Immunotherapy significantly increases the number of patients free from bowel cancer

Dr Kai-Keen Shiu - UCL Cancer Institute, London, UK

I was delighted on behalf of my co-authors and co-investigators to present the first results of the NEOPRISM colorectal trial as a late breaking abstract at ASCO 2024. I’m the Chief Investigator of this study and I thought about this study around 2019 and it took a little while to set up for various reasons, but we managed to open this trial in July of 2022. What is the trial? It is giving preoperative immunotherapy, just nine weeks, that’s three-weekly pembrolizumab immunotherapy for operable high-risk stage 2 or stage 3 MMR deficient MSI high bowel cancers.

The idea was to maybe add to the data of other studies in which we’ve already shown that four or three months of doublet immunotherapy or single immunotherapy is very good but this is the first trial where we also stratified the treatment according to something called tumour mutation burden prospectively. The idea of the tumour mutation burden is that we know in more advanced disease that this high neoantigen load may allow a better response to immunotherapy but we’ve never tested it in the early stage setting.

So we recruited 32 patients across 4-5 sites across the UK, very rapidly indeed, and we gave immunotherapy to all 32 of them. The design of the trial was that we would give one cycle of immunotherapy whilst we did some extra profiling including extra trial colonoscopies, blood tests and microbiome and then use those tests longitudinally, pre-cycle 1, pre-cycle 2, pre-cycle 3, pre-op and post-op, but do surgery about four weeks after the last cycle of treatment and then after surgery decide if they needed or wanted adjuvant chemotherapy. The primary endpoint was pathological complete response, that means complete disappearance of the tumour in the bowel wall and the lymph nodes. The secondary endpoints were relapse free survival at three years, overall survival, safety and  health-related quality of life. But the other translational endpoints were by doing all those tests to see whether there were other biomarkers, which we desperately need for our patients, to decide whether we could predict such good responses, and indeed there were. So we achieved a 59% pathological complete response rate in 32 resected primaries. All bar one were TMB high and all of them did very well from a surgical point of view.

The other thing is that it was very well tolerated. Only a few patients had grade 3 side effects and the main problems were the bulkiness of the tumours, that they were big and bulky and they caused the patients anaemia, nausea and pain. Then also after surgery, or pre-surgery, there were a few complications but all very manageable. What we also showed in the study were a few cases where there were such dramatic responses, shrinkage, that the tumour melted away through the bowel wall and caused a fistula. Or actually didn’t melt away but caused stricturing and caused narrowing of the bowel to make the bowel obstruct. So the surgeons, rather than doing the elective operation four weeks after immunotherapy actually had to do it urgently, within days, yet the patients actually did very well, it looked like they were bulky tumours but there was no cancer left in the specimen.

So it’s obviously a really good trial for the patients, they’ve all been happy they’ve been on it. Because of these very good results we are expanding the trial to achieve a three-year relapse free survival endpoint. We’re also still doing a lot of translational work which we hopefully can show in the next few years, or conferences. I think that it just adds to the weight of data that neoadjuvant treatment seems to be extremely good for a lot of our cancer patients, particularly immunotherapy in patients who are MMR deficient. So those were my main results.

What is the significance of these results?

It’s still early days because this trial is only 32 patients and, as I just said, we do need more patients to really know whether there’s a definite new standard of care. But there have been other trials already, some called the NICHE and NICHE-2 trials, the NICHE-3 trials and indeed the rectal dostarlimab trial that shows that these immunotherapy drugs seem to be extremely good at shrinking down these early stage cancers. There’s even already talk about how can we randomise these patients if already single agent or doublet immunotherapy is so good because the standard of care is normally surgery followed by chemotherapy. But there are those trials coming out and it will be interesting to see which wins out.

The other thing is that we think that the neoadjuvant setting will give us answers more quickly. This is what the patients want, they don’t want to wait. These patients are very well read nowadays about the power of immunotherapy so I do think that the implications are, in this particular trial, a little bit early to say whether it becomes standard of care but I hope it adds to all the weight of data that really patients who have this particular genetic subtype, MMR deficient, MSI high cancer, should be accessing immunotherapy early, or earlier, and in particular trying to get them into clinical trials so that we can get those answers much more quickly to decide whether it will become a standard of care, not just in the UK but globally.