Biotech Strategy Blog

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Posts tagged ‘Cabozantinib Prostate Pain’

$EXEL Share Price Jan 6 2014The share price of Exelixis ($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?

To learn more about these sentiments and insights, subscribers can log-in or you can purchase access to BSB Premium Content below… 

Maha Hussain MB ChB is Professor of Medical Oncology at the University of Michigan.  She is an international expert into genitourinary malignancies with a focus on clinical research into prostate and bladder cancer.

Cabozantinib is a new drug in development by Exelixis for multiple indications.  It captured a lot of attention at the ASCO 2011 annual meeting last year, when Dr Hussain presented data from a phase 2 prostate cancer trial that showed a dramatic improvement in bone scans and pain reduction in those men receiving it.

Unlike other new prostate cancer drugs such as abiraterone (Zytiga) or MDV3100 that target the androgen receptor, cabozantinib is a multi-kinase inhibitor of MET and VEGFR.  It has both an anti-tumor effect and an effect on bone metabolism.

At the AACR Advances in Prostate Cancer Research conference last month, chaired by Charles Sawyers (MSKCC) and Arul Chinnayan (Michigan), Dr Hussain gave a presentation on “Cabozantinib (XL-184) and prostate cancer: preclinical and clinical profile of a novel agent.”

I was privileged to have the opportunity to interview Dr Hussain by phone recently and obtain her insight into cabozantinib as a potential new treatment for prostate cancer.

We covered a lot of ground, too much for one blog post, so I’ve broken down the interview into segments that I will be posting separately.

Cabozantinib & Pain

As many readers will be aware, one of the dramatic results presented at ASCO last year, was the impact that cabozantinib had on pain.

AACR-Molecular-Targets-2011-Cabozantinib-Pain-DataAt the AACR Molecular Targets meeting in San Francisco last November, further pain data was presented by Howard Scher’s group at Memorial Sloan-Kettering Cancer Center. They showed in a non-randomized phase 2 trial that:

Cabozantinib treatment resulted in high rates of pain improvement and analgesic reduction or discontinuation in patients with moderate to severe pain at baseline

–  Rapid and durable pain relief

–  Pain relief observed regardless of prior lines of therapy

–  Improvement in pain accompanied by reduced interference with sleep and daily activity

Exelixis has since moved forward with clinical trials focusing on prostate cancer pain.

Pain response is the primary outcome in the phase III trial (COMET-2) of cabozantinib (XL184) Versus Mitoxantrone Plus Prednisone in Men With Previously Treated Symptomatic Castration-resistant Prostate Cancer (COMET-2 trial formerly known as XL184-306). Overall survival is a secondary endpoint.

The challenge with using pain as a primary endpoint is that all the advanced prostate cancer drugs that have recently been approved by the FDA such as cabazitaxel (Jevtana), abiraterone (Zytiga), and those for whom approval is expected, such as MDV3100 and radium-223 (Alpharadin), have all shown an improvement in overall survival.

I was, therefore, interested to hear Dr Hussain’s perspective on cabozantinib and its effect on pain in prostate cancer.

BSB: Can pain be a surrogate for survival that regulatory agencies might accept?

Dr Hussain: Honestly, I am not the expert on what the regulatory agencies will do. I know what they have done and I would say that pain has been an indication for regulatory approval of prostate cancer. That’s a long story, it’s an old story. Mitoxantrone was approved based on pain, so I don’t think that is going to be an issue.

Whether it is a surrogate for survival remains to be seen, and to be honest with you, I think that it may not be if you are really using it in far advanced cancer. As we have seen with mitoxantrone, it didn’t seem to make an impact on survival and it is really more about disease progression and pain and quality of life type issues. 

I am not aware of a trial that has been done with a primary endpoint being pain, and another key primary endpoint or a secondary endpoint being survival, that has been positive.  Having said that, I think in my view, it is a mistake to just focus on the pain. 

Pain, as far as I can tell from our experience and others, it’s very late in the setting of the disease by a nowadays standard. I would argue that using this drug as a pain only type drug, you could do it cheaper and less toxic with other agents, with morphine for example. 

My point here is, I go back and say to focus it on pain only, my average patient is interested in living longer, not just in controlling their pain. 

You can hear more about this in the SoundCloud audio clip below.  Prostate cancer patients are not just interested in “how will this drug make me feel,” but also “will I live longer?”  Click here if you can’t see the audio file.

Dr Hussain: My point is in a perfect world if the drug delivers, the importance is going to be a totality of effect, that is prolonging life and improving quality of life overall.

BSB: Thank you

The next installment of the Biotech Strategy Blog interview with Dr Hussain will focus on the clinical significance of the dramatic bone scans seen with cabozantinib.

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