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Patient-centric trials for therapeutic development in precision oncology

Nature volume 526, pages 361–370 (2015)Cite this article

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Abstract

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine.

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Figure 1: Randomized controlled trial designs for defining and testing precision-medicine strategies.
Figure 2: Design principles that generate efficiencies in clinical trials of targeted therapies.
Figure 3: Master protocols for therapeutic development: a framework for the clinical testing of precision-oncology strategies — or 'finding the trial for the patient'.
Figure 4: Adaptive study designs.
Figure 5: Early stratified therapeutic development.
Figure 6: Clinical-testing strategies.

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References

  1. Chin, L. & Gray, J. W. Translating insights from the cancer genome into clinical practice. Nature 452, 553–563 (2008). A review that outlines the opportunities, challenges and approaches associated with the advancement of genomics-based medicine.

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  2. Stratton, M. R. Exploring the genomes of cancer cells: progress and promise. Science 331, 1553–1558 (2011).

    Article  CAS  ADS  PubMed  Google Scholar 

  3. Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009). A review of recent progress in cancer genomics and the potential of its application to medicine.

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  4. Hudson, T. J. et al. International network of cancer genome projects. Nature 464, 993–998 (2010); erratum 465, 966 (2010).

    Article  CAS  ADS  PubMed  Google Scholar 

  5. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008); erratum 494, 506 (2013).

  6. Chin, L., Andersen, J. N. & Futreal, P. A. Cancer genomics: from discovery science to personalized medicine. Nature Med. 17, 297–303 (2011). A review that addresses the accumulating knowledge acquired through large-scale genomic sequencing efforts and discusses strategies for translating these discoveries into patient care.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang, B. et al. Proteogenomic characterization of human colon and rectal cancer. Nature 513, 382–387 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Verweij, J. et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364, 1127–1134 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Gerber, D. E. & Minna, J. D. ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. Cancer Cell 18, 548–551 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sosman, J. A. et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 366, 707–714 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Slamon, D. et al. Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 365, 1273–1283 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Ledermann, J. et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 15, 852–861 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Kris, M. G. et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. J. Am. Med. Assoc. 311, 1998–2006 (2014).

    Article  CAS  Google Scholar 

  16. Jänne, P. A. et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 372, 1689–1699 (2015).

    Article  PubMed  Google Scholar 

  17. Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Green, E. D., Guyer, M. S. & National Human Genome Research Institute. Charting a course for genomic medicine from base pairs to bedside. Nature 470, 204–213 (2011). A Perspective article that describes the past, present and future trajectories of genomic medicine.

    Article  CAS  PubMed  Google Scholar 

  19. Von Hoff, D. D. et al. Pilot study using molecular profiling of patients' tumors to find potential targets and select treatments for their refractory cancers. J. Clin. Oncol. 28, 4877–4883 (2010). This paper and refs 20 and 21 are some of the first descriptions of the use of molecular targeted therapies to improve patient outcomes.

    Article  CAS  PubMed  Google Scholar 

  20. Tsimberidou, A.-M. et al. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin. Cancer Res. 18, 6373–6383 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hollebecque, A. et al. Molecular screening for cancer treatment optimization (MOSCATO 01): a prospective molecular triage trial — interim results. J. Clin. Oncol. 31, 2512 (2013).

    Google Scholar 

  22. Dienstmann, R. et al. Molecular profiling of patients with colorectal cancer and matched targeted therapy in phase I clinical trials. Mol. Cancer Ther. 11, 2062–2071 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Association of the British Pharmaceutical Industry. The Stratification of Disease for Personalised Medicines http://www.abpi.org.uk/our-work/library/medical-disease/Documents/strat_med.pdf (2014).

  24. The Academy of Medical Sciences. Realising the Potential of Stratified Medicine https://www.acmedsci.ac.uk/viewFile/51e915f9f09fb.pdf (2013).

  25. Cook, D. et al. Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework. Nature Rev. Drug Discov. 13, 419–431 (2014).

    Article  CAS  Google Scholar 

  26. Lee, C. K., Lord, S. J., Coates, A. S. & Simes, R. J. Molecular biomarkers to individualise treatment: assessing the evidence. Med. J. Aust. 190, 631–636 (2009).

    Article  PubMed  Google Scholar 

  27. Sargent, D. J., Conley, B. A., Allegra, C. & Collette, L. Clinical trial designs for predictive marker validation in cancer treatment trials. J. Clin. Oncol. 23, 2020–2027 (2005). A description of the fundamental basis of clinical-trial designs that are used to assess biomarkers.

    Article  PubMed  Google Scholar 

  28. Mandrekar, S. J. & Sargent, D. J. Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. J. Clin. Oncol. 27, 4027–4034 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Printz, C. Failure rate: why many cancer drugs don't receive FDA approval, and what can be done about it. Cancer 121, 1529–1530 (2015).

    Article  PubMed  Google Scholar 

  30. Sleijfer, S., Bogaerts, J. & Siu, L. L. Designing transformative clinical trials in the cancer genome era. J. Clin. Oncol. 31, 1834–1841 (2013).

    Article  PubMed  Google Scholar 

  31. Kim, E. S. et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 1, 44–53 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Esserman, L. J. et al. Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res. Treat. 132, 1049–1062 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Esserman, L. J. et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL–CALGB 150007/150012, ACRIN 6657. J. Clin. Oncol. 30, 3242–3249 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hylton, N. M. et al. Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy–results from ACRIN 6657/I-SPY TRIAL. Radiology 263, 663–672 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lin, C. et al. Locally advanced breast cancers are more likely to present as Interval Cancers: results from the I-SPY 1 TRIAL (CALGB 150007/150012, ACRIN 6657, InterSPORE Trial). Breast Cancer Res. Treat. 132, 871–879 (2012).

    Article  PubMed  Google Scholar 

  36. Lindsay, C. R., Shaw, E., Walker, I. & Johnson, P. W. Lessons for molecular diagnostics in oncology from the Cancer Research UK Stratified Medicine Programme. Expert Rev. Mol. Diagn. 15, 287–289 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Le, D. T. et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Le Tourneau, C. et al. Designs and challenges for personalized medicine studies in oncology: focus on the SHIVA trial. Target. Oncol. 7, 253–265 (2012).

    Article  PubMed  Google Scholar 

  39. Le Tourneau, C. et al. Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer: results of the SHIVA trial. J. Clin. Oncol. 33, 11113 (2015).

    Article  Google Scholar 

  40. Watson, I. R., Takahashi, K., Futreal, P. A. & Chin, L. Emerging patterns of somatic mutations in cancer. Nature Rev. Genet. 14, 703–718 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. US Food and Drug Administration. Nucleic Acid Based Tests. US Food and Drug Administration http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm330711.htm (2015).

  42. US Food and Drug Administration. List of Cleared or Approved Companion Diagnostic Devices (In vitro and Imaging Tools). US Food and Drug Administration http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm (2015).

  43. US Food and Drug Administration. Drug Approvals and Databases. US Food and Drug Administration http://www.fda.gov/Drugs/InformationOnDrugs/ (2015).

  44. European Medicines Agency. European public assessment reports. European Medicines Agency http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125 (2015).

  45. Hay, M., Thomas, D. W., Craighead, J. L., Economides, C. & Rosenthal, J. Clinical development success rates for investigational drugs. Nature Biotechnol. 32, 40–51 (2014).

    Article  CAS  Google Scholar 

  46. Yap, T. A., Sandhu, S. K., Workman, P. & de Bono, J. S. Envisioning the future of early anticancer drug development. Nature Rev. Cancer 10, 514–523 (2010).

    Article  CAS  Google Scholar 

  47. Chantrill, L. A. et al. Precision medicine for advanced pancreas cancer: the Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial. Clin. Cancer Res. 21, 2029–2037 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. National Cancer Institute Molecular Analysis for Therapy Choice http://deainfo.nci.nih.gov/advisory/ncab/164_1213/Conley.pdf.

  49. Lung Cancer Master Protocol (Lung-MAP) Clinical Trials. About Lung-MAP. Lung-MAP http://www.lung-map.org/about-lung-map (2015).

  50. EORTC. About SPECTAColor. SPECTAColor EORTC Colorectal Cancer Screening Platform http://spectacolor.eortc.org/about (2015).

  51. EORTC. EORTC, through SPECTAlung, participates in EU consortium validating blood-based cancer biomarkers. EORTC The future of cancer therapy http://www.eortc.org/news/eortc-through-spectalung-participates-in-european-consortium-validating-blood-based-cancer-biomarkers/ (2015).

  52. Zardavas, D. et al. The AURORA initiative for metastatic breast cancer. Br. J. Cancer 111, 1881–1887 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Matsumoto, S. et al. Nationwide genomic screening network for the development of novel targeted therapies in advanced non-small cell lung cancer (LC-SCRUM-Japan). J. Clin. Oncol. 33 (suppl. 15), 8093 (2015).

    Article  Google Scholar 

  54. Kalf, R. R. et al. Variations in predicted risks in personal genome testing for common complex diseases. Genet. Med. 16, 85–91 (2014).

    Article  PubMed  Google Scholar 

  55. Roper, N., Stensland, K. D., Hendricks, R. & Galsky, M. D. The landscape of precision cancer medicine clinical trials in the United States. Cancer Treat. Rev. 41, 385–390 (2015).

    Article  PubMed  Google Scholar 

  56. Simon, R. & Roychowdhury, S. Implementing personalized cancer genomics in clinical trials. Nature Rev. Drug Discov. 12, 358–369 (2013).

    Article  CAS  Google Scholar 

  57. Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015). A report that demonstrates how different genomic readouts could be important biomarkers for therapeutic responsiveness.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Campbell, P. J. & Stratton, M. R. Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 3, 246–259 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Frampton, G. M. et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nature Biotechnol. 31, 1023–1031 (2013).

    Article  CAS  Google Scholar 

  60. Dawson, S. J. et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368, 1199–1209 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Douillard, J. Y. et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J. Thorac. Oncol. 9, 1345–1353 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lewin, J. & Siu, L. L. Cancer genomics: the challenge of drug accessibility. Curr. Opin. Oncol. 27, 250–257 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Lara, P. N. Jr et al. Prospective evaluation of cancer clinical trial accrual patterns: identifying potential barriers to enrollment. J. Clin. Oncol. 19, 1728–1733 (2001).

    Article  PubMed  Google Scholar 

  64. Institute of Medicine. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary (The National Academies Press, 2010). Part of a report from a workshop at which issues relating to clinical-trial-recruitment statistics were presented and specific challenges were identified.

  65. Cancer Research UK. Stratified medicine and the lung cancer 'Matrix' trial — part of a cancer care revolution. Cancer Research UK http://scienceblog.cancerresearchuk.org/2014/04/17/stratified-medicine-and-the-lung-cancer-matrix-trial-part-of-a-cancer-care-revolution (2014).

  66. Tam, A. L. et al. Feasibility of image-guided transthoracic core-needle biopsy in the BATTLE lung trial. J. Thorac. Oncol. 8, 436–442 (2013).

    Article  PubMed  Google Scholar 

  67. Seguin, L. et al. An integrin β3–KRAS–RalB complex drives tumour stemness and resistance to EGFR inhibition. Nature Cell Biology. 16, 457–468 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. ISPY-2 Clinical Trials. About. I-SPY 2 TRIAL http://ispy2.org/about (2015).

  69. Barker, A. D. et al. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin. Pharmacol. Ther. 86, 97–100 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. National Institutes of Health. Molecular profiling-based assignment of cancer therapy for patients with advanced solid tumors. National Institutes of Health Clinical Center http://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2013-C-0105.html.

  71. TrialReach. Clinical study for patients with cancer (Ve-Basket 120326). TrialReach http://trialreach.com/study/clinical-study-for-patients-with-cancer-ve-basket-/CT120326/ (2012).

  72. Worldwide International Networking. WIN Clinical Trials/Scientific Projects. Worldwide International Networking in personalised cancer medicine http://www.winconsortium.org/page.jsp?id=104.

  73. André, F. et al. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol. 15, 267–274 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Medical Research Council Clinical Trials Unit. Welcome to FOCUS4. FOCUS4 Molecular selection of therapy in metastatic colorectal cancer: a molecularly stratified randomised controlled trial programme http://www.focus4trial.org/ (2014).

  75. Biankin, A. V. & Hudson, T. J. Somatic variation and cancer: therapies lost in the mix. Hum. Genet. 130, 79–91 (2011). A review article that addresses the challenges presented by the molecular diversity in cancer that is uncovered through genomic sequencing.

    Article  PubMed  Google Scholar 

  76. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank A. Ewing for her assistance in compiling the manuscript. They also thank L. Musgrove, D. Chang and P. Bailey for proofreading the manuscript and for their helpful suggestions.

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Authors and Affiliations

  1. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, Scotland, UK

    Andrew V. Biankin

  2. Cancer Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, 2010, New South Wales, Australia

    Andrew V. Biankin

  3. Department of Surgery, Bankstown Hospital, Sydney, 2200, New South Wales, Australia

    Andrew V. Biankin

  4. South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, 2170, New South Wales, Australia

    Andrew V. Biankin

  5. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, 90095, California, USA

    Steven Piantadosi

  6. Innovative Medicines & Early Development Oncology, AstraZeneca, Cambridge Science Park, Cambridge, CB4 0FZ, UK

    Simon J. Hollingsworth

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Correspondence to Andrew V. Biankin.

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Biankin, A., Piantadosi, S. & Hollingsworth, S. Patient-centric trials for therapeutic development in precision oncology. Nature 526, 361–370 (2015). https://doi.org/10.1038/nature15819

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