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Immunotherapy Advances in CRC
Expert Insights Into Recent Immunotherapy Advances in CRC

Released: April 23, 2025

Expiration: October 22, 2025

Christopher Lieu
Christopher Lieu, MD, FASCO
Michael Overman
Michael Overman, MD, MSHCT
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Key Takeaways
  • For patients with locally advanced dMMR/MSI-H rectal cancer, neoadjuvant/definitive immune checkpoint inhibitor therapy with dostarlimab, nivolumab, or pembrolizumab for up to 6 months is now preferred.
  • For patients with pMMR/MSS mCRC, ongoing trials are assessing the potential for immunotherapy, with preliminary benefits seen for patients without liver metastases in clinical trials.

Introduction
During a recent webinar, experts answered key questions about immunotherapy to treat colorectal cancer (CRC) across the disease spectrum.

How do you test for dMMR/MSI-H rectal cancer?
Christopher Lieu, MD, FASCO:
I believe in running both immunohistochemistry (IHC) and polymerase chain reaction–based next-generation sequencing (NGS). However, I probably rely more on NGS testing for microsatellite instability (MSI).

Michael Overman, MD, MSHCT:
I also typically order both tests. NGS provides a good picture of the tumor mutational burden and MSI, even though it takes longer than IHC. I often rely more on IHC for deficient mismatch repair (dMMR) because testing results return faster and it is generally accurate, but it is always preferable to have backup verification with NGS.

Of note, sometimes IHC and NGS test results are discordant. This can happen when the protein is expressed but is nonfunctional. What is driving the response is the high amount of frameshift mutations and neoantigens, so if NGS results show MSI-high (MSI-H), I would trust the NGS.

What is the current guidance for treating locally advanced dMMR/MSI-H rectal cancer?
Christopher Lieu, MD, FASCO:
According to the National Comprehensive Cancer Network (NCCN) guidelines for locally advanced dMMR/MSI-H rectal cancer, the preferred treatment is neoadjuvant/definitive immune checkpoint inhibitor therapy with dostarlimab, nivolumab, or pembrolizumab for up to 6 months. If patients do receive immunotherapy, the disease status should be reevaluated every 2-3 months. If there is a complete clinical response (cCR), continue surveillance. If the disease persists at 6 months, the recommendation is to proceed with total neoadjuvant therapy, which includes long-course chemotherapy/radiation therapy or short-course radiation therapy followed by chemotherapy and surgery.

One preferred agent, dostarlimab, proved outstanding in a single-arm phase II study in patients with stage II/III dMMR rectal cancer. Participants received dostarlimab 500 mg IV every 3 weeks for 9 cycles. Those patients with residual disease were moved into the standard treatment regimen of chemoradiation and possible surgery, but if a cCR was achieved, patients were allowed to proceed with nonoperative management and surveillance. The primary endpoint was the overall response to dostarlimab with or without chemoradiation. Of note, every patient receiving dostarlimab achieved a cCR (N = 42), with a median follow-up of approximately 18 months.

How long do you treat with immunotherapy in locally advanced dMMR/MSI-H rectal cancer?
Michael Overman, MD, MSHCT:
I think the answer is 6 months based on the results from the dostarlimab trial. I think there is an ongoing question of how long to treat when there is an early cCR. How much more therapy do you need? I think this is a very valid question to ask, but the answer is presently uncertain. In my practice, I treat for that 6-month period. From there, if a cCR is achieved, observation. Standard observation should last 5 years post surgery. Whether this duration or the frequency of imaging should differ following a complete PD-1 inhibitor-based response is unknown.

Christopher Lieu, MD, FASCO:
I agree. Some patients have a great response on single-agent dostarlimab, pembrolizumab, or nivolumab, but the guidelines recommend 6 months of treatment.

What is the best approach to measuring response in locally advanced dMMR/MSI-H rectal cancer ​that has been treated with immunotherapy?
Michael Overman, MD, MSHCT:
It is important to perform an endoscopic assessment to determine cCR. Occasionally, we do see radiologic residual findings in patients treated with immunotherapy. If the scan is unclear, it can be helpful to wait for an endoscopic evaluation prior to decision-making.

Christopher Lieu, MD, FASCO:
Absolutely. I recently had a young patient with locally advanced dMMR/MSI-H rectal cancer who was treated with immunotherapy. In this case, the radiologist continued to tell us on every MRI that there was persistent disease. This can be hard to ignore because the patient is seeing this result and we are seeing it as well. Biopsy can sometimes be helpful if the result is negative, but an endoscopic examination is critical in the surveillance period. This particular patient who continued to have radiologic findings of persistent disease did end up getting a low anterior resection. Luckily, the patient did not have to have a permanent ostomy, and there was indeed a complete response to therapy. However, this does prove the point that endoscopic examination is a critical part of the surveillance period.

Is there a benefit to treating patients with pMMR/MSS mCRC with immunotherapy?
Michael Overman, MD, MSHCT:
There have been 2 notable clinical trials in this patient population where patients were treated with pembrolizumab plus lenvatinib: LEAP-005, a nonrandomized phase II study performed in patients with previously treated advanced solid tumors, including CRC; and LEAP-017, a randomized phase III study in patients with previously treated proficient MMR (pMMR)/microsatellite stability (MSS) metastatic CRC (mCRC). LEAP-005 showed antitumor activity and a manageable safety profile in the pMMR/MSS CRC cohort. In LEAP-017, there was no statistically significant improvement in survival with pembrolizumab plus lenvatinib vs regorafenib or trifluridine/tipiracil (TAS-102). However, in the prespecified subgroup of patients without liver metastases (~30%), there was evidence of greater activity in terms of improved survival and response with pembrolizumab plus lenvatinib compared with those with liver metastases. There have also been smaller phase II trials in this population exploring other PD-1–based combinations—such as regorafenib, ipilimumab, and nivolumab or regorafenib and nivolumab—that also suggested improved clinical benefit in pMMR mCRC that did not have liver metastases. These results clearly show that liver metastases cause immune resistance. In the absence of such metastases, low-level activity can be observed with immunotherapy combinations.

Some of the most promising data, in my opinion, are those on botensilimab plus balstilimab, a novel CTLA-4/PD-1 inhibitor combination. Data from a phase II study in patients with previously treated pMMR/MSS mCRC with no liver metastases showed a 19% overall response rate and durable responses with this combination, which historically has been a challenge. I think the current challenge is obtaining randomized data that undoubtedly prove that this combination, or any immunotherapy, is better than the current standard of care for previously treated pMMR/MSS mCRC. For patients with pMMR mCRC without liver metastases, I would consider enrollment in a clinical trial of a novel immune therapy combination.

Christopher Lieu, MD, FASCO:
I completely agree. These data are so compelling that I would recommend clinical trial enrollment for a patient without liver metastases. As these studies mature, I think the picture will become more clear.

In your practice, is dMMR/MSI-H reflex testing performed on colonoscopy biopsy?
Michael Overman, MD, MSHCT:
Yes. Our pathology team tests reflexively, which helps not only with NCCN guideline adherence, but also with identifying patients who may be eligible for immune therapy. 

Would you support MSI testing in all patients with stage III disease?
Christopher Lieu, MD, FASCO:
Yes. All patients with CRC should undergo dMMR or MSI testing as a screen for Lynch syndrome, and as Dr Overman stated, testing also helps to identify patients who may be eligible for immune therapy.

Your Thoughts
Do you perform MMR/MSI testing for your patients with CRC? How do you now approach treatment for patients with locally advanced or metastatic dMMR/MSI-H CRC? Get involved in the discussion by posting a comment below.

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Poll

1.

A 31-year-old woman with no past medical history presents with stage III rectal cancer (cT3N1 rectal mass 2.6 cm from the anal verge, 2 suspicious mesorectal nodes; no evidence of distant metastatic disease). Testing reveals dMMR/MSI-H disease.

In your current practice, what would be your recommendation for this patient’s initial treatment?

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