Biotech Strategy Blog

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

Posts tagged ‘Exelixis’

New developments in renal cell carcinoma

Continuing our focus on genitourinary (GU) cancers this week, today we turn our focus from prostate cancer to renal cell carcinoma (RCC).

There were two important announcments on Monday this week relating to renal carcinoma.

Firstly, Exelixis announced positive top line data from a phase 3 pivotal trial of cabozantinib versus everolimus in relapsed metastatic renal cell carcinoma (METEOR).  The study met the primary endpoint (i.e. significantly improved progression free survival) and the company revealed the following data:

  • Cabozantinib reduced the risk of disease progression or death by 42%; Hazard Ratio = 0.58, (p < 0.0001) compared to everolimus
  • Interim Analysis of OS demonstrated a trend in favour of cabozantinib; Hazard Ratio = 0.67, (p = 0.005) compared to everolimus
  • Exelixis to complete US and EU regulatory filings in early 2016

Secondly, a press release from BMS highlighted the phase 3 CHECKMATE–025 trial comparing nivolumab to everolimus, also in relapsed metastatic RCC, where the independent Data Monitoring Committee recommended early stoppage on the basis of the primary endpoint (OS) being met. The company likely be seeking discussions with Health Authorities with a view to filing the data with the FDA and EMA.

There are some interesting points that fall out of these releases. To learn more, subscribers can log-in below or you can purchase a subscription in the box below.

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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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.

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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.

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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It’s hard to believe that the countdown to the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) is now underway, but yesterday at 6pm, the ASCO abstracts were released.

Oliver Sartor at the recent annual meeting of the American Urological Association (AUA) highlighted the prostate cancer potential of cabozantinib (XL184), an oral inhibitor of MET and VEGF kinases, so it was interesting to see that new data will be presented at ASCO.

What makes cabozantinib interesting?

The preliminary data shows that it not only has an anti-tumor effect, but also has an effect on bone metabolism.

The data presented at EORTC last year and at ASCO GU this year confirms what was seen in animal models, in that it had both an anti-metastatic effect on soft tissue and blockade of bone lesions.  Such dual action on both bone mets and the tumor microenvironment makes it an exciting new compound in prostate cancer.

By all accounts, the novel effect of cabozantinib on bone mets is unexpected.

At the forthcoming ASCO meeting, abstract 3010, whose lead author is Dr Michael Gordon of Pinnacle Oncology Hematology in Scottsdale, AZ  will present data on:

“Activity of cabozantinib (XL184) in soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) with advanced solid tumors.”

According to Dr Gordon in the ASCO press teleconference yesterday, the phase II data at ASCO for cabozantinib in prostate cancer will show:

Complete or partial bone scan resolution in majority of patients (86%), often accompanied by pain relief

Unprecedented bone scan improvement

On the basis of these promising results, according to Dr Gordon, “Exelixis plans to initiate the first pivotal trial in prostate cancer by the end of 2011.

It will be interesting to see whether cabozantinib can impact overall survival (OS) in advanced prostate cancer, something that denosumab (Xgeva®) failed to show in the 147 trial that was just presented at AUA.

There are several abstracts on cabozantinib at the ASCO 2011 annual meeting. Another one that caught my attention was abstract 4516, whose lead author is Maha Hussein of the University of Michigan.

Dr Hussein will present data on cabozantinib in metastatic castrate resistant prostate cancer (mCRPC). The abstract’s conclusion is that:

Cabo showed clinical activity regardless of prior D in mCPRC pts, particularly in pts with bone disease, as reflected by high rates of b-scan resolution and pain relief, in addition to improvements in Hb and tumor regression.

I’ll be at ASCO in a few weeks time, so look forward to hearing more detail on the cabozantinib results.  The data is still very preliminary, but cabozantinib (XL184) is certainly a drug to watch, and may be an exciting new prostate cancer drug in the future.


There is a lot of focus at the annual meeting of the American Urological Association (AUA) here in Washington DC on metastatic castrate resistant Prostate Cancer (mCRPC), and the recently FDA approved adrenal steroid inhibitor, abiraterone acetate (Zytiga®).

Drugs in development that target the androgen receptor, such as MDV3100, are also generating a lot of interest from urologists.

However, Oliver Sartor (Tulane) in the Saturday morning satellite symposia that I attended, focused on emerging therapies in CRPC, beyond the androgen axis. His hypothesis:

“Cancers are devious and some of the mechanisms of AR activation appear to be ligand-independent and resistant to all current androgen-axis targeted therapies.”

What this means is that focusing on adrenal steroid inhibition or blocking the androgen receptor may not be sufficient to prevent disease progression. If we are looking for a Prostate Cancer cure, then will it take multiple drugs, including those that target various stromal sites? That is the intriguing question that Sartor raised.

Indeed, if there is one take home from this meeting, it is that the “desert” of prostate cancer therapies has now blossomed into a multiplicity of potential new therapies and development, which will mean that urologists and oncologists will soon be spoilt for choice as abiraterone and MDV3100 are not the end of the story.

Sartor highlighted some interesting ones on the horizon to watch out for:

Alpharadin: This is a bone targeted therapy that uses radioactive Radium 223 to kill cancer cells. It is being developed by Norwegian company, Algeta in partnership with Bayer Schering Pharma AG. The 900 patient phase III trial completed accrual earlier this year in Jan 2011. Phase II data was published in the Lancet in 2007 by Nilsson et al. Data from alpharadin will be “coming soon” according to Sartor.

XL-184 (cabozantinib): Activated MET is highly expressed in prostate bone metastases. Exelixis XL-184 is a small molecule tyrosine kinase inhibitor that specifically inhibits both MET and VEGFR2.

Data from a phase 2 study of XL-184 in castrate resistance patients was presented last year at the EORTC-AACR-NCI Symposium on Molecular Targets and Cancer Therapeutics in Berlin by David Smith et al (Abstract 406).

Both XL-184 and alpharadin would be potential competitors to Amgen’s denosumab (Xgeva®).

Other new products in development “Beyond the Androgen Axis” that Dr. Sartor mentioned included Prostvac-VF, BPX-101 and ipilimumab. A phase III trial of ipilimumab, both pre- and post- docetaxel is now underway in mCRPC. A phase III trial of Prostvac-VF will start later this year with 1200 patients in a placebo controlled study with minimally symptomatic, castration-resistant metastatic prostate cancer patients.

Over the next few years a lot of data may emerge on exciting new treatment options. Coupled with the basic research that is going on, tremendous progress in the treatment of Prostate Cancer is already taking place.

According to Sartor “multiple drugs will be necessary to cure mCRPC and that is our greatest challenge today.” Major progress is now being made towards this.

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