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

Posts tagged ‘colon cancer’

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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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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Chinatown Chicago

One of the things we try to do on BSB is tread paths that aren’t well travelled.

It’s a bit like coming to Chicago and visiting areas such as Chinatown that are beyond the common tourist sights. It can take a bit of effort, but often delivers a memorable experience in the process.

In this final preview of #ASCO19 before the educational sessions start tomorrow, we’re offering up 10 abstracts that we think are underrated and noteworthy of closer attention.

Like any guide book our recommendations are subjective, but if you’d like to read more then subscribers can login or you can purchase access.

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We’ve been following the work of Dr Jérôme Galon, a French immunologist, on Immunoscore for a while now, and many readers will remember the last interview he kindly gave BSB from the European Cancer Conference in September [Link].

IMG_6454In 2015 the large global trial to validate Immunoscore as a biomarker was still ongoing, so if you want some background to this important concept, do check out Dr Galon’s interview as it’s well worth reading as a primer on immunosurveillance, the importance of immune cells – the type, density and location, as well as background on the Immunoscore test as a marker of outcome.

Since then, the group have also published some related data that both moves the field forward and offers a way to unify some important concepts in colorectal cancer.

In Chicago, the really good news was that the final results of a large global study involving nearly 4,000 patients were presented to a packed audience in the main hall where the plenary is held. It’s not often you see the gastrointestinal oral session allocated the prime time room over lung or breast cancers – the atmosphere was certainly electric with anticipation!

This week’s post ASCO mini series focuses on colorectal cancer, with a look at several important aspects of this disease as we learn more about the underlying biology, as well as how the immune system functions and how we can use that scientific knowledge to improve outcomes for patients, sometimes in a dramatic way.

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Continuing our series on the ASCO GI meeting, today marks the end of the conference coverage with an interesting look at overcoming resistance to EGFR therapies such as Erbitux and Vectibix.

One of the hallmarks of EGFR monotherapy in colorectal cancer is stable disease with eventual relapse, but few dramatic responses. This suggests that other factors may play a role in driving oncogenic activity.

Dr Tejpar, Leuven

Dr Tejpar, Leuven

Recently, patient derived xenografts (PDX) have begun to play an increasingly important role in helping to understand the biology of the disease and facilitate improved trial design.

Earlier this week, we discussed the molecular characterisation of the disease based on the keynote talk by Dr Sabine Tejpar. Her group in Belgium as well as others in Italy and Spain have been very active in European translational work in this area to identify and map the pathways influencing EGFR therapy in GI cancers.

What can we learn from the latest findings in this space?

The answer may well surprise you.

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Over the last decade or so, we’ve seen a lot of new targeted agents approved in a variety of different tumour types. Of the big five cancers (breast, lung, melanoma, prostate, and colorectal) one clearly stands out as missing out on exciting new developments in the last 5 years.

In fact, we haven’t really seen anything startlingly new in the colorectal cancer (CRC) space since 2004, when the FDA approved cetuximab (Erbitux) and bevacizumab (Avastin) to much fanfare a few weeks apart at the beginning of that year. Sure, there have been other EGFR and VEGF inhibitors approved since, including panitumumab (Vectibix), z-aflibercept (Zaltrap) and regorafenib (Stivarga) in various lines of therapy, but you could argue that they’re all more of the same (type of inhibitors) and incremental in their improvements, rather truly game changing or disruptive.

Why is this? Why is there a discrepancy?

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After the recent raft of posts on immunotherapy, it’s time to turn our attention back to oncogenic addiction.  A couple of key topics have dominated colorectal cancer over the years, namely what causes EGFR resistance and why don’t patients with the BRAF V600 mutation do as well with RAF monotherapy compared to melanoma patients?

In today’s post, we take a more detailed look at BRAF mutant colon cancer in terms of what we’ve learned so far and what the potential therapeutic solutions are, which could influence patient outcomes in a positive way.

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ASCO GI 2015 LogoThe metastatic colorectal cancer landscape is slowly changing after decades of multiple chemotherapies followed by the addition of biologics to the base chemo regimen including VEGF (bevacizumab, z-aflibercept, regorafenib) and EGFR inhibitors (cetuximab and panitimumab).

Each of these approvals have led to an incremental improvement in outcomes in different lines of therapy (LOT), but sadly with only one clinically meaningful biomarker identified (KRAS exon 2 mutant vs. wild type for EGFR inhibitors). We still don’t have a more comprehensive way to better select the likely responders from non-responders.

Progress, you might think, has been painfully slow, although the current data suggests that we have now reached a new plateau of around 30 months in overall survival. That’s going to be hard for new entrants to beat without some form of different paradigm shift.

There is only so much that can be achieved with the current strategies. You only have to look at second line VEGF inhibitors to see this incremental effect on survival:

  • Bevacizumab – 1.4 months
  • z-Aflibercept – 1.5 months
  • Ramucirumab – 1.6 months

Overall, we can say that none of them add 2 extra months of life in that setting (never mind the cumulative cost or ‘financial toxicity’ as many attendees referred to it) and you might even consider the benefit to be fairly marginal.  No biomarker has yet been identified for any of these therapies, making it impossible to select upfront those who are most likely to respond.

At the ASCO Gastrointestinal Cancers Symposium (ASCO GI) last week, we saw a repeat of the usual studies looking at new VEGF inhibitors (e.g. ramucirumab in the 2L RAISE study) and an update on the TRIBE trial (FOLFOXIRI vs FOLFIRI when either are combined with bevacizumab/Avastin).

Are there other targets that might have a meaningful impact though? If we truly want to see a more precision medicine approach evolve then we have to first find the oncogenic drivers.

With this in mind, one study in particular caught my eye and attention, but you won’t find it written up in the medical lay press and it’s not that obvious unless you know what you’re looking for.

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