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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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January 20, 2012

Zelboraf: Treat One Cancer, Speed Up Another?

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Posted by Derek

You may well recall the excitement around the late-stage clinical data for Zelboraf (vermurafenib, PLX4032) in metastatic melanoma. The drug was approved late last summer, but (like all the other therapeutic options in oncology), it has its issues.

One of those appears to be speeding up the course of squamous cell carcinoma. (Here's the NEJM article and the accompanying editorial). A significant number of patients on Zelboraf have turned up with this other form of skin cancer. To be sure, they surely had these cancerous cells beforehand (which tend to feature RAS mutations), but the effects of the drug on the MAP-kinase pathway seem to kick up their activity. (The same effect is seen on melanoma cells that don't have the V600E mutation - if you give Zelboraf without genotyping the patient first, you risk making things much worse). One obvious fix would be to give a combination, something to target those squamous cells, and thus the idea of co-administering an MEK inhibitor. Squamous cell carcinomas can be removed, and are nowhere near as bad as melanoma (particularly metastatic melanoma), but this is still a problem.

A bigger problem is that (as mentioned in my older post on this drug) resistant melanoma crops up pretty quickly after initial treatment with Zelboraf. Virtually all of the people taking the drug will eventually die of metastatic melanoma; it's just going to take longer. But how much longer, we don't know. The numbers still aren't quite in on overall survival - it's going to be more than the previous standard of care, but it's probably not going to be overwhelmingly more. Of course, the definition of "more" and the value that an individual patient places on it (or an insurance company places on it), well, those are the very things that keep us arguing about health care. Maybe that MEK co-therapy will make it an easier call?

Comments (5) + TrackBacks (0) | Category: Cancer


1. exCHEM on January 20, 2012 9:00 AM writes...

Early clinical results from the GSK BRAF and MEK combo trials look very interesting, could delay progression and also stop the development of SCCs. By all accords the development of SCC's, though of course distressing to patients, are not a major concern to oncologists as they can be readily removed. Really good work from the ICR and others to do these studies.

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2. Anonymous on January 20, 2012 1:46 PM writes...

There's another really interesting paradigm here at work with the "resistant" melanomas. In many cases, the resistant melanomas that develop after BRAF treatment are DEPENDENT UPON the BRAF inhibitors. If you withdraw Zelboraf, the tumors will shrink! So it looks like the melanomas are somehow switching over to this activation mechanism, and maybe drug holidays, or interleaving BRAF with MEK inhibitors would prove beneficial.

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3. Anonymous on January 20, 2012 2:46 PM writes...

It's worth noting that Shokat and Neal Rosen figured out the mechanism of this activation by BRaf inhibitors in 2010:

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4. Sue Denim on January 21, 2012 1:17 AM writes...

Wait a second, they're using the MEK inhibitor Genentech inlicensed from Exelixis? That can't be right, plenty of commenters like Big Freddy keep saying things like Exelixis was only good at finding "me-too" drugs.

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5. Wwjd on January 22, 2012 9:42 PM writes...

There is a very good webinar at the Melanoma International Foundation website that discusses the very promising phase 2 study ongoing with the GSK BRAF & MEK inhibitors. They seem to counter act each others most severe side effect.

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