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Colorectal CancerImmunotherapy

First-Line Immunotherapy New Standard of Care in Some Patients with Metastatic Colorectal Cancer

A new study was presented at the 2020 ASCO meeting that compared, for the first time, the use of immunotherapy versus chemotherapy for treating patients with metastatic colorectal cancer and microsatellite instability-high or mismatch repair-deficient abnormalities.
August 2020 – Immunotherapy
Chase Doyle

New results presented at the 2020 meeting of the American Society of Clinical Oncology suggest that there is a new standard of care for the first-line treatment of some patients with advanced colorectal cancer. This was the first study to compare the use of immunotherapy versus chemotherapy to see which is the best first treatment for patients with metastatic (spreading) colorectal cancer and microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) abnormalities.

MSH-I and dMMR are 2 biomarkers present in about 5% of patients with advanced or metastatic colorectal cancer. The study results showed that using immunotherapy as the first treatment in these patients doubled the average of time without disease progression (progression-free survival).

Immunotherapy versus Chemotherapy

These results come from a new analysis of a phase 3 clinical trial called KEYNOTE-177, which showed that the use of immunotherapy with Keytruda (pembrolizumab), a PD-1 inhibitor (or a checkpoint inhibitor), improved the average time without disease progression by more than 8 months compared with chemotherapy. The average time patients had without disease progression was twice as long with immunotherapy than chemotherapy: 16.5 months with Keytruda compared with 8.2 months with chemotherapy,

“Pembrolizumab [Keytruda] provided a clinically meaningful and statistically significant improvement in progression-free survival versus chemotherapy in patients with MSI-H or dMMR tumors, with fewer treatment-related adverse events,” said Thierry André, MD, of the Sorbonne Université and Hôpital Saint Antoine in Paris, France.

Thierry André, MD

“It [Keytruda] should be considered a new standard of care as first-line therapy in these patients,” Dr. André emphasized.

Keytruda has been approved by the FDA for the treatment of all patients with solid tumors and MSI-H or dMMR, regardless of the type of cancer, after they received other treatments. The FDA also approved the immunotherapy Opdivo (nivolumab), another PD-1 inhibitor, for the treatment of patients with colorectal cancer and the MSI-H or dMMR after they receive a chemotherapy regimen.

This is the first study to show the benefits of the use of immunotherapy as the first treatment for this specific group of patients. The study included 307 patients with metastatic colorectal cancer and the MSI-H or dMMR biomarker who have not received any previous therapy. The patients were randomly divided to receive first-line treatment with the immunotherapy Keytruda or with a chemotherapy regimen that included several chemotherapies and other drugs.

Patients continued to receive the treatment until their disease progressed, they had unacceptable side effects, they or their doctor decided to stop the treatment, or until the patient received 35 cycles of Keytruda. Patients who were in the group that received chemotherapy first were permitted to switch over to receive the immunotherapy for up to 35 weeks after their disease progressed with chemotherapy.

Immunotherapy Improves Outcomes

The improvement with Keytruda was significant, doubling the average time without disease progression from 8.2 months with chemotherapy to 16.5 months with immunotherapy. Almost half (48.3%) of the patients using Keytruda had no disease progression after 2 years compared with less than one-fifth (18.6%) of patients who received chemotherapy, Dr. André said.

Overall, 43.8% of patients who received first-line treatment with Keytruda had a response to the therapy compared with only 33.1% of the patients who received first-line chemotherapy. In addition, the duration of response was longer with immunotherapy. By the time of the study analysis at 2 years, the average duration of response has not been reached with Keytruda, meaning patients were still responding to treatment, compared with an average of response of 10.6 months with chemotherapy.

In addition, 36% of patients who received chemotherapy crossed over to receive Keytruda after their disease progressed with chemotherapy, said Dr. André.

After more than 24 months from the start of the study, 83% of patients who responded to the immunotherapy continue to have a response to treatment compared with only 35% of the patients who were receiving chemotherapy.

h3p>Reduced Side Effects

Keytruda was also associated with fewer serious side effects. Among patients who received immunotherapy with Keytruda, 22% had serious (grade 3 or 4) side effects related to treatment compared with 66% among patients who received chemotherapy as first line, according to Dr. André. The study is continuing, so the information related to overall survival is still not available.

New First-Line Standard

Michael J. Overman, MD, Professor of Gastrointestinal Medical Oncology at M.D. Anderson Cancer Center in Houston, Texas, said that the 2.5-fold increase in 24-month time without disease progression with Keytruda compared with chemotherapy (48.3% versus 18.6%) was “clinically meaningful,” meaning that it had a real difference for patients.

He also said that these results mean that doctors should now use immunotherapy as the first treatment for patients with metastatic colorectal cancer and the MSI-H or dMMR biomarker instead of a chemotherapy regimen.

However, Dr. Overman added that although the time without disease progression was twice as long with first-line immunotherapy than with chemotherapy, the percentage of patients whose disease eventually progressed after treatment was higher with Keytruda (29%) than with chemotherapy (12%), meaning that almost 30% of patients may have resistance to therapy with a PD-1 inhibitor, such as Keytruda or other immunotherapies.

Key Points

  • This is the first study to show benefits using immunotherapy as the first treatment for patients with metastatic colorectal cancer and the MSI-H or dMMR biomarker
  • The average time patients had without disease progression was twice longer with immunotherapy than chemotherapy
  • The duration of response was also much longer with immunotherapy than with chemotherapy
  • Almost 30% of patients may have resistance to therapy with a PD-1 inhibitor such as Keytruda or other immunotherapies

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Last modified: October 16, 2020

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