Systematic review of combinations of targeted or immunotherapy in advanced solid tumors
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 con...
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BMJ Publishing Group
2021-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/7/e002459.full |
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| author | Mustafa Khasraw Susan M Chang Amy B Heimberger Michael Lim John Simes Solmaz Sahebjam Michael Platten Wolfgang Wick David M Ashley Patrick Y Wen Aaron C Tan Stephen J Bagley Howard Colman Evanthia Galanis Alireza Mansouri Simon Khagi Minesh P Mehta Vinay K Puduvalli Scott J Antonia Don Berry |
| author_facet | Mustafa Khasraw Susan M Chang Amy B Heimberger Michael Lim John Simes Solmaz Sahebjam Michael Platten Wolfgang Wick David M Ashley Patrick Y Wen Aaron C Tan Stephen J Bagley Howard Colman Evanthia Galanis Alireza Mansouri Simon Khagi Minesh P Mehta Vinay K Puduvalli Scott J Antonia Don Berry |
| author_sort | Mustafa Khasraw |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5fb3fb4dbf464e6b9e23b9714b84f3ae |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-07-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-5fb3fb4dbf464e6b9e23b9714b84f3ae2025-08-20T02:12:46ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-07-019710.1136/jitc-2021-002459Systematic review of combinations of targeted or immunotherapy in advanced solid tumorsMustafa Khasraw0Susan M Chang1Amy B Heimberger2Michael Lim3John Simes4Solmaz Sahebjam5Michael Platten6Wolfgang Wick7David M Ashley8Patrick Y Wen9Aaron C Tan10Stephen J Bagley11Howard Colman12Evanthia Galanis13Alireza Mansouri14Simon Khagi15Minesh P Mehta16Vinay K Puduvalli17Scott J Antonia18Don Berry19Duke Cancer Institute, Duke University, Durham, North Carolina, USA2 Department of Neurosurgery, University of California San Francisco, San Francisco, California, USADepartment of Neurosurgery, Northwestern University, Chicago, Illinois, USADepartment of Neurosurgery, Stanford University, Stanford, California, USA4 NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia15Moffitt Cancer Center, Tampa, FL, USAGerman Cancer Consortium (DKTK), Clinical Cooperation Unit (CCU), Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, GermanyDepartment of Neurology, Heidelberg University Hospital, Heidelberg, GermanyDuke Cancer Institute, Duke University, Durham, North Carolina, USACenter for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADivision of Medical Oncology, National Cancer Centre Singapore, SingaporeAbramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USAHuntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USADivision of Medical Oncology, Mayo Clinic Rochester, Rochester, Minnesota, USANeurosurgery, Penn State Cancer Institute, Hershey, Pennsylvania, USADivision of Medical Oncology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USADepartment of Radiation Oncology, Miami Cancer Institute, Miami, Florida, USADepartment of Neurooncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA2Duke University, Durham, NC, USADepartment of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USAWith 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.https://jitc.bmj.com/content/9/7/e002459.full |
| spellingShingle | Mustafa Khasraw Susan M Chang Amy B Heimberger Michael Lim John Simes Solmaz Sahebjam Michael Platten Wolfgang Wick David M Ashley Patrick Y Wen Aaron C Tan Stephen J Bagley Howard Colman Evanthia Galanis Alireza Mansouri Simon Khagi Minesh P Mehta Vinay K Puduvalli Scott J Antonia Don Berry Systematic review of combinations of targeted or immunotherapy in advanced solid tumors Journal for ImmunoTherapy of Cancer |
| title | Systematic review of combinations of targeted or immunotherapy in advanced solid tumors |
| title_full | Systematic review of combinations of targeted or immunotherapy in advanced solid tumors |
| title_fullStr | Systematic review of combinations of targeted or immunotherapy in advanced solid tumors |
| title_full_unstemmed | Systematic review of combinations of targeted or immunotherapy in advanced solid tumors |
| title_short | Systematic review of combinations of targeted or immunotherapy in advanced solid tumors |
| title_sort | systematic review of combinations of targeted or immunotherapy in advanced solid tumors |
| url | https://jitc.bmj.com/content/9/7/e002459.full |
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