VEGF & Colorectal Cancer: How Do You Know When to Stop?

Fifty million Elvis fans can't be wrong. What about nine Phase III trials?

Avastin is a $5.7 billion drug, with activity in at least five tumor types with every indication of gaining more (it's pending for approval in gastric cancer based on data presented at the 2009 ASCO annual meeting [it is not (Herceptin is!); IVB regrets the error] and positive data in ovarian cancer was presented at the plenary of the 2010 meeting). Some projections have it becoming the top selling drug in the world in 2014 with annual sales of $9 billion. (For more on Avastin's performance in ovarian cancer, check out "The Pink Sheet.")

But it all started out with colorectal cancer.

With success like that, and the VEGF mechanism of action seemingly proven in the setting, of course other drug development projects followed. "There is clearly room to improve on anti-angiogenic therapy in CRC," Scott Kopetz from MD Anderson Cancer Center said at this year's ASCO meeting, and agents with oral bioavailability and lower production costs could have real market advantages.

But, as Kopetz reminded us during an ASCO session on novel possibilities for treating colorectal cancer, small molecule angiogenesis inhibitor options – including the multi-targeted receptor tyrosine kinase inhibitors – haven't worked. Fourteen small molecule VEGF receptor antagonists have been tested (and failed) in CRC – among them early disappointments like AstraZenenca/Schering's PTK787 and more recent failures with Pfizer's sunitinib, GlaxoSmithKline's pazopanib, Bristol-Myers Squibb's brivanib, and AstraZeneca's vandetanib and cediranib just weeks ago. (see Pharmaceutical Approvals Monthly). That includes a total of nine Phase III trials and over 10,000 patients studied, by Kopetz's calculations.

And - "despite over 10,000 patients enrolled," he said, "unfortunately there's no evidence yet that anti-angiogenic agents, besides bevacizumab, confer benefit."

With such a host of attempts and no positive results, maybe it's time to move beyond VEGF in colorectal cancer. After all, there's scads of other pathways to pursue – from MEK to PI3 kinase to Src to Notch to Hedgehog, as Wells Messersmith from the University of Colorado mapped out.

Maybe it isn't quite time to call it quits on angiogenesis, though. Kopetz held out a little hope – and from the back of a McCormick Place hangar it was hard to see how much of a veil of Avastin glory was in his eyes – there's still the large molecule angiogenesis projects out there.

The Phase III on VEGF-Trap, sanofi-aventis/Regeneron's aflibercept, should report out in December. So perhaps we should all keep our hopes up a little longer.