Biotech Strategy Blog

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

Posts tagged ‘Zelboraf’

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.

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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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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 – sign in or sign up below to learn the latest developments in BRAF-driven malignancies.

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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