Biotech Strategy Blog

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

Posts tagged ‘vemurafenib’

Are we overpromising with protein degraders?

Degrading proteins, block by block

Our KRAS review last week included a lot of different inhibitor compounds (well over 30 of them), illustrating just how complex this niche is rapidly becoming, with only a brief mention of targeted protein degrader (TPD) compounds since these are much further behind their small molecule inhibitor counterparts.

Since then there’s been some more big picture talks or three about the TPD space, which are well worth discussing, as well as a flurry of relevant questions from BSB readers to be addressed.

Here we discuss the KRAS niche in the context of protein degraders and look at the promise and some of the inherent challenges faced…

To continue reading our latest discussion on oncology new product development plus commentary and analysis BSB subscribers can log-in or you can click to access the content.

This content is restricted to subscribers

Sorting signals from the noise

The annual ASCO-SITC meeting (#ImmunoOnc19) was held in San Francisco this year and has come a long way from the inaugural event we attended in Orlando.

Finding the signals amongst the noise

In the original 2017 event, I vividly recall as stirring presentation from Dr Limo Chen on targeting CD38 in solid tumours, last year we wrote an update on GU cancers including the STING pathway.

What’s in store from San Francisco and how do we go about finding key signals from the noise?

Over the next two posts I’m going to focus on new findings in various approaches that either look interesting and worth watching, or where there are lessons that can be learned for future developments.

This time around, some of the highlights surprised even me…

To learn more from our latest conference coverage and oncology insights, subscribers can log-in or you can click to gain access to BSB Premium Content.

This content is restricted to subscribers

New developments in advanced colorectal cancer

San Francisco: ASCO Gastrointestinal symposium 2017 – Update on metastatic colorectal cancer

It might surprise quite a few people that colorectal cancer (CRC) is the third most commonly diagnosed cancer globally, especially in the western hemisphere where hereditary, dietary and lifestyle factors can be important.

The bedrock of therapeutic approaches in this disease have largely centred around chemotherapy (FOLFOX or FOLFIRI) along with targeted therapies against EGFR (cetuximab, panitumumab) or VEGF (bevacizumab, ziv-aflibercept, regorafenib etc).

In our second report from #GI17, we take a look at some of the emerging monotherapy and combination approaches that are showing early signs of moving the needle in advanced CRC, an area that has been relatively dormant of late.  This is partly because it’s a cold tumour and with the focus on cancer immunotherapies, it’s not the first tumour type that companies will necessarily rush to evaluate.

Things are changing though, even in colorectal cancer so it’s time to look at some key studies that may teach us more about this disease.

To learn more insights, subscribers can log in

This content is restricted to subscribers

ESMO16 Preview 1 Novel Target Data Offers Potential to Overcome Barriers to Cancer Drug Resistance

September 1st… as the hot summer floats away from London town and cooler autumn days draw in, it’s time to think about the upcoming fall cancer conference season – it’s quite a busy one this year!

In the coming weeks, I will be rolling out our series on the ESMO 2016 Previews (Twitter #ESMO16) and taking a more in-depth look at various topics of interest. The Copenhagen meeting is later than usual and also more compressed, with numerous sessions now held simultaneously. It used to be that you could take a break between key sessions, but not any more – there’s a lot going on this year.

View of Thames BarrierOne of the things that jumped out to me from a preliminary review of this year’s hectic ESMO program is an interesting novel target that had some early preclinical data at AACR, but that sadly got lost in the tsunami of data there.

It is good to have that reminder and be able to return to it in the context of broader data because overcoming barriers to drug resistance with targeted therapies is still an important issue that is worth researching.

You likely won’t see it in many analyst reports or previews, however, although it’s a hidden gem of great interest and well worth exploring in terms of what we know so far. This means that readers will be both prepared and intrigued – don’t be surprised to hear about some BD&L deals in this niche in the future.

Curious? Subscribers can go here now to get all the details…

This content is restricted to subscribers

ECC Vienna Preview 1 Late Breaking Abstracts

A decade or so ago, the annual conferences for the European Congress of Clinical Oncologists (ECCO) and European Society of Medical Oncologists (ESMO) were considered convenient dumping grounds for negative or failed trials. This was largely because they received much less attention than their big brother, the American Society of Clinical Oncology (ASCO).

In the last few years, this trend has shifted with excellent clincial and scientific data being presented at both meetings – they alternate as hosts each year – under the European Cancer Congress (ECC) umbrella.

Just to confuse a global audience long used to referring to the meetings as ESMO and ECCO, while the logical Twitter hashtag might appear to be #ESMO14 and #ECCO15, respectively, based on the standard nomenclature of conference acronym followed by the year, the vagaries of European politics mean we end up with… #ECC2015.

It will be interesting to see how they compete for attention because this hashtag signal will be dirty (more than one usage) and noisy (many disparate voices) with the European Curling Championship, a European Cheerleader Convention and another on e-cigarettes and vaping, all seemingly using the same moniker!

ECCO 2015 Vienna

Still, what many readers are really eager to learn though, is this a great, middling, or poor year for exciting new data in the field of cancer research and what can we expect to hear about in Vienna later this month?

To learn more insights on this intriguing topic, subscribers can log-in or you can purchase access to BSB Premium Content. 

This content is restricted to subscribers

The value of BRAF targeted cancer therapies in lung and colorectal cancer

It’s time for the August mailbag where we answer questions about cancer research and R&D from subscribers.

After the recent queries about immuno-oncology, it’s time to focus a little on targeted therapies again. Neither chemotherapies nor targeted therapies are going to go away – they are still the bedrock of many treatment approaches in the clinic today. Sadly though, much of the new data for the latter trials were easily swamped by the sheer tsunami of immunotherapy data in Philadelphia (AACR) and Chicago (ASCO).

One important area that we have been discussing on both blogs for some time is the value of well designed basket trials.  It’s time to revisit this concept in the light of new data relating to the BRAF V600 mutation outside of metastatic melanoma.

To learn more about our latest insights, subscribers can log-in or you can purchase access to BSB Premium Content. 

This content is restricted to subscribers

What impact will nivolumab & pembrolizumab have on advanced melanoma?

Today’s post focuses on another question from a reader, who asked: “How will we decide which therapies to give patients with metastatic melanoma once the new immunotherapies are available?”

This is not an easy question to answer, but first let’s remember that as little as five years ago there were only treatments such as DTIC (dacarbazine), temozolamide, interferon, chemotherapy and not much else as choices for people with advanced melanoma. Survival rates were generally poor, yet despite the low barrier to entry, many agents failed miserably to beat them. The disease was therefore widely considered to be a graveyard for Pharma R&D.

Fast forward to 2014. We now have several targeted therapies and combinations approved including BRAFV600E (vemurafenib and dabrafenib) and MEK inhibitors (trametinib), as well as a number of others that may soon be on the way in the near term such as cobimetinib in combination with vemurafenib.  Along similar lines, GSK recently announced that the combination of dabrafenib plus trametinib was superior to vemurafenib alone in terms of overall survival.  Hopefully, we will see the full data for both combinations at a medical meeting such as ESMO or EADO in the Fall.

Immunotherapies such as ipilimumab (Yervoy) have also been shown to improve patient outcomes. In addition, others are also in the queue including anti-PD–1 antibodies, which are likely to be reviewed soon by the Health Authorities (e.g. pembrolizumab and nivolumab). Indeed, Japan already approved nivolumab (Opdivo) in advanced melanoma on July 4th, making it the first anti-PD–1 checkpoint inhibitor to be available globally. Meanwhile, in the US Merck had a jump start with their rolling NDA for pembrolizumab already started (the PDUFA is Oct 28th, 2014). Their data at ASCO included probably one of the largest trials I’ve seen in advanced melanoma with over 400 patients included. BMS are not far behind with nivolumab, however, and are expecting to begin their filing in the 3Q this year following the frontline trial (CHECKMATE 037) in BRAF wild type (wt) metastatic melanoma versus dacarbazine successfully meeting its primary endpoint earlier than expected.

You can read about the clinical results relating to the three key melanoma trials reported at ASCO by Ribas et al., Hodi et al., and Sznol et al., in our earlier review but today, I wanted to focus on a broader, more strategic perspective, now that several events post meeting are shaking out more clearly.

A couple of years ago (was it really that long?!), many of us were quite disappointed to see the combination of vemurafenib plus ipilimumab scuttled due to unexpected liver toxicity, although the good news from ASCO is that a dual immunotherapy combination (ipilimumab plus nivolumab) appears not to have met the same fate.

The landscape for metastatic melanoma is therefore rapidly changing, but where is this field likely to go and what can we expect to see?

To learn more about our insights, you can log-in.

This content is restricted to subscribers

ASCO 2014 Preview #1: When triple combinations make sense

The ASCO 2014 season kicks off with the release of the embargo on main abstracts (other than the late breakers and plenary sessions) yesterday evening. Over the next week, I’m planning to cover some of the highlights (positive and negative) that I found interesting or worthwhile discussing. While there was nothing particularly earth shattering or new in the press briefing at lunch time yesterday, that’s not to say there aren’t some important data this year buried amongst the 5000+ abstracts.

Today I’m driving to Orlando and on Friday will be at the American Urological Association (AUA) meeting, so a lighter post will appear here on BSB regarding my initial topline highlights and lowlights tomorrow.

I decided to kick off the ASCO Previews first and focus on an altogether different topic, one that we’ve covered longitudinally on either PSB and BSB – originally with some scientific and translational data – and now with some initial clinical trials that look pretty encouraging thus far. The bench-to-bedside transition is often fraught with many challenges, but occasionally, they actually turn out quite well in practice.

To learn more insights on this intriguing topic, subscribers can log-in or you can purchase access to BSB Premium Content. 

This content is restricted to subscribers

Bench to bedside and back again with BRAF and NRAS mutant cancers

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

The story is truly a fascinating one.

To learn more insights on this intriguing topic, subscribers can log-in or you can purchase access to BSB Premium Content. 

This content is restricted to subscribers

Update on overcoming resistance in metastatic melanoma

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.

Subscribers can log-in to read our latest insights or you can purchase access to BSB Premium Content. 

This content is restricted to subscribers

error: Content is protected !!