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 metastatic colorectal cancer treatment landscape.
In the third segment, the panel discusses evolving strategies for immunotherapy in colorectal cancer, including the long-anticipated ATOMIC trial and widespread adoption of neoadjuvant checkpoint inhibition in MSI-high colon and rectal cancer. They explore real-world use of protocols like NICHE, the growing role of non-operative management, and the complexities around treatment duration, patient selection, and toxicity. The conversation also highlights the importance of multidisciplinary collaboration and accurate MSI testing in shaping treatment decisions.
View the next segment on <a href="https://www.gioncologynow.com/post/breakwater-breakthrough-a-new-era-for-braf-v600e-crc" target="_blank" rel="noopener">BREAKWATER Breakthrough: A New Era for BRAF V600E CRC</a>.
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Dr. Parikh: Let us briefly talk about the exciting gastrointestinal data coming tomorrow in the plenary session, particularly the ATOMIC trial. We will finally see results from a long-awaited study of chemotherapy and immunotherapy in the adjuvant setting. There has also been a lot of progress in the neoadjuvant space. The tricky aspect of ATOMIC is that it was slightly ahead of its time, using chemotherapy and immunotherapy in the comparator arm.
Dr. Eng: In six months.
Dr. Parikh: Yes, in six months. But we also have data from NICHE, which used just one dose of ipilimumab and two doses of neoadjuvant therapy. There is also dostarlimab. So how are people thinking about immunotherapy for colon and rectal cancer? Let us begin with colon cancer, since it is arguably the more interesting of the two right now. Is anyone considering neoadjuvant immunotherapy yet?
All: Yes.
Dr. Parikh: Same here. It has become a bit of a pet peeve for me to receive MSI-high patients after surgery.
Dr. Eng: Yes, completely agree.
Dr. Parikh: And while immune-related toxicities are a concern, we also know that adjuvant therapy can harm patients. Before ATOMIC, we had no data to support treatment, which made it hard to justify adjuvant therapy in Stage III MSI-high cases when we already had compelling neoadjuvant data. Are people using NICHE protocols off-study?
Dr. Eng: I have done a couple of cases off-protocol, and fortunately, they were successful. Those patients are now under surveillance.
Dr. Parseghian: And many of these patients are older adults, right?
Dr. Eng: Yes, two were older individuals. One was a man with two primary MSI-high tumors and Lynch syndrome. He is doing extremely well.
Dr. Parseghian: I have had similar experiences. At MD Anderson, we are seeing a trend where patients present to surgeons first with Stage II or III disease, and the surgeons often ask, “Can you take this patient? Do I even need to operate?” And increasingly, the answer seems to be no. We are using NICHE criteria more often and also running clinical trials to better understand outcomes. We have had success with this approach.
Dr. Eng: This really emphasizes the importance of multidisciplinary discussions with our surgical colleagues in colon cancer.
Dr. Parikh: Yes, we are trying to implement a workflow in Epic that flags MSI-high status when a surgeon sees a patient. It acts as a hard stop to ensure the surgeon has checked for it. Given their busy schedules and high volume, we want a system that prompts them to simply call me. I am always happy to talk.
Dr. Cohen: I want to bring up a more complex issue: in rectal cancer, we are becoming more comfortable with non-operative management, even beyond MSI-high cases to include MSS as well. However, in colon cancer, even as we grow confident in using neoadjuvant immunotherapy, we are still hesitant to skip surgery. I recently had a patient with a sigmoid tumor where surveillance was technically feasible, but we lacked the imaging quality of rectal MRI and the surgery was less morbid. It led to a long and nuanced discussion, because patients want answers faster than we can generate data. We all know some patients probably do not need surgery, but clinical complete response is not the same as pathological complete response.
All: Exactly.
Dr. Cohen: So it remains difficult to justify skipping surgery.
Dr. Eng: It is important to remember that in Miriam’s data, all patients went on to surgery, right?
Dr. Parikh: Exactly.
Dr. Eng: In NICHE-2 and NICHE-3, all patients underwent surgery, unlike in rectal cancer studies where sphincter preservation is often the goal. So the questions of treatment duration and surgical necessity remain interesting.
Dr. Parikh: In rectal cancer, non-operative management and dostarlimab have been widely adopted. But we can all admit we are not consistently achieving the 100 percent response rate reported by Andrea.
Dr. Kopetz: We are not quite there.
Dr. Eng: We will have future trial results to help validate that.
Dr. Parikh: Absolutely. Are there situations where, in rectal cancer with bulky disease and a goal of downstaging, you are opting for ipilimumab and nivolumab rather than monotherapy? I have done that.
Dr. Eng: I did the same in a younger patient.
Dr. Parseghian: I would probably do that in a younger patient as well. I have not had one recently, but I would consider it.
Dr. Eng: My patient had a bulky tumor with some lymphadenopathy, not obstructing. That was the rationale.
Dr. Cohen: I wonder if the doublet offers significant improvement. Single-agent dostarlimab is already very effective in the real-world setting. I am not sure it is necessary to expose patients to the added toxicity of ipilimumab and nivolumab.
Dr. Eng: But what if the doublet shortens the duration of treatment?
Dr. Cohen: Yes, that could be a trade-off. We just do not have enough data yet. I have mostly used monotherapy.
Dr. Eng: Kristin’s study will inform us further.
Dr. Cohen: Yes, exactly.
Dr. Eng: Before that study launched, I treated a few patients off-protocol. It was interesting. I am looking forward to the results.
Dr. Parikh: Has anyone had a case where you started with monotherapy and then considered adding ipilimumab midway due to signs of disease progression?
Dr. Kopetz: Yes.
Dr. Parseghian: I did that once. There is no real data to support it, but it seemed to help slightly. I should probably write up a case report. It did not lead to a cure, but we saw some benefit.
Dr. Parikh: Are there any specific outcomes you are looking for in the 8HW data that could help guide clinical decisions? We have discussed treatment duration and toxicity.
Dr. Kopetz: I am interested in how the first-line data compares with the pooled analysis. Most patients were first-line, so I am comfortable with the existing data, but I know there are colleagues waiting to see the first-line subset specifically.
Dr. Eng: Perhaps you could describe that briefly, in case the audience is unfamiliar.
Dr. Kopetz: Certainly. The 8HW study enrolled immunotherapy-naive patients, but they did not all have to be first-line. Most turned out to be, but the analysis combined data across lines of therapy.
Dr. Eng: For the comparison of doublet versus single-agent therapy, yes. The chemotherapy control arm, however, consisted entirely of treatment-naive patients.
Dr. Cohen: I appreciate that the trial required central confirmation of MSI status. That was not done in the pembrolizumab study, so we do not know what percentage of those patients were truly MSI-high. It was surprisingly low in 8HW. This underscores the importance of how we test. While IHC provides a quick result, confirmation with NGS is essential, especially since it significantly affects treatment choices.
Dr. Kopetz: There is data showing that some patients who were not centrally confirmed as MSI-high were actually MSS. It is a mixed picture, but there were definitely false positives.
Dr. Eng: That was also reported in the KEYNOTE study, correct?
Dr. Kopetz: Yes.
Dr. Parikh: It sometimes feels like gastrointestinal oncologists are late adopters of immunotherapy, and many community oncologists actually have more experience with it across other tumor types. But we are learning quickly and have multidisciplinary teams to support us in managing toxicities. We even have a dedicated immunotherapy toxicity team now.
Dr. Cohen: We are fortunate to have support from GI, pulmonary, and rheumatology specialists. Some have taken a particular interest in immunotherapy-related complications. But for those in the community without that kind of support, it can be very challenging. Steroids are not always the answer, and in severe cases, we need more nuanced care to avoid losing patients to toxicity.
Dr. Parikh: Absolutely. Are there any additional toxicity tips you would share?
Dr. Eng: The most important thing is for patients to contact us at the first sign of a problem. And as providers, we should not hesitate to act if we suspect an immune-related adverse event. Do not assume it is just a mild infection or dietary issue. Address it early.

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 metastatic colorectal cancer treatment landscape.In the third segment, the panel discusses evolving strategies for immunotherapy in colorectal cancer, including the long-anticipated ATOMIC trial and widespread adoption of neoadjuvant checkpoint inhibition in MSI-high colon and rectal cancer. They explore real-world use of protocols like NICHE, the growing role of non-operative management, and the complexities around treatment duration, patient selection, and toxicity. The conversation also highlights the importance of multidisciplinary collaboration and accurate MSI testing in shaping treatment decisions.View the next segment on <a href="https://www.gioncologynow.com/post/breakwater-breakthrough-a-new-era-for-braf-v600e-crc" target="_blank" rel="noopener">BREAKWATER Breakthrough: A New Era for BRAF V600E CRC</a>.—Dr. Parikh: Let us briefly talk about the exciting gastrointestinal data coming tomorrow in the plenary session, particularly the ATOMIC trial. We will finally see results from a long-awaited study of chemotherapy and immunotherapy in the adjuvant setting. There has also been a lot of progress in the neoadjuvant space. The tricky aspect of ATOMIC is that it was slightly ahead of its time, using chemotherapy and immunotherapy in the comparator arm.Dr. Eng: In six months.Dr. Parikh: Yes, in six months. But we also have data from NICHE, which used just one dose of ipilimumab and two doses of neoadjuvant therapy. There is also dostarlimab. So how are people thinking about immunotherapy for colon and rectal cancer? Let us begin with colon cancer, since it is arguably the more interesting of the two right now. Is anyone considering neoadjuvant immunotherapy yet?All: Yes.Dr. Parikh: Same here. It has become a bit of a pet peeve for me to receive MSI-high patients after surgery.Dr. Eng: Yes, completely agree.Dr. Parikh: And while immune-related toxicities are a concern, we also know that adjuvant therapy can harm patients. Before ATOMIC, we had no data to support treatment, which made it hard to justify adjuvant therapy in Stage III MSI-high cases when we already had compelling neoadjuvant data. Are people using NICHE protocols off-study?Dr. Eng: I have done a couple of cases off-protocol, and fortunately, they were successful. Those patients are now under surveillance.Dr. Parseghian: And many of these patients are older adults, right?Dr. Eng: Yes, two were older individuals. One was a man with two primary MSI-high tumors and Lynch syndrome. He is doing extremely well.Dr. Parseghian: I have had similar experiences. At MD Anderson, we are seeing a trend where patients present to surgeons first with Stage II or III disease, and the surgeons often ask, “Can you take this patient? Do I even need to operate?” And increasingly, the answer seems to be no. We are using NICHE criteria more often and also running clinical trials to better understand outcomes. We have had success with this approach.Dr. Eng: This really emphasizes the importance of multidisciplinary discussions with our surgical colleagues in colon cancer.Dr. Parikh: Yes, we are trying to implement a workflow in Epic that flags MSI-high status when a surgeon sees a patient. It acts as a hard stop to ensure the surgeon has checked for it. Given their busy schedules and high volume, we want a system that prompts them to simply call me. I am always happy to talk.Dr. Cohen: I want to bring up a more complex issue: in rectal cancer, we are becoming more comfortable with non-operative management, even beyond MSI-high cases to include MSS as well. However, in colon cancer, even as we grow confident in using neoadjuvant immunotherapy, we are still hesitant to skip surgery. I recently had a patient with a sigmoid tumor where surveillance was technically feasible, but we lacked the imaging quality of rectal MRI and the surgery was less morbid. It led to a long and nuanced discussion, because patients want answers faster than we can generate data. We all know some patients probably do not need surgery, but clinical complete response is not the same as pathological complete response.All: Exactly.Dr. Cohen: So it remains difficult to justify skipping surgery.Dr. Eng: It is important to remember that in Miriam’s data, all patients went on to surgery, right?Dr. Parikh: Exactly.Dr. Eng: In NICHE-2 and NICHE-3, all patients underwent surgery, unlike in rectal cancer studies where sphincter preservation is often the goal. So the questions of treatment duration and surgical necessity remain interesting.Dr. Parikh: In rectal cancer, non-operative management and dostarlimab have been widely adopted. But we can all admit we are not consistently achieving the 100 percent response rate reported by Andrea.Dr. Kopetz: We are not quite there.Dr. Eng: We will have future trial results to help validate that.Dr. Parikh: Absolutely. Are there situations where, in rectal cancer with bulky disease and a goal of downstaging, you are opting for ipilimumab and nivolumab rather than monotherapy? I have done that.Dr. Eng: I did the same in a younger patient.Dr. Parseghian: I would probably do that in a younger patient as well. I have not had one recently, but I would consider it.Dr. Eng: My patient had a bulky tumor with some lymphadenopathy, not obstructing. That was the rationale.Dr. Cohen: I wonder if the doublet offers significant improvement. Single-agent dostarlimab is already very effective in the real-world setting. I am not sure it is necessary to expose patients to the added toxicity of ipilimumab and nivolumab.Dr. Eng: But what if the doublet shortens the duration of treatment?Dr. Cohen: Yes, that could be a trade-off. We just do not have enough data yet. I have mostly used monotherapy.Dr. Eng: Kristin’s study will inform us further.Dr. Cohen: Yes, exactly.Dr. Eng: Before that study launched, I treated a few patients off-protocol. It was interesting. I am looking forward to the results.Dr. Parikh: Has anyone had a case where you started with monotherapy and then considered adding ipilimumab midway due to signs of disease progression?Dr. Kopetz: Yes.Dr. Parseghian: I did that once. There is no real data to support it, but it seemed to help slightly. I should probably write up a case report. It did not lead to a cure, but we saw some benefit.Dr. Parikh: Are there any specific outcomes you are looking for in the 8HW data that could help guide clinical decisions? We have discussed treatment duration and toxicity.Dr. Kopetz: I am interested in how the first-line data compares with the pooled analysis. Most patients were first-line, so I am comfortable with the existing data, but I know there are colleagues waiting to see the first-line subset specifically.Dr. Eng: Perhaps you could describe that briefly, in case the audience is unfamiliar.Dr. Kopetz: Certainly. The 8HW study enrolled immunotherapy-naive patients, but they did not all have to be first-line. Most turned out to be, but the analysis combined data across lines of therapy.Dr. Eng: For the comparison of doublet versus single-agent therapy, yes. The chemotherapy control arm, however, consisted entirely of treatment-naive patients.Dr. Cohen: I appreciate that the trial required central confirmation of MSI status. That was not done in the pembrolizumab study, so we do not know what percentage of those patients were truly MSI-high. It was surprisingly low in 8HW. This underscores the importance of how we test. While IHC provides a quick result, confirmation with NGS is essential, especially since it significantly affects treatment choices.Dr. Kopetz: There is data showing that some patients who were not centrally confirmed as MSI-high were actually MSS. It is a mixed picture, but there were definitely false positives.Dr. Eng: That was also reported in the KEYNOTE study, correct?Dr. Kopetz: Yes.Dr. Parikh: It sometimes feels like gastrointestinal oncologists are late adopters of immunotherapy, and many community oncologists actually have more experience with it across other tumor types. But we are learning quickly and have multidisciplinary teams to support us in managing toxicities. We even have a dedicated immunotherapy toxicity team now.Dr. Cohen: We are fortunate to have support from GI, pulmonary, and rheumatology specialists. Some have taken a particular interest in immunotherapy-related complications. But for those in the community without that kind of support, it can be very challenging. Steroids are not always the answer, and in severe cases, we need more nuanced care to avoid losing patients to toxicity.Dr. Parikh: Absolutely. Are there any additional toxicity tips you would share?Dr. Eng: The most important thing is for patients to contact us at the first sign of a problem. And as providers, we should not hesitate to act if we suspect an immune-related adverse event. Do not assume it is just a mild infection or dietary issue. Address it early.

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