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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)

PUBLISHED: 30 April 2025

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

Relevance 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 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 drugs target cancers that are or . People with who have colorectal cancer commonly have MSI-H or cancers.

is more effective than chemotherapy against these or 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 drugs, Opdivo plus Yervoy, more effectively prevented the growth of 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 or metastatic colorectal cancer that has grown after treatment with standard chemotherapy. This combined treatment was also approved for or 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 or 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 or 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.

What does this mean for me?

While the new combination therapy of Opdivo plus Yervoy was more effective than Opdivo alone for MSI-H colorectal cancer in this study, choosing the right treatment depends on individual factors and preferences. If you have or unresectable colorectal cancer that is MSI-H, ask your doctor if Opdivo plus Yervoy might be right for you. If you have not been tested for status, talk to your doctor about whether this testing would be useful. Also, consider the potential side effects when deciding if a new treatment is an option for you. Discussing the risks and benefits of treatment options with your doctor is helpful before you start treatment.

Reference

Andre T, Elez E, Lenz HJ, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high colon cancer (CheckMate 8HW): a randomised, , phase 3 trial. The Lancet. 2025; 405(10476):383-395.

U.S. Food and Drug Administration. approves nivolumab with ipilimumab for unresectable or MSI-H or colorectal cancer. Published April 8, 2025. Accessed April 15, 2025.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 4/30/25

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • Has my tumor been tested for ? What was the result of that test?
  • How does this test result affect my treatment options?
  • Is Opdivo plus Yervoy an option for me?
  • What are the possible side effects of Opdivo plus Yervoy?

Guidelines
Guidelines

 

If you have been diagnosed with colorectal or endometrial cancer and have any of the following factors, National Comprehensive Cancer Network (NCCN) guidelines recommend you speak with a genetics expert about genetic testing:

  • A tumor test result that suggests an (for example, an MSI-H or tumor)
  • A blood relative who tested positive for an  linked to cancer
  • Colorectal, endometrial cancer or other Lynch syndrome-related cancer diagnosed before age 50
  • Diagnoses of more than one cancer
  • A family history of one or more first- or second-degree relatives with any of the following types of cancer diagnosed before age 50 or two or more first- or second-degree relatives with any of the following cancers diagnosed at any age:
    • colorectal
    • endometrial
    • ovarian
    • gastric
    • small bowel
    • biliary tract
    • pancreatic
    • urothelial
    • brain (usually glioblastoma)
    • certain skin cancer or growths (sebaceous adenomas, sebaceous carcinomas or keratoacanthomas)
  • Colorectal cancer and a personal history of polyps:
    • 10 or more adenomatous
    • 2 or more hamartomatous
    • 5 or more serrated close to the rectum

Updated: 04/28/2025

Related resources
Related resources

The following resources focus on colorectal cancer.

Updated: 12/21/2022

Open Clinical Trials
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

Article Rating Details

Study Rating Details

Relevance: High

  • This study identifies a new standard treatment for MSI-high unresectable or metastatic colon cancer that grows with chemotherapy treatment.
  • This combined drug may benefit people with Lynch syndrome who are at greater risk of developing this type of colorectal cancer.
  • This study is the first to show that this combined immunotherapy is more effective than one immunotherapy drug alone.

Scientific Strength: High

  • This is a randomized, phase 3 trial.
  • MSI-High status was confirmed by testing by the same lab ensuring testing consistency.
  • Strengths: 
    • The number of study participants was relatively large.
    • Progression-free survival was confirmed by blinded independent review.
  • Limitations:
    • Some groups included only a few people, limiting the conclusions.
    • This trial did not include many Black or Hispanic people, so it is unclear if these findings are generalizable to these populations.
    • The follow-up time was less than 5 years. Additional study is required to understand the impact on longer-term survival.

Research Timeline:  Post-Approval

  • The FDA gave accelerated approval in 2018 to this immunotherapy combination as a treatment for metastatic MSI-High colon cancer. The FDA granted regular approval in April 2025 for MSI-High unresectable or metastatic colorectal cancer that has progressed after treatment with fluoropyrimidine, oxaliplatin and irinotecan chemotherapy.