Biotech Strategy Blog

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

Posts tagged ‘KRAS G12C’

In our latest AACR Preview series we now turn our attention to the evolving KRAS niche of inhibitors and degraders.

It’s not that long ago we only had G12C mutations to talk about in terms of what was considered ‘druggable’ and now we have another mutant (G12D) with at least two agents in the clinic already and more soon to come.

Of course, there are also the pan inhibitors in the mix and these will be covered separately.

For now though, it’s the turn of the selective agents with much more going on than many observers may realise, including some interesting novel developments coming through…

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Are scientists and observers taking a distorted fish eye view of the KRAS world?

I’ve often wondered if in putting so much focus on ripping the progress of the G12C inhibitors to shreds, people simply lose focus of the progress being made elsewhere especially with different, yet related targets.

Here we offer some emerging highlights on several fronts, some of which ought to be well worth watching out for and others perhaps not so much…

Curious to learn more?

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Old Post Office, Barcelona

What started out as a short update from the recent EORTC-NCI-AACR (ENA / Triple Meeting) in Barcelona on new data in the KRAS niche turned out to be a much more in-depth review in light of the explosion of corporate interest in this area.

At this meeting several companies provided updates on compounds, which either recently entered the clinic or were imminent, including the very first KRAS G12D degrader to make it past IND enabling studies. We also saw initial data for many new drugs on the horizon, including some in discovery or preclinical development. There were definitely some gems to be found in the poster hall!

If you didn’t make it to Barcelona for what turned out to be one of the most informative Triple meetings of recent years then this piece is for you if you’re following the burgeoning KRAS space.

In this post we highlight and discuss various direct KRAS approaches, as well as indirect upstream (SHP2), downstream (MEK, ERK, and ULK), and even cross-stream (PI3K) targets of interest.  KRAS G12C inhibitors were just a start, while the future may well look quite different…

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One of the questions we routinely think about at BSB and ask researchers is what are the mechanisms of resistance underlying the therapy they are evaluating in preclinical or clinical studies?

If you understand what these are from the get-go then you can better design rational combination trials to address them and improve outcomes rather than leave things to the vagaries of chance.

In this post, we’re looking at novel approaches researchers are thinking about in relation to resistance with protein degraders and what this may mean for cancer new product development.

Curious to learn more?  Then check out the post below…

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Et tu, Brutus?

Perhaps the most controversial readout from ESMO22 this week was the phase 3 readout on Amgen’s pivotal trial for their KRAS G12C inhibitor in second line non-small cell lung cancer (NSCLC).

Instead of being an obvious shoo-in, quite a few surprising issues came to the fore – almost in a perfect storm fashion – acting to hobble the results in an unexpected fashion.

Here we review the issues and challenges facing sotorasib and also explore the potential impact on the field at large…

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Oper Wien

It’s time for our second post on WCLC22, which also happens to be on the hot KRAS G12C niche.

The first part analysing the sotorasib plus checkpoint combo was posted here for anyone who missed it.

This time around we’re going to explore different combinations and look at some of the fast-follower agents coming up on the rails.

After all, this is more than a two-horse race where the winner isn’t necessarily the first past the post, but rather the one either with the widest therapeutic window or who figures out the optimal combination partners.

Curious to learn more?  Check it out…

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Degrading proteins, block by block

Our KRAS review last week included a lot of different inhibitor compounds (well over 30 of them), illustrating just how complex this niche is rapidly becoming, with only a brief mention of targeted protein degrader (TPD) compounds since these are much further behind their small molecule inhibitor counterparts.

Since then there’s been some more big picture talks or three about the TPD space, which are well worth discussing, as well as a flurry of relevant questions from BSB readers to be addressed.

Here we discuss the KRAS niche in the context of protein degraders and look at the promise and some of the inherent challenges faced…

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It seems astonishing to realise only a couple of years ago KRAS was considered undruggable intractable and here we are, not only with one drug approved, another filed and veritable long list of fast followers, but a whole ecosystem of different agents vying for a place at the table.

The wonderful news is we are starting to think more broadly about life beyond G12C mutations, not only with different combinatorial approaches, but also also in the context of how to tackle other related mutations as well.

Here, we wanted to explore the evolving universe more broadly and assess criticality as well as applicability – which agents might shine tomorrow if clinical data turn out positive?  The simple answer is more than you know.

So just who are the rising stars in this emerging landscape and what can we learn about them?

Be warned in advance – this is one of our longest and most comprehensive reviews on BSB with over 30 compounds highlighted in different guises, so grab a cup of Joe and be prepared to come with an open mind…

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One of the many challenges in the oncology space is seeing the bigger picture of how companies evolve their early stage pipelines.

For some, it’s a bit like taking a walk in the forest and not being able to see the wood from the trees – the targets chosen are rarely random, especially those involving collaborations.  There’s a reason for pursuing a given approach, particularly i it is intended to be employed in combination with an existing, approved therapy.

There are many choices out there and even those with the deepest pockets can’t have everything, so often I’m fascinated by the selections that are taken and how they might fit in.

In our latest company review, we talked to a big pharma company active in the immunotherapy niche and sought to explore the early stage agents they are developing in the context of future doublet and triplet combinations.

Why are they doing what they’re doing and how might their approach be differentiated from others?

To find out more, check out our latest expert interview, which has a few surprises in store…

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Can we scale new heights with next generation anti-cancer agents?

One of the fascinating things about ASCO is how early new product development readouts outside of ‘hot’ names (or stock tickers) can often be ignored, forgotten, or simply dismissed as me-toos with seemingly comparable data.

The thing is, two people can look at a mountain and see it differently, much like five blindfolded people might describe various aspects of an elephant based on their perceptions of what’s in front of them – imagine what a tail versus a trunk or ear might produce, for example.

This is also particularly true with targeted therapies, which are undergoing something of a renaissance of late.

In this post, we look at five targets (and tumour types) where we are seeing some solid progress either with single agent therapy or with combination approaches, some of which – be warned – are rather controversial…

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