Expert Highlights Latest Immunotherapy Efforts in CRC


Michael J. Overman, MD, discusses the current state of immunotherapy in patients with CRC and how to optimally manage immune-related adverse events.

Michael J. Overman, MD

The role of checkpoint inhibitors in regulating host immune response to cancer has provided practice-changing therapeutic targets for clinicians. This has significantly shaped the treatment landscape in colorectal cancer (CRC), but much work remains for certain subtypes, particularly the microsatellite stable (MSS) patient population, said Michael J. Overman, MD.

Data have proven that tumors that are mismatch-repair deficient (dMMR) and microsatellite instability-high (MSI-H) are effective biomarkers predictive of immunotherapy response.

There are currently 3 FDA-approved immunotherapy options for the subgroup of patients with metastatic MSI-H or dMMR CRC. One option, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), was approved by the FDA in July 2018.

The approval was based on durable phase II results from the CheckMate-142 study, which showed that a cohort of 119 patients with MSI-H or dMMR CRC were treated with the combination.1 Findings showed that the overall response rate (ORR) was 49%; among the 58 responders, there were 5 complete responses and 53 partial responses. Eighty-three percent of the responders had a response of ≥6 months.

Eighty-two patients had progressed on a fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimen, which is the setting in which nivolumab and ipilimumab is approved. In that subgroup, the ORR was 46%.

While this combination shows promise over monotherapy, Overman mentioned more data are necessary before it makes a mark on the standard of care.2

Nivolumab alone was granted an accelerated approval by the FDA in August 2017 for the treatment of adult and pediatric patients with MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

In May 2017, the FDA approved pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative therapy options, as well as for patients with MSI-H or dMMR CRC after progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

OncLive: How has the rise of immunotherapy impacted patients with CRC?

In an interview with OncLive, Overman, an associate professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed the current state of immunotherapy in patients with CRC and how to optimally manage immune-related adverse events.Overman: Fundamentally, we've identified a subset within colon cancer that is very immune-responsive. For that subset, we have generated 3 different approvals for immunotherapy. In part, this was based on nonrandomized studies because for that subset, this kind of treatment works tremendously well. It's been a real success because, generally, we give therapy to everyone and it works in a small fraction of people. That has sort of been the normal cancer paradigm.

Immunotherapy comes with new toxicity complications. What steps are being taken to manage those?

Here, we actually have a biomarker, MSI-H, which identifies a small group of patients where immunotherapy works great. Our data show that it works in over 50% of these patients. These responses aren't just durable, they're dramatic and could even be curable. For the other patient population, immunotherapy doesn't seem to work. Therefore, we have a really effective biomarker here. If you understand colorectal biology and understand the different subsets, then you can find a biomarker that separates a unique biology and is in tune with that. That is really the landscape right now. Immunotherapy toxicities are very different from those related to systemic chemotherapy. In gastrointestinal (GI) cancers, the first approval was in CRC—this dMMR group—and this was the first immunotherapy experience we had. People who treat melanoma or lung cancer have had more experience with immunotherapy toxicity because these approvals have been in place for a little while now.

First off, there's no doubt that it takes time to get familiar with and used to these new toxicities. The steps are appreciation, diagnosis, and treatment. For the GI cancer space, this is all new to us. The key points are we need to have a heightened awareness of the symptoms with our patients and make sure they're communicating with us. The challenge is that, in the past, when people were treated with chemotherapy, they got sick with a fever, infection, or dehydration. Now, it's a little different. It's a cough with no fever, but it eventually turns into pneumonitis. It's diarrhea without a fever that turns into colitis. It's lack of energy in a patient that turns out to be pituitary dysfunction.

If patients have symptoms, they have to let us know because it could turn out to be serious. We have to immediately create that dialogue with our patients when they start immunotherapy. Another problem is that if these patients go to a local hospital with these symptoms, they might not get the treatment they need. They might be prescribed simple antibiotics when they really need high-dose steroids.

How has the FDA approval of nivolumab and ipilimumab for MSI-H patients changed the treatment landscape?

Part of it is getting the emergency room physicians up to speed. Education is a huge thing across the whole spectrum of people who treat patients with cancer. For oncology practitioners, especially for someone who has been around for 20 years, this is a whole new concept and we all have to learn. We have had a lot of education sessions at various medical meetings. People are learning about it. This is still very recent so we haven't seen a pattern that has changed our practice just yet. However, the question of how this will impact our practice is a very interesting one. The trade-off that we always see with this combination is that it has a little more toxicity. But, it's clear that it works better than monotherapy. We see a durable progression-free survival that we hope eventually turns into curability. If you're doing something dramatically meaningful like this, we all agree that added toxicity is OK. Patients will go through a lot to essentially have their cancer fixed.

For the patients who have MSS tumors, what treatment options do they have?

Looking ahead to the next 5 years, what can be accomplished in the treatment of patients with CRC?

Are there any ongoing trials you wanted to mention?

The elephant in the room is related to melanoma. We've learned from that disease that it's really the sequence that matters here. A patient can get ipilimumab, but it doesn't really matter when they receive it. In melanoma, you start with nivolumab, and if that doesn't work, you give it with ipilimumab. Here's the question for us, “Does this combination work for MSI-H patients?” We have zero data that this combination works after nivolumab monotherapy. Is it similar to melanoma where you only have to give this combination to the patients who didn't respond to nivolumab? Maybe this is the case. In time, we'll have a better sense of what this combination can do. Right now, there is a little concern there just because we have zero data in the MSI-H space. For immunotherapy right now, there are none outside of clinical trials. There was the large clinical trial presented at the 2018 World Congress on GI Cancer of atezolizumab (Tecentriq), but it was a negative phase III study. This sort of confirmed that in patients with MSS CRC, anti—PD-1/PD-L1 therapy alone doesn't really work. In that area, we need to investigate more. We're definitely excited to find a combination that works. Right now, this is just a clinical trial–based setting. There are a lot of ongoing efforts. I'm a little bit of an optimist. I think we will see immunotherapy in MSS CRC in the next 5 years. It will likely work in a subset of patients. We are making headway slowly, and this is definitely something we can do. The rate we see response to immunotherapy in MSI-H patients is outstanding; it's some of the best we have seen across all cancers. There is no way we see this kind of advancement in the near future in MSS patients, but we can definitely see some new agents and treatments cross the finish line. The challenge is that a lot of immunotherapy agents work in just a small subset of patients. One study that I'm looking forward to is the KEYNOTE-177 study (NCT02563002), which has finished enrollment. We're looking at pembrolizumab (Keytruda) in the frontline setting versus standard chemotherapy for MSI-H patients. We hope to see results in a few years.


  1. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773-779. doi: 10.1200/JCO.2017.76.9901.
  2. Overman MJ, Ernstoff MS, Morse MA. Where we stand with immunotherapy in colorectal cancer: deficient mismatch repair, proficient mismatch repair, and toxicity management. doi: 10.1200/EDBK_200821. American Society of Clinical Oncology Educational Book 38 (May 23, 2018) 239-247.
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