Biotech Strategy Blog

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

Posts tagged ‘KRAS G12C’

Do any of the early trials in advanced cancers aspire to be great?

Not in Chicago – Of relevance to the ongoing ASCO20 coverage, in the Preview series this year, two of the companies we highlighted going into the meeting (Innovent and Alphamab) both announced deals this week with Roche and Sanofi, respectively – talk about highlighting hot topics ahead of time 😉

After last week’s look at winners and losers in hematologic malignancies, this time around we now turn our attention to explore what’s happening on the new product development front regarding solid tumours.  In this review, we critique some of the trials presented and put them in broader context.

As always, there are both some important learnings we can glean as well as some, well, head/desk moments to contemplate…

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It occurred to me after several such events this year that virtual meetings create a very different pattern for spectators from live events where we all dash from one hall to another trying to optimise the viewing experience and catch as many key talks as we can.

Gems from the ASCO Poster Halls

Instead of the annual rugby scrum in the ASCO poster halls, we can imagine ourselves in an entirely different world with social distancing virtually

Many people will no doubt be eager to listen to the various oral presentations of phase 3 data come Friday morning, while the poor posters may well languish until some undetermined time later, so why not take a step back and highlight some of the early work in developmental therapeutics ahead of time?

In the final part of our ASCO Preview series, we offer our independent take and candid commentary on ten abstracts in developmental therapeutics to watch out for.

A word of warning – we don’t take a particular perspective through the lens of rose tinted glasses, so not all the analyses are positive and there are some firm words against some of the selections regarding continued development or the researchers conclusions/recommendations.

Some of these are agents in early development, some are biomarkers or even emerging trends, but all are intriguing in their own unique fashion.

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A saying for the ages from Albert Einstein

Oncology R&D is – perhaps surprisingly – very much like the bicycle analogy Albert Einstein described.

There are many ways we can see this happening at meetings such as AACR and ASCO as companies struggle to finesse the therapeutic window and balance efficacy with toxicity, for example.

Or how about finding creative ways to extend and broaden a particular drug class?

Another approach might be to take an entirely different angle to tackling a tumour type by targeting an antigen few others are pursuing. Just because the herd is going in one direction doesn’t mean you should follow them down the same path as well.

Then there’s switching modalities, orthosteric versus allosteric inhibitors, or how about some med chem magic where researchers seek to enhance the good properties and minimise the weaknesses while still hitting a target selectively?

All of these methods require some kind of balancing act if you want your pipeline to move forward rather remain still or fall over in the doldrums.

Today’s post has all of this and more – there are some novel compounds and targets, emerging biotechs and big pharmas, as well as innovative thinking to make a difference. Several of these agents are first-in-class, which means the rest of us can learn much from the lessons they have shared.

What’s not to like?

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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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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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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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Barcelona – Today is going to be a very long and complex day at ESMO, with a multitude of key data expected from several trials ranging from the phase 1 Amgen data update on their KRASG12C inhibitor, AMG 510, AstraZeneca’s osimertinib in the FLAURA study plus a raft of others, including the phase 3 PAOLA–1 and CheckMate–227 trials.

In order to keep all the information straight and manage the various embargo deadlines at wildly different times, we’re going to break with tradition and post three different articles at different times on KRAS, FLAURA, and the daily running log of various studies and posters that catch our interest. Yes it’s a lot more work, but it’s the only way to manage all the deadlines!

This post will focus solely for the KRAS updates at ESMO19, including the initial data release, the presentation, analyses, and commentary. No doubt that means a series of updates will ensue so do check back regularly or follow the alerts on Twitter via @biotechstrategy.

Let’s roll!

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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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Chariots of Fire in Barcelona?

Barcelona – Gosh, what a weekend chock full of lung cancer data at the World Congress on Lung Cancer hosted by the IASLC!

There’s nothing like a bit of controversy to get riled up or crash with disappointed hopes under the weight of expectation, but if we go under the hood and look carefully, what do we find?

There was a lot of topics that we’re going to cover the important highlights and learnings in a two parter series – today we focus on KRAS with targeted therapy, while tomorrow we look at other topics of interest, both targeted and immunologic.

Without much ado, let’s roll with the Amgen update as there are many subtleties and nuances to consider…

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