Personalized Approaches to Treatment of Metastatic Colorectal Cancer - Episode 17

Dual I-O Therapy for mCRC

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Drs Cathy Eng and Joleen M. Hubbard discuss the rationale for studying dual immunotherapy approaches for metastatic colorectal cancer treatment.

Tanios S. Bekaii-Saab, MD: I want to move back to the concept of dual IO [immunotherapy]. I've been thinking about Cathy's point about how impressed she is with the data, and she's completely right, thinking about all of these single-arm studies. You have that single-arm study. You have a patient who's 32-years-old performing status of 0. You're going to choose the study with the more aggressive regimen, the double IO for them. For the patient who's much older with a less-performed status, you're going to go with single IO, unless there's randomization in the mix. You've introduced a selection bias.

Joleen, the study that Cathy mentioned that got updated, tell us more. What do you think about this concept? The whole concept is around using low-dose ipi [ipilimumab], little on the toxicities; that's not been achieved as much and certainly higher cost. How do you integrate if you do an IO, and what are we looking forward into the horizon in the MSI-high [microsatellite instability] population?

Joleen Hubbard, MD: What's interesting is the response rates are higher. But you are right; these are single-arm studies, so the CheckMate 142 is not a randomized study. It's certainly cohesive, the bias of which patient went into what arm. The toxicity profile with adding low-dose ipi to nivolumab isn't significantly altered, and it is a reasonable option to think of for the first line.

Until I had randomized data, there is not necessarily a need to add the combination upfront. Fortunately, there is an ongoing study right now that's randomizing patients of microsatellite instability first-line setting to nivolumab plus ipilimumab versus single-agent nivolumab versus standard-of-care chemotherapy.

In the near future, we'll have an answer. Is this the right thing to do? Even though the response rates may be robust initially, if we keep following these patients out, as many people have said in the study, they continue to respond over many months. Is the addition of ipi going to add to overall survival? It's certainly possible, and it looks like it's trending that way. But we don't know for sure without the randomized results.

Tanios S. Bekaii-Saab, MD: You would want to wait until we have more data. Cathy, any patient today in your clinic that gets ipilimumab and why?

Cathy Eng, MD, FACP, FASCO: I have done it off protocol in 1 patient because he is a patient that presented with 2 primary tumors. His first primary was hepatic flexure. It was a walled-off perforation that was resected, and his second tumor, unfortunately, is a rectal cancer tumor. He is a young gentleman and he does not want an APR [abdominoperineal resection], his job is very active. He's on his feet all day, so he did not want a colostomy. We decided to go with a doublet approach to try to give him the best chance possible. He's completed 4 months of therapy, had a biopsy, saw his surgeon, and it was negative. We're very pleased. He's now going for some radiation therapy, then knowing him because he doesn't want the surgery, we're doing our own version of IO, and then watch and wait on him. He's just a young gentleman, that's what he would prefer.

Kristen Ciombor, who's one of my colleagues here at Vanderbilt-Ingram Cancer Center, I've had the pleasure of working with her on a concept called EA2201 which, hopefully, will be open this spring/summer, specifically in this scenario; MSI-high rectal carcinoma patients, providing the doublet with short-course radiation therapy and is going to be a Phase-2 study. We're looking forward to opening that up and the secondary endpoint is consideration of sphincter preservation in patients that want to do a watch/wait approach.

Tanios S. Bekaii-Saab, MD: That's an MSI-high, right?

Cathy Eng, MD, FACP, FASCO: MSI-high, yes.

Tanios S. Bekaii-Saab, MD: We’re all excited about it, we will support it and, hopefully, everyone else will. Joleen, so that's MSI-high. We're seen some intriguing data with colon cancer, microsatellite stable with ipilimumab, a recently published paper. With MSS [microsatellite stable], where we don't see these responses and in MSS more advanced tumors, can you tell us more about this? It is very intriguing data.

Joleen Hubbard, MD:It is intriguing. The number of responses was fairly low and off-trial it is not something that I would recommend for patients. It's intriguing enough that we're tempted to do it. But in those settings, I would look for other things that would also convince me to do it, such as a TMB [tumor mutational burden], POLE [polymerase ε], POLD mutations, as we've said. With such few patients responding, I don't know that I would do that off-study right now.

Tanios S. Bekaii-Saab, MD: But worth studying further.

Transcript Edited for Clarity