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RCC: Tivozanib beats sorafenib in later lines

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Place for tivozanib remains unclear

Although tivozanib demonstrated longer progression-free survival and higher tolerability than sorafenib in the recent phase 3 TIVO-3 trial conducted by Rini and colleagues, the role of tivozanib in the treatment of metastatic renal cell carcinoma remains unclear. Critically, treatment with tivozanib in TIVO-3 was not associated with longer median overall survival than treatment with sorafenib.

In contrast, two previous phase 3 trials, METEOR and CheckMate 025, which also involved patients who had received two lines of a vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor, showed that cabozantinib or nivolumab were associated with better overall survival than standard everolimus. While the comparator was different than the TIVO-3 trial, the evidence of benefit from these previous studies is superior, based on larger population size and overall survival advantage.

Therefore, it is too early to recommend a place for tivozanib, or to say that it should be preferred over other VEGFR tyrosine kinase inhibitors.

Axel Bex, MD, PhD, is with the Royal Free London NHS Foundation Trust at the University College London. Dr. Bex reported financial relationships with Pfizer, Ipsen, Novartis, and others. His remarks are adapted from an accompanying editorial (Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30781-8).



For third- or fourth-line treatment of metastatic renal cell carcinoma, the vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor tivozanib may offer better progression-free survival than sorafenib, another VEGFR inhibitor, based on results from the TIVO-3 trial.

Dr. Brian I. Rini, professor of medicine at Case Western Reserve University, Cleveland, and leader of the genitourinary oncology program at the Cleveland Clinic Susan London/MDedge News

Dr. Brian I. Rini

Tivozanib also had fewer dose reductions and dose interruptions than sorafenib, likely because of less off-target activity, reported lead author Brian I. Rini, MD, of the Cleveland Clinic and Case Western Reserve University, also in Cleveland, and colleagues.

“These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy,” the investigators wrote in Lancet Oncology.

The open-label, phase 3 trial involved 350 patients with metastatic renal cell carcinoma who had been treated with two or more systemic therapies, at least one of which was a VEGFR inhibitor. Patients were randomized in 1:1 ratio to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily on a continuous basis. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rates, and duration of response. Endpoints were evaluated by independent review. Safety was reported for all patients who received one or more doses of therapy.

After a median follow-up of 19 months, tivozanib was associated with a median progression-free survival of 5.6 months, compared with 3.9 months for sorafenib (P = .016). Significantly more patients in the tivozanib group achieved a response, and at 1 year, 71% of patients in the tivozanib group maintained a response, compared with 46% of the patients in the sorafenib group. At data cutoff, median overall survival was not significantly different between groups.

The most common treatment-related grade 3-4 adverse event was hypertension, which occurred in a slightly higher rate among those treated with tivozanib (20% vs. 14%). Serious treatment-related adverse events occurred at comparable rates in each treatment arm, at 11% for tivozanib and 10% for sorafenib. Compared with patients who received sorafenib, those in the tivozanib group had fewer dose reductions (24% vs. 38%) and dose interruptions (48% vs. 63%) because of adverse events, a benefit that the investigators attributed to relatively lower class-related off-target activity.

“To our knowledge, TIVO-3 provides the largest amount of prospective data generated to date regarding the use of VEGFR tyrosine kinase inhibitors after checkpoint inhibitor treatment,” the investigators wrote. “Notably, the benefit of tivozanib extended to patients who had previously received checkpoint inhibitors and those treated with two previous tyrosine kinase inhibitors.”

The study was funded by AVEO Oncology. The investigators reported additional relationships with Pfizer, Eisai, Astellas, and others.

SOURCE: Rini BI et al. Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30735-1.

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