Biotech Strategy Blog

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

Posts tagged ‘Exelixis Cabozantinib Strategy’

Maha Hussain MB ChB is Professor of Medical Oncology at the University of Michigan. I was privileged to interview her about cabozantinib (XL184), a novel drug in development for multiple indications, including prostate cancer.

You can read part 1 of the interview on cabozantinib and pain here, and part 2 about the bone effect seen with cabozantinib, here.

In this final post, Dr Hussain discusses the scientific rationale behind the mechanism of action for cabozantinib, a multi-kinase inhibitor of C-MET, VEGF and others.  She also shares her thoughts on where the scientific data suggests it should have most impact on prostate cancer.  I have emphasized in bold a few sections that stood out to me.

BSB:  We saw that the VEGF inhibitor bevacizumab (Avastin) failed in prostate cancer, so what is the scientific rationale behind targeting c-MET & VEGF? 

Dr Hussain: Let me just begin with a little background. The c-MET pathway and VEGF pathway from a generic perspective in cancer are specifically of interest.  The trial [with cabozantinib] was originally designed, not that there was any specific preclinical data with the drug in prostate cancer, but rather because of the fact that the MET signalling pathway appears to be relevant in a variety of tumors where there is an overexpression.  This potentially causes us, or at least the sponsor I should say, to believe this is worth targeting.

In retrospect, the sponsor targeted diseases where there seems to be overexpression of MET and that’s how it started.  Now, there is data though in terms of overexpression, if you looked at tissues from primary versus lymph node versus metastatic disease there appears to be a stepwise increase in the rate of overexpression of MET in specifically prostate cancer.  

In the short audio clip below Dr Hussain next discusses the key finding that if you block Androgen Receptor (AR) signaling, MET expression goes up. Click here if you can’t see the SoundCloud audio player.


Dr Hussain continuesWhat happened is serendipity occurred, and that is the drug appeared to be very active.  In essence, we are now going back to the lab to try to figure out exactly why does it work?  Is it just a bone only issue, and when I say bone I mean microenvironment issue, or is it actually more than that, is it a totality of both microenvironment and an anti-tumor effect?

What’s interesting is in the literature, there is data that would indicate that when you activate MET, one protects the cancer cells from potential damaging effects of DNA damaging agents. There is also some data, not in prostate cancer specifically, that MET actually mediates resistance to other growth factors like EGFR and Src and so on.  When you try to inhibit them, MET actually appears to potentially mediate resistance to those inhibitors.  There is also data that potentially MET pathway stimulates angiogenesis in the context of sunitinib resistant tumors.

Now in prostate cancer, what we we know is that VEGF is critical for the osteoblast, osteoclast action, and both MET and VEGF seem to crosstalk to regulate the interaction between the tumor cells, the bone cells, the endothelial cells and so on. There are several trials that have targeted the microenvironment. 

You mentioned Avastin, but the reality of it is that sunitinib was a negative trial also, and  the bone targeted drugs have been generally negative trials. 

The question is, why does this thing work when everything else has failed?  My guess is that it may very well may be that pure targeting of one pathway is not enough and that you need a multi-targeted approach. 

The drug, while it is targeting VEGF and MET, it is not a pure target of VEGF and MET, it has multiple other effects, and truthfully no one can say the reason it is working in prostate cancer is because it is inhibiting MET.  I honestly don’t think that we have demonstrated that. 

We do have a clinical trial actually that has just started to specifically look at what happens in the tumors in the bone in patients who are going to be treated with this drug.

BSB:  Did you see the recent paper in Cancer Discovery that talked about suppression of tumor invasion and metastasis by concurrent inhibition of C-MET and VEGF signaling in pancreatic neuroendocrine tumors? 

[As an aside for those interested, Sally Church, PhD has an excellent post on Pharma Strategy Blog, Combined VEGF and MET inhibition in some cancers may be better than either alone,” which discusses the Cancer Discovery paper by Sennino et al.)

Dr Hussain:  In my [AACR] presentation, I do put the data from the pancreas neuroendocrine [research]. It is not from that paper, but I think it is data from previous papers that were published that looked at how the drug works. This was data that I was able to get through the sponsor from Drs Sennino and McDonald.

BSB: Would we we better off combining separate c-MET and VEGF inhibitors rather than have one drug like cabozantinib that has multiple targets?

Dr Hussain: I think you want to go with what works and thus far, this is the first drug that has again what we think is a MET and VEGF targeting based on the preclinical data, that seems to work.  But I would also point that it is not a pure VEGF & MET it also has RET, KIT, FLT and AXL.  My point here is, we assume that this is the reason.

But I would point out is, that I think the notion that you are going to declare victory on cancer by targeting one pathway in a disease that has multiple redundant pathways, in my view is a naive assumption.  We have known for example, with even diseases that are chemosensitive that you couldn’t cure them with one drug and Testes cancer is a perfect example.  Probably, the model of a curable cancer is Testes cancer. Because there is no other cancer, a solid tumor that you actually target, treat in metastatic disease and can cure at a high rate.  There is just nothing else, with all these new discoveries with targeted drugs, none of them have thus far cured a metastatic patient.  And I would stand corrected if I am not right.

BSB: So your suggestion is that we will need to combine these drugs?

Dr Hussain:  Absolutely! The problem is if you are a scientist and you put in for a grant and you put in a drug that is quote unquote a “dirty drug” because it is has multi-targeting, that is not scientifically good enough. Yet from a clinical perspective, I think that what is clear is we are not curing people by having one target targeted. I would argue that all of the “progress” that has occurred if you look at the drugs, they are targeting pathways that are isolated pathways that are not necessarily highly prevalent in all diseases. In some diseases it is a small percentage of patients that have those pathways.

If you look at the outcomes, these are clearly not what I would call huge victory, because you are basically either causing a response or a short lived remission and not significantly impacting survival, as in curing cancer, prolonging life by years.  So I go back to the model of Testes cancer, which is again one of the most curable cancers that we have in the metastatic disease setting.  And even then, we do not cure it with one drug.

BSB:  Can I take you back briefly to something you said earlier that caught my attention. You said earlier that expression of c-met was increased after attenuation of the androgen receptor signaling, so one strategy would be to inhibit activation of both the c-MET and AR signaling pathways.

Dr Hussain:  Correct, correct.

BSB:  I saw that there is a phase 1 trial just starting looking at abiraterone in combination with cabozantinib, so is the theory there that we could potentially delay time to castration resistance if we inhibit both AR signaling and the c-met/VEGF pathway?

Dr Hussain:  Correct, but I would say that the place to start is not with abiraterone, but with primary hormonal treatment when the tumor is still sensitive to hormones.

BSB: So when we are doing androgen deprivation therapy?

Dr Hussain: Correct. I personally think that is where we need to start.  And in fact because of that, in partnership with one of my colleagues here who is also my co-leader for the prostate cancer program at Michigan, we have some preclinical data that is in progress looking at hormone sensitive tumor model.

The question comes up where is the right time to put these drugs, and the truth of it is you brought up the issue of expense, and while I am not the person who says how much life is worth, clearly if it is my life or my family’s life or my patients life, it is worth a lot. But society has to decide how much money to spend on what and for what magnitude of benefit. That is something that I think we are all struggling with, as you point out, because healthcare dollars are going down and a lot of these drugs are very expensive. And when they work we talking about prolongation of life anywhere from 2 months to 5 months, and that’s average. The reality of what that means is that you are treating thousands of patients to get benefits in a smaller number of patients, and is this something sustainable and is this the way we should go?

I would argue that, life is very precious and very valuable, the more that we can do to impact it, the better we will be as doctors, patients and society.  But that in order to get a bigger bang for the bucks, so to speak, for the drug itself is we need to begin to think about moving these drugs in settings whereby you have cancers that are not as resistant where the impact might be higher.  Imagine then, we would then prolong life by maybe years, as opposed to months.  I think that would be much more worth it.

Yes, it will be more costly to test these drugs earlier, and certainly there is the financial aspect of it for Pharma. They would want to go in a setting where they can get the results sooner rather than later, and not treat ten times more patients to find the results. I would say from the big picture perspective as a doctor, that’s not my focus, my focus is to move these drugs to settings where we can have more impact for more patients, and more meaningful impact on their outcomes.

BSB: In essence, you do think that is where cabozantinib could have most effect at that time?

Dr Hussain:  Maybe. I think this is a question that should be asked. We have proposed to look at in the preclinical setting, to try to justify a clinical trial potentially.  Recognizing that it is one of those things, clearly we are limited by access to drugs and $ to support these type of questions. And if it is not cabozantinib, it’s the next in line targeting that pathway. I do think someone needs to ask that question and we could envision trial designs that can give you short-term answers that will give you a sort of Go/No-Go type strategy.  It is a complex process, obviously. I would say if the world was perfect, and if it was my money and my drug, I would go that way to see how it behaves.

BSB: Thank you!

This brings to an end the series of posts covering my interview with Dr Maha Hussain, a thought leader in prostate cancer clinical research. I would like to sincerely thank her for the time she took out of her busy schedule to talk to Biotech Strategy Blog.

To effectively treat prostate cancer will require drugs to be given in combination. A VEGF/MET inhibitor may have a role to play in the treatment of prostate cancer, but whether Exelixis have the appropriate clinical trial strategy in place with cabozantinib to achieve this, remains to be seen.

Other pathways that we didn’t have time to discuss may also need to be targeted e.g. Src and PI3-Kinase.  It will be interesting to see what new data is presented at the annual meeting of the American Association for Cancer Research (AACR) in Chicago later this month.

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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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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