Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘melanoma’

A new opportunity for vemurafenib in BRAFV600E colon cancer

There’s been quite a flurry of commercial news on the Pharma front this morning, with Amgen buying Micromet (whose leading product is blinatumumab in ALL) and Celgene announcing their acquisition of Avila Therapeutics who have a Bruton Kinase Inhibitor (BTK) AVL-292 in phase IB development for lymphomas, which was all the rage at the recent American Society of Hematology (ASH) meeting last month.

The big news for me today, though, wasn’t the commercial acquisitions but a gem of a paper relating to science and its significance for future cancer treatment.

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European Hematology Association meeting 2011

Well, after just getting back from the American Society of Clinical Oncology (ASCO) meeting in Chicago, I’m heading off to Europe for the European Hematology Association (EHA) meeting – no rest for the wicked!

ASCO was a rather flat meeting this year – the stars were undoubtedly the imatinib 36 vs 12 month data in adjuvant GIST (clearly superior) and Roche/Plexxikon/Daiichi Sankyo’s vemurafenib in BRAF V600E metastatic melanoma. The ipilimumab data was strangely disappointing in the upfront setting – only 2 months improvement in survival when added to DTIC.

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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:

MEK mutations confer resistance to MEK and BRAF inhibitors in melanoma

The other day, we discussed resistance in melanoma and how COT can reactivate BRAF signalling through MAPK reactivation.  Previously, we reviewed how MEK inhibitors may potentially be useful when combined with BRAF inhibitors in overcoming resistance due to cross-talk.  There are also other methods of preserving this oncogenic activity, which are highly relevant to current clinical development.

At the recent American Association for Cancer Research (AACR) meeting, Levi Garraway (Dana Farber) presented at the plenary session on “Navigating the interface of tumor biology and therapeutic development through integrative genomics.” He first discussed the history and context of targeted therapy, then focused on the progress in metastatic melanoma, highlighting some dramatic responses to the BRAF inhibitor PLX4032 (vemurafenib) using before and after pictures of his patients.

GRIN2A gene may be a new target in metastatic melanoma

This is turning out to be quite a week for posts on interesting and new things happening in melanoma.

120px Melanoma 03 GRIN2A gene may be a new target in metastatic melanoma

Source: Wikipedia: metastatic melanoma that has invaded the pancreas

Yesterday, we discussed novel mechanisms of resistance to BRAF inhibitors such as PLX4032 and tomorrow we will review new findings associated with MEK resistance, but today I wanted to draw your attention to more basic research, that is, the identification of a new mutation in melanoma.

In a fascinating Letter to Nature Genetics, Wei et al., (2011) described how they used exome sequencing to systematically look at alterations in the DNA seen in the disease in 14 matched normal and metastatic tumours:

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COT drives resistance to PLX4032 through MAPK reactivation

At the recent annual American Association for Cancer Research (AACR) meeting, Keith Flaherty from Mass General Hospital discussed the latest developments in metastatic melanoma in a plenary session.

Much of the talk focused on progress to date with existing therapies, new mechanisms of resistance in BRAF V600E driven melanoma relating to COT, based on a recent Nature publication at the end of last year (see references below) and the potential for new compounds in the pipeline.

Remember that BRAF mutations are expressed in only 7% of cancers, but 60% of melanomas and mutant BRAF was seen as a poor prognostic factor until PLX4032 (now known as vemurafenib) came along and achieved some starting results in some patients.

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PLX4032 phase III data in metastatic melanoma announced by Roche

Some of the most frequently searched words on this blog or those that arrive via organic Google searches centre around:

  • Melanoma
  • Ipilimumab
  • PLX4032

Interestingly, few are searching for RG7204, the Roche code for their compound being developed in partnership with Plexxikon or BRAF, the actual kinase target involved.

As background, you can read up on the past developments with BRAF V600 mutated melanoma herehere and here, including the phase II NEJM data, mechanisms of resistance (MEK or AKT) and how targeting CRAF as well as BRAF can lead to the development of squamous cell lesions in some patients.

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