It was my privilege to speak at the recent IGILUC meeting in Cairo earlier in July where we had
stimulating debates and discussions about advances in gastrointestinal malignancies. I gave an
overview talk on advances in gastric cancer because this is an area that we’ve made slow and steady
progress in recent years, particularly with the advent of more active targeted therapies and
immunotherapy.

In the course of my talk I reviewed the progress that we’ve made in adjuvant therapy. We now know
that perioperative chemotherapy added to surgery with the FLOT regimen improves survival. We
know that adjuvant chemotherapy after up-front surgery with chemotherapy is beneficial and there’s a
limited role for the use of radiation in the surgical management of gastric cancer.

I also reviewed the evolving area of MSI high locally advanced gastric cancers. These are patients
that have a better prognosis and in which chemotherapy may or may not offer a benefit. These might
be patients, particularly with MSI high primaries, who might benefit from up-front surgery alone and
there is now interest in using immune checkpoint inhibitors as neoadjuvant treatment in this subgroup
of patients that are highly responsive to immunotherapy.

I then reviewed advances in immunotherapy in the treatment of gastric cancer. Immunotherapy drugs
are now approved in the first line treatment of metastatic gastric cancer and we saw recent approvals
for pembrolizumab combined with chemotherapy in oesophageal and GE junction adenocarcinomas
and squamous cancers of the oesophagus, as well as approval for the drug nivolumab combined with
first line chemotherapy with FOLFOX in gastric and GE junction adenocarcinomas.

Immunotherapy has resulted in improvement in response rates, progression free survival and time on
treatment and we have now crossed the one-year survival threshold. Patients are now achieving
median survivals in excess of 14 months with initial treatment with checkpoint inhibitors plus
chemotherapy. There is some debate about the relative benefit of checkpoint inhibitors in patients that
have low testing for CPS scores for the target PD-L1. In Europe the approval of these drugs is more
restricted to patients that have CPS scores that are ≥5-10% whereas in the United States really
agnostic approval was granted for using these drugs in first line treatment in gastric cancers,
regardless of CPS score. It’s also important to remember that in metastatic MSI high gastric cancers
checkpoint inhibitors should really be part of first line treatment, given the high degree of activity,
using checkpoint inhibitors alone or in combination with chemotherapy.

I also reviewed the promise of new targets. HER2 is the focus of a lot of research. We know now that
trastuzumab is combined with first line chemotherapy in HER2 positive gastric cancer and we also
combine pembrolizumab now, given the very high response rate that pembrolizumab adds, a 75%
response rate to pembrolizumab added to first line trastuzumab-based chemotherapy in HER2
positive gastric cancer. We now have regulatory approval of a second line treatment – trastuzumab
deruxtecan – which has substantial activity as a second line treatment in HER2 positive gastric
cancer. This agent is now being studied in earlier line treatments as well. There are other HER2
targeted therapies that are promising, including the tyrosine kinase inhibitor tucatinib as well as the
engineered trastuzumab molecule margetuximab and also zanidatamab which targets two different
epitopes on HER2. We look forward to advancing these agents in earlier line treatment as studies
evolve.

Then we talked about other novel targets including claudin 18.2, that’s a gap junction protein that’s
overexpressed in the vast majority of gastric cancers targeted by the antibody zolbetuximab and,
based on very promising phase II data in claudin positive patients, adding zolbetuximab to
chemotherapy appears to improve progression free and overall survival. So we now have recently
completed first line trials of chemotherapy combined with zolbetuximab in claudin overexpressing
tumours.

The other promising target that’s moving forward now in phase III is the FGFR receptor. This is
overexpressed by immunohistochemistry in about 30% of gastric cancers. Very promising data for
IHC positive patients using the humanised antibody bemarituzumab that targets and blocks the FGFR
receptor, very promising data with this drug in combination with FOLFOX in first line. So now we hope
to see studies moving forward targeting FGFR positive patients in the advanced disease setting.
So we’ve seen advances in adjuvant treatment, we’ve seen advances in immunotherapy treatments,
HER2 targeted therapy and novel targeted agents and now with the advent of genomic profiling of
cancers, which we should do routinely now in the initial diagnostic workup of gastric cancers, we hope
to identify other targets for which we can study new agents. It’s an exciting