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000169711 1001_ $$00000-0001-7292-1114$$aTan, Aaron C$$b0
000169711 245__ $$aSystematic review of combinations of targeted or immunotherapy in advanced solid tumors.
000169711 260__ $$aLondon$$bBioMed Central$$c2021
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000169711 520__ $$aWith 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.
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000169711 650_7 $$2Other$$aclinical trials as topic
000169711 650_7 $$2Other$$acombination
000169711 650_7 $$2Other$$adrug therapy
000169711 650_7 $$2Other$$aimmunotherapy
000169711 7001_ $$aBagley, Stephen J$$b1
000169711 7001_ $$aWen, Patrick Y$$b2
000169711 7001_ $$aLim, Michael$$b3
000169711 7001_ $$0P:(DE-He78)5ef8651b0f857b9c640aa5b1498c43b5$$aPlatten, Michael$$b4
000169711 7001_ $$aColman, Howard$$b5
000169711 7001_ $$aAshley, David M$$b6
000169711 7001_ $$0P:(DE-He78)92e9783ca7025f36ce14e12cd348d2ee$$aWick, Wolfgang$$b7$$udkfz
000169711 7001_ $$aChang, Susan M$$b8
000169711 7001_ $$aGalanis, Evanthia$$b9
000169711 7001_ $$aMansouri, Alireza$$b10
000169711 7001_ $$aKhagi, Simon$$b11
000169711 7001_ $$aMehta, Minesh P$$b12
000169711 7001_ $$00000-0002-9970-8695$$aHeimberger, Amy B$$b13
000169711 7001_ $$aPuduvalli, Vinay K$$b14
000169711 7001_ $$aReardon, David A$$b15
000169711 7001_ $$aSahebjam, Solmaz$$b16
000169711 7001_ $$aSimes, John$$b17
000169711 7001_ $$aAntonia, Scott J$$b18
000169711 7001_ $$aBerry, Don$$b19
000169711 7001_ $$00000-0003-3249-9849$$aKhasraw, Mustafa$$b20
000169711 773__ $$0PERI:(DE-600)2719863-7$$a10.1136/jitc-2021-002459$$gVol. 9, no. 7, p. e002459 -$$n7$$pe002459$$tJournal for ImmunoTherapy of Cancer$$v9$$x2051-1426$$y2021
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