Biotech Strategy Blog

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

Posts tagged ‘AMG 510’

Not in Madrid – with the global pandemic continuing to exert a significant effect on the cancer conference season, the annual meetings continue apace virtually.

Plaza de Cibeles, Madrid

For this year’s ESMO meeting we have already covered immunotherapies, both early and late stage pipeline highlights and now it’s time to explore what to watch out for over the weekend on the early to mid stage targeted therapy front.

The good news is there is some potentially practice changing data being presented, as well as some novel approaches in preclinical development emerging. These should be hitting the clinic in the near to medium term future.  On the other extreme is the more common problem whereby a few agents are showing signs of not holding up to their early promise/hype.

Let’s now take a look at what we can learn in the fourth and final ESMO Preview for 2020…

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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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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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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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Continuing our bispecific mini-series, we now switch from small to large biotech with a look at what Amgen are doing in this niche. They have both regular bispecifics, as well as T cell bispecifics in their early pipeline.

Our latest company interview focuses on several early phase 1 new product developments.

Aside from the BiTEs, we also discuss the clinical program with one of their most promising small molecules, AMG 510, a KRAS selective inhibitor that has been drawing much attention since the chemical structure was unveiled at AACR earlier this year.

There was much ballyhoo and yet more garish headlines in the media at ASCO regarding ‘Amgen showed it had developed a medicine that shrank tumors in 50% of lung cancer patients’ – in 10 patients. Was it really 10 people or a much higher number if we consider intent to treat amongst evaluable patients? Then of course, taking a small sample size into consideration, the next 10 might produce quite different results. We might also see resistance set in down the road (e.g. at 9 to 12 months as we have with BRAFi), so these are really very early days, something we pointed out during the daily ASCO coverage.

To be clear, I can say that both companies included in yesterday’s (Neon Therapeutics) and today’s (Amgen) articles were sensible, thoughtful, and well measured in how they handled the data rollouts, but the media frenzy that occurred with each is quite something else.

Since we had quite a few BSB readers ask about both sets of data, having discussed Neon’s yesterday, today we offer an interview with an Amgen exec at the heart of their early stage programs…

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Chicago – here we are with highlights and insights from Day 4 of #ASCO19 and time is running down on this meeting with just half a day to go – whew!

One of the highlights of medical and scientific meetings we go to is meeting early career researchers, especially those who are doing translational research.

On Monday at ASCO19 we particularly enjoyed talking with Dr Wungi Park (@W_Park_MD) from Memorial Sloan Kettering Cancer Center who presented a poster on homologous recombination deficiency (HRD) as a biomarker in pancreatic cancer (abstract 4132).

We look forward to hearing more from him and colleagues as data is generated from the clinical trial they plan to start later in this year to investigate this further. Translational research in action!

What were some of our other highlights of Manic Monday at ASCO19? We’ve shared a few in the post below for BSB subs.

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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 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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