Biotech Strategy Blog

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

Posts tagged ‘cobimetinib’

ASCO 2016 Preview 1 – Novel Combination Approaches

For years we’ve followed the trials and tribulations of targeted therapies seeing many approved and quite a few disappear forlornly (and officially) off to dog drug heaven. Many more sit in no-man’s land as companies eagerly wait in a holding pattern for other trial readouts in different tumour types. Sadly, sometimes these studies don’t generate enough compelling data either. With so much competition about, there are no shortcuts or low-hanging fruit in biotech or cancer drug development any more.

ASCO16 Chicago 1

En route to Chicago and ASCO!

Then along came antibody drug conjugates (ADCs), with some encouraging results in a range of cancers in both solid tumours and hematologic malignancies that lead to the approval of several new therapies.

After that, the next big advance was immunotherapies, specifically checkpoint blockade, with encouraging single agent activity in melanoma, lung, and even urothelial bladder cancer. We’ve also seen the promise fo combining two different checkpoints such as nivolumab and ipilimumab together in metastatic melanoma, albeit with an increase in toxicities.

This is all very well and good, although the challenge remains that the majority of patients either respond to therapy and relapse, or do not respond at all, depending on the circumstances, the tumour type and the regimen. We still have a long way to go in moving the needle and creating a new paradigm shift on a broad scale.

So what happens when we start to combine modalities – such as targeted therapies with immunotherapies?

Uh-oh, I hear the distant cries of disagreement erupt…

  • Remember vemurafenib plus ipilimumab in metastatic melanoma was scuppered by severe hepatitis?
  • What about osimertinib plus durvalumab in NSCLC and the increased incidence of ILD?

Both of these statements are true, and yet… we should not assume that all mixed therapy combination approaches are doomed on the basis of a mere n of 2. What happens if some are synergistic or additive? What happens of there are hidden gems that teach us new ways of doing things rather than doing the same old thing just because it’s always been done that way?

With this in mind, I’d like to open the door on our first ASCO 2016 Preview series with a look at novel combination approaches in development that caught my eye.

What are the early hints and signals that we can learn from the data? Which companies are evaluating imaginative new ideas that may turn the tables on traditional thinking?  The ideas discussed here may well surprise a few people.

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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?

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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?

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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.

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AACR 2014 Preview: Novel targets and approaches

For the third part of the series on the AACR Previews, I wanted to switch directions and take a broad look at five completely different approaches in cancer research that we haven’t discussed on Biotech Strategy before and look at how they are doing and which ones might be promising going forward. Some of these scientific developments could potentially impact existing compounds in development.

Companies mentioned: Exelixis, Roche/Genentech, GSK, Clovis, AstraZeneca, Oncoethix

Compounds discussed: cobimetinib, DEDN6526A, ipatasertib, dabrafenib, trametinib, OTX015, JQ1, CO–1686, AZD9291

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Update on anti-PD-L1 cancer immunotherapy

In the second part of our mini-series on immuno-oncology, I thought it would be a nice idea to share a recent interview conducted with one of Roche/Genentech’s leading researchers in this field.  I was particularly interested in their approach because while BMS and Merck have clearly focused on anti-PD-1, Roche and Genentech have effectively zigged with their development of an anti-PD-L1 inhibitor.  Does this matter?

Here, we explore the general background to this approach and, in particular, where the company are going with their anti-PD-L1 inhibitor, MPDL3280A.

Topics discussed:

anti-PD-L1, anti-PD-1, anti-CTLA-4, checkpoint point inhibitors, T cells, biomarkers.

Drugs mentioned:

MPDL3280A, nivolumab, MK-3475, ipilimumab (Yervoy), lirilumab, BMS-986016 (anti-LAG3), bevacizumab (Avastin), erlotinib (Tarceva), vemurafenib (Zelboraf), cobimetinib.

If you are interested in more background on how the PD-1 and PD-L1 inhibitors work, you can check out the mechanism of action (MOA) in our video preview from ASCO last year, which explains this in fairly simple terms.

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