Adopting Immunotherapy in MSI-High/dMMR Colorectal Cancers

— Van Karlyle Morris, MD, discusses the success of checkpoint blockade in this population


In this exclusive MedPage Today video, Van Karlyle Morris, MD, of the University of Texas MD Anderson Cancer Center in Houston, discusses the adoption of immunotherapy for patients with microsatellite instability [MSI]-high or deficient mismatch repair (dMMR) colorectal cancers.

Following is a transcript of his remarks:

One of the really exciting advances in recent years has been the adoption of immunotherapy in patients with MSI-high or deficient mismatch repair colorectal cancers. And while the initial data came out years ago now in patients with metastatic disease, what we've seen in the last year with data from dostarlimab [Jemperli] in patients with rectal cancer and with the niche data in patients with localized colon cancer, is that the benefit of immune checkpoint blockade therapy can certainly be extended, probably across all stages of patients with MSI-high colorectal cancer.

When I think about ASCO last year, we saw in a small cohort of patients from Memorial Sloan Kettering -- Dr. [Andrea] Cercek presented data for patients with localized rectal cancer -- a complete clinical response rate of 100% in their initial cohort of patients they examined. And of course, this is very, very exciting because that offered patients an opportunity for a presumably curative outcome without ever having to receive, potentially, chemotherapy, radiotherapy, or surgery.

I think one of the things in real-world experience and one of the things that we've seen in further studies at our institution, at MD Anderson, Dr. Kaysia Ludford led a study published in the Journal of Clinical Oncology this year in patients with localized MSI-high/deficient mismatched repair gastrointestinal cancers. In her study, the majority of those patients were patients with colon cancer. We didn't see 100% complete response rate. The number seems to be about two-thirds of patients have a complete response.

In patients with colon cancer, it's a little bit more difficult to evaluate that endoscopically [versus] the rectal cancer patients, in whom a proctoscopy can can give you a quick endoscopic answer.

So I think historically we have relied on CT imaging studies to gauge response. And I think there's a very interesting and provocative research project being presented at ASCO this weekend from Dr. Fox -- who's coming from Baylor College of Medicine in Houston -- where they looked and compared radiographic responses in patients with localized MSI-high colon cancers with endoscopic responses on endoscopy. And what they found was that endoscopy, as you would expect, did a better job, and that radiographic imaging undercalled the true depth of response in patients who had complete clinical responses.

So I think there are a couple of kind of take-home points from that, which is, again, as we're pursuing immune checkpoint blockade therapy in patients with localized colon and rectal cancers, not 100% of patients [respond]. And we have to be cognizant of that when we're having these conversations with patients. But also it's absolutely critical that we're getting endoscopic evaluations for patients with localized colon cancers as well. And that's something that is very much our practice at MD Anderson.

I think in the metastatic setting for patients with MSI-high or deficient mismatch repair metastatic -- we saw from the KEYNOTE trial several years ago at ASCO and subsequently in the New England Journal of Medicine -- that pembrolizumab [Keytruda] fared better than chemotherapy in patients with untreated MSI-high/deficient mismatch repair metastatic colorectal cancer. While it led to prolonged success in the majority of patients, there's still, based on that data, 40% of patients with MSI-high metastatic colorectal cancer who progressed on, at least 40% who progressed on, pembrolizumab.

So we have to keep in mind that, while this is a very effective option for many patients in this context, there are still some patients who don't [respond]. And characterizing the nonresponders or the progressors on immunotherapy in this context has been challenging, just by virtue of the small subset of patients with colorectal cancer.

But I think there was an interesting study that came out of the Tempus group this week at ASCO as well, where they looked at RNF43 mutations, which we know, kind of, are enriched in patients with MSI-high colorectal cancer. I don't think that they saw that there was any difference between the RNF43-mutated and wild-type. But I think that these are the kinds of studies that are very much worth doing because we really do need to parse out and be able to predict better who responds in the metastatic setting and who doesn't, so that we could potentially think about strategies which consolidate or go more aggressive in patients who may be at higher risk for not having the benefit that we've historically associated in patients with MSI-high metastatic colorectal cancer.

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    Greg Laub is the Senior Director of Video and currently leads the video and podcast production teams. Follow