Tivozanib improved PFS but not OS in renal cell carcinoma

Tivozanib extended PFS but conferred no improvement in OS compared with sorafenib in patients with metastatic renal cell carcinoma, according to results of a phase 3 trial.

The trial was designed to evaluate tivozanib (AVEO Oncology and Astellas Pharma) — a selective tyrosine kinase inhibitor of VEGF receptor-1, -2, and -3 — as first-line targeted therapy in patients with a clear cell component, prior nephrectomy, measurable disease, and zero or one previous treatments.

The study included 517 patients; of them, 260 received tivozanib and 257 received sorafenib (Nexavar, Bayer Healthcare).

Study protocols called for the exclusion of patients with VEGF-targeted therapy and mammalian target of rapamycin inhibitor experience.

PFS assessed by independent review served as the primary outcome measure.

Overall, median PFS was 11.9 months in the tivozanib group and 9.1 months in the sorafenib group (HR=0.797; 95% CI, 0.639-0.993). More than half (61%) of patients in the sorafenib group with disease progression crossed over and received tivozanib.

Median OS was 29.3 months in the sorafenib arm and 28.8 months in the tivozanib arm (HR=1.245; 95% CI, 0.954-1.624).

Patients in the tivozanib arm demonstrated higher rates of hypertension (44% vs. 34%) and dysphonia (21% vs. 5%). Incidence of hand-foot skin reaction (54% vs. 14%) and diarrhea (33% vs. 23%) were higher in the sorafenib arm.

Marc B. Garnick

Marc B. Garnick, MD, a professor in the department of medicine at Beth Israel Deaconess Medical Center, raised questions about the study protocols in an accompanying editorial.

“[The study design] had features that have made it difficult to fully appreciate the potential importance of [tivozanib],” Garnick wrote. “Though some aficionados may have argued that sunitinib [Sutent, Pfizer] may have been a more logical and robust comparator for first-line renal cell carcinoma therapy, at the time of study creation, sorafenib provided a very realistic and wholesome test of tivozanib activity.”

Garnick acknowledged that tivozanib shows promise in metastatic disease, but that the lack of availability of TKIs in Eastern Europe may have limited crossover rates. This could have, in turn, compromised OS as an endpoint.

“In particular, differences in OS in favor of the sorafenib arm could not be adequately assessed because this study represents, in essence, a sequential trial of two agents (sorafenib [to] tivozanib) compared with one agent (tivozanib),” Garnick wrote. “This study design would have been predicted to pose a potential hurdle to overcome in the approval process for tivozanib.”

Garnick described the situation as “painful” for the sponsors, clinicians, researchers and patients involved.

“The lesson is that the approvability of a drug in which the primary endpoint leading to marketing authorization is [PFS] cannot have any study design weaknesses, which even in the most miniscule fashion compromise interpretation of OS,” he wrote.

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Disclosure: The researchers report research funding and honoraria from, employment or leadership positions, and consultant or advisory roles with Astellas, AVEO Pharmaceuticals, Bayer Healthcare, GlaxoSmithKline, Novartis and Pfizer. Garnick reports no relevant financial disclosures.