Tivozanib in renal cell carcinoma: a systematic review of the evidence and its dissemination in the scientific literature

Tivozanib (Fotivda) is an anti-angiogenic tyrosine kinase inhibitor that was denied access to the US market by the Food and Drug Administration (FDA). In contrast, it was granted approval by the European Medicines Agency (EMA) for the treatment of Renal Cell Carcinoma in adults. Given the conflictin...

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Bibliographic Details
Published in:	BMC cancer Vol. 22; no. 1; p. 381
Main Authors:	Caquelin, Laura, Gewily, Mohamed, Mottais, Wendy, Tebaldi, Chloé, Laviolle, Bruno, Naudet, Florian, Locher, Clara
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 09-04-2022 BioMed Central BMC
Subjects:	Adult Angiogenesis Angiogenesis inhibitors Cancer Carcinoma, Renal cell Carcinoma, Renal Cell - pathology Citation analysis Clinical trials Co authorship Design Drug approval Drug therapy Efficacy Enzyme inhibitors FDA approval Humans Kidney cancer Kidney Neoplasms - pathology Licensing, certification and accreditation Life Sciences Oncology Oncology, Experimental Phenylurea Compounds - therapeutic use Protein-tyrosine kinase Quinolines - therapeutic use Renal cell carcinoma Tivozanib France Efficacy Tivozanib Citation analysis Renal cell carcinoma
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Summary:	Tivozanib (Fotivda) is an anti-angiogenic tyrosine kinase inhibitor that was denied access to the US market by the Food and Drug Administration (FDA). In contrast, it was granted approval by the European Medicines Agency (EMA) for the treatment of Renal Cell Carcinoma in adults. Given the conflicting decisions from these regulatory agencies, the objectives of the following study are (i) to critically review the evidence supporting the approval of tivozanib; (ii) to analyse the dissemination of this evidence in the literature by way of a citation analysis. Pivotal trials were searched by two independent reviewers using Medline, Cochrane Library, ClinicalTrials.gov and the European Public Assessment Report. The risk of bias for each trial was then inductively assessed. Articles citing any of these trials were identified using Web of Sciences. Finally, the quality of the citations was evaluated by two independent reviewers according to standard data extraction methods. The search for primary evidence identified two pivotal studies: TIVO-1 upon which the FDA and the EMA decisions were based, and TIVO-3 which was conducted after the agencies' decisions had been issued. The TIVO-1 trial presented several limitations that compromised causal inference, in relation to (i) design (absence of blinding, inappropriate comparator, and one-way crossover), (ii) poor internal consistency in the results for the primary endpoint, (iii) a discrepancy between a benefit observed for progression-free survival (HR: 0.80, 95% CI [0.64-0.99]) and the absence of difference for overall survival (HR: 1.25, 95% CI [0.95 - 1.62]). Our citation search protocol identified 229 articles that cited TIVO-1 in the 7 years following its publication, among which 151 (65.9%) citing articles discussing efficacy. Presence of spin was identified in 64 (42.4%) of these 151 citing articles, and 39 (25.8%) additional articles citing results without providing enough elements to interpret the TIVO-1 results. EMA's approval was based on a single pivotal trial presenting critical limitations, rendering the results from the trial potentially inconclusive. The broad dissemination of TIVO-1 results in the scientific literature may have been affected by spin or results were presented in an inadequate critical manner.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	1471-2407 1471-2407
DOI:	10.1186/s12885-022-09475-7