Aveo Oncology Inc. is moving closer to a potential NDA filing for its renal cell carcinoma (RCC) drug, tivozanib, following a recently conducted analysis of the ongoing phase III trial Tivo-3. Updated results evidenced "durable improvements" for study participants, all of whom have refractory metastatic RCC, said primary investigator Brian Rini. Company shares (NASDAQ:AVEO) climbed 30.9% to 92 cents Tuesday as Aveo said it would discuss the data with the FDA, which rejected the company's first attempt at approval in RCC in the summer of 2013.

Tivozanib is already approved for the treatment of adults with advanced RCC, a type of kidney cancer, in the EU and several other countries. But inconsistent progression-free survival (PFS) and overall survival (OS) results plus an imbalance in post-study treatments in the earlier Tivo-1 study left the FDA unwilling to approve Aveo's initial NDA for the drug. Tivo-3, a randomized, controlled, open-label trial comparing tivozanib to Nexavar (sorafenib, Bayer AG) and running since early 2016 is designed to change the agency's stance. (See BioWorld, May 1, 2013, June 11, 2013, and June 26, 2017.)

With 350 patients who failed at least two prior regimens enrolled at the outset, including VEGFR-TKI therapy and checkpoint inhibitors, it randomized participants 1-to-1 to receive either tivozanib or sorafenib, with no crossover between arms. The company provided an initial readout on PFS, the study's primary endpoint, in November 2018, with tivozanib demonstrating a statistically significant 44% improvement in median PFS and 26% reduction in risk of progression or death (hazard ratio [HR]=0.74, p=0.02). Median PFS hit 5.6 months for tivozanib vs. 3.9 months for sorafenib.

Tuesday's announcement, representing a second prespecified analysis from the study, addressed a key secondary endpoint of interest to the U.S. regulator: overall survival (OS). With the OS hazard ratio of 0.99, the data are showing "there's no difference between the survival of patients with tivo or sorafenib," Aveo CEO Michael Bailey told BioWorld.

The outcome is sparking optimism at Aveo about tivo's prospects at the FDA because of the "not-too-distant precedent" in the Inlyta (axitinib, Pfizer Inc.) approval in kidney cancer. Inlyta was compared to sorafenib, but in second-line refractory RCC patients. It was later approved "with a favorable improvement in progression survival, like us, and a hazard ration of .997," he said.

The data cutoff date for the most recent prespecified analysis was Aug. 15, two years from the time the last patient enrolled in the study and about 10 months from the data cutoff date for the first prespecified analysis. Between the two data cutoff dates, 16 additional deaths were reported in the tivozanib arm and 28 deaths in the sorafenib arm, resulting in a total of 114 deaths in the tivozanib arm and 113 in the sorafenib arm. Median OS was 16.4 months for tivozanib (95% CI: 13.4-22.2) and 19.7 months for sorafenib (95% CI: 15-24.2), the company reported. Twenty patients remain progression-free on the tivozanib arm and two on the sorafenib arm, with a median duration on study of 32.5 months.

Over the course of tivo's U.S. development saga, much has changed in the RCC landscape. Nexavar was widely used to treat the condition at launch. But subsequent launches of Sutent (sunitinib, Pfizer Inc.), Torisel (temsirolimus, Pfizer Inc.), Avastin (bevacizumab, Roche Holding AG), Votrient (pazopanib, Novartis AG), Afinitor (everolimus, Novartis AG) and Inlyta, and more recently Cabometyx (cabozantinib, Exelixis Inc.), Lenvima (lenvatinib, Eisai Inc.) in combination with Afinitor and the PD-1 checkpoint inhibitor Opdivo (nivolumab, Bristol-Myers Squibb Co.) have eroded its share, according to Cortellis.

But with the new Tivo-3 data in hand, Bailey positioned Aveo's latest readout as something unique: a positive outcome in the most highly refractory phase III population that the company is aware of. He also highlighted a "wonderful tolerability profile" for tivo, measured by a low rate of dose reductions or dose interruptions.

The company is hoping to get definitive guidance from the FDA during the fourth quarter on whether it should or should not file its NDA. For now, commercial infrastructure and launch planning, at least on paper, is underway. "When we get hopefully good feedback from the FDA we can really start implementing that commercial ramp-up," Bailey said.

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