At the conference I was giving an overview about the new advances in the treatment algorithm for
metastatic colorectal cancer. In my presentation I particularly highlighted the significant advances we
have made in the molecular characterisation of colorectal cancer. They have started to analyse the
DNA mutation analysis and integrated now next generation sequencing technology to better
understand the genetic makeup of colorectal cancer. What happens in the future, and it already has
started, is that in addition to next generation sequencing we are now doing transcriptome analysis to
better understand the downstream effect of DNA mutations as well as activated pathways which could
be targets for new drug development.

There were significant advances over the last twelve months which I included in my presentation. One
of them was the development and the presentation of G12C inhibitors for metastatic colorectal
cancer. The data suggested that the G12C inhibitors are not as effective compared to the inhibitors in
non-small cell lung cancer and the recent publication and presentation at ASCO as well as ESMO GI
showed why – because you have a negative feedback loop in colorectal cancer upregulating
significant activation of the MAP kinase signalling pathway which is not present in non-small cell lung
cancer. This actually has a consequence that not only the single agent is not effective but should lead
to more successful combinational treatment strategies by combining the G12C inhibitor with EGF
receptor inhibitors or SHP2 inhibitors. So this actually leads the way for better, more effective
treatment regimens. Early studies show that a G12C inhibitor, adagrasib, has a response rate over
40%. So colorectal cancer, because of its tumour heterogeneity is a different disease and needs
different treatments even when we are targeting the same mutation compared to other cancers.

The other advances, we have all seen the use of immune checkpoint inhibitors in microsatellite stable
metastatic colorectal cancer and unfortunately they have not been very effective. Data from ESMO GI
showed that maybe FC engineered antibodies targeting CTLA-4 in combination with PD-1 inhibitors
showed for the first time significant and promising response rates with overall 24% and when tumours
with metastatic disease to the liver were excluded the response rate was over 40%. We have learned
that metastatic disease in the liver, this significantly immune suppressive environment, does not allow
efficacy of immune checkpoint inhibitors as we use them today to be very effective. So we are on the
way to optimise our immune checkpoint inhibitors and this is the first time we could really understand
that modification of these antibodies may lead to higher response rates.

One other major progress was the presentation at ESMO GI on tucatinib, it’s a HER2 inhibitor, in
combination with trastuzumab in HER2 amplified and overexpressing metastatic colorectal cancer.
The response rate was 38% in a highly refractory patient population which actually leads to a new
paradigm for this patient population.

So, all this data suggests that identifying more and more important targets for colorectal cancer and
the development of targeted treatments and modification of our antibodies will further increase the
efficacy of our treatment strategy and algorithm for patients with metastatic colorectal cancer. So the
future is bright; more molecular technologies will further advance the identification of targets and
pathways and we will see more efficacy in the future.