16 ] Division of Cancer Prevention , National Cancer Institute, NIH, Bethesda, MD, USA
                [17 ] Case Comprehensive Cancer Center , Case Western Reserve University, Cleveland, OH, USA
                [18 ] University of Texas Southwestern Simmons Cancer Center , Dallas, TX, USA
                [19 ] University of Pennsylvania , Philadelphia, PA, USA
                Author notes
                [†]

                Deceased.

                [‡]

                NCI-MATCH co-principal investigators.

                [§]

                Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.

                Correspondence to: Peter J. O’Dwyer, MD, Division of Hematology Oncology, Perelman Center for Advanced Medicine, 10th Floor, South Pavilion, Office #10-301, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA (e-mail: peter.odwyer@ 123456uphs.upenn.edu ).
                Article
                djz245
                10.1093/jnci/djz245
                7566320
                31922567
                © The Author(s) 2019. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contactjournals.permissions@oup.com

                Page count
                Pages: 9
                Product
                Funding
                Funded by: ECOG-ACRIN Cancer Research Group;
                Funded by: National Cancer Institute of the National Institutes of Health;
                Award ID: CA180820
                Award ID: CA180794
                Award ID: CA180858
                Award ID: CA180870
                Award ID: CA180867
                Award ID: CA180857
                Award ID: CA180853
                Categories
                Articles

                Oncology & Radiotherapy

                Comments

                Comment on this article