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Posts tagged ‘Cabozantinib Bone Scans’

$EXEL Share Price Jan 6 2014The share price of Exelixis ($EXEL) is starting a run-up (after months in the doldrums) in advance of anticipated results from the COMET-1 phase 3 trial in metastatic castrate resistant prostate cancer (mCRPC) for cabozantinib (Cometriq, formerly XL184).

Cabozantinib is a small molecule tyrosine kinase inhibitor of c-Met and VEGFR2. It has been shown to significantly improve bone scans and decrease pain, but the $64,000 questions are will patients taking it live longer and feel better?

The answers will come from the COMET-1 trial that has a primary end point of overall survival (OS). It’s a placebo-controlled trial of 960 men with advanced prostate cancer randomly assigned to cabozantinib 60mg (n=640) or prednisone (5mg twice daily) (NCT01605227) who have disease progression after treatment with docetaxel chemotherapy and abiraterone (Zytiga) or enzalutamide (Xtandi).

We previously predicted this trial would be a miss, but did it turn out that way and why?

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This is part 2 of my interview with Dr Maha Hussain, Professor of Medical Oncology at the University of Michigan.  You can read part 1 about cabozantinib and pain here.

Cabozantinib-Prostate-Cancer-Bone-Effect

At the 2011 ASCO annual meeting, Dr Hussain presented data from a non-randomized phase 2 trial with cabozantinib that showed dramatic improvements in bone scans before and after treatment.

Bones are living tissues that are constantly being remade, a dynamic process that involves formation of new bone and taking up of old bone, a process known as bone resorption.  Cancer cells can interfere with bone remodeling, resulting in increased new bone formation (osteoblastic response) or excessive bone resorption (osteoclastic response).

Bone scans involve the injection of radioactive tracers such as technetium-99m-MDP. In simple terms, the radioactive material detects bone turnover and areas of high bone metabolism.  These show up as darker “hot spots” where the tracers accumulate.

Bone scans have poor specificity because tumors, fractures and infection all lead to hot spots. Also, not all tumors or lesions are detected by a bone scan.  Bone scans have a sensitivity of around 62-89%.

At the 2011 Society for Translational Oncology Prostate Cancer Symposium, Professor Johann de Bono (The Institute for Cancer Research) noted that bone scans do not accurately reflect the activity of the disease in men with prostate cancer.

This raises the question as to what we should conclude from the bone scans seen with cabozantinib.  I put this question to Professor Hussain.

BSB: What is the significance of the bone scans that we see and what should we interpret from them given that bone scans don’t accurately reflect the disease?

Dr Hussain: I will refer you back to my presentation at ASCO originally and my recent AACR presentation.

I have specifically put a slide (together) to address, is what we are seeing a fluke, a function of a technique issue because you are targeting the osteoblasts?  Consequently if you inhibit osteoblastic function, you are not going to see much changes on the scan, or is there more too it?

Dr-Maha-Hussain-ASCO-2011-Cabozantinib-Presentation

The specific slide actually puts in columns the (percentage of) patients who had a partial or a complete resolution on the bone scan, versus those who had stable or progressive disease, and then matches it with other evidence of an anti-tumor effect as in target lesion regressions, progression free survival at I think the 6 month mark if I recall correctly, as in the pain improvement, narcotic use.

Recognizing that by the way the pain and narcotic use, both of these were post-hoc assessments that were done.  Once we saw the observation, the sponsor went back and began asking all the investigators to record these things.  Clearly, the ALK phosph going down, the bone turnover markers going down.

The short audio clip below expands on Dr Hussain’s viewpoint about cabozantinib and bone. Click here if you can’t see the SoundCloud audio player.

Dr Hussain’s conclusion is interesting from a marketing strategy perspective.  She does not position cabozantinib as a bone targeted drug such as Xgeva or a bone targeted radiopharmaceutical such as Alpharadin.  Instead, her view is that cabozantinib should be developed as a “prostate cancer specific drug that does have the added advantage of significant anti-tumor effect in the bone” ie an anti-cancer tyrosine kinase inhibitor (TKI).

This is at odds with how Exelixis appear to be positioning it.  The corporate presentation at the Cowen Annual Healthcare Conference on March 6, 2012 had a strong focus on bone metastases: “Cabozantinib demonstrates unique ability to resolve bone metastases and decrease bone pain in CRPC,” one slide said.

If Dr Hussain is correct and we should consider cabozantinib as a prostate cancer specific drug, then it will need to compete on endpoints with other drugs that have shown an impact on overall survival.

Cabozantinib will likely not obtain regulatory approval on the basis of the bone scans, whatever they may show.

Without demonstrating a significant effect on overall survival, it’s hard to believe that cabozantinib will be able to compete effectively in what is fast becoming a very competitive prostate cancer market.

The final installment of the Biotech Strategy Blog interview with Dr Hussain will cover her perspective on the mechanism of action of cabozantinb, and where the drug, theoretically, might be expected to have most impact in prostate cancer.

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The recent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics international conference in San Francisco was an informative meeting.

What I particularly liked was the strategic overview that took place in many of the plenary sessions.

As an example, Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research/The Royal Marsden in London highlighted the potential drug development targets based on prostate cancer biology:

  • Androgen Receptor (AR)
  • Heat Shock Proteins (Hsp)
  • Signaling: HER3, MET, IGF-1R, CCL2, IL-6, Src
  • PI3K/AKT/TOR signaling
  • PARP and BRCAness
  • Estrogen receptor (ER)
  • c-MYC & CHK1

His presentation discussed the possible therapeutic approaches, and complexity involved in developing novel targeted therapies for prostate cancer.

This is something that I expect we will hear more of at the AACR special conference on Advances in Prostate Cancer Research early next year.

In particular, de Bono discussed drug development strategies to target androgen receptor signaling, and some of the future challenges including:

  • Proving to the regulatory authorities that circulating tumor cell (CTC) count falls are a robust immediate endpoint of overall survival
  • Developing improved imaging for bone metastases

As a side note, there were several posters for cabozantinib (XL184) at the meeting (available on the Exelixis website), including preliminary research on computer-aided quantitative bone scan assessment.

However, as de Bono mentioned in his presentation, “diffusion weighted MRI shows hot spots not detected by bone scans.”

2010 and 2011 were good years for prostate cancer drugs, and with new approvals for MDV3100 and radium-223 (Alpharadin) expected, 2012 is set to be another “grand cru” year, to paraphase Bertrand Tombal.

If you were not able to make it to San Francisco for the Molecular Targets and Cancer Therapeutics conference, webcasts of many sessions will be available on the AACR site.

 

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