Dr Michael Foote - Memorial Sloan Kettering Cancer Center, New York, USA

So our study was very interesting. We studied a group of patients with a type of tumour called mismatch repair deficient tumours or microsatellite unstable tumours. This is a very rare population of patients but it’s an important one because these tumours have lots and lots of mutations and we think that they are very attractive to the immune system. So we selected patients that had early-stage solid tumours, so colon cancer, rectal cancer, stomach cancer, oesophageal cancer, any type of cancer that was in a solid organ, and all of the patients had mismatch repair deficiency which, as I said, is a fairly rare variant of cancer but in some tumours such as endometrial cancer can be up to a fourth of patients.

So all the patients we examined in the trial were given neoadjuvant, meaning they were given immunotherapy with an anti-PD-1 inhibitor called dostarlimab. This is an antibody that patients are given and we tried to see if we could cure the patients of their tumour, make the tumour completely disappear, without giving them surgery, radiation or chemotherapy which are all the standard treatments for each respective cancer to try and cure people in the early-stage setting.

What we found was really amazing. What we found is that 100% of the patients with rectal cancer had a complete response, meaning their tumour completely disappeared in the rectal cavity and it was amazing, with just this immunotherapy drug. None of the patients in that arm required radiation or chemotherapy and almost all of the patients didn’t get a surgery which is really incredible. They all had a complete response. For the other solid tumours as well – gastric cancer, colon cancer, liver cancer – those patients also had… many of them had a complete response. In the entire study we had 80% of the patients that avoided surgery because of our immunotherapy drug which was really incredible.

What is the importance of these results and what is next for this study?

Patients that have these early-stage tumours, and many of them were a stage 3 cancer so they had lymph nodes that were positive, these were tumours that were a little bit higher risk of recurring, meaning spreading to the rest of the body. These cancers can be very dangerous and that’s why the treatments for them normally are pretty aggressive. So, to give you an example, a patient with a rectal cancer normally would undergo about a month and a half of radiation followed by up to 4-6 months of chemotherapy and then after those treatments about a little over half of them would need to undergo a major surgery to remove their rectal cavity, sew up that area and have a permanent ostomy bag for the rest of their life. Those treatments, as you might imagine, are life changing, they change everything from the relationship that the patient has with their family, their romantic significant other, it’s a big deal.

So to prevent all of that with just a very simple immunotherapy drug that had very few side effects and really in 100% of rectal patients, out of 49 patients 100% of them had a complete response, that was incredible. We’ve had people on the trial who have since had children, had babies, and we know that giving people radiation and chemotherapy can lower their chance of fertility. So we spared them all of those side effects by giving them the immunotherapy drug.

The other really important thing about this study is we looked at it in many different types of cancer. So all the cancers had this mismatch repair deficiency characteristic but they arose in different organs – stomach cancer, oesophageal cancer, endometrial cancer. The amazing thing was that this therapy was very, very effective for all of those different types of cancers. So we really spared people from surgery, radiation, chemotherapy, all of the applicable treatments that they would have gotten with a high amount of side effects, we were able to spare them that with just giving them this immunotherapy drug.

The responses have been very durable. We found that even months or years later most of these patients are doing just great, almost everyone, and this strategy really didn’t hurt anybody. There were five patients on the study that did have a recurrence but all of them were saved by either giving them immunotherapy again or doing a surgery. So this strategy was very safe and effective.

Is there anything else you would like to add?

One of the most important things in when you have an early-stage cancer it’s a curable situation. So, many of these patients, of course, want to do everything they can to prevent the cancer from coming back. So I would just suggest to viewers, if you are a patient or a family member of a patient, do some research – read about trials that are in your area, whether you’re in the UK, in Europe or in the United States. There are a lot of really exciting, innovative studies that are coming out to try and do what we did, to try and spare people from side effects from treatment. A lot of them focus on the genomics of the cancer, looking at the DNA and figuring out exactly what made that tumour happen. Most of the best drugs for cancer right now are really aimed at these genomic profiles. So make sure you talk with your oncology team and ask them what are the genomics of my tumour? Is there a new way that I could go about this that might be a little bit more advanced, a little bit more modern? It’s really, really important for patients to ask for mismatch repair deficiency. If you have a mismatch repair deficient tumour we strongly suggest you pursue our strategy of giving you immunotherapy.

So one of the really important things about our study is it showed the importance of somatic and germline profiling for even early-stage tumours. Across the spectrum of solid cancers, not only colorectal cancer but oesophago-gastric cancer, small bowel cancer, even some of the more uncommon cancers, we found patients with mismatch repair deficiency that really benefitted from our approach, including prostate cancer. These are patients that did very, very well with immunotherapy only  and really it helped them a great deal.

So we advocate for next generation sequencing even in the early-stage setting. This is a great way for organ preservation in these patients. If a patient has a rectal tumour they really should undergo IHC for mismatch repair deficiency. Now at our institution and others around the country we’re also sending next generation sequencing even on early-stage cancers, especially stage 3 cancers. The complete response rate was really incredible.

We do see a difference between upper and lower malignancies and we presented this at AACR. One of the reasons for this may be a difference in the microenvironment. We were looking into that in our laboratory as well as maybe some co-alterations that may be more present in lower GI tumours that might give them an advantage for a complete response. It’s quite obvious that there’s something going on between the rectal cancer and the colon cancer – both sites did very well but 100% of the rectal tumours had a complete response and just over 80% of the colon tumours did. Still an incredible result but there’s a lot to learn from this.