Cabozantinib, sunitinib, pazopanib, and tivozanib show similar efficacy for the treatment of metastatic renal cell carcinoma (mRCC), but tivozanib’s safety profile is superior to the profiles of the other 3 tyrosine kinase inhibitor (TKI) drugs, according to the results of a network meta-analysis published in the journal Advances in Therapy.1 Tivozanib is currently approved for the treatment of advanced renal cell carcinoma in Europe2 but is not currently approved for use for this indication in the United States.

For the study, researchers conducted a literature review and network meta-analysis of phase 2/3 randomized controlled trials of approved first-line TKI therapies for mRCC. The researchers searched several major databases, including PubMed, ClinicalTrials.gov and the Cochrane Central Register of Controlled Trials, for related English-language publications using relevant search terms.

The researchers selected progression-free survival (PFS) or in some cases, time-to-progression (TTP) as the measure indicating a drug’s efficacy. The investigators analyzed toxicity by examining the proportion of patients who experienced grade 3/4 adverse events. After conducting the literature search, the authors identified 12 studies involving more than 4200 patients that met the authors’ criteria. The researchers then performed statistical analyses to determine the efficacy and toxicity outcomes.

And, many experts warn that direct comparisons of treatments should only occur in head-to-head randomized controlled trials, as study conditions within each trial vary.


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When the researchers looked at the indirect efficacy of treatments compared with placebo, they noted a significant difference between cabozantinib, sunitinib at standard regimen (50 mg qd 4/2), pazopanib, tivozanib, and sorafenib treatments vs placebo. However, the efficacy of sunitinib (administered at 50 mg qd 2/1 and 37.5 mg continuous daily dose) was not significantly different from placebo.

Cabozantinib appeared to have the highest probability of being the best treatment option in terms of PFS among the TKIs, with a P score .948. In comparison, the P score for sunitinib was .7411, .6914 for pazopanib, and .5988 for tivozanib. But indirect comparison of treatments with cabozantinib showed that there was no significant difference in PFS between the TKIs. This finding, however, did not apply to sorafenib, which was linked to a shorter PFS.

When the authors compared the toxicity of cabozantinib and other TKIs, they found that tivozanib, placebo, and interferon-alpha yielded a lower likelihood of grade 3 or grade 4 adverse events than sunitinib, pazopanib and sorafenib. Other analyses showed that tivozanib was most likely to have the least toxicity compared with the other TKI treatments, and that its safety profile for grade 3/4 adverse events was superior.

“Taken together, it is not possible to produce a clear hierarchy of first-line TKIs based on significant differences in efficacy,” the authors wrote in the paper. “Consequently, the toxicity of these TKIs may play a more significant role in treatment decisions.”

Anas Al-Janadi, MD, vice president of oncology for Spectrum Health Cancer Center in Grand Rapids, Michigan, who was not involved in the study, said that the finding about the equal efficacy of the drugs was not unexpected. However, “the statement about toxicity may not reflect a true difference between the drugs and it might be simply as a result of improved clinical skills of treating physicians and better knowledge and management of expected toxicities,” he said.

Thomas Bradley, MD, the system head of genitourinary oncology at Northwell Health Cancer Institute in Lake Success, New York, who was not involved in the new research, pointed out that tivozanib is not approved in the US. The FDA declined to approve the drug after trial results showed an inferior overall survival rate for tivozanib compared with sorafenib even though the PFS was superior in the tivozanib arm, he said.

Disclosure: EUSA Pharma (UK) Ltd. funded the development of the original study.

References

  1. Manz KM, Fenchel K, Eilers A, et al. Efficacy and safety of approved first-line tyrosine kinase inhibitor treatments in metastatic renal cell carcinoma: a network meta-analysis [published online December 14, 2019]. Adv Ther. doi: 10.1007/s12325-019-01167-2
  2. AVEO Oncology. AVEO Oncology announces FOTIVDA® (tivozanib) approved in the European Union for the treatment of advanced renal cell carcinoma. Published August 28, 2017. Accessed January 21, 2020.