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].
In 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.
To learn more about these promising new developments and read what Dr Galon had to say, subscribers can log-in below or you can sign-up via the blue box.
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
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 the 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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The 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.
Interested readers can sign up or sign in to learn more about this novel concept in advanced colorectal cancer below. This could be the start of a new era of research for this disease.