Biotech Strategy Blog

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

Posts tagged ‘AACR 2012 Meeting’

A standing room only audience at the recent annual meeting of the American Association for Cancer Research (AACR) heard from several distinguished speakers on what the future of cancer drug therapy is likely to look like: combinations of novel cancer agents.

This AACR session was one of the highlights of the meeting and would have merited from being part of the plenary program.

Jeffrey Engelman from MGH persuasively presented on why we need combination therapies to overcome resistance. He noted that:

  • Most cancers are not sensitive to currently available single-agent therapies
  • Even when sensitive to single-agent therapies, cancers develop resistance, often necessitating combinations

One of the challenges of this approach will be “identifying effective combinations,” he said.

Roy Herbst from Yale, presented on some of the practical challenges involved with the early phase testing of two drugs, and challenged the audience with a critical question:

“Do we possess the necessary translational tools that will help us identify the right drug combinations, ratios and schedules with the right patient?”

Stuart Lutzker from Genentech described their experiences of clinical trials with rational drug combination of trastuzumab and pertuzumab for HER2+ breast cancer.  He concluded that:

“Rational drug combinations have begun to yield exciting Phase III results and should be preferred over empiric drug combinations.”

The Pharma Strategy Blog video interview with Gordon Mills from ECCO/ESMO 2011 in Stockholm offers some interesting insights into how MD Anderson are helping to facilitate academia-industry combination trials with novel compounds from different companies in order to achieve more rational drug design and improve outcomes for people with cancer.

If two or more novel cancer drugs are required to interrupt key pathways or to avoid adaptive resistance, what does this mean for the regulatory strategy?

Janet Woodcock addressed some of these challenges in her AACR presentation, and discussed how the:

“FDA would not want to approve a combination regimen with two new agents unless each contributed to the effect.”

Draft guidance on “Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination” was published by the Agency in December 2010. Click here for a PDF copy.

The document gives examples of a number of different phase II trial designs that can be used to demonstrate the contribution each drug makes to the combination, and the additive effect seen.

As an example, if each drug in a combination has activity and can be administered individually then the guidance document suggests a multi-arm phase II trial may be needed that compares the impact of either drug alone versus the combination and standard of care.  An adaptive trial may also be used if appropriate.

Dr Woodcock noted that future cancer drug development is likely to include increasing use of combinations, adaptive trials to evaluate various drug and diagnostic combinations and increasing attention to the use of novel biomarkers.

The message I took home from the AACR annual meeting is that the future of cancer therapy is in combinations, and we can expect more clinical trials with two unapproved agents (novel-novel combinations) in the future.

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There was so much good science on display at the recent 2012 annual meeting of the American Association for Cancer Research (AACR) in Chicago that any blog posts are but a personal snapshot or postcard.

Bill Sellers VP Global Head Oncology Novartis Institutes for BioMedical ResearchOne enduring image I have from the plenary presentation on “The Genetic Basis for Cancer Therapy” by Bill Sellers, VP/Global Head Oncology at Novartis Institutes for BioMedical Research was the video he showed of the robots that are used for automated cell profiling.

Imagine the advertisements that show robots being used to build cars, but now the robots are undertaking automated laboratory work in pursuit of new cancer compounds. Wow!

During his presentation, Sellers described how Novartis have built a robust preclinical translational infrastructure.

He went on to say that, “many experiments we have done in the past, and even many molecules that were put in the human, really were only profiled against a limited number of preclinical models such as one cell line.”

In order to make preclinical data more reproducible, Novartis had the goal to move from testing against one cell line to testing against an encyclopedia of cell lines.

This has now become a reality with the launch of the Cancer Cell Line Encyclopedia (CCLE) in collaboration with the Broad Institute. The CCLE was recently announced by Novartis in a media release, and details were published online on March 28, 2012 in a letter to “Nature” (doi:10.1038/nature11003).

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity

As described in “Nature”:The Cancer Cell Line Encyclopedia (CCLE) is a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines.

When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity.

Sellers noted in his AACR plenary presentation that the key to using the CCLE is for profiling and to:

“identify subsets of cancer cell lines that are sensitive to a given therapeutic versus those that are not. And then better yet to identify the markers of sensitivity that are differentially expressed or present in the sensitive versus insensitive cell lines.”

Novartis Institute for Biomedical Research Automated Robotic Drug DiscoveryTo do this, Sellers described how Novartis have built a robotic system that e.g. automates cell profiling.  In approx 3 months with this system we can profile 600 cell lines for about 1500 compounds, he said.

This type of preclinical automation is speeding up cancer drug discovery through the ability to more rapidly identify those compounds that are associated with and have activity against different mutations.

In my view, this will drive innovation through the effective and efficient screening of potential new cancer compounds, with the result that only those compounds with demonstrable promise progress.

AACR have made Bill Sellers plenary presentation available as a free webcast from the 2012 annual meeting (along with several others).  I encourage anyone interested in how cancer biology is driving cancer drug development to watch this.

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