Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘BRAF V600E’

Over the last decade or so, we’ve seen a lot of new targeted agents approved in a variety of different tumour types. Of the big five cancers (breast, lung, melanoma, prostate, and colorectal) one clearly stands out as missing out on exciting new developments in the last 5 years.

In fact, we haven’t really seen anything startlingly new in the colorectal cancer (CRC) space since 2004, when the FDA approved cetuximab (Erbitux) and bevacizumab (Avastin) to much fanfare a few weeks apart at the beginning of that year. Sure, there have been other EGFR and VEGF inhibitors approved since, including panitumumab (Vectibix), z-aflibercept (Zaltrap) and regorafenib (Stivarga) in various lines of therapy, but you could argue that they’re all more of the same (type of inhibitors) and incremental in their improvements, rather truly game changing or disruptive.

Why is this? Why the discrepancy?

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After the recent raft of posts on immunotherapy, it’s time to turn our attention back to oncogenic addiction.  A couple of key topics have dominated colorectal cancer over the years, namely what causes EGFR resistance and why don’t patients with the BRAF V600 mutation do as well with RAF monotherapy compared to melanoma patients?

In today’s post, we take a more detailed look at BRAF mutant colon cancer in terms of what we’ve learned so far and what the potential therapeutic solutions are, which could influence patient outcomes in a positive way.

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At the annual AACR meeting last year, I wrote about an awesome piece of research from Meghna Das (NIBR) who looked at intermittent dosing of vemurafenib in animal models of BRAF driven melanoma and found that such an approach reduced resistance and improved outcomes.

GarrawayLeviMany of us are unlikely to forget the fascinating sequence of photos shown by Levi Garraway (Broad/MIT) two years earlier at the same conference, when he highlighted the before and after impact of vemurafenib therapy on a patient with advanced melanoma in glorious technicolour. Sadly, the subsequent photo six to nine months later showed that the lesions came back with a vengeance and the patient passed away.

Given that the disease is exquisitely sensitive to BRAF inhibitors, how can we improve this situation and overcome the resistance for future patients?

Das’s work was one of the highlights of that conference for me, since it involved creative thinking and a series of very well done, logical experiments that clearly showed an impact. The post drew a lot of ire and attention though, with many researchers emailing me to say they thought the idea was crazy and utterly against their understanding that you need to continually hit the target 24/7 or risk sudden relapse.  It drew as much surprised reaction as a related and controversial post on minimally effective dose, where I argued that we needed new approaches to hitting the target.

Today, it’s time for an update on this controversy – what happens when we go from bench to bedside and back again? What can we learn from an N of one that helps us figure out the optimal strategies for overcoming acquired resistance to TKI therapy?

Therapies mentioned: vemurafenib, dabrafenib, trametinib, cobimetinib

Companies mentioned: Roche/Genentech, Novartis, GSK, Exelixis

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Every year at AACR meetings there seems to be a new update on how researchers are doing with their work on overcoming resistance in metastatic melanoma. We’ve seen some stunning photos where targeting the BRAF V600E mutation with a specific kinase inhibitor such as vemurafenib (Zelboraf) or dabrafenib (Tafinlar) results in dramatic reduction, and sometimes even complete disappearance of the lesions, only for resistance to set in and the melanoma sadly comes back with a vengeance. Adding a MEK inhibitor such as trametinib (Mekinist) was originally thought to be a rather promising strategy, until it became clear that this only gave a few extra months with exactly the same result.

Over on Pharma Strategy Blog, I’ve written a lot about the fascinating research on various mechanisms of resistance in this disease. They range from specific mutations emerging to activation of COT or MEK and others in response to therapy. There are a number of questions we can ask that need to be addressed:

  • Do we need a better/more potent BRAF inhibitor?
  • Do we need a better/more potent MEK inhibitor?
  • What other combinations and targets can be explored?
  • Is timing and dosing important? (e.g. continuous vs. intermittent dosing)
  • And many others…

Bill Sellers VP Global Head Oncology Novartis Institutes for BioMedical ResearchAt the recent AACR Molecular Targets meeting in Boston I chatted with Dr Bill Sellers, who is the Global Head of Oncology Research at the Novartis Institutes for Biomedical Research (NIBR) and oversees the drug discovery efforts in this space for Novartis.

Yesterday we highlighted NIBR’s work with CDK4/6 inhibition in breast cancer, but this compound may have surprising utility in metastatic melanoma.

Novartis also have several other melanoma agents in their pipeline in the clinic, including a BRAF inhibitor (LGX818), a MEK inhibitor (MEK162) and more recently, an Mdm2 inhibitor (CGM097) in preclinical development.

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Following on from yesterday’s post about learnings from the Boston AACR-NCI-EORTC conference in immuno-oncology, today’s post focuses on learnings from non-immune R&D, namely monoclonal antibodies and TKIs.

We know that cancer is a very complex topic and that adaptive resistance is increasingly a huge focus, but where are the new developments in this area and what can we learn from them in order to improve outcomes?

Another key area to consider is therapeutic index, that is are we shutting down enough of an oncogenic target’s activity in order to ensure efficacy? We’ve seen this in the anti-angiogenesis field, for example, where many VEGF inhibitors failed before bevacizumab (Avastin) finally cracked the nut in colorectal cancer and shifted the needle in terms of improving overall survival. We are now seeing this happen in other areas too, which will be covered below.

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