Biotech Strategy Blog

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

Posts tagged ‘KRAS G12D’

It’s the dog days of summer and time for some meaty controversy to read!

For the longest time there have been several cancer types which have been incredibly difficult to treat therapeutically.

Metastatic melanoma and non-small cell lung cancer (NSCLC) both used to be in this category, as did glioblastoma and advanced pancreatic ductal adenocarcinoma (PDAC).

We have made great strides in changing the face (and more importantly outcomes!) for people with both metastatic melanoma and lung cancer, so what’s happening on the pancreatic cancer front?

The last two years gave certainly thrown up a series of disappointing clinical trial readouts such as RESOLVE, HALO–301, CanStemIIIP, and SEQUIOA, for example, where in each and every case the findings favoured the control arm of gemcitabine plus nab-paclitaxel over the experimental arm in terms of improving survival.  Not one of them was able to raise the bar and show a significant improvement over standard therapy, which is pretty disappointing.

So what can be done to change the face of PDAC?

If we want to improve further then we need to go back to basics and enhance not only our understanding of the funadamental biological mechansisms and processes, but also the models we use to interrogate the systems involved.

In this post, we look at six key new areas of research in PDAC and explain what we’ve learned and why they matter if we are to see new therapeutic developments arise from the ashes of the past…

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As we continue to follow the emerging KRAS niche longitudinally, we can easily imagine the kind of roller coaster ride that ensues with new product development in oncology R&D.

Early last year we posted an interview with Mirati’s CEO, Dr Chuck Baum, discussing their selective KRASG12C inhibitor.  A year on much has happened in the intervening time – additional competitors and potential collaborators have entered the clinic, a few mechanisms of resistance identified, and numerous combination partners have been suggested.  The company have also aired their own phase 1 data and new trials are expected to open during 2020.

This time around we talk to both Dr Baum and the company’s CSO, Dr James Christensen, about their experiences in the front line in terms of translating the preclinical data into clinical trials, their thoughts on important scientific data as well as the competition, and what to watch out for going forward.

This field is going to not only go fast judging by the emerging research published to date, but it’s also going to get way more complicated than many observers realise.

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The calm before the storm as the KRAS competition heats up and also gets more complex in the process

I was very tempted to tease everyone and say something along the lines of… ‘while you were all partying, there was some new KRAS clinical data being presented somewhere in the world’ but that would be rather naughty, I suspect.

Instead, I’ll simply point out that it’s time to take a look at the latest phase 1 data in the KRAS niche.

What more clinical data already?!

Yes there is and what’s more it doesn’t belong to the either of the leading two in the early race to market, aka Amgen and Mirati.  There’s a whole bigger world out there for those interested in following the broader slate runners and riders.  It pays to pay attention because this is not a race about single agent therapies, rather it’s about who figures out the optimal combinations and is able to finesse that better than their competitors.  Like real horse races, an unexpected runner can surprise a few folks by making a strong push on the rails or a bounding leap round the outside like Lester Piggott was famous for doing.

This highly specialised field is moving much faster than the BRAFV600E arena was a decade ago and there’s also more players involved too, plus multiple different approaches and targets to consider, which I expect we will be covering quite a few times during 2020.

Are you ready?

Get set, GO!

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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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With all the furore surrounding the new developments with KRAS G12C inhibitors in lung and colon cancer, it is easy to forget that there are plenty of other promising related ideas in the pipeline too. After all, there’s more than one KRAS mutation that can act as an oncogenic driver in patients that can portend poorer prognosis.

Aside from the obvious small molecules, there are other modalities to consider.

Here’s one such novel design that caught our attention — it has the potential to be elevated into an elegant platform approach with different molecules targeting a variety of critical mutations in tumour cells including KRAS G12D, which is prevalent in colon and pancreatic cancers.

I’ve had my eye on this work for a couple of years and now it’s a good time to showcase it in the spotlight given the sheer energy and attention focused on this niche…

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It has to be said that this is one of the most jam-packed ESMO schedules that I’ve seen in a while!

Usually one has a few sessions they are interested in and lots of ‘free’ time to conduct interviews. That is definitely not the case this year with even parallel sessions at the same time as the Presidential (plenary) symposia, making for some very hard choices that need to be made.

Barcelona

Immune suppression can take the form of many targets – just taking out one of them may not be enough

As we start to see a renewed focus evolve on how to make immunotherapy work in or help more patients, there has been much attention on what we can learn from the addition of chemotherapy, additional checkpoint targets, immune agonists, various innate targets from KIR and NK cell checkpoints to TLRs and STING, neoantigen and dendritic cell vaccines, a telephone directory of cytokines, oncolytic viruses, etc etc to name a few, all with varying degrees of success.

What about exploring the inhibitory factors that induce immune suppression?  If we can reduce the cloaking and hostile tumour microenvironment, would that lead to more effectiveness with checkpoint blockade?  Maybe, maybe not.

In principle, it’s a sound idea yet these factors are both broad and incredibly varied in scope as a topic as to seem overwhelming at first.  The good news is that there are some emerging targets and hints of activity to come that are slowly beginning to emerge, making ESMO a good place from which to take stock of some new early stage developments.

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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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