Going After Mismatch Repair Deficiency in Solid Tumors for Powerful Tumor Response
MSKCC’s Dr Andrea Cercek talks about the impressive results of a dostarlimab clinical trial in rectal cancer, what her group is seeing as they explore dostarlimab in other solid tumors, and her work supporting young people with colorectal cancer diagnoses.
What was the initial hypothesis for the dostarlimab trial?
The initial idea behind the study came from patients with rectal cancer, and we saw that a proportion of patients with mismatch repair deficient (MMRd) tumors did not do well with standard therapy (chemotherapy, chemoradiation and surgery).
Our idea was: “Could we treat this population with MMRd early-stage rectal cancers with immunotherapy first?” The overarching goal was, if they responded to immunotherapy, we could potentially omit chemoradiation, chemotherapy and surgery in select patients.
To investigate that idea, we wrote a study in which we treated patients MMRd locally advanced rectal cancer with dostarlimab, which is a PD-1 monoclonal antibody, first for 6 months. At that time in 2018, immunotherapy was approved for patients with advanced disease or refractory disease only. We found when immunotherapy was introduced first in early stage disease, the tumors responded very well.
"The overarching goal was, if they responded to immunotherapy, we could potentially omit chemoradiation, chemotherapy and surgery in select patients."
What did the study find?
In that initial group of patients, 100% of them responded to immunotherapy and none needed chemoradiation or surgery. We’ve now treated 50 patients on that study, and all 50 achieved a clinical complete response to dostarlimab alone. That was exciting to see how sensitive these tumors are, and how much patients benefitted from this intervention.
Because it was working so well in rectal cancer, we expanded the study to all patients with MMRd solid tumors of any type: esophagus, stomach, pancreas, liver, colon, bladder, urothelial, because a proportion of all solid tumors, about 2-3%, have MMRd.
That second cohort was anyone with this MMRd at early-stage disease. They received six months of dostarlimab and depending on response, they either didn’t need any other intervention, or they got whatever the standard of care was for that disease type.
Why is MMRd so distinctive in its susceptibility to immunotherapy, and therefore a good biomarker?
When tumors make mutations, and create neoantigens, the immune system is engaged and looking at these tumors. That MMRd was sensitive to immunotherapy and enabled the immune system to fight tumors, and in the case of rectal cancer get rid of it completely, was something discovered by Dr Luis Diaz, who was the senior author and did this study with me, in advanced disease in the mid 2010s. We had the approval for treating Stage IV refractory advanced disease for all MMRd solid tumors.
What is unique about our study is that we took it into early-stage disease and discovered that they were even more sensitive, to the point where we were able to replace standard of care in 80% of MMRd solid tumors across the board.
"Because it was working so well in rectal cancer, we expanded the study to all patients with MMRd solid tumors of any type."
What is your hypothesis for why rectal cancers had a complete response, and some of the other MMRd solid tumors didn’t?
We don’t know quite yet. What we do know is that the majority of the patients did respond and had tumor shrinkage, but not always enough to say that immunotherapy was sufficient to completely eliminate the tumor. Now, we are studying the tumors as well as the microenvironment to better understand the changes occurring, how the immune system gets into the TME (tumor microenvironment), and if there are certain cells already present that get turned on faster when we give immunotherapy.
Certain tumor types, for example gastric tumors, we had around 60% of patients had a clinical complete response, but even those that didn't have a complete response had significant down staging. The question is, “Did they need more time? Would they have benefited if we did another six months on immunotherapy or perhaps stronger immunotherapy using combination instead of single agent?”
That's what we're investigating now, because we did show separately in a retrospective paper in NEJM by Benoit Russeau from our group, that in trials across all tumor types with single agent immunotherapy, that the longer duration of treatment does lead to better responses.
Can you talk more about utilizing immunotherapy in earlier lines of therapy?
One reason we wanted to avoid standard of care is that for rectal cancers, all of these treatments, but especially radiation and surgery, can be curative, but very morbid. For women in particular, they go into immediate menopause after radiation. It causes infertility. A third of patients need a permanent colostomy because of the location of the tumor. These standard of care treatments can be very affective to quality of life for survivorship.
With earlier introduction of immunotherapy, we see much better responses as opposed to waiting after chemotherapy or after treatments where the immune system has changed or in later lines of therapy and advanced disease, where the immune system is already exhausted from all the therapies that have been ongoing.
Early introduction into a chemo-naive patient is not only beneficial with response, but potentially also with augmentation of the immune system. It’s the idea of an autovaccination, that it works better with the tumor in situ, as opposed to once the tumor is removed. Head-to-head comparisons haven’t been done, but that’s the data that’s emerging and the understanding that has emerged from our study, as others as well.
What do you feel like this trial tells us about immunotherapy?
It is additional information and I think the big difference here is that we're learning how much benefit there is in the neoadjuvant, first line of treatment setting, before the tumor is removed or before it's treated in any other way.
For us, it’s the use of immunotherapy not only to augment responses and improve survival, but also to potentially also eliminate standard of care treatments that have significant morbidity to improve the quality of life in survivorship.
Beyond that, we’re learning about benefit with subsequent potential cancers. For example, in our group, Emily Harold and, and Zsophia Stadler, along with Dr. Diaz, have published a paper in Nature Medicine, where they looked at secondary cancers in patients with Lynch syndrome that have MMRd tumors. After they were exposed to immunotherapy, they saw lower rates of visceral tumors, suggesting that there is a protective effect from immunotherapy.
"With earlier introduction of immunotherapy, we see much better responses as opposed to waiting after chemotherapy or after treatments where the immune system has changed or in later lines of therapy and advanced disease, where the immune system is already exhausted from all the therapies that have been ongoing."
You also started a center focused on the phenomenon of younger people getting colorectal cancer. Tell us about that.
Yes, we opened the first-of-its-kind center for young onset colorectal and GI cancers at MSK in 2018. The center had two goals one was to provide better and more comprehensive care for young adults with GI cancers. This support stemmed from diagnosis through treatment and into survivorship. Having treated a lot of young patients with colorectal and rectal cancer, you realize how drastically different their lives are in survivorship. It’s not just about eliminating the cancer; it’s preparing them for the entire journey and what life will be like post-cancer. It’s difficult to navigate cancer when you’re a young adult. You have young kids, or you’re getting a career off the ground, and everything has to go on hold. Our goal is to have a center where we’ve introduced support services early on. Fertility planning, sexual health, social work, psychosocial support, etc.
The second goal is a research question. We want to understand why this is happening. We set up a research biospecimen repository and prospective database. We’ve looked at the tumor genomics and we're taking a deeper dive now into a number of translational projects based on the samples and data we’ve collected.
What are you excited about for the future of immuno-oncology?
I'm optimistic and excited about the future because we’re making huge leaps in progress with immunotherapy and understanding how to improve responses even in advanced disease for all cancers.
Specifically for colorectal cancer, the future is exciting. Even outside of immunotherapy, we're making good advances in therapies, but we need better diagnostic tools. It would make a huge difference if we can either figure out who the individuals at risk are or if we can detect as early as possible.
What advice would you give young professionals entering the life sciences?
You have to love what you do. And if you do that, then anything is possible. And take it one day at a time and do not get overwhelmed in the moment.
For those entering academia specifically, it’s constantly changing, it’s exciting, and you get to pave your own path. I always say that to my young fellows, particularly the female fellows, to think about academia that way.
