What’s the elephant in the KRASi room?
It’s time to look at the latest update on KRAS mutation specific agents in clinical development as we turn the spotlight from the Amgen sotorasib data at ESMO to Mirati’s G12C selective agent, MRTX849, now known as adagrasib.
At the Targets meeting last year in Boston, Dr Pasi Jänne presented the initial findings from phase 1/1b the lung cancer cohort. This time around we get to hear him provide an update on the combined phase 1/1b plus phase 2 results, plus there’s an additional presentation from Dr Melissa Johnson on the non-lung cancer cohort i.e. GI and other cancers.
Ahead of the presentation this morning (US east coast time), BSB caught up with Dr Jänne for his perspectives on the progress made and where things are headed in the near-term. He offers a thoughtful and candid approach to tackling a hard to treat cancer subset with targeted therapy.
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A look through the window at the evolving KRAS landscape
It’s time for an important update on the KRAS landscape and emerging opportunities in this niche.
I’ve mentioned this a few times, but the real kicker is going to come from rational combinations in different settings. Those companies who figure these out will emerge a stronger player than their competitors who focus on monotherapy.
With this idea in mind it behooves us to be alert and aware of what’s going on in the broader landscape beyond selective KRAS inhibitors against certain mutants.
Here we discuss the latest findings from two such targets, each quite different and yet both could have important roles to play going forward…
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George Martin’s quote seems rather apt this morning as NextCure announced there was disappointing single agent activity with their Siglec–15 directed agent (NC318) in an ongoing phase 1/2 trial.
There were a couple of initial partial responses reported at SITC last year and now it may seem as if the wheels are falling off the wagon.
What can we learn from the latest update?
It turns out quite a bit…
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Time for some reflections from ASCO
Many eyes at ASCO this weekend will be eagerly turned towards the plenary session on Sunday and the stunning osimertinib data in the ADAURA (adjuvant osimertinib therapy for EGFR positive disease) where 69% were stage II/IIIA and for those patients, DFS HR was 0.17 with a 2 year DFS rate of 90% (only 44% with placebo).
There is no doubt this is the data of the meeting for me – when was the last time we saw a hazard ratio of 0.17?! More on this development after the data has been presented.
Beyond the plenary there are plenty of interesting studies to discuss and ponder at various stages of development. Over the next couple of days a number of other stories and interviews will be also posted.
Here, we provide an update on one of the early drug development stories we’ve been following longitudinally over the last five years from preclinical through to the clinic and offer some reflections on progress to date.
A KOL interview and commentary are included as well…
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Time for some additional colour commentary!
There has been some incredibly intense interest surrounding TIGIT as a new therapeutic target in oncology of late, to the point where some observers have been wildly claiming this is the new universal checkpoint everyone has been waiting for.
But is it?
It’s early days yet with little data presented from people with cancer, so at this point it could well be a bit of a stretch to find another anti-PD–1/PD-L1 equivalent, but this doesn’t mean there isn’t utility in seeing clinical activity in some tumour types, far from it.
In our latest post, we take a look at what’s coming up in the TIGIT niche, along with an interview from a company active in this niche.
What do the company have to say and how do they see this panning out?
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First in class or best in class?
Which paths will ultimately lead to success with novel targeted therapies?
Ah this question often seems a perennial one to consider at AACR annual meetings – and this year is no different in this respect.
Personally, to me, it doesn’t really matter what you claim aspirationally based on preclinical or even early phase 1 dose escalation data because… a lot can happen between then and later registrational studies.
Think about it carefully – weak efficacy, wrong tumour selection or setting, adverse event profiles, even narrow therapeutic windows can all too soon interfere and play havoc like a wrecking ball with many a well intended clinical program, especially once you start looking at combination strategies!
No, it’s not as easy as it looks sometimes.
In our latest AACR Preview series, we take a look at a number of targeted agents in development, many aimed at novel targets at are not run-of-the mill…
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Attention on small molecule inhibitors – after being in the doldrums for a while – seem to be making a comeback over the last year with much attention focused on a few companies developing new selective agents in specialised niches.
Time for a KRAS spring clean!
One such space is KRAS inhibition. Not just in terms of direct or indirect inhibition, but also with regards to tackling acquired resistance mechanisms such as SHP2. While there has been quite the frenzy over what Amgen, Mirati, Revolution Medicine and a few others are all doing, other companies are quietly getting on with the business of producing some nice work and will soon be ready for the off.
In our latest review we explore some of the factors involved, which companies will need to be concerned about going forward, especially in the context of future combination strategies.
In solid tumours, with targeted therapies the winners are not always the ones who reached the market first, but rather the crafty ones who optimise the combination strategies and become ingrained in protocols across multiple situations.
Here we look at one of the hidden gems in the KRAS space and explore what it does, why it’s important and how it might fit in. We also include a company interview with a scientist who gets the broader implications…
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As we head into the AACR-NCI-EORTC Triple meeting in Boston this weekend, excitement is growing around a suite of RAS inhibitors in lung, colon and other cancers.
Charles River, Boston in October
Over the last couple of weeks we’ve received a bunch of questions from readers on several topics relating to this niche that I thought would be useful to spend some time on to set the scene ahead of the data dump expected on Monday and Tuesday.
Some people do like to try and simplify things thinking that it’s just a matter of adding in a checkpoint blocker or something else and boom! off we go… Except that we know from past experience with similar agents against different related targets that this won’t necessarily be the case and we look at some of the reasons why.
Yes I know folks are likely expecting too much in terms of efficacy, but we can put some framework and structure around the issues on which to build on, which are actually more than many may realise plus it could also be tumour and even patient dependent.
So here we go with a joint KRAS mailbag, together with a short expert interview with a view to highlighting some crucial roadblocks that are likely heading our way…
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The calm before the morning storm surge at ESMO19!
Barcelona – I can’t recall the last time we published three long form posts from a conference before high noon (US time) on the same morning, but that certainly illustrates how busy this year’s ESMO is and there’s a lot more to come yet.
The initial starting coverage for today includes hot topics in ovarian, lung, and colorectal cancers and more will be added in due course.
If you are looking for osimetinib in FLAURA and AMG 510 in KRASm colorectal cancers, click on the BSB log in the top left corner to check out the front page slider for more information on those write-ups and commentary!
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The many faces of lung cancer requires an appreciation of nuance in treatment
Barcelona – Many observers seem to so be single mindedly focused on immunotherapies of late that they may well be forgiven that, hey, there’s still much going on the world of targeted therapies!
If there is one thing we can learn from the lung cancer (and CML) communities it is their dedication to identifying resistance mechanisms and along with them, novel targets for subsequent therapy in order to set about improving outcomes for people with the disease.
As a result, lung cancer can now be segmented into many subsets, each requiring careful consideration of appropriate therapy options, not only in newly diagnosed disease, but also what to do with subsequent lines of therapy.
In this review, our third from the WCLC 2019 meeting, we pull together a lot of disparate loose ends on targeted therapies and draw some important themes together…
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