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January 20, 2012

Zelboraf: Treat One Cancer, Speed Up Another?

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?

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Source: http://pipeline.corante.com/archives/2012/01/20/zelboraf_treat_one_cancer_speed_up_another.php

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