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BRAF mutations in hairy cell leukemia

By MaverickNY on July 18, 2011

Last month an interesting article was published in The New England Journal of Medicine describing how BRAF^V600E mutations may have a key role to play in hairy cell leukemia (HCL), which came out around the same time as the European Hematology Association (EHA) meeting that I attended in London. The news certainly caused a buzz at the conference!

Source: Wikipedia

Hair cell leukemia is a fairly rare type of leukemia that affects B cells (lymphocytes), which are distinguished by their hairy like appearance under the microscope because they have fine projections coming from their surface.

Over the past year, we have heard much about how the BRAF^V600E mutation plays a critical role in melanoma and the progress with the testing of a specific inhibitor, vemurafenib (PLX4032), in the clinic, leading to some initial clinical success in this indication. What’s particularly interesting about the NEJM article is that it describes, for the first time, how the BRAF^V600E mutation may be a key genetic alteration in HCL.

The researchers used Sanger sequencing to undertake an extensive analysis of the genome in normal and HCL peripheral blood samples. The findings were also validated in additional patients with HCL (n=47). The results were a little surprising:

“Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein.”

The mutation was only found in patient samples who had HCL, not other types of leukemia or lymphomas:

“None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias.”

Some immunohistologic and Western blot studies, were performed. They found that:

“HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF–MEK–ERK mitogen-activated protein kinase pathway in HCL.

In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK.”

PLX-4720 is another BRAF inhibitor that Plexxikon have in development in addition to the original one, PLX-4032 that became vemurafenib.

Now, while is promising evidence that needs to be researched further, we must exercise caution. Remember that just because a mutation exists, does not mean that it is a key driver. We saw this with colon cancer and BRAF^V600E mutations – where vemurafenib had little of no effect in patients, despite promising preclinical data – a stark contrast to the results in metastatic melanoma! Why does the same target produce entirely different results when inhibited by an effective agent? One reason could be that that BRAF is a passenger not a driver in colon cancer.

In the meantime, I will be keenly following any progress with testing of specific BRAF inhibitors for patients with hairy cell leukemia to see whether it will be a useful clinical approach in managing the disease or not.

References:

Tiacci, E., Trifonov, V., Schiavoni, G., Holmes, A., Kern, W., Martelli, M., Pucciarini, A., Bigerna, B., Pacini, R., Wells, V., Sportoletti, P., Pettirossi, V., Mannucci, R., Elliott, O., Liso, A., Ambrosetti, A., Pulsoni, A., Forconi, F., Trentin, L., Semenzato, G., Inghirami, G., Capponi, M., Di Raimondo, F., Patti, C., Arcaini, L., Musto, P., Pileri, S., Haferlach, C., Schnittger, S., Pizzolo, G., Foà, R., Farinelli, L., Haferlach, T., Pasqualucci, L., Rabadan, R., & Falini, B. (2011). Mutations in Hairy-Cell Leukemia New England Journal of Medicine, 364 (24), 2305-2315 DOI: 10.1056/NEJMoa1014209

AACR has free journal access online until end of August

By MaverickNY on July 14, 2011

Gotta love Twitter for finding useful and helpful things that make a difference to scientific research… Last night I saw a tweet from the delightful Tara Yates of AACR:

Yes please!

Whether you are a subscriber or interested in the offer like I was, you can download the AACR app on iTunes.

I couldn’t resist – did it immediately on my iPad and discovered the AACR app was beautiful – well designed UI, nicely integrated and intuitive features, easy to use. The sharp interface looks like this:

You can scroll through, choose a journal, read Online first, Current Issue or the previous three issues. Very neat. You can also favourite articles for later reading:

Note the “Download the PDF” button at the top right. This is where the app really shines. In the iPad, you can download the PDF and save it to any readers you have such as iBooks, Goodreads, Stanza or whatever you have installed. The app let’s you choose your preferred option. I like iBooks and save PDFs to there for easy reading while travelling or even while working or writing blog posts.

The other option I use is to save PDFs to Evernote as well. The reason for this is that the readers all search on title alone, whereas Evernote is OCR based and will find words in an article, not just the title. This is very handy if you need to find something quickly and only have a vague idea of what you remember. The other day I needed an article on VEGF biomarkers but only remembered vaguely reading it was about ‘myeloid’ factors and couldn’t remember the journal, authors, the institution, the drug or anything else other than VEGF and myeloid. Evernote found it in seconds after searching for ‘myeloid’. Very cool.

Evernote also syncs seamlessly across my iPad, iPhone, laptop and Desktop computers making it the ultimate database and search tool for scientific data and papers. It has certainly saved my bacon more than a few times when doing consulting projects!

I highly recommend this app from AACR – even if you’re not a member, it’s well worth checking out the free access offer and reading a lot of high quality articles on a range of topics from basic and translational research, to biomarkers, clinical research and even cancer prevention. It’s really very easy to get engrossed reading the interesting journal articles on a iPad and forgetting to download or save them… I’m going to be very sad when the free trial runs out next month 🙁

Nice job, AACR!

Update on triple negative breast cancer

By MaverickNY on July 12, 2011

One of the challenges of triple negative breast cancer is that it is defined by what it is not (ie ER/PR-, HER2-), rather than what it is. This broad subgroup of breast cancer is therefore more heterogeneous in nature than many people actually realise. It also means that unless we uncover the various driving mutations underlying it, we are sadly doomed to the world of repeatedly poor response rates. We can do better than this.

The other day I saw a new paper in the Journal of Clinical Investigation (open access) that caught my eye:

“Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies”

Researchers from Vanderbilt-Ingram cancer centre identified six different subtypes relating to this disease. Six!

They found the subtypes by looking at gene expression profiles in 21 different breast cancer sets and identified the triple negative cases (n=587). From these cases, cluster analysis identified the six TNBC subtypes. These subtypes included:

two basal-like (BL1 and BL2)
an immunomodulatory (IM)
a mesenchymal (M)
a mesenchymal stem–like (MSL)
a luminal androgen receptor (LAR)

Here’s where it gets very interesting though – these newly identified subtypes are sensitive to different therapies:

“BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin.

M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor).

The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling.”

In other words, based on identifying a women with triple negative breast cancer’s precise subtype, they could be used as a potential biomarker for selection into appropriate clinical trials. By doing this we may be able to screen those women more likely to respond to a given therapy and then determine in randomised controlled clinical trials whether the molecular hypothesis is indeed correct before treatment in a broader population.

Many of you will no doubt be wondering how this relates to PARP inhibitors such as iniparib, which until recently were the hottest thing in breast cancer. The simple answer is, it doesn’t. None of the subtypes identified appear to have a known sensitivity to PARP inhibitors, that I know of. What is important is that new molecular subtypes have been identified and these appear to be sensitive to therapies either already available commercially or in clinical development for other tumour types.

Overall, this is an excellent and well designed study with the most useful and instructive findings. It’s like finding 6 needles in a haystack at once and will hopefully guide us in a much more focused way. I really do hope that clinical researchers respond quickly and get some new clinical trials going up and running soon with appropriate patient selection criteria in triple negative breast cancer.

We need more cowbell like this in cancer research. This is the stuff dreams are made of.

References:

Lehmann, B., Bauer, J., Chen, X., Sanders, M., Chakravarthy, A., Shyr, Y., & Pietenpol, J. (2011). Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies Journal of Clinical Investigation, 121 (7), 2750-2767 DOI: 10.1172/JCI45014

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Using social media to improve awareness of clinical trials in rare lymphomas

By MaverickNY on July 8, 2011

Slowly but surely, we are seeing more use of social media in one area where I really think it can help a lot – clinical trials.

Regular readers will know of my passion for use of biomarkers in studies to ensure that the patients most likely to respond and therefore benefit will get treatment, thereby sparing those unlikely to respond of the debilitating systemic side effects. This also helps to reduce false hope and raise more realistic expectations.

I was therefore delighted to see a new video from the folks at MD Anderson Cancer Center where Dr Anas Younes, a lymphoma expert, is explaining about the new trials they have open in a rare form of lymphoma, Peripheral T-Cell Lymphoma (PTCL), with some new agents in development.

The groups stated mission is abundantly clear and admirable:

“Our mission is to improve the cure rate of patients with PTCL and reduce treatment-related toxicity by developing novel targeted therapy using rationally designed small molecules, antibodies and combination regimens of biologic agents.”

Check out the short video below – if you can’t see it, you can click this link to take you directly to it:

http://youtu.be/UTCBWQtk65s

PTCL is very rare indeed, but…

It is good to see companies invest in clinical trials to continue to improve outcomes
Social media sharing through YouTube, Facebook, Twitter and blogs is a great way to aid awareness of clinical trials for those are suffering
More awareness will hopefully lead to faster enrolment and earlier readouts that can be publicly shared with all
Dr Younes is a fellow believer in targeted agents in a targeted fashion based on the underlying biology of the disease. Love this – using targeted agents in an untargeted fashion is both silly and a waste of time/research dollars
Academia is probably the ideal way to provide this sort of education – are you more likely to believe or be persuaded by a passionate medical specialist from a top cancer center or a pharma company advertising clinical trials?

There has been some excellent research from Pew Internet recently that showed, as Susannah Fox summarised for me via Twitter:

“Most patients say professionals are more helpful than peers for diagnosis, Rx, treatments.”

She has also published another in-depth report that looked at Peer-To-Peer healthcare. I particularly liked the aims:

“This report shows how people’s networks are expanding to include online peers, particularly in the crucible of rare disease.”

Those online peers could be connections from all walks of life, who like me, like to share fascinating stuff from reputable sources such as Pew Internet, Manhattan Research and top cancer centers such as MD Anderson. The beauty of social media is that we can all share information and help improve medical education and awareness across a broad church. As Thomas Friedman said, the world is indeed getting flatter.

For those of you who know someone who has been diagnosed with PTCL or other rare lymphomas and is in need of treatment, do share Dr Younes’ video with them – they may be able to help.

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Self-Educated Patients and The Future of Cancer Care

By MaverickNY on July 5, 2011

Love this video from TEDxOverlake, where Dr Jack West (Swedish) describes what he is doing with his excellent forum and site, the Global Resource for Advancing Cancer Education (GRACE). Currently, the main focus is on his specialty, Lung Cancer, but more tumour types are planned in the near future.

Jack talks about how physician led sites can actively and effectively reach out in a many-to-many fashion to improve education and learning, rather than in the traditional one-to-one fashion seen in a consultation.

He uses a great example of how a young patient with lung cancer was empowered to seek out better care for his condition and ended up in the crizotinib trial for ALK+ non-small cell lung cancer…

Check it out – it’s a compelling and very powerful story:

If you can’t see the video in your email subscription, you can find it here.

Disclosure: I’m an unpaid member of the GRACE Advisory Board (so of course, I will be biased 😉

Should Pharma and Biotech be engaging in social media?

By MaverickNY on July 1, 2011

Today several people have reminded me that it’s Canada Day and also the Independence Day weekend in the US. Although I’m British and celebrate neither, there will be a short hiatus from blogging in honour of my Canuck and American friends.

We’ll be working unfortunately, such is the life as a consultant, with deadlines galore due next week!

For those of you anxious not to miss anything hot on the social media front, check out this article from BioWorld on Biotechs and Social Media, kindly sent in by Drs Brian Orelli and Al Lalani.

Here’s an interesting quote from the research:

In an informal BioWorld Today survey, more than 44 percent (95) of the 215 respondents said their firms are not engaging in social media. The No. 1 reason, listed by 42 percent, was that social media “was not the place for us.”

I can understand that approach completely – social media is about engagement and sharing; dealing with the challenges of unhappy patients complaining publicly online via social media puts Pharma in an awkward spot regarding how to handle issues that may arise:

The biggest concern the companies had with social media was how to balance the risks and benefits. That balance was cited by nearly half the respondents. Other top concerns were dealing with third-party comments and opening themselves to liability.

The short article is well worth reading. It reminds me of the dilemma a client recently expressed:

“Do we continue to focus strategically on research & development, trying to find cures for cancer, or do we allow ourselves to be distracted by other issues like shiny new tools and tactics? I only have so much time in a day.”

Fair point indeed and a dilemma that many of you will already be discussing offline. There is no right or wrong answer – you can only do the best you can with the time and resources you have available.

In the meantime, Pharma Strategy Blog will resume as usual on Tuesday.

Happy Holidays to all!

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National Lung Cancer Screening results and their potential impact

By MaverickNY on June 30, 2011

“Current and former heavy smokers can now be screened more effectively for lung cancer. Results from the National Lung Screening Trial (NLST) revealed that detecting small lung cancers with computed tomography (CT) reduces lung cancer specific mortality by 20 percent.”

MD Anderson Cancer Center (MDACC) press release

Wow, how amazing is that? Thanks to the MDACC Provost, Dr Ray DuBois for sharing it on Twitter and to Dr Jack West (Swedish) for Re-Tweeting it or I may well have missed it. The action is as a direct result of The National Lung Screening Trial (NLST), which was conducted to evaluate whether screening with low-dose CT scans could reduce mortality from lung cancer.

Yesterday, The National Lung Screening Trial Research Team published the results of a landmark study (see references below) that may well have a huge impact on cancer centres around the USA. Here are the basic details of the study:

“Eligible participants were between 55 and 74 years of age at the time of randomization, had a history of cigarette smoking of at least 30 pack-years, and, if former smokers, had quit within the previous 15 years.

Persons who had previously received a diagnosis of lung cancer, had undergone chest CT within 18 months before enrollment, had hemoptysis, or had an unexplained weight loss of more than 6.8 kg (15 lb) in the preceding year were excluded.

A total of 53,454 persons were enrolled; 26,722 were randomly assigned to screening with low-dose CT and 26,732 to screening with chest radiography.”

Emphasis mine. That’s a huge epidemiology study that took place over two years of enrollment and 5 years of screening!

What did the results show?

Essentially, my understanding is that screening with the low-dose CT did indeed reduce mortality from lung cancer compared with radiography:

“In the NLST, a 20.0% decrease in mortality from lung cancer was observed in the low-dose CT group as compared with the radiography group.

The rate of positive results was higher with low-dose CT screening than with radiographic screening by a factor of more than 3, and low-dose CT screening was associated with a high rate of false positive results.”

Until only very recently, people with lung cancer were given radiography, tested for histology and categorised according to small cell or non-small cell, and then the latter in to squamous or non-squamous and then treatment (mostly with chemotherapy) decided from there on.

As MDACC noted:

“Prior to the trial, lung cancer, often diagnosed in the later stages of the disease, had shown no benefit from screening because screening with standard chest X-rays did not detect cancers early enough.”

We’ve come a very long way in five years.

These results now mean that with the advanced in low dose CT, we can now potentially detect lung cancer earlier, thereby improving their chances of better outcomes. On the Global Resource for Advancing Cancer Education, GRACE, Dr Thomas Hensing (U. of Chicago) summarised it succinctly:

“As the first trial that shows lung cancer screening can save lives, the NLST will no doubt have a significant impact on how we practice in this country and should be viewed as a very hopeful result for lung cancer advocates.”

Curious as to what the impact might be at major cancer centres, I asked Dr West on Twitter whether Swedish would be doing screening following the response. His response, I’m delighted to say, was enthusiastic:

“Yes, Swedish is very inclined to roll out screening program for current/ex-smokers.”

The results of this study, coupled with rapid implementation in many cancer centres, may have a huge impact on earlier detection, diagnosis and outcomes five years from now. That’s great news for patients and caregivers and gives hope to all. In fact, it gives me goosebumps thinking about it!

Imagine if we can detect lung cancer earlier, that not only means a better chance of outcomes per se by dint of treating earlier disease, but add in what we now know about molecular aberrations in adenocarcinomas and squamous cell carcinomas as well, and things really start to snowball. The overall impact may well be greater than we can imagine at present.

If you are interested in more information, MDACC put together a short video explaining the background and impact of the NLST study that is well worth checking out.

Disclosure: I’m an unpaid member of the GRACE advisory board.

References:

The National Lung Screening Trial Research Team (2011). Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening New England Journal of Medicine DOI: 10.1056/NEJMoa1102873

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ODAC votes unanimously against Genentech and Avastin in metastatic breast cancer

By MaverickNY on June 29, 2011

Finally, we have a result from the public hearing in Washington DC on whether Avastin is a safe and effective drug in first line treatment of metastatic breast cancer after the Oncology Drugs Advisory Committee (ODAC) voted 6-0 against on all three questions (was Avastin effective, safe and should the indication continue to be upheld).

An overwhelming victory for CDER’s case rather than Genentech/Roche’s.

For those of you wondering whether there was any wriggle room for manoeuvre, take a look at the data for yourselves from the original ODAC meeting last year when the FDA reviewed it. I put together the response rates and survival curves from the RIBBON1 and AVADO trials at the time, based on the publicly available data on the FDA site for all to see.

Essentially, the 5.5 month survival advantage seen in the original trial (E2100) that garnered approval was not confirmed, with the PFS in the follow up trials virtually disappearing. The systemic side effects of the drug were however, repeated. It should be noted that none of the three trials showed any improvement in overall survival, so patients sadly did not in fact, live longer on Avastin than with chemotherapy alone.

Like many people, I ardently wish the results were more positive and significantly so – we would at least have better options for women with breast cancer. Sadly, they are not and the data wasn’t even close. Had the two additional trials showed a 5 month benefit per the original E2100 trial that was used to support the initial approval, then I don’t think we would have seen the FDA move to suggest withdrawal of Avastin in December. In fact, it would have been a clear slam dunk the other way.

It’s easy to say that some women benefited (they clearly did) and that some were harmed by the toxicities or did worse (that is equally clear), but as Francis Collins of the NIH recently said, “anecdote is not the plural of data.”

In the absence of any biomarker to help predict response or suggest who is most likely to benefit from treatment with Avastin, we are left with the totality of the aggregated data. This showed no overall benefit from the addition of Avastin to chemotherapy, even though we may sense that there must be something there to indicate who are the responders from the shape of the curve. Indeed, after two years, the chemotherapy arm actually did better overall in the AVADO trial, as the arms crossed over.

Dr Len

If anyone wants to read the live public Twitter commentary, I highly suggest you check out Dr Len Lichtenfeld’s (American Cancer Society) tweets from the public hearing – a modicum of thoughtful sensitivity and accuracy in his reporting and colour commentary. He also writes a blog that is well worth reading. Well done, Dr Len!

Finally, rather than suggest yet another confirmatory trial in metastatic breast cancer at the hearing today, I only wish Genentech had made this offer to the FDA last year when there was more flexibility – a public hearing at your request is hardly the best time for negotiation, but rather a review of the existing evidence.

It isn’t often I agree with the FDA 100%, but in the final analysis they called it correctly on this one. It’s not over yet though, as FDA Commissioner Margaret Hamburg is expected to make the final decision soon.

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Biotechnology, Genomics and Personalized Medicine

By MaverickNY on June 29, 2011

Ruby (@divabiotech) talking at Singularity U

My friend Ruby Gadelrab is the very dynamic and vivacious Head of Marketing and Clinical Development for International Markets at Affymetrix.

She was recently invited to give a talk at the prestigious Singularity University meeting.

I was thrilled to see that Ruby has generously posted her talk online on her blog, Diva Biotech, which I’m a big fan of, and check out regularly in my RSS feeds. The excellent presentation well worth reading if you want to come up to speed on the basics, as well as see her personal view on where the field is going in the near future.

I learned a lot from her synopsis and thought it was a nice thing to share here with PSB readers who may be interested in the topic, as this is a subject that will be very much to the fore in the next 5-10 years.

You can read all about it and download Ruby’s slides on Biotechnology, Genomics and Personalized Medicine.

Check it out!

Some thoughts on cancer research and the pipeline cliff…

By MaverickNY on June 28, 2011

This morning I was pondering a triangulation of several random thoughts that appeared in my Twitter stream, many from BIO, about various topics:

Discussing the patent cliffs and lack of revenue generation some companies such as Lilly will no doubt be facing with John Carroll (Fierce Biotech) and Matt Herper (Forbes Health)
Christiane True (PharmaLive) at the annual BIO meeting quoted a speaker as saying “doing more with less” which seems pretty much de rigeur these days
Ron Leuty tweeted a quote from Chris Viehbacher’s (Sanofi) presentation at BIO, “Not doing more with less, but doing different things.”
Christiane also quoted Viehbacher, “Still not enough of bright science making its way to patient benefit.”

The last point particularly made me wonder, because quite a few oncology companies have broad and deep pipelines, often with more compounds than they can possibly advance at once. Even big Pharma or Biotech has to rationalise resources, budgets and people or nothing would get done.

How do those decisions get made?

Some are smart at life cycle management (GSK and Roche spring to mind), some think strategically about their portfolios, others get mired down in politics or – even worse – distracted by numerous committees focusing on what I call ‘fluffy puffy’ abstract things instead of moving the compounds rapidly through the pipeline to become safe and effective drugs that make a difference to patients lives.

The future of successful cancer drug development is likely going rest heavily on investment in basic science, molecular biomarkers and diagnostics, and novel-novel clinical trials that target multiple aberrations driving the disease.

Investors aren’t interested in any of these things, though; most just want a rapid or high return on their investment. Spending less on R&D is much more in tune with their short term thinking:

Viebacher: If you sit down with investors, they clamor to stop spending on R&D, just do a buyback. #BIO2011

Tweet from Christiane True (PharmaLive) at BIO

The thing is, if pharma companies are going to rely on buying or licensing late stage compounds from Biotech, there is only so much small to medium Biotechs will be able to do going forward, because the future will mean more diagnostics and biomarkers, which are very expensive in cancer research, and in some cases, prohibitively so. This will require closer, earlier collaboration with Academia and even different types of trials thanwe have been used to in the old chemotherapy world.

There are sometimes more challenges with clinical trial designs in small biotechs going from phase II to III, as Sanofi discovered with BiPar and iniparib and Novartis with Antisoma and ASA-404. If we want to reduce the number of phase III failures, we have to get smarter about more iterative studies in phase II, better patient selection, incorporation of biomarkers, more logical combinations and yes, all of these will cost more dollars that will likely give investors insomnia.

Finding out more about the compound earlier will be the new name of the game – it is obviously better to abandon a weak agent on phase I or II than expensive phase III trials.

In the end, the companies who will win out in the long run are often those who think strategically, drive innovation, focus on science-based research, license earlier rather than later, invest in biomarker/diagnostic research, work in close knit cross-functional collaborative groups, avoid the twin pitfalls of bad karma and politics and ultimately ‘see’ things more clearly than the pack allows them to translate that into meaningful action.

It occurred to me that if you have to ask who the KOLs and experts are, then you have a long way to go and that doesn’t inspire confidence in the agent you’re developing. If you have too much greed in the boardroom C-level that’s clearly going to hamper things as well, especially if they want to implement cuts down the line. All of these myriad of factors surprisingly do matter when it comes to riding out patent cliffs and maintaining R&D momentum.

I should probably add ‘corporately ignore the short term investors for long term solid gains,’ but that would be a bit cheeky, perhaps 😉

Ultimately, what I would really like to see is less talk and more effective action:

A lot of talk about benefits and challenges with personalised healthcare but no mention of solutions #BIO2011

Tweet from Pieter Droppert in the Personalised Medicine session at BIO

I guess that’s why the American Association for Cancer Research (AACR) remains my favourite meeting in the annual conference calendar – at least Academic attendees are presenting data and discussing solutions in informal chats in corridors or poster sessions on how to address the practical issues of improving cancer research. Inevitably, the smart companies are tapping into this resource and working alongside each other to unravel the complex mysteries.