Biotech Strategy Blog

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

Posts tagged ‘vismodegib’

A diagnosis of stage IV pancreatic cancer is pretty much a death sentence.

People are often diagnosed in the advanced stage of the disease – 49.5% are diagnosed in stage IV – and the prognosis is generally not good.  Sadly most don’t live long, even with the latest treatments.

According to the National Cancer Institute (NCI) SEER survival monograph, the relative survival rates are extremely poor. Across all types of pancreatic cancer, only 5% of people live for 5 years, and only 23% survive 1 year.  Three to five months is the median survival time for those with untreated metastatic pancreatic cancer.

In the United States, there were 33,730 new cases of pancreatic cancer in 2006 and 32,300 deaths!  There is, therefore, an unmet need for effective new pancreatic cancer treatments.

Lake Tahoe Pancreatic Cancer ConferencePreclinical data presented by Nicole Teichmann and colleagues at the recent American Association for Cancer Research (AACR) special conference on Pancreatic Cancer in Lake Tahoe, NV suggests that BAY 86-9766 may be an interesting compound to watch as it moves forward in clinical development.

“We showed in our endogenous mouse model that our novel chemotherapeutic agent leads to dramatic tumor shrinkage after only one week of treatment,” said Nicole Teichmann, Ph.D., of the Klinikum rechts der Isar at the Technische Universität München in Munich, Germany in an AACR press release.

Although impressive tumor shrinkage was seen in the preclinical trial of BAY 86-9766, a novel MEK1/2 inhibitor, “in most animals the tumors relapsed typically after 3 weeks of treatment,” according to Teichmann’s abstract.  This suggests that there is an escape pathway that may also need to be targeted for the drug to be more effective.

One of the signaling pathways involved in pancreatic cancer is the Raf-MEK-ERK pathway (75-90% of pancreatic cancers have a K-ras mutation), which is why a MEK inhibitor such as BAY 86-9766 that targets this pathway may be effective.

However, pancreatic cancer represents a challenge for drug development and many drugs have failed in clinical development.

Sorafenib despite being an inhibitor of Raf-1 kinase and EGFR2, failed to show any effect in pancreatic cancer.  Adding sorafenib to gemcitabine did not improve survival significantly.

Recently, Infinity Pharmaceuticals terminated a pancreatic cancer phase 2 trial with their Hedgehog inhibitor, saridegib (IPI-926).

Despite scientific evidence suggesting that hedgehog signaling plays an important role in pancreatic cancer, patients receiving saridegib with gemcitabine did worse (i.e. lived for a shorter period) than they would if they had just received gemcitabine alone.

The Infinity news release noted that “the median survival for patients receiving saridegib plus gemcitabine was less than the historical median survival for single-agent gemcitabine of approximately six months.” Not surprisingly, the trial was terminated.

Other Hedgehog compounds being evaluated in pancreatic cancer include Roche’s vismodegib (Erivedge), which was initially approved in advanced, refractory basal cell carcinoma last year.  The drug is also being tested in trials for pancreatic cancer, including one with gemcitabine and another with gemcitabine plus nab-paclitaxel (Abraxane).

Interestingly, Celgene are waiting for the final data to mature on their phase III trial in pancreatic cancer with nab-paclitaxel and gemcitabine.  The interim results were encouraging, but it is too early to tell if the outcomes will be significantly improved by the combination. You can read more about the scientific rationale for nab-paclitaxel in pancreatic cancer on Pharma Strategy Blog.

The efficacy and safety of BAY 86-977 in combination with gemcitabine is currently being evaluated in a phase 2 trial of patients with non-resectable, locally advanced or metastatic pancreatic cancer.

Caution must, therefore, be expressed as to whether BAY 86-9766 will be effective given that so many promising pancreatic cancer drugs have failed in drug development.

It remains to be seen whether BAY 86-9766 will live up to the promise of the preclinical data presented at the AACR pancreatic meeting in Lake Tahoe.

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San Francisco – the AACR-NCI-EORTC international conference on Molecular Targets and Cancer Therapeutics kicked off last Saturday with two educational sessions, including one that I attended on “Clinical Trial Paradigms in the Era of Novel Therapies.

The session had an impressive line-up of speakers:

  • New paradigms for early-phase trials (James Doroshaw)
  • Phasing out phase III trials: How much evidence do we need if the target is clearly hit? (Jaap Verweij)
  • Development of clinical trials incorporating genomic signatures: Lessons learned? (Lisa McShane)
  • Clinical trial designs for targeted therapies (John Crowley)

James H. Doroshow, deputy director for clinical and translational research at the National Cancer Institute, started his presentation by reviewing the causes of phase II trial failure:

  • 19% Safety
  • 51% Efficacy
  • 29% Strategic

He stated that the overall success rate of recent phase II trials was 18%.

As the debate continues about whether more cancer clinical trials should be done in Phase 2, the key issue according to Doroshow remains lack of a demonstrable proof of mechanism (POM) in many drug trials. That goes hand-in-hand with a lack of molecular markers which can be used to select trial subjects.

“Lack of molecular markers with proven clinical utility follows lack of clinically-demonstrable proof of mechanism”

He provocatively asked:

Should we perform early phase trials without generating evidence supporting POM patient by patient?

His view was that to obtain POM, you need to demonstrate drug action on intended tumor target early in development, prior to expectation of efficacy.

Jaap Verweij in his presentation used the examples of crizotinib, vismodegib, vemurafenib and imatinib in GIST as examples of drugs that had:

  • functionality for a target
  • aimed at a specific population
  • availability of a selection marker.

They are the poster children of targeted therapy, and he convincingly showed that the phase 1 trials of those compounds were largely predictive of the phase 3 results.

His conclusion was that phase I trial can be considered predictive of a phase III study so long as there is a large enough sample size.

We may need to look for bigger increments which should allow us to perform smaller trials,” he said. This would allow trials that are quicker and cheaper. However, he acknowledged that it was not likely we can completely eliminate phase 3 trials particularly for combination therapies or chemotherapies.

John Crowley reviewed the different phase III trial designs, including my least favorite, the “all comer” design.  The ridaforolimus sarcoma phase 3 trial presented at ASCO this year is a good example of how an “all comer” design yielded less than stellar results, and failed to identify the subset of sarcoma patients that optimally respond.  This is the type of phase 3 trial that runs the risk of failure if there are too many non-responders in the heterogeneous patient population.  This problem can often be avoided by more rigour in phase 2 trials to identify the optimal treatment period, relevant biomarkers and subsets of patients most likely to respond.

There is a lot of interest in how to design cancer clinical trials better, bring drugs to market more quickly and more efficiently.  While I enjoyed the content of this session, I did wonder whether it would have been better presented as a roundtable with more audience interaction and engagement rather than the perspective of a few.

A webcast of this session will be available on December 8 from the American Association for Cancer Research (AACR).

I will be flying to Stockholm next week for the European Multidisciplinary Cancer Congress (twitter #EMCC2011), more commonly known as ECCO or ESMO 2011.

What are the sessions that look interesting at the meeting? I previously wrote about the phase III ALSYMPCA trial data for Alpharadin that will be presented as a late breaking abstract.

In addition, the best abstract at ECCO 2011 is on vismodegib in basal cell carcinoma.  Sally Church on Pharma Strategy Blog has written extensively about the hedgehog pathway and role of smoothend inhibition in the treatment of cancer.

What else has attracted my attention at ECCO 2011 in Stockholm? In looking at the preliminary program I was struck by the large number of scientific symposia throughout the meeting. However, many occur at the same time! On Saturday 24th two in particular caught my attention:

Molecular Imaging of Hypoxia

Nanotechnologies for Targeted Drug Delivery

Having written about hypoxia and nanotechnology on this blog, I will probably go to one of those two sessions.

Later in the conference, there is another block of scientific symposia on Monday 26th, again all at the same time! Several that look particularly interesting include:

  • How to understand and to Reverse Drug Resistance in Metastatic Breast Cancer
  • From New Targets to New Drugs in Prostate Cancer
  • Tailoring Personalized Medicine for the Future
  • The Role of IGFs/IGF-1R Pathway in Paediatric Malignancies

And in case one still hasn’t had enough science, there’s another group of scientific symposia on the final day of the conference on Tuesday, 27 September including:

  • Unravelling Ras PI3 Kinases Targets 
  • PARP inhibiting strategies: from Molecular Mechanisms to Rational Clinical Applications

I expect Stockholm to be expensive, they jokingly say you can buy a brewery in America for the price of a beer in the city, but it looks like there’ll be some interesting news and scientific data from the meeting. Hopefully I’ll have a few hours sometime to see something of what looks like a stunningly beautiful city.

If you plan to be in Stockholm do let me know. I can be reached via twitter (@3NT).

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