Single-agent PD-1 blockade as curative-intent treatment in mismatch repair-deficient locally advanced rectal cancer

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Published: 5 Jun 2022
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Dr Andrea Cercek - Memorial Sloan Kettering Cancer Centre, Manhattan, New York

Dr Andrea Cercek speaks to ecancer about her study on repair-deficient colorectal cancer and how responsive it is to PD-1 blockade in the metastatic setting.

“We hypothesised that locally advanced mismatch repair-deficient rectal cancer is sensitive to checkpoint blockade and may alter the requirements for chemoradiotherapy and surgery.”

Patients who achieved a clinical complete response were eligible for omission of chemoradiation and surgery.

She concludes by discussing the mismatch repair deficient locally advanced rectal cancer is exceptionally sensitive to single-agent PD-1 blockade. However, a longer follow up is needed to assess response duration.

Patients with locally advanced rectal cancer typically get treated with chemotherapy, radiation and
surgery. Although we do really well in terms of cure, there’s a lot of toxicity associated especially with
radiation and surgery. There’s a subset of these patients that are mismatch repair deficient, it’s about
5-10% of them, and typically standard of care is the same approach but we actually noted that they
don’t respond as well to chemotherapy. In fact, up to nearly 30% of them actually progressed through
chemotherapy, which we really don’t see in the repair proficient group. Our idea was to see if we
could replace the chemotherapy with PD-1 blockade and the reason we thought about PD-1 blockade
or checkpoint blockade in this population is that it works really well in the metastatic setting. So in
metastatic disease patients with mismatch repair deficient colorectal cancer respond very well to
immunotherapy, they have durable responses, and the complete responses are about ten percent.

So, given the fact that the patients progressed on the chemotherapy, and that we’d have to do
radiation and surgery which were curative but quite toxic, we thought could we replace chemotherapy
with immunotherapy and then design the study in such a way that if the patients responded very well
to immunotherapy alone, so to PD-1 blockade alone, after six months of therapy we would evaluate
them, and if there was no tumour remaining they could undergo non-operative management or
observation as opposed to getting radiation and surgery. If they had some residual disease then they
would get standard of care radiation and surgery. So the idea was how well can we do with PD-1
blockade alone in this patient population – can we go all the way and see these complete responses
to PD-1 blockade alone and, if not, then can we do just radiation, with the addition of PD-1 blockade
or do we need to do the full trimodality therapy and include surgery?

What did you find?

We were very thrilled to see that all of our patients, 100% of them, had complete disappearance of
tumour, with PD-1 blockade, with dostarlimab alone, so no-one has required radiation or surgery to
date. This is really remarkable because it’s 14 consecutive patients, so every single patient that has
been treated the tumour has completely disappeared with just immunotherapy.

What’s next?

It’s very exciting, we’re still actively accruing on this study. Given these robust responses we are
planning a larger expansion trial, and hopefully this is continued and this will be the new treatment for
mismatch repair deficient, locally advanced disease. Our thinking is could we apply the same
approach to other early stage tumours that are mismatch repair deficient where definitive therapy
typically involves a combination of chemotherapy, radiation and surgery, and could we achieve the
same types of responses and could potentially spare them radiation or surgery or both?

Anything else to add?

I’d just point out that many of these patients are very young, many of them have Lynch syndrome, so
they’re diagnosed in their early twenties or thirties. So being able to spare them radiation and surgery
is huge and has significant implications because radiation and surgery cause bowel and bladder
dysfunction, they case sexual dysfunction, and importantly for this very young population, they cause
infertility, especially in women. So now we’re able to treat them just with immunotherapy alone, they
have preserved organ function, they have preserved sexual function and preserved fertility, which is
hugely impactful.