Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘V600E’

Will vemurafenib receive early approval for metastatic melanoma?

A Reuters press release on vemurafenib (Zelboraf) caught my eye this morning, suggesting that it might be approved in BRAFV600E metastatic melanoma by the FDA might be “imminent” according to an unnamed source and much earlier than the expected PDUFA date in November October 28th (now confirmed by Roche/Genentech).

If so, that’s very good news.

However, what really caught my eye was a quote from a spokesperson at Roche Diagnostics, suggesting that the BRAFV600E test would could around $150.  That’s lower than I was expecting, although no doubt it will be considerably offset by the cost of vemurafenib itself.

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Roche files vemurafenib for metastatic melanoma in Europe and US

Yesterday, Roche/Genentech announced that they have submitted the New Drug Application (NDA) filing for PLX4032 (vemurafenib) in BRAF V600E mutation-positive metastatic melanoma, based on BRIM2 and BRIM3 trials to both the FDA and EMA.

I’ve posted quite a bit on BRAF inhibitors such as vemurafenib on this blog – check out the related posts feature at the bottom if you want to learn more about the history of this class of drugs.

Interestingly, Roche have also submitted the companion diagnostic, cobas 4800 BRAF V600 Mutation Test, which means that oncologists in the community will be able to more easily test patients for the mutation, since these patients are more likely to respond to therapy with BRAF inhibitors such as vemurafenib.

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An overview of mechanisms of resistance to BRAF

A new paper has just been published on the mechanisms associated with BRAF resistance by Corcoran et al., (2011).  One of the things I liked about this paper, other than it’s clarity and simplicity, is that you can find it in OncoTarget, an open access cancer journal (see references below), with a prestigious editorial board including Carlo Croce, Bert Vogelstein, Pier Palo Pandolfi, Wafik El Deiry, and Brian Druker to mention a few of the researchers.

The article essentially describes ERK and non-ERK dependent methods by which resistance occurs to BRAF inhibitors such as PLX4032 (vemurafenib).  These are summarised in the table below:

What can Zebrafish tell us about metastatic melanoma?

This week’s Nature is chock full of interesting articles on various cancer related topics so it was quite hard to pick just one to discuss in a blog post.   Nevertheless, two on Zebrafish was very striking, since the Letters discusses how models have revealed oncogenes and potential new drug targets in a particularly difficult to treat tumour type, i.e. melanoma.

250px Zebrafisch What can Zebrafish tell us about metastatic melanoma?

Zebrafish, source: wikipedia

We now know that in melanoma, the BRAF V600E mutation drives signaling and proliferation of the MAPK pathway and that resistance also develops to treatment with targeted therapies such as PLX4032 and other inhibitors after six months or so.  The question then is what factors are driving the resistance and are other (druggable) oncogenes involved?

What causes resistance to BRAF inhibition in melanoma?

Last week there was lot of excitement and interest surrounding the blog post on Roche/Plexxikon's data on PLX4032 in metastatic melanoma published in the New England Journal of Medicine. A number of the discussions on Twitter and email centred around what is causing resistance to the BRAF inhibitor?

If we take a look at the BRAF pathway alone, we would get a sense of the flow from the PDGF ligand through RAS, RAF and MAPK, which essentially drives angiogenesis and proliferation, like this 2004 review article:

 What causes resistance to BRAF inhibition in melanoma?
Source: Nature Reviews Cancer

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Inhibition of mutated, activated BRAF in metastatic melanoma

Hot on the heels of last week's New England Journal of Medicine article on ipilimumab (BMS) comes another article on metastatic melanoma, this time from Keith Flaherty's group in Pennsylvania and Boston on BRAF inhibition with PLX4032, an exciting compound being developed by Plexxikon/Roche (see link below in the references for the article).

I've written a few posts on this interesting compound recently (e.g. here and here), for those interested in getting up to speed on the concept and data.

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