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Colorectal Cancer

First-Line Treatment with Keytruda Doubles the Time without Disease Progression in Patients with MSI-H or dMMR Metastatic Colorectal Cancer

New study results presented at the 2020 ASCO annual meeting 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 Keytruda (pembrolizumab), a PD-1 inhibitor, 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.
ASCO 2020 Highlights
Chase Doyle

New study results presented at the 2020 ASCO annual meeting 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 Keytruda (pembrolizumab), a PD-1 inhibitor, 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 pembrolizumab as the first treatment in these patients doubled the average of time without disease progression (progression-free survival).

Pembrolizumab versus Chemotherapy

These results come from a new analysis of a phase 3 clinical trial, KEYNOTE-177, which showed that the use of pembrolizumab improved the average time without disease progression by more than 8 months compared with chemotherapy. The average time patients lived without disease progression was twice as long with pembrolizumab than with chemotherapy: 16.5 months with pembrolizumab compared with 8.2 months with chemotherapy.

“Pembrolizumab 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.

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

Pembrolizumab 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 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 pembrolizumab or with a chemotherapy regimen that included several chemotherapies and other drugs.

Patients continued to receive the treatment until their disease progressed (got worse), they had unacceptable side effects, they or their doctor decided to stop the treatment, or until the patient received 35 cycles of pembrolizumab. 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 pembrolizumab was significant, doubling the average time without disease progression from 8.2 months with chemotherapy to 16.5 months with immunotherapy. A total of 48.3% of the patients who received pembrolizumab had no disease progression after 2 years compared with 18.6% of the patients who received chemotherapy, Dr. André said.

Overall, 43.8% of patients who received first-line treatment with pembrolizumab 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 pembrolizumab. By the time of the study analysis at 2 years, the average duration of response has not been reached with pembrolizumab, meaning patients were still responding to treatment, compared with an average response of 10.6 months with chemotherapy.

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

After 24 months and longer 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.

Reduced Side Effects

Pembrolizumab was also associated with an improved safety profile compared with chemotherapy, meaning that it had fewer serious side effects. Among the patients who received pembrolizumab, 22% had serious (grade 3 or 4) side effects related to treatment compared with 66% of the patients who received chemotherapy as first-line treatment, according to Dr. André. Data for overall survival are still not available.

New First-Line Treatment Standard

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

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

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

“It is critical that we develop biomarkers of resistance to identify those patients who are not benefiting from pembrolizumab,” Dr. Overman pointed out.

Key Points

  • This is the first study to show benefits using pembrolizumab 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 as long with pembolizumab as with chemotherapy
  • Overall, 43.8% of patients who received first-line treatment with pembrolizumab had a response to the therapy compared with only 33.1% of those who received first-line chemotherapy
  • Pembrolizumab was also associated with fewer serious side effects compared with chemotherapy

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Last modified: September 11, 2020

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