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Expert Highlights Latest Immunotherapy Efforts in CRC

Brandon Scalea
Published: Thursday, Aug 23, 2018

Michael J. Overman, MD
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.

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.

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

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.

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

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.




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