FDA Approves Keytruda as Initial Treatment for Advanced Colorectal Cancer with DNA Repair Defects

Keytruda bested chemotherapy, delaying disease progression or death by 40%, in a clinical trial that led to the drug’s approval for use as a single initial treatment for patients with colorectal cancer.

The Food and Drug Administration (FDA) approved the immunotherapy Keytruda (pembrolizumab) for use by itself as an initial treatment for inoperable or metastatic colorectal cancer (CRC) that has trouble repairing its own DNA. Specifically, the approval allows the use of the drug to delay the progression of advanced CRC that is microsatellite instability-high (MSI-H) or mismatch repair deficient, alterations that interfere with DNA repair.

The approval is based on the results of the phase 3 KEYNOTE-177 trial, which found that Keytruda reduced the risk of disease progression or death by 40% compared with chemotherapy, which is the standard treatment currently given to these patients. In the study, the drug doubled the time from the start of treatment until disease worsened from 8.2 months with chemotherapy to 16.5 months with Keytruda.

Keytruda works by inhibiting the activity of the protein PD-1; this prevents cancer from using the protein to camouflage itself, allowing the immune system to better recognize and attack the disease.

“Patients with (inoperable) or metastatic MSI-H colorectal cancer have historically faced poor outcomes, and until today, chemotherapy-containing regimens were the only FDA-approved first-line treatment options,” Dr. Luis A. Diaz, head of the division of solid tumor oncology at Memorial Sloan Kettering Cancer Center in New York, said in a press release issued by the drug’s developer, Merck. “In (the 67) patients who were treated with Keytruda and responded in the KEYNOTE-177 trial, 43% of patients experienced a duration of response lasting two years or longer. This approval helps address the unmet need to provide a new monotherapy treatment option for patients.”

The trial included 307 patients with inoperable or metastatic CRC with a DNA repair defect. About one-quarter of them had received previous chemotherapy. The patients received either Keytruda every three weeks or chemotherapy every two weeks; chemotherapy consisted of the regimen known as mFOLFOX6, with or without either of the targeted drugs Avastin (bevacizumab) or Erbitux (cetuximab), or the regimen known as FOLFIRI, with or without either Avastin or Erbitux. Treatment continued for 24 months or less if disease progressed or the side effects were unacceptable.

Patients who received Keytruda had an overall response rate (ORR) including all complete and partial responses of 44%, with a complete response rate of 11% and a partial response rate of 33%. Patients who received chemotherapy had an ORR of 33%, with a complete response rate of 4% and a partial response rate of 29%, Merck reported.

Response to treatment lasted a median 10.6 months with chemotherapy, while a median number had not yet been reached in those taking Keytruda. Among those receiving immunotherapy, 75% responded for 12 months or more compared with 37% in the chemotherapy arm. In the Keytruda group, 43% had a response that lasted 24 months or longer compared with 18% in the chemotherapy group.

Among the 153 patients treated with Keytruda whose cancer had DNA repair defects, the median amount of time receiving the drug was 11.1 months.

Side effects were similar to side effects that occurred in previously studied patients with melanoma or non-small cell lung cancer who took Keytruda by itself, Merck stated.

In those studies, the most common side effects included fatigue, diarrhea, rash and nausea. Potentially severe or fatal immune system-related side effects can occur with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis/renal dysfunction, skin problems, reactions related to infusion and fetal harm in pregnant women.