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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Until recently, we followed the race to market in EGFR T790M lung cancer with Clovis’s rociletinib and AstraZeneca’s osimertinib (Tagrisso). In phase 2, AstraZeneca caused quite a stir when they came from behind and leapfrogged their biotech rival with a large global randomized controlled trial seemingly out of nowhere. They never looked back.
Can they do the same thing with durvalumab (Imfinzi), one of their IO therapies that targets PD-L1?
If there’s one thing that many astute observers of the IO space have learned this week it’s that irrational exuberance and the hopeful sentiment that ‘everything’ will just tweak the immune system and work positively no matter what has thankfully come to an end.
We’ve seen several highs and lows already with Merck’s pembrolizumab gaining accelerated approval in 1L NSCLC in allcomers when combined with chemotherapy and AstraZeneca reporting positive phase 3 data for durvalumab in unresectable (stage 3) NSCLC based on meeting the study endpoint (PFS).
There is much to be learned because the nivolumab disaster in 1L NSCLC last year was not a singular aberration given that durvalumab has seen some missteps in the past and even atezolizumab had some unexpected news with urothelial cancer this week (Check out our insights), as compared to chemo in the second line setting. Just like mutations, there will be many more to come, perhaps even some additional ones before the year is out.
What about today’s news from AstraZeneca in unresectable NSCLC?
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We’re overdue a roundup and discussion on various key topics of interest to BSB readers, so here goes…
Today’s topics include an in-depth look at the impact of some negative events:
- Kite and the cerebral oedema death with axi-cel
- Genentech’s atezolizumab OS miss in urothelial cancer
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Dr James Gulley is Chief of the Genito-Urinary malignancies branch and Director of the Medical Oncology service at the National Cancer Institute (NCI) in the National Institutes of Health. He’s a world-leading GU cancer expert and at the forefront of pioneering research to make cancer immunotherapy work in prostate cancer.
We last spoke to him at ASCO 2015 (See post: The future of prostate cancer immunotherapy). You can listen to excerpts from this interview on Episode 4 of the Novel Targets podcast (See: The non-inflamed tumour show).
Almost two years on, and new research by Dr Gulley and colleagues from the NCI shows that the STING pathway may have an important role to play in prostate cancer immunotherapy. Activation of this pathway through a novel mechanism could turn a cold non-inflamed tumor into a more inflamed or hotter one in men with advanced prostate cancer. How cool is that?!
At the 2017 annual meeting of the American Association for Cancer Research (AACR) that was recently held in Washington DC, Dr Gulley graciously spoke to BSB about some of the novel trials that are underway at the NCI, with the aim of making cancer immunotherapy work in men with advanced prostate cancer.
Dr Jim Gulley, NCI at AACR17
This is the seventh expert interviews in our series from AACR17 where we explore the conundrum:
How does Dr Gulley plan to light the immune camp fire in prostate cancer?
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Over the years we’ve interviewed folks from numerous pharma and biotech companies here on BSB, including those with targeted therapies (small and large), as well as immunotherapies.
Some companies have small pipelines and may be forced by circumstances to explore what they have or seek collaborations with bigger partners.
For big pharmas with large pockets plus broad and deeper pipelines, the challenge is quite different – how do you prioritise potential combinations and tumour targets given it is impossible to evaluate them all in the clinic? How do you create differential advantage and value when you’re relatively later to market compared to your competitors?
In the BSB spotlight this week we have two researchers in clinical development and R&D from the same company, who happen to have both elements in their pipeline in areas of high competition.
Part one of our latest mini-series explores the IO side of the business as we look ‘Through the Keyhole’ at what’s going on in terms of biomarkers, monotherapy trials, combination studies (both IO-IO and IO-targeted) and what to expect in the near-term future later this year. It’s a wide ranging, candid, and fascinating discussion that highlights a lot of potential in terms of what could happen with a large pipeline.
In all, it makes for rather interesting reading and certainly changed how I perceived the company’s efforts in the IO sphere (for the better, I might add). So what’s fascinating about their approach and what can we learn from their progress to date?
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We’ve been saying for a while that 2017 and onwards would be when we start to see a few IO combination trials start to shake out. Interestingly, that process seems to have already started, if recent news is any thing to go by.
With this in mind, the annual meeting of the American Association for Cancer Research (AACR) coming up this weekend gives us a timely moment to explore combinations that are looking interesting… or not.
In the last of our AACR 2017 Conference Previews, we take a look at what to expect on this year’s program in the IO and Checkpoint arena. In short, it’s quite a lot and not without some controversy either!
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There’s no secret or surprise with our latest AACR Preview as this week the focus takes a slight turns or detour to the annual meeting of the Society for Gynecology Oncology being held in National Harbor, Maryland.
PARP inhibitors in ovarian cancer have been a hot topic since last autumn when the PARP inhibitor data dropped at ESMO in Copenhagen, and was not without controversy either.
We’ve been following the trials, tribulations and even machinations, of the clinical development of olaparib, rucaparib and niraparib for a while now so what’s in store in the latest round of salvoes?
And importantly, what else can we expect to see in DC at AACR next month?
For a tumour type that hasn’t received much attention over the last decade or two, things are distinctly picking up. Is it all good though?
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Challenges and Opportunities in the evolving 1L NSCLC Landscape
Rolling English Landscape in Devon
Following a series of events – from BMS’s failure with nivolumab monotherapy… to Merck’s sudden announcement to file their combination of pembrolizumab plus chemotherapy… to AstraZeneca’s delay of the MYSTIC trial exploring durvalumab plus tremelimumab this week, there’s never a dull moment in lung cancer!
So can we expect some more surprises in store in 1L NSCLC?
I say yes we can!
The big questions are what are they and what impact will they have?
2017 is ironically, the year of the Rooster – so who’s going to crow loudly at dawn and who is going to get strangled in the process?
In the world of cancer research it is unlikely that everything wins or is successful, so figuring out the early signs and hints is an important part of the process.
One thing I learned early in this business is that it pays for companies to be humble, flexible and open minded rather than arrogant and dogmatic in their thinking… otherwise you can easily be blindsided.
There were a few examples of that in oncology R&D last year, a repeat could very well follow in 2017 for the unwary.
Here we look at 1L NSCLC in the context of multiple phase 3 trials that are slated to read out… from AstraZeneca, BMS, Merck and Genentech.
If you want to know what the potential impact of these events are on the landscape, including what we can expect from MYSTIC, CheckMate-227 and several others, then this is the post for you because some surprises are likely in store.
We cut through the chase to explain the what and the why in clear simple language.
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This is the third in our mini-series previewing the forthcoming European Society for Medical Oncology 2016 Congress in Copenhagen (Twitter #ESMO16).
In this post we’re taking a look at what’s hot in head and neck cancer.
It’s not a cancer type we typically hear a lot about, but there’s an unmet medical need for effective new treatments.
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The 2016 Congress of the European Society for Medical Oncology (ESMO) is fast approaching. It takes place next month from October 7th to 11th and we will be on site covering the meeting for Biotech Strategy Blog. We’re looking forward to a great meeting!
If you are sitting on the fence as to whether you should go to Copenhagen, then hopefully our series of Previews will help you decide.
Be warned that accommodation is in already in short supply and ESMO are now putting people up across the Oresund bridge in Malmo, Sweden.
The Congress App has a lot of useful information and is well worth downloading, if you haven’t done so already.
Last week many of the late breaking abstract (LBA) titles were announced, although there are still some placeholders. While we won’t know the actual late-breaking data until the meeting, the LBA titles offer insights into what will be presented in Copenhagen.
In the second in our ESMO 2016 Preview series, we’re highlighting the lung cancer late breakers that we’re looking forward to hearing, providing some background on why they may be of interest, and a look at how some of subset landscapes may be a-changing in the future.
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