Biotech Strategy Blog

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

Posts tagged ‘CDK4/6’

In Pharmaland it is frequently the case that once a target has been validated there’s always new developments in the form of novel agents that emerge, as well as emerging new related targets to consider.

Standing from the KRAS crowd

Here we combine an update on some new market entrants in the KRAS niche with an expert interview discussing how to address a known area of acquired resistance that has recently been highlighted.  Naturally, that also brings with it yet more novel targets and potential combination strategies that may need to be considered by players in this space.

Yes, KRAS G12C is now a rapidly evolving area with multiple players and many moving parts, whereas even just back in January this year many observers saw it as a three horse race – think again, it’s much deeper and broader than that somewhat naive hypothesis already!

As usual, we follow these races longitudinally with regular updates and explain why new scientific findings need to be considered if we are to make a difference in the clinic with future combination strategies.

Are you ready for the latest game of 3D chess?

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Chicago – here we are with highlights and insights from Day 4 of #ASCO19 and time is running down on this meeting with just half a day to go – whew!

One of the highlights of medical and scientific meetings we go to is meeting early career researchers, especially those who are doing translational research.

On Monday at ASCO19 we particularly enjoyed talking with Dr Wungi Park (@W_Park_MD) from Memorial Sloan Kettering Cancer Center who presented a poster on homologous recombination deficiency (HRD) as a biomarker in pancreatic cancer (abstract 4132).

We look forward to hearing more from him and colleagues as data is generated from the clinical trial they plan to start later in this year to investigate this further. Translational research in action!

What were some of our other highlights of Manic Monday at ASCO19? We’ve shared a few in the post below for BSB subs.

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Padstow, Cornwall – It’s May Day or ‘Obby ‘Oss, as it’s known locally in this little corner of south west England.  The quaint festival means that it’s the biggest day of the year as over 30,000 people crowd into the tiny fishing village.

Obby Oss Blue

Centuries old traditions are still alive and well in this part of the country and the big question of the day (are you red and white or blue and white?) is a far cry from the complex high tech world of cancer research.

Still, with all the time and attention focused on immunotherapy and targeted therapies of late, it is all too easy to forget what’s happening on the epigenetics front, which is quite a bit in practice.

We often see random allcomer approaches to clinical trials, which are find for phase 1 studies where you want to gather data on responders and non-responders in order to conduct PK/PD and immune profiling, as well as biomarker and signature development, but a potential recipe for disaster in phase 3 if you have no idea exactly what’s driving the efficacy since you can all too easily end up with unbalanced arms that you didn’t control for and thus skew your survival curves in a way you didn’t anticipate.

Why on earth would you use a targeted therapy in an untargeted fashion? Hmmm obvious question and yet, many companies still do this all the time.

There are some biotechs out there, I’m pleased to say, who do conduct extensive translational and biomarker research.  Obviously finding those markers is a lot more tricky than choosing red or blue.

One biotech company we have been keenly following for a while is Syros.

We first wrote about them in Spring 2014 and now, five years on, I thought it would be a nice idea to catch up with one of their founders and learn more about the science underpinning what they’ve done and where they’re going with future projects. Not only do they invest in smart medicinal chemists, profiling and translational research, but they also seek to identify rational reasons why people respond to their compounds.

The answers were rather interesting and there’s quite a bit that readers might be curious to learn more about…

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Post 2016 US Election, we move on and get back to business with an in-depth review of some new science and clinical data.

ash-2015Yes, it’s time for another Bushidō – “Way of the Warrior” – guide to the key ASH abstracts!

Here we focus on acute myeloid leukemia (AML), a difficult and challenging disease to treat with a high unmet medical need for new effective therapies.

In this Preview we look at key companies in the AML space, as well as a look at what’s happening in classic targets and also some new ones that are receiving notable attention, both preclinically and also in the clinic.

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There was a time when it seemed that all the good news emerging in cancer research was on breast cancer, that is clearly no longer true as other tumour types have seen some leaps and bounds with different modalities, including areas previously thought to be a graveyard for big Pharma, such as metastatic melanoma, for example.

new-dawn-houses-of-parliament

New Dawn at the Houses of Parliament

That said, after the excellent developments in hormone-sensitive disease and the identification of the HER2 oncogene, we now have CDK4/6 as a validated target in metastatic breast cancer.

Pfizer’s palbociclib (Ibrance) lead the way, with two approvals in previously untreated and relapsed ER+ HER2- advanced breast cancer. Two other companies in this field are Novartis with ribociclib and Lilly with abemaciclib. Data is being presented on all three therapies at ESMO this year.

In addition, there are some other abstracts of note that are well worth discussing.

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Yesterday, Lilly and Boehringer Ingelheim announced a clinical trial collaboration in metastatic breast cancer with the CDK4/6 inhibitor, abemaciclib, and the IGF antibody, BI 836845. The goal of the phase Ib study is to evaluate potential of combination therapy in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+, HER2-) metastatic breast cancer (mBC).

Braving the ASCO 2016 Poster Hall

Braving the ASCO 2016 Poster Hall

A couple of BSB readers wasted no time and wrote in asking what we thought of this development, so this presents an excellent opportunity to turn the spotlight on combining targeted therapies in a rational fashion, especially as there was data presented on these agents at the recent ASCO annual meeting.

There are ceratinly a number of important considerations to explore with this type of approach.

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If you had told me several weeks ago that we would write over 28 posts on #AACR16 and become very interested in mouse models, then most likely I would have laughed out loud and told you not to be so ridiculous!  Here we are with the 29th one and, another, on the bromododomain landscape yet to go.  Such was the vast richness of data and concepts being discussed or presented in New Orleans for those who chose to look.

Today, I want to start the segue from AACR to ASCO coverage.

Nawlins MGRAS FIOne way to do that is through the second part of the Gems from the Post Hall series. This latest one looks at a range of intriguing new targeted therapies and novel targets that are emerging, including a pharma company with a particularly interesting early pipeline.

Several pharma companies presented interesting data on their very early compounds currently in development, plus I noticed a trend for a new class of targeted therapies to emerge, MNK inhibitors, which we will also discuss.

Companies mentioned: Bayer, Orion Pharma, Lilly, Novartis, Pfizer, Agios.

Targets mentioned: PI3K, CDK, Akt, TWEAK, FGFR, BUB1, IDH1, SMYD2, MNK

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Beyond the late breaking abstracts and plenary sessions at the European Cancer Conference being held in Vienna, Austria later this month, what other important topics can we expect to hear about?

ECCO 2015 Vienna

We covered the former in the last article on Biotech Strategy Blog, today we turn our attention to the proffered (oral) sessions and what we can learn from those sessions and the expected data that is due to be presented.

There are a number of interesting topics and new data slated for presentation that are worthy of review and highlighting in a What To Watch out For (W2W4) format.

Here’s our take on the potential highlights at the meeting.

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Dr Richard Finn Source: UCLA

Dr Richard Finn Source: UCLA

At AACR this weekend, Dr Richard Finn (UCLA) presented the much anticipated front-line phase II data for Pfizer’s CDK4/6 inhibitor, palbociclib (palbo) plus letrozole versus letrozole alone in ER+ HER2- breast cancer.

The PALOMA series of trials are designed to show that adding a specific CDK inhibitor to an aromatase inhibitor enhances efficacy and improves outcomes.

There are three metastatic breast cancer trials in all, with PALOMA–1 being the phase II study while PALOMA–2 and –3 are phase III randomised controlled registration studies aimed at confirming the initial phase II results in combination with letrozole and fulvestrant, respectively. In addition, palbociclib is also being evaluated in combination with standard endocrine therapy (PENELOPE-B) for certain early-stage breast cancers.

In short, an analysis demonstrated that the primary endpoint of progression free survival (PFS) was met, but the overall survival (OS) data was not significant at the time of the analysis.

What does this does this data mean and in what context should we look at the results?

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Boston: Fallowing on from yesterday’s post about learnings from the AACR-NCI-EORTC conference in immuno-oncology, today’s post focuses on learnings from non-immune R&D, namely monoclonal antibodies and TKIs.

We know that cancer is a very complex topic and that adaptive resistance is increasingly a huge focus, but where are the new developments in this area and what can we learn from them in order to improve outcomes?

Another key area to consider is therapeutic index, that is are we shutting down enough of an oncogenic target’s activity in order to ensure efficacy? We’ve seen this in the anti-angiogenesis field, for example, where many VEGF inhibitors failed before bevacizumab (Avastin) finally cracked the nut in colorectal cancer and shifted the needle in terms of improving overall survival. We are now seeing this happen in other areas too, which will be covered below.

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