Do doctors treating advanced renal cell carcinoma need a fourth VEGF targeting tyrosine kinase inhibitor (TKI) to turn to? According to the FDA's panel of experts who backed approval of Pfizer’s axitinib yesterday the answer is yes, a vote of confidence that means the drug is likely to reach the US market next year.
To be sold as Inlyta, the pill will be the seventh targeted agent approved to treat this cancer. Data on an eighth – another TKI called tivozanib from Aveo Pharmaceuticals – are due early next year. Despite this full toolbox, once at an advanced stage the disease is rarely cured, although survival can be extended by a number of months and sometimes years. New mechanisms of action to treat this cancer are still needed (Vantage Point - Swelling TKI field prompts calls for new approaches in kidney cancer, June 7, 2011).
Jostling for position
Inlyta will follow Sutent, Nexavar and Votrient on to the market in the TKI class for this type of kidney cancer. All are slightly different and target a unique set of kinase pathways and therefore have individual side effect profiles – for example whereas Sutent can cause rash and hand-and-foot syndrome, Inlyta is more likely to prompt hypothyroidism or high blood pressure.
Comparing the agents' efficacy is harder due to the lack of head-to-head data, but currently Sutent is most commonly used first line, due to a perceived longer duration of action. In the US physicians are likely to reach for a different class of drug when this fails, one of the two mTOR inhibitors approved in the setting, Torisel or Afinitor. Avastin, which also works by targeting VEGF, is also available but used later, as is Nexavar.
GlaxoSmithKline is aggressively going after Sutent’s first line status in this setting with Votrient, and is running a head-to-head study called Comparz. Initial data could be available next year.
It seems that Inlyta’s unique side effect profile helped win the backing of the expert panel. The drug’s record on overall survival in the registration study was very similar to Onyx/Bayer's Nexavar’s – 20.1 months for Pfizer’s contender versus 19.2 - although progression free survival was significantly better. However, with other options available the regulator will want to see a differentiating factor to justify approval, and a unique safety profile could provide it.
The sticking point that could still make the regulator hesitate and that was raised in briefing documents was the drug’s much better performance in patients who first received cytokines, an immune-boosting therapy that is very rarely used in the US, over Sutent.
The panel’s unanimous 13-0 backing of a second-line label makes approval likely; an FDA decision is due by February 27. As such, a green light in the second-line setting would make Pfizer’s biggest challenge persuading doctors to try the drug ahead of more established agents, once a patient’s disease has progressed after Sutent therapy.
For Aveo, meanwhile, the fact that essentially a “me-too” TKI looks set for approval on the back of comparable efficacy and a differentiated side effect profile is encouraging. However, the company will be hoping that tivozanib will do much better than this (Event - Adcom to consider axitinib's worth in kidney cancer, November 29, 2011).
The study, called Tivo-1, pits the experimental agent against Nexavar in a first line setting. Given Nexavar is rarely used first line this is an interesting choice – the Bayer drug might be easier to beat but in terms of establishing tivozanib as a first line agent over Sutent or even Votrient, an unequivocal picture may not emerge.
Either way, if the tivozanib data are as strong as some predict - some analysts reckon the drug could extend progression free survival to more than 12 months compared to Sutent's 11 month track record - Inlyta’s future will look even more challenging.