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Posts tagged ‘XL-184’

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.

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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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The 102nd Annual meeting of the American Association for Cancer Research (AACR) ended yesterday in Orlando, and it was only the diehards who kept going till the last session of the last day for an update on “Novel Androgen Receptor Antagonists.”

As I mentioned in an earlier post, there is a lot of excitement in the prostate cancer field at the moment with three new therapies approved last year (cabazitaxel, sipuleucel-T, denosumab), and more expected over the next two years (abiraterone acetate, MDV3100, cabozantinib/XL-184).

What I took from the AACR session I attended, is that there are also other products in the pipeline that are worth watching.  Below is a list of some of the products that were mentioned. It’s not intended to be a comprehensive review of the prostate cancer landscape, only my notes and thoughts on some of the new products that the speakers touched upon.

Abiraterone Acetate: The postive phase III trial results were reported last year at ESMO and ASCO GU, and the approval of this drug is currently being considered by the FDA.  Approval is expected shortly, and possibly in time for launch at the forthcoming annual meeting of the American Urological Association (AUA) meeting in Washington, DC.

Abiraterone (brand name Zytiga) inhibits the enzymes (17-alpha hydroxylase and C17, 20 lyase) responsible for adrenal androgen formation.

The phase III results were impressive in very sick patients who were close to the end of their lives in very advanced disease.  Overall survival increased from 10.9 to 14.8 months in the second line chemotherapy setting post docetaxel.  It’s expected that the results will be more dramatic pre-chemotherapy.

Once the FDA approval is obtained, it’s hard to see how oncologists will not consider abiraterone instead of cabazitaxel in the second-line chemotherapy setting.  An easily taken pill with fewer less side effects may be a more convenient option for elderly or frail men with prostate cancer.  Abiraterone’s approval will not be good news for sanofi-aventis.

I also expect we will see significantly off-label usage of abiraterone pre-chemotherapy by urologists as they seek to maintain hormone-sensitivity in their patients after several lines of anti-hormonal therapies.  There is a phase III trial ongoing in this setting that is expected to show promising data by the end of the year.

However, it’s a good strategy to come market as soon as possible to provide wider access to patients in need, and the post-docetaxel second line setting allowed the overall survival benefit to be shown before the pre-chemo data would be available.

However, what I learned at the meeting is that abiraterone acetate may not be the best product in the long term.  Currently it requires the corticosteroid, prednisone, to be given at the same time to attenuate the mineralocorticoid effects.  Questions that were raised in the AACR session about long-term treatment with abiraterone included, “Must a corticosteroid be given concurrently?” and “What about hypertension?”

Other questions remain, such as possible development of resistance to abiraterone. Often the first drug to market is not the best, and it’s possible that second generation new products in the pipeline may be better than abiraterone and delay the time to resistance further.

However, what abiraterone does have is first mover advantage and depending on the pricing strategy adopted by Johnson & Johnson, the ability to capture market share earlier.  It will be interesting to see what happens with this drug, but it’s certainly an exciting time for patients with prostate cancer.

TAK-700: This drug from Takeda/Millennium is a more potent inhibitor of C17α-hydroxylase than abiraterone.  One of the panelists at AACR believed that TAK-700 “may in the long run surplant abiraterone acetate due to less need for mineralocorticoids.” TAK 700 entered phase III clinical trials late last year.

MDV3100:  This drug is being developed by Medivation/Astellas and is also in phase III trials, with data expected by the end of this year or early 2012.  It has a high affinity for the androgen receptor. However, what came across in the AACR presentation by Howard Scher, was his view that the second compound developed by Charles Sawyers, ARN-509 may be better than MDV3100.

ARN-509: This drug from Aragon Pharmaceuticals is in phase I/II clinical trials and is definitely one to watch.  As Dr Scher pointed out, ARN-509 is more potent than MDV3100 and I expect we will see publication of more data on ARN-509 in the near future.

If you are interested in prostate cancer, AACR are offering webcasts and podcasts of scientific sessions this year.  Further information can be found on their website.  AACR have also announced a scientific special session on “Advances in Prostate Cancer Research” from February 6-9 2012.  It’s certainly an interesting and exciting time in this field as new products become available, something that is likely to make a real difference to how this disease is treated.

 

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