Positive Trial Result Might be Considered Negative News
On Jan. 3, 2012, AVEO announced that tivozanib demonstrated superiority over Nexavar (sorafenib) in the primary endpoint of progression-free survival (PFS) in a global, randomized Phase 3 clinical trial in 517 patients with advanced renal cell carcinoma (RCC). All patients in the trial had clear cell RCC, had undergone a prior nephrectomy, and had not previously been treated with either a VEGF or mTOR therapy.
· tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 11.9 months compared to a median PFS of 9.1 months for sorafenib in the overall study population
· tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 12.7 months compared to a median PFS of 9.1 months for sorafenib in the pre-specified subpopulation of patients who were treatment naïve (no prior systemic anti-cancer therapy); this subpopulation was approximately 70% of the total study population
· tivozanib demonstrated a well-tolerated safety profile consistent with the Phase 2 experience; the most commonly reported side effect was hypertension, a well established on-target and manageable effect of VEGFR inhibitors
On surface, the news is positive for an investigational drug against an approved drug. However, by looking at advanced RCC competitive landscape, the news might be negative.
Bayer/Onyx’s Nexavar (sorafenib) was approved first in 2005 for advanced RCC who had received one prior systemic therapy. Pfizer’s Sutent (sunitinib) was approved as a first-line treatment for RCC in 2006, and quickly established itself, and is now considered the new standard of care (SOC) for treatment-naïve patients. Pfizer’s Torisel (temsirolimus), Novartis’ Afinitor (everolimus), Roche’s Avastin (bevacizumab), GlaxoSmithKline's Votrient (pazopanib) were approved for advanced RCC subsequently. On Dec 7, 2011, the Oncologic Drugs Advisory Committee (ODAC) voted unanimously to recommend the approval of Pfizer's Inlyta (axitinib) for the second-line treatment of patients with advanced RCC based on the results of the Phase III trial comparing axitinib and sorafenib. Note: Torisel and Afinitor inhibit mTOR while others mentioned above are VEGF inhibitors.
To crack into the crowded space for advanced RCC, new drug entering the space needs to be armed with superior or differentiated data. Tivozanib's 3-month PFS advantage over sorafenib was a significant disappointment for the market. AVEO stock ended down almost 20% to $13.83 from $17.2 on Dec. 30.
With Sutent firmly established as SOC for treatment naive patients, competition is fierce in the second and third line settings. There are currently four major targeted agents for the second line treatment of advanced RCC. Nexavar was the leading therapy but with steady declining market share, followed by Torisel, Afinitor and Avastin. Axitinib most likely will enter this space shortly. It's not entirely clear where tivozanib fits in.
The tivozanib registration trial is geared toward competition against Sutent, 70% of patients in the registration trial were treatment naive. It's not clear from the data released whether tivozanib has advantage over Sutent. If it were to compete against Nexavar and others in 2nd line setting, they should have included at least 50% patient population with prior systemic treatment. AVEO didn't breakdown number from that 30% patient population, based on other numbers provided, my guess is it didn’t achieve statistical significance, and the median PFS number didn't differ from Nexavar that much. This kind of leaves tivozanib in searching for an identity. One possible differentiation for tivozanib is safety profile, which remains to be seen when full data are presented at ASCO 2012. Tivozanib might become a niche product for treatment naïve patients with advanced RCC who cannot tolerate Sutent, rather than the leading VEGF TKI for advanced RCC many had expected before.
Posted on Jan. 4, 2012











