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Tan AC, Bagley SJ, Wen PY, et al. Systematic review of combinations of targeted or immunotherapy in advanced solid tumors. J Immunother Cancer. 2021;9(7)doi: 10.1136/jitc-2021-002459.
Tan, A. C., Bagley, S. J., Wen, P. Y., Lim, M., Platten, M., Colman, H., Ashley, D. M., Wick, W., Chang, S. M., Galanis, E., Mansouri, A., Khagi, S., Mehta, M. P., Heimberger, A. B., Puduvalli, V. K., Reardon, D. A., Sahebjam, S., Simes, J., Antonia, S. J., Berry, D., & Khasraw, M. (2021). Systematic review of combinations of targeted or immunotherapy in advanced solid tumors. Journal for immunotherapy of cancer, 9(7), . https://doi.org/10.1136/jitc-2021-002459
Tan, Aaron C, et al. "Systematic review of combinations of targeted or immunotherapy in advanced solid tumors." Journal for immunotherapy of cancer vol. 9,7 (2021). doi: https://doi.org/10.1136/jitc-2021-002459
Tan AC, Bagley SJ, Wen PY, Lim M, Platten M, Colman H, Ashley DM, Wick W, Chang SM, Galanis E, Mansouri A, Khagi S, Mehta MP, Heimberger AB, Puduvalli VK, Reardon DA, Sahebjam S, Simes J, Antonia SJ, Berry D, Khasraw M. Systematic review of combinations of targeted or immunotherapy in advanced solid tumors. J Immunother Cancer. 2021 Jul;9(7). doi: 10.1136/jitc-2021-002459. PMID: 34215688; PMCID: PMC8256733.
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J Immunother Cancer. 2021 Jul;9(7). doi: 10.1136/jitc-2021-002459.

Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.

Journal for immunotherapy of cancer

Aaron C Tan, Stephen J Bagley, Patrick Y Wen, Michael Lim, Michael Platten, Howard Colman, David M Ashley, Wolfgang Wick, Susan M Chang, Evanthia Galanis, Alireza Mansouri, Simon Khagi, Minesh P Mehta, Amy B Heimberger, Vinay K Puduvalli, David A Reardon, Solmaz Sahebjam, John Simes, Scott J Antonia, Don Berry, Mustafa Khasraw

Affiliations

  1. Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
  2. Duke-NUS Medical School, National University of Singapore, Singapore.
  3. Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  4. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  5. Department of Neurosurgery, Stanford University, Stanford, California, USA.
  6. Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
  7. DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Centre, Heidelberg, Germany.
  8. Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
  9. Duke Cancer Institute, Duke University, Durham, North Carolina, USA.
  10. Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
  11. Division of Medical Oncology, Mayo Clinic Rochester, Rochester, Minnesota, USA.
  12. Department of Neurosurgery, Penn State Cancer Institute, Hershey, Pennsylvania, USA.
  13. Division of Medical Oncology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
  14. Department of Radiation Oncology, Miami Cancer Institute, Miami, Florida, USA.
  15. Department of Neurosurgery, Northwestern University, Chicago, Illinois, USA.
  16. Department of Neurooncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  17. Department of Neuro-oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
  18. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia.
  19. Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  20. Duke Cancer Institute, Duke University, Durham, North Carolina, USA [email protected].

PMID: 34215688 PMCID: PMC8256733 DOI: 10.1136/jitc-2021-002459

Abstract

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords: clinical trials as topic; combination; drug therapy; immunotherapy

Conflict of interest statement

Competing interests: ACT reports consultant or advisory roles for Amgen. SJB reports research grants from Incyte, Eli Lilly, Novocure, GSK; consultant or advisory roles for Bayer and Novocure; and US

References

  1. Ann Oncol. 2006 Jun;17(6):952-6 - PubMed
  2. Cancer Discov. 2011 Nov;1(6):508-23 - PubMed
  3. Lancet Oncol. 2020 Oct;21(10):1353-1365 - PubMed
  4. J Hematol Oncol. 2014 Oct 03;7:70 - PubMed
  5. JAMA Oncol. 2019 Jul 1;5(7):934-935 - PubMed
  6. Cancer Discov. 2012 Mar;2(3):227-35 - PubMed
  7. Lancet Oncol. 2019 Jun;20(6):849-861 - PubMed
  8. Nat Rev Clin Oncol. 2018 May;15(5):325-340 - PubMed
  9. J Natl Cancer Inst. 2017 Sep 1;109(9): - PubMed
  10. PLoS One. 2019 Feb 27;14(2):e0212513 - PubMed
  11. Clin Cancer Res. 2015 Apr 1;21(7):1639-51 - PubMed
  12. Lancet Oncol. 2018 Apr;19(4):451-460 - PubMed
  13. J Clin Oncol. 2012 Jun 10;30(17):2046-54 - PubMed
  14. Lancet Oncol. 2010 Aug;11(8):753-62 - PubMed
  15. Ann Oncol. 2018 Jan 1;29(1):154-161 - PubMed
  16. Clin Cancer Res. 2007 May 1;13(9):2728-37 - PubMed
  17. Nat Rev Cancer. 2015 Aug;15(8):457-72 - PubMed
  18. Sci Transl Med. 2017 Apr 12;9(385): - PubMed
  19. Future Oncol. 2017 Feb;13(4):307-320 - PubMed
  20. Cell. 2017 Dec 14;171(7):1678-1691.e13 - PubMed
  21. Immunity. 2016 Mar 15;44(3):609-621 - PubMed
  22. Cancer Res. 2008 Nov 1;68(21):8643-53 - PubMed
  23. Gynecol Oncol. 2020 Mar;156(3):575-582 - PubMed
  24. N Engl J Med. 2007 Nov 15;357(20):2040-8 - PubMed
  25. Lancet. 2019 Jun 15;393(10189):2404-2415 - PubMed
  26. Nat Rev Clin Oncol. 2014 Feb;11(2):81-90 - PubMed
  27. JCO Precis Oncol. 2019 Oct 24;3: - PubMed
  28. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4275-80 - PubMed
  29. Nature. 2012 Jan 26;483(7387):100-3 - PubMed
  30. Front Immunol. 2018 May 03;9:978 - PubMed
  31. Ann Oncol. 2020 May;31(5):609-618 - PubMed
  32. Clin Cancer Res. 2014 Apr 1;20(7):1965-77 - PubMed
  33. J Natl Cancer Inst. 2020 Feb 1;112(2):128-135 - PubMed
  34. Ann Oncol. 2020 Mar;31(3):412-421 - PubMed
  35. Clin Cancer Res. 2017 Aug 1;23(15):4066-4076 - PubMed
  36. Clin Cancer Res. 2016 Nov 15;22(22):5461-5471 - PubMed
  37. J Clin Oncol. 2015 Dec 1;33(34):4032-8 - PubMed
  38. Immunity. 2020 Jan 14;52(1):17-35 - PubMed
  39. Lancet Oncol. 2018 Apr;19(4):521-536 - PubMed
  40. Clin Exp Immunol. 2013 Jun;172(3):500-6 - PubMed
  41. PLoS One. 2013 Jul 03;8(7):e67583 - PubMed
  42. Cancer Sci. 2018 Dec;109(12):3993-4002 - PubMed
  43. Mol Cancer Ther. 2016 Apr;15(4):533-47 - PubMed
  44. Clin Cancer Res. 2017 Sep 15;23(18):5339-5348 - PubMed
  45. N Engl J Med. 2018 Apr 05;378(14):1277-1290 - PubMed
  46. N Engl J Med. 2019 Oct 24;381(17):1632-1643 - PubMed
  47. Clin Cancer Res. 2021 Mar 1;27(5):1236-1241 - PubMed
  48. Clin Cancer Res. 2017 Sep 1;23(17):4959-4969 - PubMed
  49. Sci Signal. 2010 Nov 23;3(149):ra84 - PubMed
  50. N Engl J Med. 2015 Aug 20;373(8):726-36 - PubMed
  51. J Natl Cancer Inst. 2019 Feb 1;111(2):118-128 - PubMed
  52. Invest New Drugs. 2016 Oct;34(5):604-13 - PubMed
  53. Cancer Discov. 2014 Jan;4(1):94-109 - PubMed
  54. N Engl J Med. 2018 May 31;378(22):2093-2104 - PubMed
  55. Nat Biotechnol. 2012 Jul 10;30(7):679-92 - PubMed
  56. Clin Cancer Res. 2017 Sep 1;23(17):4980-4991 - PubMed
  57. J Clin Oncol. 2015 May 1;33(13):1430-7 - PubMed
  58. J Immunother. 2007 Nov-Dec;30(8):825-30 - PubMed
  59. Cancer Res. 2013 Jun 15;73(12):3591-603 - PubMed
  60. Lancet Oncol. 2019 Apr;20(4):518-530 - PubMed
  61. Ann Oncol. 2017 Jan 1;28(1):34-43 - PubMed
  62. JAMA Oncol. 2020 May 1;6(5):661-674 - PubMed
  63. Pharmacoepidemiol Drug Saf. 2020 Oct;29(10):1201-1212 - PubMed
  64. N Engl J Med. 2019 Mar 21;380(12):1103-1115 - PubMed
  65. N Engl J Med. 2012 Jan 12;366(2):109-19 - PubMed
  66. Ann Oncol. 2019 Jan 1;30(1):44-56 - PubMed
  67. N Engl J Med. 2017 Oct 5;377(14):1345-1356 - PubMed
  68. Clin Cancer Res. 2018 Feb 15;24(4):737-743 - PubMed
  69. Lancet Oncol. 2019 May;20(5):711-718 - PubMed
  70. J Clin Oncol. 2018 Jan 1;36(1):7-13 - PubMed
  71. Lancet Oncol. 2018 May;19(5):603-615 - PubMed
  72. Clin Cancer Res. 2015 Dec 15;21(24):5519-31 - PubMed
  73. N Engl J Med. 2019 Nov 21;381(21):2020-2031 - PubMed
  74. Br J Cancer. 2010 Jun 8;102(12):1724-30 - PubMed
  75. Nat Rev Cancer. 2017 Apr;17(4):239-253 - PubMed
  76. J Clin Oncol. 2017 Aug 1;35(22):2535-2541 - PubMed
  77. Clin Cancer Res. 2020 Oct 1;26(19):5062-5067 - PubMed
  78. Cancer Discov. 2016 Sep;6(9):956-62 - PubMed
  79. Lancet Oncol. 2013 Mar;14(3):249-56 - PubMed
  80. Lancet. 2011 Dec 3;378(9807):1931-9 - PubMed
  81. PLoS One. 2016 Sep 09;11(9):e0161779 - PubMed
  82. Cancer Discov. 2018 Nov;8(11):1358-1365 - PubMed
  83. J Pharmacol Exp Ther. 2014 Jun;349(3):408-16 - PubMed
  84. N Engl J Med. 2017 Jun 22;376(25):2415-2426 - PubMed
  85. N Engl J Med. 2014 Nov 13;371(20):1877-88 - PubMed
  86. Clin Cancer Res. 2013 Feb 1;19(3):657-67 - PubMed
  87. Ann Oncol. 2018 Jan 1;29(1):84-91 - PubMed
  88. Front Oncol. 2015 Sep 22;5:202 - PubMed
  89. Nat Med. 2017 Oct 6;23(10):1113 - PubMed
  90. N Engl J Med. 2014 Nov 13;371(20):1867-76 - PubMed

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