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

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Contents

At a glance Clinical trials
Why this approval is important Guidelines              
Keynote 177 study findings Questions for your doctor 
What does this study mean for me? Resources

 

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 MSH2Lynch 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.

This article is relevant for:

People with advanced colorectal cancer and a type of biomarker called MSI-High (MSI-H)

This article is also relevant for:

People with a genetic mutation linked to cancer risk

Newly diagnosed

People with a family history of cancer

People with metastatic or advanced cancer

Be part of XRAY:

Expert Guidelines

The National Comprehensive Cancer Network (NCCN) provides expert-developed guidelines for tumor testing for people with colorectal cancer. NCCN recommends the following for tumor testing in people with colorectal cancer:

  • All newly-diagnosed colorectal cancers should be tested for microsatellite instability (MSI) or mismatch repair deficiency (dMMR or MMR-D).  
    • People diagnosed with advanced MSI-H/dMMR cancers may benefit from treatment with a type of immunotherapy known as immune checkpoint inhibitors.
  • Depending on MMR/MSI test results, referral for genetic counseling for an inherited gene mutation associated with Lynch syndrome
  • Additional tumor tests may help determine treatment options in metastatic colorectal cancer. This includes testing for:
    • BRAF V600E
    • KRAS
    • NRAS
    • HER2

Updated: 12/04/2021

Questions to Ask Your Doctor

  • What are the best drug options for treating my colorectal cancer?
  • What are the side effects of my treatment drugs?
  • Which biomarkers was my cancer tested for? What were the results?
  • Is my cancer due to microsatellite instability or mismatch repair deficiency?
  • Can you provide a copy of my biomarker test results?
  • Do I meet criteria for genetic counseling and testing for an inherited mutation?
  • Can you refer me to a genetic counselor?
  • Should I consider a clinical trial?

Open Clinical Trials

The following are studies enrolling people with advanced colorectal cancer.  

A number of other clinical trials for patients with colorectal cancer can be found here.

Updated: 12/04/2021

Peer Support

The following organizations offer peer support services for people with, or at high risk for colorectal cancer:

Updated: 12/04/2021

Who covered this study?

PMLive

ASCO: Merck’s Keytruda tops chemo in MSI-H colorectal cancer This article rates 5.0 out of 5 stars

Cancer Network

Phase III KEYNOTE-177 study of pembrolizumab doubles PFS in MSI-H/dMMR mCRC This article rates 4.0 out of 5 stars

Journal of Managed Care

Pembrolizumab as first-line treatment doubles PFS in certain patients with colorectal cancer This article rates 3.5 out of 5 stars

How we rated the media

IN-DEPTH REVIEW OF RESEARCH

Study background:

Keytruda (pembrolizumab) was recently FDA-approved for use in patients with colorectal cancer that has spread (metastasized) and whose tumors have tested positive for microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR or MMR-D). Keytruda is an immunotherapy that belongs to the drug class of checkpoint inhibitors . It works by blocking the PD-1 protein on T cells. This allows the cells to find and kill cancer cells that express this protein.

FDA approval was based on results from KEYNOTE-177, a study that looked at Keytruda as a first-line therapy for metastatic colorectal cancer in patients with MSI-H/MMR-D tumors. Prior to this approval as a first-line therapy for colorectal cancer, Keytruda was approved as a second-line therapy to treat people whose MSI-H/dMMR tumors progressed or returned after initial chemotherapy.

Researchers of this study wanted to know:

whether Keytruda or chemotherapy works better as a first-line treatment for metastatic colorectal cancer in people with MSI-H/dMMR tumors.

Populations looked at in this study:

The study included men and women (ranging from ages 24 to 90) with newly diagnosed stage 4 colorectal cancer who have never received treatment for the disorder. All patients’ tumors were positive for MSI-H/dMMR deficiency.

Study design:

The study was a multi-site phase 3 clinical trial that was performed at 192 sites throughout 23 countries, including the U.S. and Canada. 

During the study, 296 participants received treatment for colorectal cancer for up to 2 years. They were divided into the following treatment groups:

  • Standard chemotherapy group (143 patients) received a form of standard chemotherapy intravenously once every two weeks*
  • Keytruda group (153 patients) received 200mg of Keytruda intravenously once every three weeks

Tumors of patients were tested for somatic mutations in BRAF V600E, KRAS and NRAS.

Primary endpoints of the study included:

  • Progression-free survival (PFS)—the amount of time it takes for cancer to return or worsen after treatment
  • Overall survival (OS) of patients

Secondary endpoints included:

  • Overall response rate (ORR)—the proportion of patients whose tumor shrunk by at least 30 percent or been eradicated by treatment

*Patients in the standard chemotherapy group were treated with of the following therapies: mFOLFOX6 alone, mFOLFOX6+bevacizumab, mFOLFOX6+cetuximab, FOLFIRI alone, FOLFIRI+bevacizumab or FOLFIRI+cetuximab.

Study findings:  

Results showed that:

  • Median progression-free survival in the Keytruda group was 16.5 months, compared with 8.2 months in the standard chemotherapy group.
  • 48.3 percent of patients in the Keytruda group had no progression of cancer at month 24 of treatment compared with 18.6 percent in the standard-chemotherapy group.
  • Overall response rate in the Keytruda group was 43.8 percent. Overall response rate in the standard chemotherapy group was 33.1 percent.
  • Patients with a BRAF gene mutation (BRAF V600) were more likely to have a response to Keytruda than standard chemotherapy. Patients with a KRAS or NRAS gene mutation were less likely to respond to Keytruda than standard chemotherapy.

According to study researchers, overall survival of patients could not be determined at the time of this study report.

Side effects of Keytruda:

Overall, the Keytruda group was three times less likely than the standard chemotherapy group to experience adverse events that required medical intervention. The most common adverse events associated with Keytruda included:

  • Diarrhea
  • Fatigue
  • Nausea
  • Decreased appetite

Strengths and limitations:

Strengths:

  • This study showed the impact of Keytruda as a first-line therapy for colorectal cancer, compared with standard chemotherapies for treating colorectal cancer.
  • Multiple forms of colorectal cancers can require specific treatment options to slow its progression. The current study restricted the patient population to those with MSI-H tumors. The results show how Keytruda can benefit this patient population.

Limitations:

  • Although the study took place in diverse locations, it did not mention race/ethnicity of participants. Drug response rates can differ across race/ethnicity.
  • The study did not include data on which patients had inherited gene mutations, such as MLH1 and MSH2, that are associated with Lynch Syndrome.

Context:

The results from KEYNOTE-177 agree with accepted data in the field of colorectal cancer research. Previous evidence has shown that people with MSI-H/dMMR tumors are likely to respond well to checkpoint inhibitors like Keytruda. Prior to the study, Keytruda was approved as a second-line treatment for MSI-H/dMMR colorectal cancer that progressed after initial chemotherapy. The current study shows that Keytruda can now be used as an initial intervention for patients with advanced MSI-H/dMMR colorectal cancer.

Conclusions:

In the current study, Keytruda was found to be safe and effective for treating metastatic colorectal cancer in patients with MSI-H/dMMR deficiency. Data also showed that study participants fared better with Keytruda compared to standard chemotherapy. Because Keytruda has recently been approved as a first-line therapy for this disorder, people with MSI-H/dMMR colorectal cancer now have more options to hinder cancer progression and improve their survival.

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