Biotech Strategy Blog

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

Posts tagged ‘cabozantinib’

There’s been another disturbance in the force – as luck would have it, after mentioning renal cell carcinoma (RCC) in yesterday’s post, BMS subsequently put out a press release on the CheckMate–214 study exploring the combination of nivolumab plus ipilimumab in the previously untreated metastatic setting.

The results to date were mixed, so what does this mean and what’s impacted by the findings?

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After an entertaining morning yesterday – two interviews completed and wrong conference centre visited (yes really, there’s always a first for everything!) by lunchtime, things thankfully settled down.

Friday, for the uninitiated, is company symposia day – the equivalent of ASCO’s Super Friday. I rarely attend these in Europe, as they are more about corporate messages than what I call “proper CME”, meaning scientific or clinical fair balance and independence. This is one area where Europe still has a-ways to catch up the US on.

Before anyone gives me a hard time on this, I’ll never forget a vendor telling me a couple of years ago that I would love a particular symposia as he had personally ‘supervised and written’ the slides for the event, thus ‘ensuring’ it would be excellent while persuading me to attend against my better judgment. Naturally, I hated it – too many company messages or perspectives, and not ones I agreed with either – and left early, sadly disappointed.

We did attend the first ECC Press Briefing Friday afternoon with Drs Sant, Chouieri and Sharma. The last two authors presented on the metastatic renal cell carcinoma (mRCC) data after initial therapy, which is being presented in the Presidential Symposium on Saturday morning. It was quite an eye opener in many ways, with some subtleties well worth exploring in additional analysis and discussion.

Beyond the obvious highlights of the day for Saturday (nivolumab and cabozantinib data in mRCC), the first official day here is pretty jam packed with lots of other data to ruminate over.  Throughout the day, we’ll be adding additional notes, commentary and insights as the data emerges – and wifi permits.

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A decade or so ago, the annual conferences for the European Congress of Clinical Oncologists (ECCO) and European Society of Medical Oncologists (ESMO) were considered convenient dumping grounds for negative or failed trials. This was largely because they received much less attention than their big brother, the American Society of Clinical Oncology (ASCO).

In the last few years, this trend has shifted with excellent clincial and scientific data being presented at both meetings – they alternate as hosts each year – under the European Cancer Congress (ECC) umbrella.

Just to confuse a global audience long used to referring to the meetings as ESMO and ECCO, while the logical Twitter hashtag might appear to be #ESMO14 and #ECCO15, respectively, based on the standard nomenclature of conference acronym followed by the year, the vagaries of European politics mean we end up with… #ECC2015.

It will be interesting to see how they compete for attention because this hashtag signal will be dirty (more than one usage) and noisy (many disparate voices) with the European Curling Championship, a European Cheerleader Convention and another on e-cigarettes and vaping, all seemingly using the same moniker!

ECCO 2015 Vienna

Still, what many readers are really eager to learn though, is this a great, middling, or poor year for exciting new data in the field of cancer research and what can we expect to hear about in Vienna later this month?

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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.

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Readers of the blog and those who’ve seen us at conferences will know that we spend a lot of time in the poster halls at meetings such as AACR, ASCO, ASH, ESMO/ECCO.

Anybody can write about data in a press briefing, or a plenary session, but if you want to have insights into the future, and identify early opportunities, you have to look at posters.

This year at ASCO 2014, others seemed to have the same strategy as the poster halls were frequently overcrowded and for a popular poster it was like a rugby scrum just to reach the poster and scan a QR code.  As for ASCO’s flawed thinking in putting two posters on one board….. the least said about that the better.

What’s interesting in the poster sessions is that there is a wisdom of crowds feel to some of the posters – if there’s a crowd of people, more will gather. It’s like a traffic accident, you can’t possibly read the poster from afar, but it must be important if everyone’s gathered round…

Feels like you're walking to Ohio

Feels like walking to Ohio to reach South 405

Anyone doing the poster circuit at ASCO, puts in the miles between the general sessions on the side of the main exhibit hall, goes over the #BlisterWalk bridge to reach E354b in the East building and then marches up and down the “road to Ohio” to reach South 405 where the Developmental Therapeutics sessions are presented. Rinse and repeat multiple times a day, you’ll soon be scowling at your ‘comfy’ shoes 😉

That said, it was worth the effort and this post offers a personal selection of some of the many posters that caught our attention.

Companies whose products are mentioned include: $EXEL, $RHHBY, $XLRN, $MRK

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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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A scientific meeting that I would have liked to have attended and one where I think attendees will obtain a lot of insight into the future of prostate cancer research is the forthcoming American Association for Cancer Research (AACR) Advances in Prostate Cancer Research meeting.

AACR Advances in Prostate Cancer Research Meeting 2012Chaired by Charles Sawyers (MSKCC) and Arul Chinnayan (Michigan) it has an impressive line-up of speakers and sessions.  The meeting takes place next week (Feb 6-9) in Orlando.

There are two presentations on cabozantib (XL184) that may offer new insights into the mechanism of action of the drug and its potential:

Cabozantinib (XL-184) and prostate cancer: Preclinical and clinical profile of a novel agent

Maha Hussain, University of Michigan Medical School, Ann Arbor, MI

Cabozantinib (XL184) inhibits androgen-sensitive and castration-resistant prostate cancer in the bone and increases bone formation in non-tumored bones
Eva Corey, University of Washington, Seattle, WA

A few of the presentations at the meeting that caught my attention include:

  • Role of inflammation (William Nelson)
  • Influence of tumor microenvironment on progression and resistance (Christopher Logothetis),
  • Novel therapeutic targets in prostate cancer (Arul Chinnaiyan)
  • Overcoming castration-resistant prostate cancer 
(Charles Sawyers)

If you have in an interest in prostate cancer research, February 6-9 in Orlando is the place to be.

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Times-Square-NYC-November-11-2011This morning the 8am session at the Chemotherapy Foundation Symposium (The Greenspan Meeting) in NYC featured a review of current developments in Prostate Cancer.

The informative 1.5 hour session covered a lot of ground with the presenters reviewing clinical data for:

  • Radium-223 Chloride: a new option for CRPC (Oliver Sartor)
  • Pomegranite extract for Rising PSA (Michael Carducci)
  • XL184 in mCRPC (David Smith)
  • Optimizing patient selection for sipuleucel-T (Simon Hall)
  • Intermittent androgen suppression for prostate cancer (Laurence Klotz)
  • Lenolidomide/docetaxel in CRPC (Daniel Petrylak)

Oliver-Sartor-MD-presenting-at-NYC-Chemotherapy-Foundation-Symposium-2011The highlight, in my opinion, was Oliver Sartor’s excellent presentation on radium-223 chloride (Alpharadin) in which he cogently outlined its mechanism of action.  He explained that radium-223:

  • targets osteoblastic bone metastases by acting as a calcium mimic
  • is a bone-seeking calcium mimetic that binds to hydroxyapatite
  • has preferential uptake in areas of new bone formation

As mentioned previously on this blog, there are critical differences between an alpha emitter such as radium-223 and other bone-seeking radiopharmaceuticals that are beta emitters.

Sartor presented some excellent slides that showed how alpha emitters require much fewer DNA hits to kill cells, are short range and have a higher initial energy per particle.  In other words they are very effective at short range within the bone microenvironment, something that Chris Parker from The Royal Marsden Hospital mentioned in his interview from ECCO/ESMO in Stockholm.

Sartor concluded his Chemotherapy Foundation Symposium presentation by reflecting on “where do we go from here” in prostate cancer?  Some of his observations were:

  • We are currently in a sequencing paradigm. Drug A then B then C
  • We need to combine active agents to give the best results, that is our next challenge
  • How are we going to afford it all?

Sartor succinctly highlighted where the rubber currently hits the road, and left the audience with plenty to reflect upon. I am sure we can expect further debate on sequencing and combination possibilities at medical and scientific meetings in 2012.

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There has been a lot of negative publicity around Dendreon and sipuleucel-T (Provenge) recently, and the lack of a clear mechanism of action remains a concern to many.

Irrespective of the company’s commercial performance, sipuleucel-T remains an FDA approved therapeutic cancer vaccine that provides a benefit to some patients.  It provided a proof-of-concept that immunotherapy can offer a survival advantage, albeit for a median of 4.1 months in asymptomatic advanced prostate cancer.

Dendreon is learning the hard way the failings in its commercial strategy, and no doubt these will be absorbed by others with other therapeutic vaccines in development.

Which brings me to an interesting paper published online first on November 8, 2011 in the American Association for Cancer Research journal, Clinical Cancer Research.

NCI-SEM-Picture-Breast-Cancer-Cell

Researchers from the National Cancer Institute (NCI) published data from a small pilot trial showing a clinical response to a poxviral vaccine (PANVAC) in metastatic breast cancer and ovarian cancer patients.

Twenty six patients were in involved in the pilot NCI trial with PANVAC, a recombinant poxviral vaccine expressing the tumor-associated antigens (TAA), carcinoembryonic antigen (CEA) and mucin-1 (MUC-1).

The results showed a median overall survival of 13.7 months in the 12 breast cancer patients with four patients having stable disease, and one patient on study for 37 months.  One patient had a 17% reduction in mediastinal mass.

In ovarian cancer, median overall survival for the 14 patients treated was 15.0 months.

This is promising early stage data in very sick patients. Mahsa Mohebtash and colleagues conclude in their paper that:

“Some patients who had limited tumor burden with minimal prior chemotherapy seemed to benefit from the vaccine. Further studies to confirm these results are warranted.”

Immunotherapy holds a lot of promise.  Research suggests that cancer vaccines once they have provoked a response may improve a patients’ response to subsequent therapies through enhanced T-cell response.

The NCI researchers in their paper noted that time to progression and tumor shrinkage may not be good endpoints for evaluating immunotherapies given that it can take a few months for the optimal result after vaccination and there is often little impact on the tumor size, as judged by classical RECIST measurement.

Instead, overall survival (OS) should be considered a more relevant endpoint.  Sipuleucel-T failed to show a benefit in progression free survival (PFS), but did show an impact on OS. In prostate cancer, OS remains the gold standard for regulatory approval, which is why Exelixis recently took a hit for not making this the primary endpoint in their phase III trial (306) for cabozantinib (XL184).

There are several challenges to consider with vaccine therapies:

  • How do we identify upfront which patients are most likely to respond to the vaccine?
  • The ideal setting is likely to be adjuvant rather than metastatic disease, but these trials will take a very long time and significant funding to come to fruition.
  • Cancer vaccines may allow some patients to live longer, but they have yet to show any meaningful benefit in other clinical measures such as bone pain, symptoms etc.
  • There are fewer side effects, but how do we evaluate how well patients are doing without clinically validated surrogate markers to aid in assessment?

This early research with a vaccine in breast and ovarian cancer, albeit on a very small number of patients, adds further support to the notion that vaccines may offer treatment benefits in the future.

We still, however, have a long way to go in understanding how best to use immunotherapy effectively and incorporate it into clinical treatment guidelines.  We should also be wary of false hope and hype – I look forward to following the progress of PANVAC going forward.

ResearchBlogging.orgMohebtash, M., Tsang, K., Madan, R., Huen, N., Poole, D., Jochems, C., Jones, J., Ferrara, T., Heery, C., Arlen, P., Steinberg, S., Pazdur, M., Rauckhorst, M., Jones, E., Dahut, W., Schlom, J., & Gulley, J. (2011). A Pilot Study of MUC-1/CEA/TRICOM Poxviral-Based Vaccine in Patients with Metastatic Breast and Ovarian Cancer Clinical Cancer Research, 17 (22), 7164-7173 DOI: 10.1158/1078-0432.CCR-11-0649

Prostate cancer is the second leading cause of cancer death in men, so it was good news this morning when Medivation & Astellas issued a press release that showed positive data from the phase 3 AFFIRM trial for MDV3100.

MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo.

MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

To put the 4.8 month survival advantage in context, this compares favorably with 3.9 months for abiraterone (Hazard Ratio =0.646), in the COU-AA-301 trial.

Positive data was expected given the sound scientific rationale behind MDV3100 and the preliminary data (abstract 4501) presented at the ASCO annual meeting this year. J Clin Oncol 29: 2011 (suppl; abstr 4501).

The drug has a high affinity for the androgen receptor (AR) that is highly expressed on prostate cancer cells.  You can read an excellent interview on Pharma Strategy Blog with Charles Sawyers, who was one of the co-inventors.

MDV3011 blocks the androgen receptor (AR) from moving into the nucleus and activating growth genes and is a more complete inhibitor of AR than bicalutamide.

One hot topic of conversation at ASCO was the potential to combine MDV3100 (androgen receptor blocker) with abiraterone acetate (Zytiga) (androgen synthesis inhibitor), thereby shutting down upstream and downstream activity of the driving receptor in advanced prostate cancer.  The scientific rationale for this appears sound, so it is likely that a combination clinical trial may well be done to test this hypothesis at some point in the future.

MDV3100 has a significant advantage over abiraterone acetate (Zytiga) in that concomitant steroids are not required. Daily steroids have their side effects.  Urologists in particular will be attracted to MDV3100 and its ease of use.

Clinical trials in prostate cancer are ongoing with a multitude of new emerging therapies including TAK-700, Cabozantinib (XL184), radium-223 chloride (Alpharadin), BPX-101, Prostvac-VF, ipilumumab, Custirsen (OGX-011), dasatinib (Sprycel), lenalidomide (Revlimid) and ARN-509 to name but a few.

It is a therapeutic area with a lot going on after very little activity for a decade. The positive interim data for MDV3100 announced today is good news for prostate cancer patients, and we await presentation of the data next year.

Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012, so US approval could be possible later next year.

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