Biotech Strategy Blog

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

Posts tagged ‘genomics’

Non-small cell lung cancer (NSCLC) is big news this morning with the announcement from Genentech/Roche that the IMpower150 trial exploring whether adding atezolizumab to the standard of care Avastin plus chemotherapy hit it’s first co-primary endpoint of PFS. The data will be presented at European Society for Medical Oncology (ESMO) Immuno Oncology Congress in Geneva, Switzerland next month. The other co-primary endpoint, overall survival, is expected in a couple of months.

I’m delighted that this trial hit a positive note, especially after a few folks were surprised at our emphatic positive prediction for both the PFS and OS outcomes in reviews this year when we looked at it in the summer and again in the fall – see: predictions in 1L NSCLC trials followed by red and green flags.

In the meantime, recently there was some very important news in the lung cancer niche relating to the field of genomics and our understanding of how tumours develop and evolve.

It’s easy for many folks to forget that even in a tumour type that is considered to be a hot/inflamed one due to the high tumour mutation burden (TMB), not all patients respond to checkpoint therapy upfront and not all will achieve lasting durable responses that go out five years. Resistance (primary and acquired), as well as immune escape, will inevitably have a large impact on many patients.

Understanding the underlying biology of the disease will not only help us figure out the causes of non-response and relapse, but also explore rational combination approaches that might improve outcomes.

Just as the triplet of atezo/bevacizumab/chemo has now been show to be superior to the control doublet, we may well see other approaches evolve in the near to medium term future.

The Dynamic Duo at #TARGETS17

Up on deck today is a timely yet rare joint interview that explores the science behind how cancers (including lung cancers) evolve and adapt to try and evade not only detection, but also being destroyed, by anti-cancer therapeutics.

Professor Charles Swanton (Crick and UCL) and Dr James Gulley (NCI) make for a thoughtful and compelling double act.

It was an absolute delight and a privilege to conduct our latest BSB fireside chat with them together. What they had to say was fascinating.

Often we have jested about putting researchers in the BSB hotseat, but frankly when it comes to people of this calibre, the tables are usually turned and the interviewer is the one in the hotseat with some selective pressure to keep up and maintain a flow of intelligent questions!

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Over the last four or five weeks we have seen some truly remarkable research published by numerous cancer researchers around the globe… which means that it’s time for another Journal Club review of key research to feature some cool science.

Here, we have selected half a dozen key papers of interest in both solid tumours and hematological malignancies that are well worth reading and digesting.  The impact from many of these may well lead to new molecules being explored.  We also include at least one review paper for BSB readers to peruse.

While much of the focus is inevitably on lung cancer and melanoma of late, we also highlight important research in pancreatic cancer, aggressive lymphomas and AML.

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Following on from yesterday’s update on how proteomics and genomics can help us make better decisions in breast cancer at the Miami Breast Cancer Conference (#MBCC14) organised by PER, today also looks at the complexity of genomics, but from a different lens – can genomics impact the way we actually treat patients?

Interestingly, last week there was a rumour (unconfirmed) that Dr Debu Tripathy (UCLA) was heading to MD Anderson to head up the breast cancer division following Gabriel Hortobaygi’s retirement. That move was confirmed yesterday, with a tweet from Dr Naoto Ueno, who is part of the group:

His talk on the increasing role of genomics in breast cancer on Friday was engaging, thoughtful and well delivered.

It also made me (and several others) stop and think.

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On Friday, I headed uptown to attend the Miami Breast Cancer Conference (#MBCC14) held at the Fontainebleau Hotel and organised by the Physicians Education Resource (PER).  It was fun to grab a local Deco Bike and furiously cycle over 45 blocks in under half an hour – most probably the only attendee who arrived on two wheels that day!

MBCC14: Dr Lance Liotta

MBCC14: Dr Lance Liotta

Now, I haven’t attended this event since it was at the Loews Hotel in midtown, which was rather low key and fairly small.  Certainly there wasn’t a big exhibition area then, as far I can recall.  Fast forward a decade on and the event is MUCH bigger, with an excellent Academic panel and an interesting mix of didactic talks and case studies.  The stage setting is also much more impressive, as you can see in the photo right.

To give you some basic background, the audience polls at the beginning of the first day were really useful to put things into context:

  1. The majority of attendees (88%) were physicians (mix of Community medical oncologists, radiation oncologists and surgical oncologists)
  2. 49% of respondents treated 1–5 patients with breast cancer per week
  3. 25% of respondents treated 6–10 patients with breast cancer per week

Being a scientist, and having missed the San Antonio Breast Cancer Symposium (SABCS) due to an overlap with the American Society of Hematology (ASH) meeting in December, I was particularly keen to catch up on the new developments in genomics and molecular profiling, with early morning talks from Drs Lance Liotta (George Mason Univ) and Debu Tripathy (USC).  There were also updates on neoadjuvant treatment for breast cancer by Drs Kathy Albain (Loyola) and Hal Burstein (Dana Farber).  Neoadjuvant therapy prior to surgery is an area that is seeing many new trials and potential therapies emerge.

In today’s post, the attention is on the important topic molecular profiling. This is something I believe we will see much more of going forward.  Two separate articles will follow on personalised treatment in advanced breast cancer (including TNBC) and also on neoadjuvant developments.

Genomics can sometimes be a bit of a dry topic, at least to some people, as anyone who has sat through slide after slide of those fuzzy green-red assays in systems biology sessions at AACR will attest. This time, much to my pleasant surprise, it was different…

What I heard blew my mind and changed the way I think about some aspects of breast cancer.

Now I’m not joking or trying to hype progress here, but sometimes you experience an epiphany when you least expect it.

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Lance Liotta always gives well organised presentations and illustrates the key facts on proteomics (a tough subject for many to follow) with critical learning points.  At this year’s MBCC, he focused his talk on a vision for combining genomic mapping with proteomic analysis of the metastatic lesion.  Part of the challenge with using genomics is the sheer heterogeneity and complexity of every single patient’s tumour.  He also had a second talk in the afternoon that was equally interesting, but more about that in another post.

One of the main findings from the SideOut trial (run by TGen and George Mason, sponsored by the Side Out Foundation; reported at ASCO 2013 – download the poster here) a proof-of-concept study, which showed that molecular profiling often yielded a treatment recommendation that was different from the one recommended by the treating physician:

Source: L Liotta, MBCC

Source: L Liotta, MBCC

You can see that some of the regimens mentioned here are quite noticeably different – patient #103 is particularly fascinating, for example.

Here’s my quick summary of some of the main points from his first talk:

  1. Basic concept of SideOut I: map the signaling network of metastatic tumour cells to understand which growth or survival pathways are functionally in use in the tissue microenvironment.
  2. Combine this information with genomic analysis from biopsies to determine true drivers from passengers.
  3. Use a combination of genomics and proteomics to recommend appropriate therapies.
  4. The trial was largely successful at generating good responses to therapy and demonstrating PFS – 40% of patients exceeded the PFS ratio of 1.3 and three pats still continue on therapy for 199, 254 and 816 days.
  5. 60% of patient samples had activation of drug targets in only 3 major clusters i.e.
    1. pan-HER-AKT
    2. EGFR/Src/ERK/mTOR
    3. IGF/RAF/MEK/PLK1
  6. Improved treatment may therefore be facilitated by biomarker-led understanding of subgroup molecular targets, which may predict benefit from currently approved agents and newer targeted drugs.
  7. Subclones are selected out based on selective pressure i.e. survival in a secondary tissue or organ during metastasis or survival in the face of therapy (adaptive resistance).  This is something we need to learn more about as our knowledge of the biology of the disease improves.

Following the success of this trial, SIDEOUT II has now opened in 9 sites looking at metastatic breast cancer patients progressing after 1–3 lines of therapy. The study will investigate genome sequencing, protein pathway mapping and multiplexed IHC before using all of the information available to provide a molecular rationale for individualising therapy.

For the SideOut I study, Liotta gave a nice example of a typical patient case study, as shown below.  The idea was to illustrate how they investigators tackled this difficult case and used the genomic and proteomic data to make better clinical decisions.  Note the patient had TNBC, yet had different findings for HER2 status based on two different tests – this isn’t an uncommon finding with lab results, unfortunately:

Source: L Liotta, MBCC

Source: L Liotta, MBCC

After the proteomic and genomic analysis, this is what they ended up with. Note the recommended treatment regimen that resulted – not something you would normally consider with such a detailed work-up!

Source: L Liotta MBCC

Source: L Liotta MBCC

To put this in better context – consider the attendee poll on what tests the physicians would order based on the biopsy of a metastatic lesion suggested that 60% would run ER, PR and HER2 only, while less than a third would test for ER, PR, HER2 and genomic profiling.  Personally, I was really surprised that so few respondents would consider genomic sequencing in the metastatic setting given the sheer molecular complexity that exists.  Clearly, there is a molecular world beyond hitting ER, PR and HER2.

Ultimately, the proof of the pudding in any clinical trial is outcome – how well did the patients do when molecular profiling was used to guide therapy?  Remember that many of these patients had quite advanced disease and were considered difficult to treat.

The answer is quite well, as this waterfall plot demonstrates:

Sideout waterfall plot

 

We have to wonder how can we possibly expect to treat any patient successfully, if we don’t know what driver mutations and targets exist?  In this respect, lung cancer has truly come out of the shadows and leap-frogged breast cancer in terms of molecular profiling and targeted therapies, at least in Academia.

In the future, it may be possible to better define triple negative breast cancers (TNBC) by what the are, rather than what they’re not i.e. ER, PR, HER2 negative, which is a broad catch-all and a very heterogenous population indeed.

Meanwhile, tomorrow we will continue the personalized theme and cover another mind blowing talk that demonstrated how far we really have to go before we can possibly expect to see major shifts in outcome based on the underlying biology and matching appropriate targeted therapy.

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This weekend I will be at the annual meeting of The Association for Research in Vision and Ophthalmology (ARVO) in Fort Lauderdale.

I’m excited about attending because earlier in my career I worked at Alcon Laboratories on European IDE clinical trials for three novel intra-ocular lenses.

ARVO is the ophthalmology equivalent of AACR and is where scientists involved in drug, device research meet to discuss new findings and early stage research.

The title of meeting is “Visionary Genomics.”  After listening to the plenary session at the recent AACR annual meeting by Lynda Chin on how insights from cancer genomics are translating into personalized medicine, I’m looking forward to seeing the impact of genomics on vision research.

Sunday’s ARVO/Alcon keynote presentation is from Roderick McInnes who is the Canada Research Chair in Neurogenetics at McGill University in Montreal.

A presentation that is already generating some advance interest is Sunday’s presentation of the results from the Comparison of Age Related Macular Degeneration Treatments Trials (CATT).

Age related macular degeneration (AMD) is the leading cause of vision loss in those over 65 in the United States, with over 7 million people estimated to be at risk.  Once you have AMD in one eye, you have a 43% risk of developing it in the other eye over a  five year period, a scary statistic!

The first CATT clinical trial is between bevacizumab (Avastin®) and ranibizumab (Lucentis®), both similar anti-VEGF inhibitors that are derived from the same monoclonal antibody.  It will be interesting to see whether the data supports the current practice of off-label use of bevacizumab given its lower cost compared to ranibizumab.

The findings from this data will also potentially impact aflibercept (VEGF-Trap) that is being co-developed by Bayer and Regeneron.  In February, Regeneron submitted a biologics license application (BLA) to the FDA for the use of VEGF-Trap in wet AMD.

The initial results from the aflibercept phase III AMD trial announced late last year showed a non-inferiority to ranibizumab.  If aflibercept is approved and comes to market in 2012, depending on the CATT results, it may have to compete on price against off-label bevacizumab in AMD.  Whether a more convenient injection once every two months for VEGF-Trap (compared to monthly for Lucentis) is sufficient to justify a price premium, it will be interesting to watch the market dynamics in this space.

You can find more about the meeting on the ARVO conference website and they have also put up a blog for the meeting.   The theme of my blog posts over the next few days will be ophthalmology related, and I expect to be live tweeting from ARVO 2011 on Sunday and Monday.  I’ll also be aggregating tweets from the meeting (hashtag #ARVO11) on this blog.

 

That is the interesting question that struck me after reading Sam Kean’s informative article in the February 4 edition of Science.  Ten years on from the sequencing of the Human Genome, the patenting of human genetic information presents unique challenges at the interface of science, law and innovation.

Researchers have obtained patents for isolating different sections of DNA that occur naturally in our bodies.  Whether this should be permitted is still open to debate. Currently, diagnostic companies who want to launch a new cancer test face the challenge that patents now cover many genes.

The Science article cites start-up Foundation Medicine in Cambridge, MA who estimated the cost of investigating possible patent infringement for a new diagnostic test at $35M, a cost that exceeded the company’s $25M of VC funding.

Add in the costs of any royalties or licensing fees and the issue of prior patents is now a nightmare for any diagnostics company.  It is simply not practical to license every gene that may be implicated in a multifactorial disease such as diabetes.  Pre-existing patents have become a barrier to market entry.

As the Science article reports, gene patents cover not only very small snips of DNA, as short as 15 nucleotides, but can prohibit the sequencing of associated DNA. Companies such as 23andMe that sequence an individual’s genome to test for the presence of certain genes may be violating patent rights of others.

What’s more so called “method” patents cover the linking of a gene sequence with a specific medical condition.

As advances in personalized medicine continue, there is a need to balance the competing interests of protecting scientific discovery and rewarding innovation, while at the same time allowing access to human genetic information that many think should be “free to all men and reserved exclusively to none.” Quotation from Bilski v. Kappos, 130 S.Ct. 3218, 3225 (2010)

A law suit currently on appeal to the US Court of Appeals for the Federal Circuit may lead to a change in the current practices of the US Patent & Trademark Office.  The American Association of Pathologists and others have challenged several patents relating to the breast cancer genes BRCA1 and BRAC2 held by Myriad Genetics and the University of Utah Research Foundation.

BRCA1 and BRCA2 genes are associated with an increased risk of breast and ovarian cancer.  The US district court for the Southern District of New York in a surprise decision by Judge Robert Sweet, invalidated Myriad’s patents.  The New York Times article about the case has a link to the Judge’s 156 page opinion.  The decision that isolated but otherwise unaltered DNA should not be patentable is now being appealed by Myriad.

In their legal brief, arguing for the decision to be upheld, the United States Government states:

“The fact that a particular segment of the human genome codes for the BRCA1 protein in a human cell, for example, rather than for adrenaline or insulin or nothing at all, is not within the power of science to alter. Such basic natural relationships may not be the subject of a patent.”

If the District Court’s decision is upheld on appeal, it would represent a fundamental policy shift on what patents can be obtained for human genetic information. Such a decision would prevent Myriad from charging royalties and exclusivity for the genetic testing of BRCA1 and potentially invalidate similar types of patents. Depending on your point of view this will either harm the biotechnology industry or increase the market opportunities.

Given the stakes involved, it is likely the Myriad case will end up being considered by the United States Supreme Court, and what they may decide is anyone’s guess.

To read more in-depth analysis about the Myriad case and the legal issues involved with the patenting of genomic information, I strongly recommend the “Genomics Law Report”, a blog written by Dan Vorhaus and others.

Ten years after the human genome was sequenced we are still working out the intellectual property rights. The question as to whether companies should be allowed to patent unaltered human genes is one that will be answered in the not too distant future.

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