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.