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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Boston – One of the most enjoyable things about writing about science and early clinical oncology data is the relationships we build with thought leaders, such that they can be open and honest about their reactions, without them being judged, misinterpreted, or misquoted. We’re on a journey with them, whatever the ups and downs might bring, in a bid to capture the realities of the oncology R&D rollercoaster.
Don’t be fooled by the gloomy Boston weather as a metaphor for data presented at Targets19!
Each story becomes a snapshot in time, a short of ‘Kodak moment’, if you will.
Imagine then, capturing a discussion with a global lung thought leader discussing the initial data from the first-in-man trial with a KRASG12C inhibitor from Mirati (MRTX849) and his experiences in treating people with advanced lung cancer who have the dreaded KRAS mutation, which until recently there were no effective options for.
Thus, we captured the exuberance of seeing objective responses in patients for the first time, “It’s fantastic!” and at the same time qualifying that with a balanced and candidly objective perspective, “it’s still early days.”
Both are true, and not mutually exclusive.
In between these two extremes there is much to think about including understanding the inevitable resistance mechanisms that evolve (primary and secondary), figuring out how to optimize the combination trials as well as reactions to other, seemingly competitive, developments. Our expert in the hot seat today had some rather thought provoking ideas on these important topics to discuss that we wanted to share and stimulate some debate on.
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Henry Moore sculpture – looks like a protein binding pocket!
Cambridge, UK – It’s somewhat ironic that we headed across town today to chat with one of the world’s leading cell biologists on MYC and RAS with a post on KRASG12C inhibitors almost ready in the bag. More on that interview in a future mini-series.
There are a number of nuances and subtleties involved in this niche, which have been somewhat lost in the frantic hype over hope melêe of late.
This review discussing KRAS and various other co-mutations such as LKB1/STK11 is a long and thorough one,, and perhaps rather contrarian in nature.
That said, I do feel that it is very important to highlight a lot of issues that are being ignored in the rush to declare the latest expected winners and losers or even potential blockbusters, if the breathless signals are to be believed.
If nothing else, there are certainly several key issues that could have a bearing on the clinical results in patients that are worthwhile highlighting for discussion and adding to the watch list because some of these factors may well take time to develop.
This is one of those ‘Ground Control to Major Tom – take your protein pills and put your helmet on’ moments… Actually, I may well be needing the helmet as protection if the analysis and commentary turn out to be unpopular!!
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While much of the attention and news flow seems to be on the big companies at the JP Morgan Healthcare conference, I also wanted to take time to explore some early oncology developments coming out of small biotech companies.
Next Gen TKIs pointing the way?
TKIs are very much still alive and kicking in many pipelines and no, not everything is all about immuno-oncology, checkpoint blockade or CAR T cell therapies.
We still have to tackle the three horsemen of apocalyse, namely MYC, RAS and TP53, and find ways of making the undruggable finally druggable if we want to succeed in tumours where these driver mutations confer unrelenting oncogenic addiction.
With that in mind, here’s an interview with Dr Charles Baum of Mirati Therapeutics and what they are doing to address some of these challenging issues…
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