AVEO/Astellas 2012 filing for tivozanib as it beats Nexavar in Ph III kidney cancer trial
This article was originally published in Scrip
Tivozanib, AVEO Pharmaceuticals' VEGF inhibitor partnered with Astellas Pharma, was better than Bayer HealthCare/ Onyx Pharmaceuticals ' Nexavar (sorafenib) in prolonging progression-free survival in patients with advanced renal cell carcinoma (RCC) in a Phase III head-to-head study, top-line data show. AVEO and Astellas said the trial results mean they will submit the drug for marketing approval in the US and Europe this year.
The global, randomised TIVO-1 registration study involved 517 patients with clear cell RCC, who had undergone a prior nephrectomy but had not previously been treated with either a VEGF or mTOR therapy. The study met its primary endpoint of superiority over sorafenib in progression-free survival (PFS). Top-line results were announced today but a full analysis will not be available until June, said AVEO.
The improvement was statistically significant both in the overall study population (tivozanib-treated patients had a median PFS of 11.9 months compared with 9.1 months for sorafenib) and in the pre-specified sub-population of patients who had had no prior systemic anticancer therapy (this sub-population was about 70% of the total study population; median PFS was 12.7 months on tivozanib and 9.1 months for sorafenib).
The firms also reported that the investigational drug demonstrated a well-tolerated safety profile consistent with Phase II studies, with the most commonly reported side-effect being hypertension. This is a "well-established on-target and manageable effect of VEGF receptor inhibitors", they noted.
The companies would not provide further details of the trial, saying they were reserving the detailed analysis for presentation at the meeting of the American Society of Clinical Oncology (ASCO) in June. However, Dr Bill Slichenmyer, AVEO's chief medical officer, reiterated that the company was "very pleased with the safety data" and had seen low rates of side-effects sometimes seen with other VEGF inhibitors, such as diarrhoea, fatigue, stomatitis and hand-foot syndrome, when questioned by analysts during a conference call on the details of tivozanib's side-effect profile.
Also called into question were the rather high rates of PFS seen in the sorafenib arm, but AVEO's president and CEO Tuan Ha-Ngoc said that actually these were consistent with previous trials, which had shown PFS ranging from five to nine months, adding that different patient demographics and study designs influenced the outcomes. Dr Slichenmyer also speculated that that the higher rate in TIVO-1 might be accounted for by the possibility that other trials had less rigorous criteria for assessing reasons for drop-out, with this potentially representing an area of study bias because patients may drop out in order to switch to a comparator therapy. In the TIVO-1 trial, patients in the sorefanib arm were required to stay on sorefanib treatment and only cross over to tivozanib therapy once progression had been independently verified by a radiologist, he noted.
Dr Slichenmyer expressed confidence in PFS as an endpoint for the trial, commenting that the FDA's Oncologic Drugs Advisory Committee had recently confirmed it as an approvable endpoint in RCC. He noted that overall survival was a secondary endpoint, but details of this and of other trial results, including time to progression, would not be released until the meeting of the American Society for Clinical Oncology in nearly a year's time.
Mr Ha-Ngoc said the company was especially pleased with "the PFS benefit demonstrated in the treatment-naive population, which represents the most significant market opportunity for tivozanib".
The company does not intend to seek accelerated approval, executives said during the conference call.
Nexavar was approved for advanced RCC in the US in 2005, and in the EU the following year. In 2010, its global sales totalled $934 million.
AVEO's CEO said the results were transformational for the company, marking its move to become a fully-integrated, sustainable pharmaceutical company. Astellas entered into a partnership around the drug last February: it will lead commercialisation in the EU while AVEO will be responsible for North American commercialisation. The product is also under earlier-stage investigation for other solid tumours, including colorectal, gastrointestinal and breast cancers. (Kyowa Hakko Kirin, from which AVEO licensed rights to tivozanib in 2007, retains Asian development and commercialisation rights.)
Last week, AVEO filed a shelf registration for the issue of up to $250 million in securities. CFO David Johnston said this was "just good corporate housekeeping practice" to have a current shelf filed, and noted that the company still had $38 million outstanding on its previous shelf registration.
The RCC market is increasingly crowded and includes VEGF receptor inhibitors like Nexavar, Pfizer's Sutent (sunitinib) and GlaxoSmithKline's Votrient (pazopanib), Genentech's VEGF antibody Avastin (bevacizumab), and mTOR inhibitors such as Pfizer's Torisel (temsirolimus) and Novartis's Afinitor (everolimus). A rival investigational VEGF-R inhbitor, Pfizer's Inlyta (axitinib), suffered a setback when FDA reviewers questioned its efficacy last month; however, this was taken as a positive for AVEO (scripintelligence.com, 6 December 2011).