Biotech Strategy Blog

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

Posts tagged ‘ovarian cancer’

Ever decreasing circles in oncology R&D

File under: intriguing binary events coming up of interest this quarter…

Source: BBC

There are a couple of phase 3 readouts likely due soon on two quite different oncology drugs in late stage development, namely Mirv and Marge, (aka mirvetuximab soravtansine and margetuximab).

For British readers, they remind me of Howard and Hilda Hughes (right) in the highly popular 1980’s comedy sitcom, lead by Richard Briers, Ever Decreasing Circles.

Aside from the fact that it’s an amusing historical analogy with more than a bit of whimsy, there are some strange parallels and hidden messages to be found here. For the record, the two characters had a penchance for wearing matching yet rather garish and ghastly jumpers.

You could either make a similar negative case for the rush from limited phase 2 data to pivotal registration study as for terribly ugly sweaters, with the reduced return on efficacy being alluded to from the show’s title.

The ripple effect – which way will it go?

Or on the other hand… the matchy matchy look could also play out the other way, in terms of positive forthcoming readouts validating phase 2 findings, so which case looks stronger overall for each agent?

To find out, we take a look at the history, what we know, and share our thoughts on how things might pan out – either way, major positive or negative outcomes can have a major ripple effect.

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Why are the SOLO1 data so compelling?

Dr Moore at ESMO18

At the recent European Society of Medical Oncology (ESMO18) Congress in Munich, arguably the data of the meeting – if the audience reaction is anything to go by – were the results from the phase 3 SOLO1 trial that were presented by Dr Kathleen Moore (right).

The results were simultaneously published in The New England Journal of Medicine in an article entitled: “Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer” (Link).

As Moore and colleagues note in the abstract:

“After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (Kaplan–Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs. 27%; hazard ratio for disease progression or death, 0.30; 95% confidence interval, 0.23 to 0.41; P < 0.001).”

Dr Moore is an Associate Professor of gynecologic oncology and the Jim and Christy Everest Endowed Chair in Cancer Research at the University of Oklahoma Stephenson Cancer Center.  She kindly spoke to BSB after her presentation in the Presidential Symposium.

In addition to Dr Moore’s personal commentary on what these results mean for women with ovarian cancer, we also have some additional insights on what this data may mean for other players in the PARP space such as Tesaro and Clovis.

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Picking PARP inhibitors apart

Picking a PARPi – what can the biology tell us?

One of the really interesting questions I recently received from a BSB subscriber related to PARP inhibitors – they asked whether the therapies are all the same and can be considered interchangeable as a class?

Around the same time, another reader wrote in asking if there was any new information on what’s happening with PARPi combinations in breast or ovarian cancers?

This got me thinking as there has actually been some useful preclinical and clinical studies reported on both fronts that at least begin to open our eyes to new information based on research that has been reported in several places.

Thus I thought it would be useful to summarise the data and take a look at what we learned in the process.

Fair warning – some of the findings turned out to be a little bit more surprising than you might normally expect to see…

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Targeting TGF-β and the tumour microenvironment

We know that not every patient responds to checkpoint therapy and some may respond but then stop responding, so what can we learn about the tumour microenvironment in order to fix it?

To do this may well require retrospective analyses of the existing trials in order to learn what happened and figure out an improved design of the next wave of clinical trials with rationally based combinations (as opposed to randomly testing two molecules simply because that’s what a company has in its pipeline).

The other thing to consider is that while some people might have a high level of a particular marker or inhibitory factor up front, others may see rise on treatment as an adaptive response to immunotherapy. Those two situations may well require quite different approaches or regimens to address, making things much more complicated than originally thought.

Dr Kunle Odunsi (Roswell Park) at #AACR18

One topic that caught our attention in the run-up to AACR and subsequently during the meeting was a cytokine called transforming growth factor beta (TGF-β). We have covered IL–2, IL–6 and IL–15 developments quite extensively on BSB, but what of TGF-β?

As such, we decided to investigate this little known target further and explore the concept from different perspectives in both academia and industry.

Today, we begin this latest mini-series with a thought leader interview from an academic institution who is researching a novel approach to combination therapy based on TGF-β – here’s what he had to say about the topic…

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Can we predict early treatment discontinuation on immune checkpoint therapy?

One of the many challenges we have seen with cancer immunotherapy and immune checkpoint blockade in particular is the thorny issue of how long should patients be treated for?

To be fair there are some studies testing a limited time period, but most are open ended in that patients are treated until progression or severe toxicities prevent continuation, whichever comes first.

Ovarian cancer TME Source: NCI

Is this the optimal approach though, especially if people receive the benefit and any more is superfluous, thereby increasing the twin burdens of clinical and financial toxicity.

Are there indicators that predict early discontinuation?

After all, if oncologists were aware of those factors then careful monitoring will be helpful in looking out for the warning signs.

Without a doubt, this is going to be a long road ahead and the path may be paved with different indicators depending on the tumour type involved. It could also become more complex as we move from monotherapy to doublets to regimens, which also increases the risk of clinical and financial toxicities.

We have to start somewhere and I’m delighted to say that I came across some elegant research that explored this issue and came up with some prediction factors of relevance. As a bonus, they actually make sound and intuitive sense too.

Here we describe the important study and look at the prediction factors that emerge…

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A potentially encouraging IO combination approach

2018 is likely to be the year of various immunotherapy combinations as we go beyond monotherapy approaches to see which doublets or triplets will yield improved outcomes. Originally, we had expected to see key data last year, but moving overall survival to a co-primary endpoint with PFS in many studies delayed the readouts by 12 or more months.

SGO 2018 – Who dat?

What’s happening now is that we have started to see some of the early data trickle out and there’s much more to come in the next few months as we head into ASCO and ESMO.

The last two months have seen much attention on lung cancer, but what about a less hyper-mutated tumour types such as ovarian or endometrial cancers? What’s happening in these women’s cancers?

Going beyond monotherapy with PARP inhibitors or checkpoint blockade is important if we truly want to start pushing the survival curves upwards and to the right.

It’s time for a new update on this hypercompetitive niche…

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The Future of Cancer Vaccines Part 5 – An Interview with Prof George Coukos

Mainz – At the recent CRI-CIMT-EATI-AACR international cancer immunotherapy conference in Germany, one of the underlying themes of the conference that attracted considerable attention from speakers and poster presenters was neoantigens, and how to generate cancer vaccines directed against them.

One of the European leaders in the field is Professor George Coukos who is Director of the Department of Oncology at the University of Lausanne Hospital and Director of the Lausanne branch of the Ludwig Institute for Cancer Research.

Lausanne is an exciting place for innovative translational oncology work with the Swiss Cancer Center, that Coukos also directs, creating synergy between partner institutions co-located in the Lausanne University Hospital (CHUV).

Mainz, Germany

We last spoke to Prof Coukos 18 months ago and much has happened since then. In Mainz, he kindly agreed to speak to BSB again and provide an update on progress.

This time we talked about the cancer vaccine research that he and collaborators such as Dr Lana Kandalaft are pioneering in Lausanne, and how this could best be applied in ovarian cancer.  It was exciting to hear him discuss his vision and some of the ambitious goals he hopes will be possible within the field.

Here’s a short excerpt from the interview – he has an interesting story to tell:

This expert interview is part 5 of our onging mini-series on the Future of Cancer Vaccines.

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The Future of Cancer Vaccines – An Interview with Dr Cathy Wu

One of the leaders in the field of neoantigen based cancer vaccine research is Dr Cathy Wu. She’s a medical oncologist at the Dana-Farber Cancer Institute (DFCI) in Boston, Associate Professor of Medicine at Harvard Medical School and a scientific co-founder of Neon Therapeutics.

Mainz Cathedral

Personalised cancer vaccines are showing exciting promise, and are at the vanguard of what many think of as a renaissance in the field, one that is now attracting the interest of many companies and researchers.

We posted on Neon Therapeutics approach and progress at the JP Morgan Healthcare conference in January, followed by an update on the clinical data from Dr Wu at AACR.

Much has happened since then, however, so it’s a timely juncture to continue the story.

At the recent CRI-CIMT-EATI-AACR international cancer immunotherapy conference in Mainz, Dr Wu kindly spoke to BSB about her research, where it’s at, progress to date, and importantly, where things are heading.

This is the first part in our latest mini-series on the future of cancer vaccines.

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The changing face of ovarian cancer

This kind of positive news is always nice to wake up and read:

“Rucaparib maintenance therapy increases progression-free survival in BRCA mutant recurrent ovarian cancer by 77%, according to late-breaking results from the ARIEL3 trial reported today at the ESMO 2017 Congress in Madrid.”

Of course, it’s not the first PARP inhibitor to show a significant effect as maintenance therapy in ovarian cancer after initial platinum therapy and we shouldn’t assume that all drugs in the same class will have an equivalent effect until we see the data.

It is good to see confirmation of a positive impact after seeing the data from two plus lines of therapy at ESMO in Copenhagen last fall.

So what does the new readout look like, what can we learn from it, and what were thought leader reactions to the data?

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Going Beyond PARP in DNA Damage Repair

We now turn our sights to targeted therapies and DNA Damage Repair (DDR). This is an important topic that has seen much focus in ovarian cancer of late and will likely see renewed interest in breast cancer at the forthcoming ASCO meeting next month. As we segue from one set of conference coverage to the next, there is inevitably going to be overlap, which is a good thing here as it helps with background and preparation in getting up to speed.

There is no doubt that DDR has had a bit of chequered history over the last decade, whether it be the spectacular (and sadly predictable) flop of Sanofi’s iniparib in triple negative breast cancer (TNBC), the negative ODAC incurred by AstraZeneca’s olaparib in ovarian cancer, or AbbVie’s more recent veliparib failures, to the much more positive events such as three PARP drugs now approved in different lines of therapy in ovarian cancer (olaparib, rucaparib and niraparib).

If ever there was a niche for the roller coaster ride that is oncology R&D, it has to be PARP inhibitors.  There’s much more to DDR than just PARP though.

Indeed, there are multiple intriguing targets to explore and also the potential for combinations with cancer immunotherapy approaches that may yield encouraging results in the future.

Can we go beyond ovarian cancer into other tumour types and if so, which ones look encouraging and how woluld we go about exploring those idesa? What makes one approach more successful than another?

Here we explore the world of DDR through the lens one company’s approach and look at what they’ve done, where are they now and where they hope to be. It certainly makes for an intriguing and candid fireside chat.

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