Tivozanib Prolongs PFS in Refractory Kidney Cancer

By Marilynn Larkin

December 20, 2019

NEW YORK (Reuters Health) - In patients with refractory renal cell carcinoma (RCC), third- or fourth-line tivozanib improved progression-free survival and was better tolerated than sorafenib, a pivotal study shows.

"The study adds a novel option for patients with previously treated RCC," Dr. Brian Rini of Cleveland Clinic in Ohio told Reuters Health by email. "If FDA approved, this would represent a unique standard of care. There are currently no drugs that specifically address the third- and fourth-line space. Tivozanib may represent an option, therefore, for these patients."

The open-label randomized controlled trial included 350 RCC patients from 120 academic centers in 12 countries who failed at least two previous systemic treatments, including at least one previous treatment with a VEGFR inhibitor.

Patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk category and type of previous therapy and randomized to either tivozanib 1.5 mg orally once daily in four-week cycles or sorafenib 400 mg orally twice daily, continuously.

As reported in The Lancet Oncology, the patients (mostly white; mean age, about 62.5; about 73% men) were enrolled between 2016-2017 and followed for a median of 19 months.

Median progression-free survival was significantly longer with tivozanib: 5.6 months, versus 3.9 months for sorafenib (hazard ratio, 0.73).

The most common grade 3 or 4 treatment-related adverse event was hypertension: 20% with tivozanib versus 14% with sorafenib. Serious treatment-related adverse events occurred in 11% of patients on tivozanib and 10% of those on sorafenib.

No treatment-related deaths were reported.

Dr. Alex Bex of University College London, UK, author of a related editorial, commented in an email to Reuters Health, "Pembrolizumab plus axitinib and nivolumab plus ipilimumab are the new standard of care for front-line therapy in metastatic clear-cell RCC."

"Randomized data on patients with disease refractory to either of these combinations in a first-line setting are lacking," he noted. "There is uncertainty about subsequent therapies and results from trials investigating further lines of treatment after immune checkpoint inhibitor therapy are therefore urgently needed."

The current study was closed for accrual before new first-line combination therapies were approved, and patients therefore likely received the old standard of first- and subsequent lines of VEGFR-TKI, including second- or third-line nivolumab, he said.

"Owing to recent changes in the treatment algorithm of metastatic clear-cell RCC and the small sample size of the stratified patient subgroups, it is difficult to predict the role tivozanib might have in the sequencing of therapies, in addition to available agents such as cabozantinib," he noted.

"With immune checkpoint inhibitor combination therapy now in front-line, indications for VEGFR-TKI in first-or second-line sequenced by nivolumab are reducing," he said. Based on the study data, he added, "it would be inappropriate to infer that tivozanib, which demonstrated superior progression-free survival following a sequence of VEGFR-TKI and immune checkpoint inhibition, should be preferred over any other available VEGFR-TKI for RCC refractory to a combination of these drugs in firstline."

The study was designed and funded by AVEO Oncology, which is developing tivozanib. On November 4, 2019, the US Food and Drug Administration told the company not to proceed with a New Drug Application (NDA) for RCC. The company is expected to narrow its proposed indication to relapsed/refractory RCC and apply for an NDA in 2020. The drug is approved in the European Union for the treatment of advanced RCC.

SOURCE: http://bit.ly/2Z3e7sz and http://bit.ly/2Z0wWN3 The Lancet Oncology, online December 3, 2019.