Study: Immunotherapy drug Keytruda received FDA approval and showed benefit for treatment of colorectal cancer

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APPROVAL AT A GLANCE

This approval is about:

The immunotherapy drug Keytruda (pembrolizumab) as initial (first-line) treatment for certain patients with advanced colorectal cancer.

Why is this approval important?

Prior to this new approval, Keytruda was approved by the FDA as a treatment for certain types of recurrent cancers, including colorectal cancer. As a result of the KEYNOTE-177 study, the FDA issued a new FDA approval Keytruda in June 2020. This drug is now approved as a first-line treatment for colorectal cancer patients whose tumors have a microsatellite instability high (MSI-H) or mismatch repair deficiency (MMR-D or dMMR) biomarker.

What are mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) cancers?

"Mismatch repair" (MMR) genes repair DNA damage that occurs during cell division. Tumors with mutations in mismatch repair genes are called "MMR deficient" (dMMR or MMR-D). MMR-D tumors have a cellular abnormality known as Microsatellite Instability or MSI-High, which may be found through tumor biomarker testing. Mutations in the following genes are associated with dMMR/MMR-D tumors: 

• MLH1
• MSH2
• MSH6
• PMS2
• EPCAM 

People with Lynch syndrome who develop cancer are more likely to develop MSI-H cancers. Testing tumors for dMMR/MMR-D or MSI-High can be important, because these tumors are more likely to respond to a type of immunotherapy known as immune checkpoint inhibitors.

What are immune checkpoint inhibitors?

Checkpoint inhibitors are a type of immunotherapy that activate the body’s immune cells to destroy cancer cells. Tumors with MSI-H/dMMR are more likely to respond to a class of drugs known as checkpoint inhibitors. Keytruda is one type of checkpoint inhibitor.

KEYNOTE-177 study

The KEYNOTE-177 study looked at how Keytruda compared to chemotherapy as an initial treatment in patients with metastatic colorectal cancer and a tumor biomarker known as MSI-H or dMMR.

What is first-line treatment?

Initial treatment given for a disease such as cancer is called a first-line treatment. Second-line treatments are used for cancers that return or do not respond to initial treatment. Second-line treatment may be a new course of chemotherapy or another type of treatment. Third-line treatment is recommended for cancers that return or do not respond to second-line treatment.

Study findings: 

The KEYNOTE-177 study included 296 patients with advanced MSI-H/dMMR colorectal cancer who were treated with either Keytruda or chemotherapy as first-line treatment.

Study results showed that patients receiving Keytruda had better outcomes after two years of treatment, compared with patients receiving chemotherapy.

• People who received Keytruda went eight months longer before their cancer or worsened.
• Patients treated with Keytruda were almost three times more likely to experience no progression of cancer.
• Tumor shrinkage was more likely to occur in patients who took Keytruda.
• Patients whose tumor cells had a V600E mutation in the BRAF gene were more likely to have better treatment outcomes with Keytruda than chemotherapy. In contrast, patients whose tumor cells had KRAS or NRAS mutations were more likely to respond to chemotherapy than Keytruda.
• People who received Keytruda experienced adverse events that required medical intervention three times less often, suggesting that it is a safer treatment.

Side effects of Keytruda:

The most common side effects reported by patients receiving Keytruda included:

• Diarrhea
• Fatigue
• Nausea
• Decreased appetite

Strengths and limitations of KEYNOTE-177:

Strengths:

• All the participants in the KEYNOTE-177 study had MSI-H/dMMR colorectal tumors. This is important because not all treatments work for all types of colorectal cancers. Results showed that Keytruda can benefit this specific group of people with metastatic colorectal cancer.

Limitations:

• The study did not include data on outcomes of participants with an inherited Lynch syndrome mutation, such as MLH1 and MSH2.  Lynch Syndrome increases risk for MSI-H/dMMR tumors.
• Although patients were diverse in gender, age, and geographical location, the study did not mention the race or ethnicity of participants. This is important because the effectiveness and side effects of Keytruda may differ for people of different races or ethnicities.
• This study is not complete. Researchers are continuing to collect data from participants. At the time of the FDA approval, no overall survival data were available.

What does this mean for me?

If you have advanced colorectal cancer and your tumor is MSI-H/dMMR you may benefit from treatment with the immunotherapy drug Keytruda. This includes newly-diagnosed people who have not yet received treatment for their advanced colorectal cancer. 

If you are diagnosed with advanced colorectal cancer, it is important to ask your doctor about tumor testing for microsatellite instability (MSI-H), mismatch repair deficiency (dMMR or MMR-D) or mutations in the BRAF, KRAS and NRAS genes. Knowing your tumor status for these biomarkers can help guide treatment options. In addition, if you are at risk of developing advanced colorectal cancer, talk with your doctor about whether you may be eligible for an ongoing clinical trial.  

Lynch syndrome may be linked to MSI-H/dMMR cancers. People diagnosed with colorectal cancer that is MSI-H/dMMR may benefit from genetic counseling and testing to learn if they have Lynch syndrome.

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References

Thierry A,  Shiu K,  Kim T, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 Study. ASCO20 Virtual Scientific Program. J Clin Oncol 2020;38(18):suppl, LBA4.

FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer. FDA website. June 2020. 

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 before publication to assure scientific integrity.