Aparna Parikh, MD

Cathy Eng, MD, FACP, FASCO

Scott Kopetz, MD, PhD

Stacey Cohen, MD

Christine Parseghian, MD

GI Oncology Now

Aparna Parikh, MD, Massachusetts General Hospital, is joined by Cathy Eng, MD, Vanderbilt-Ingram Cancer Center; Scott Kopetz, PhD, MD Anderson Cancer Center; Stacey Cohen, MD, Fred Hutchinson Cancer Center; and Christine Parseghian, MD, MD Anderson Cancer Center, for a roundtable discussion on the upper GI treatment landscape.In the second segment, the panel explores the evolving treatment landscape for patients with MSI-high metastatic colorectal cancer. They discuss the compelling data behind dual checkpoint inhibition with nivolumab and ipilimumab, shifting practice patterns away from monotherapy and even surgical resection in oligometastatic cases. The conversation also highlights emerging questions around treatment duration, the use of ctDNA and PET scans to monitor response, and the need for future research on post-immunotherapy progression.View the next segment on <a href="https://www.gioncologynow.com/post/redefining-treatment-for-msi-high-crc-neoadjuvant-io-niche-and-non-operative-pathways" target="_blank" rel="noopener">Redefining Treatment for MSI-High CRC: Neoadjuvant IO, NICHE, and Non-Operative Pathways</a>.&mdash;Dr. Parikh: Let us dive in. We briefly discussed earlier-stage disease, and we will return to that when we talk about circulating tumor DNA. I definitely want to spend some time on that. But for now, let us move to the most relevant biomarkers. It is exciting to see biomarkers now entering the first-line setting. Let us begin with MSI-high testing or MSI-high patients. Previously, we had the KEYNOTE-177 data with monotherapy, and we saw rapid adoption given the remarkable outcomes. Over the past year, we have also seen exciting results with dual checkpoint inhibition using ipilimumab and nivolumab. How has that been adopted in clinical practice? Are you now using the doublet for everyone, or are there still patients for whom you are choosing monotherapy? Let us discuss that.Dr. Cohen: Before this week, I felt we had a choice between pembrolizumab or ipilimumab and nivolumab, depending on how intensive a therapy we believed the patient could tolerate or what made the most sense in their situation. But I think the data supporting the combination therapy is becoming increasingly compelling. For younger, fit patients, it is difficult to justify offering anything else, given the impressive responses.Dr. Kopetz: Absolutely. It is the tail of those survival curves that is particularly compelling. The fact that a significant number of patients are alive without progression at two years suggests that many may actually be cured. I believe the data have matured enough for us to feel comfortable using that word. We are often hesitant to say &ldquo;cure,&rdquo; but in this context, I truly believe it applies. That shift in mindset has been important. When you consider the potential for curing a meaningful portion of patients, the modest increase in early toxicity becomes less of a concern.Dr. Parikh: Yes. Now, are there any patients for whom you would still offer monotherapy?Dr. Eng: I am very compelled by the data supporting nivolumab and ipilimumab. It is highly effective. That said, I would still consider pembrolizumab for some frail patients. I have had patients achieve long-term survival with monotherapy, so it is certainly still effective. As we all know, not every therapy is appropriate for every patient, but the nivolumab and ipilimumab data are indeed compelling.Dr. Parikh: It is interesting surgically as well. A few years ago, we used to take oligometastatic MSI-high patients to surgery, but that has changed. As you pointed out, you operate and find no cancer.Dr. Kopetz: It is just scar tissue.Dr. Parikh: It is just fibrosis.Dr. Kopetz: That is such an important point. There is always some anxiety about whether to stop treatment after two years if something still appears on scans. People ask, &ldquo;Should I really stop?&rdquo;Dr. Parikh: ctDNA?Dr. Kopetz: Yes, ctDNA is helpful, but it is also about having confidence in the data. The experience shows that what we see at two years is generally not viable disease. There are very few exceptions. We continue to monitor, but we can now confidently tell patients that it is safe to stop at two years and continue with surveillance.Dr. Cohen: The next question then becomes, do all patients really need two years of therapy?Dr. Parikh: That is what I was going to ask.Dr. Cohen: We have seen a shift in the field, and it is natural to be cautious when considering scaling back. But some patients might only need six months or a year. Given the toxicity associated with dual checkpoint inhibitors, both early and cumulative, there is a real need to explore shorter treatment durations.Dr. Kopetz: I saw the 8HW data recently, which broke down the timing of different toxicities. It was a compelling figure. I plan to share it with the fellows.Dr. Parikh: Watch out, Dr. Kopetz is back from ASCO.Dr. Kopetz: That is right. Brace yourselves.Dr. Parseghian: One interesting issue is what to do when patients progress. Should we switch to a different checkpoint inhibitor? Or if they were on nivolumab alone, do we add ipilimumab at progression? The data are not yet definitive. My takeaway is that the initial treatment choice matters, but we clearly need more clinical trials in the post-immunotherapy progression setting, since we know those patients do not respond well to chemotherapy.Dr. Parikh: Yes, I think there are some promising early-stage trials in that space. Even though patients can do well for a long time, it may be challenging to enroll them. Still, I am encouraged by the ongoing efforts. Is anyone here using ctDNA in this setting to monitor patients with immune-related response?Dr. Eng: I have not used it as much in this context.Dr. Parikh: You are nodding.Dr. Kopetz: Yes. I typically use it at baseline and then later in the course of treatment. It helps me feel more confident when trying to assess potential pseudoprogression. Especially around the one-year mark, if patients are experiencing toxicity and we are deciding whether to continue to two years or stop early, I find ctDNA helpful. And at the two-year mark, it can provide reassurance, especially when radiology reports still show stable disease in the peritoneum.Dr. Eng: Do you get PET scans in these situations too? I have found them helpful.Dr. Parseghian: I have been using them.Dr. Parikh: That is actually not a bad idea.Dr. Eng: For patients who have questionable findings on CT, a PET scan that shows no active disease can be very reassuring.Dr. Parikh: That is a good point.Dr. Eng: You can use both.Dr. Kopetz: Exactly.Dr. Cohen: I think it just shows that we need reassurance as much as our patients do. We are always worried about making the wrong call.

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Redefining Treatment for MSI-High CRC: Neoadjuvant IO, NICHE, and Non-Operative Pathways

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The Case for Dual I/O in MSI-High mCRC: Is Two Better Than One?

The panel explores the evolving treatment landscape for patients with MSI-high metastatic colorectal cancer.