Biotech Strategy Blog

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

Posts tagged ‘DDR agents’

ESMO18 is rapidly approaching with only a week to go before the conference kicks off in Munich this year.

Munich

So far in our Preview series we have highlighted what to watch out for in the late breakers, neoantigens, as well as the oral talks and poster discussions.

Now it’s time to turn our focus on the nuggets or gems that can be gleaned from the poster halls – there’s always a few pleasant surprises in store. There are small and large pharma/biotech companies included in this latest list on a wide range of therapeutics and tumour types.

There are also some interesting emerging trends, as well as hints of what might happen with some future phase 3 readouts that could catch a few people by surprise.

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The convergence between targeted therapies and immunotherapies with genomics has already started in many areas of cancer research – we can imagine the intersections more as a Venn diagram than as separate entities these days.

Lobster pots on the shore

While former graveyards of R&D such as metastatic melanoma and lung cancer have seen a dramatic revival in positive trials over the last five years, things have languished somewhat in other areas.

Womens cancers such as high grade serous ovarian cancer (HGSOC) and triple negative breast cancer (TNBC) have seen some new developments with the advent of PARP inhibitors as monotherapy or maintenance, but there is still a ways to go in terms of overcoming resistance and improving outcomes further.

You might be puzzled what on earth lobster pots have to do with cancer research? In short it’s an apt analogy from life because while there is much promise in the right situation (under the sea in a good situation), they can also look like a helpless mess (abandoned on the shore).  Oncology R&D is a bit like that too and finding the right situation viz molecule development and clinical trial design, not to mention discontinuation is very similar in that respect too.

In our latest AACR18 Preview, we take a look at an underappreciated oncology drug class and look at the opportunities for future combinations that may take a few readers by surprise…

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Last October I posted two updates on small cell lung cancer (SCLC). One explored the broad SCLC landscape, while the second was a detailed analysis highlighting the red and green flags to watch out for in the Rova-T TRINITY study.

My sombre conclusion or prediction, if you will, was not particularly well received at that time:

“My sense is that the median PFS and OS in the allcomer ITT population will remain modest and in line with what we might expect from historical chemos in 3L SCLC.”

Dismal happenings are to be expected…

This morning AbbVie announced that they will not be filing for accelerated approval of Rova-T in 3L SCLC based on the interim analysis.  In other words my expectations for this trial were met, although there are many who will be very disappointed at the results.

What matters though is not just how disappointing topline results might be per se, but why they occurred, what we can do about it, and most importantly, where we go next.  There’s a lot more to this than might initially be obvious from the press release.

That’s what this new post is all about… first a post mortem, then the obstacles to be addressed, and finally, what we can look forward to in SCLC…

On a happier note: there may be some surprises ahead!

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It amuses me to realise that I’ve been writing about and following PARP inhibition since 2006 or so, when the field was in that twilight zone of early drug development between preclinical and clinical, thus just beginning to hit some sort of consciousness and broader interest in cancer research.

The AACR Molecular Targets meeting in 2009 was the first scientific meeting I covered as a science writer on the old Pharma Strategy Blog, which focused on early drug development from preclinical to phase 2 – after that I would rapidly lose interest and move on to the next new shiny scientific lure to research and discuss. No doubt this eager new writer ran about like an overenthusiastic little puppy in the poster halls chatting to scientists about their research, much to the amusement of the more staid press room, who at that time probably never ventured out of the darkened basement gloom.

In one of the press briefings there, I met an engaging and thoughtful scientist who was presenting his poster on PARP and synthetic lethality. He kindly took the time to explain in plain English a commonsense analogy that was most helpful for grasping complex concepts. Having sat through several long talks from luminaries in the field such as Drs Hillary Calvert and Alan Ashworth that covered double strand breaks and DNA repair mechanisms, it was a most welcome respite in the hurly burly of the conference!

Imagine his imagery…

You have a four legged coffee table or wooden chair and one of the legs breaks off or is damaged. The table remains standing, albeit less stable than before. Now a second leg breaks, and inevitably, the table is so unstable that it falls over.

Once you grasp that simple analogy for synthetic lethality, you have the basic idea of DNA double strand breaks and how inefficient repair can lead to vulnerabilities in the tumour that can be exploited.

The scientist I spoke to in Boston back in 2009 was Dr Mark O’Connor.

He was involved in DNA damage response research at a little known private company in Cambridge, UK called KuDos, who were subsequently acquired by AstraZeneca. Nearly a decade on and Dr O’Connor is still at the company; he now heads up their DNA damage response area.

Dr Mark O’Connor, AZN

With olaparib (Lynparza) since approved by the FDA in ovarian cancer and slated for the ASCO 2017 plenary session for HER2- breast cancer, things have certainly changed a lot since those early heady days of KuDos and the R&D journey has not been without its notable ups and downs along the way.

In Chicago earlier this month, I had the pleasure of catching up again with Dr O’Connor to learn more about the journey, and importantly, where things are going next.  It’s quite an interesting roller coaster ride, to be sure!

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