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Study: Two immunotherapy drugs are better than one for some metastatic colorectal cancers

Combining two immunotherapy drugs is a more effective treatment for certain metastatic colorectal cancers than using either treatment drug alone. Used together, Opdivo (nivolumab) plus Yervoy (ipilimumab) slowed cancer growth in MSI-High metastatic colorectal cancers, a type of colorectal cancer often found in Lynch syndrome. The FDA approved this combined treatment for MSI-High metastatic colorectal cancer after progression with chemotherapy. (Posted 4/30/25)

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RELEVANCE

Most relevant for: People with unresectable or metastatic colorectal cancer that is MSI-High or dMMR.

It may also be relevant for:

  • people with colorectal cancer
  • people with metastatic or advanced cancer

Relevance: High

Strength of Science: High

Research Timeline: Post Approval

More rating details

What is this study about?

This study tested a combination of two drugs to treat colon cancer with a known as microsatellite instability-High (MSI-H), also known as deficient in mismatch repair (). Specifically, the study looked at the effectiveness and safety of using two immunotherapy drugs, Opdivo (nivolumab) plus Yervoy (ipilimumab), together as a first treatment compared to Opdivo alone or chemotherapy to see which treatment is more effective at blocking cancer growth and spread.

Why is this study important?

Advanced colorectal cancers can be challenging to treat and often come back after the first treatment. Doctors often make treatment recommendations based on tumor tests that classify the type of cancer, including tests for (mismatch repair).  Some immunotherapy drugs target cancers that are or dMMR. People with who have colorectal cancer commonly have MSI-H or dMMR cancers.

Immunotherapy is more effective than chemotherapy against these MSI-High or dMMR cancers, but the benefit does not always last, and the cancer may stop responding to the treatment. This study tested a combined and potentially more powerful treatment option for these hard-to-treat cancers. The researchers found that compared to Opdivo alone, combining two immunotherapy drugs, Opdivo plus Yervoy, more effectively prevented the growth of MSI-High metastatic colon cancers. Opdivo in combination with Yervoy was also more effective than chemotherapy.

On April 8, 2025, the approved Opdivo plus Yervoy for treating MSI-High or dMMR metastatic colorectal cancer that has grown after treatment with standard chemotherapy. This combined treatment was also approved for MSI-High or dMMR colorectal cancers that cannot be removed surgically. This approval was based on the results of the CheckMate 8HW clinical trial.

Study findings

The CheckMate 8HW study enrolled 839 people diagnosed with MSI-High or dMMR colorectal cancer that was 4 or could not be removed by surgery (unresectable). Participants were randomly assigned to receive Opdivo plus Yervoy (354 participants), Opdivo only (353 participants) or chemotherapy (132 participants).

  • Cancers treated with Opdivo plus Yervoy grew or spread 38% less often than those treated with Opdivo only.
  • The average time without cancer growth was:
    • 54.1 months for people in the Opdivo-plus-Yervoy group.
    • 18.4 months for people in the Opdivo-only group.
    • 5.9 months for people receiving chemotherapy.
  • After three years of treatment, 68% of people receiving the combined treatment were alive without cancer progression compared to 51% in the Opdivo-only group and 11% in the chemotherapy group.
  • Opdivo plus Yervoy was more effective than chemotherapy as a first treatment.

 Understanding the side effects of Opdivo plus Yervoy versus Opdivo only
While Opdivo plus Yervoy effectively treated MSI-High or dMMR colorectal cancers, it is important to be aware of the different side effects that participants experienced, which varied in severity.

Most participants had mild side effects. Overall, 81% of people who received Opdivo plus Yervoy reported a side effect, compared to 71% who received Opdivo only. The most common mild side effects included:

Side effect

Opdivo plus Yervoy

Opdivo only

Itching

26%

18%

Diarrhea

20%

17%

Mild weakness

16%

13%

Underactive thyroid

17%

5%

Joint pain

11%

7%

Underactive adrenal gland

10%

3%

Rash

10%

8%

 

Moderate to serious side effects
Moderate to serious side effects (grades 3 or 4) were more frequent in people taking Opdivo plus Yervoy (22%) compared to those taking Opdivo alone (14%). These side effects included diarrhea, inflammation of the pituitary gland and adrenal gland problems. Inflammation of the pituitary gland can disrupt pituitary hormones, impacting adrenal and thyroid activities, and may become irreversible if not treated promptly. These side effects are less common but require prompt medical attention.

Rare but severe reactions
In very rare cases, some individuals may experience life-threatening conditions. In this study, two people who received Opdivo plus Yervoy died—one of heart disease and one of lung disease related to treatment. Additionally, one person who was in the Opdivo-only group died of treatment-related lung disease.

Open Clinical Trials

The following studies enroll people with advanced colorectal cancer:

Several other clinical trials for patients with colorectal cancer can be found here.

Updated: 04/27/2025