The European Commission has approved Keytruda ( Pembrolizumab ), an anti-PD-1 therapy, as a monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high ( MSI-H ) or mismatch repair deficient ( dMMR ) colorectal cancer.
This approval is based on results from the pivotal phase 3 KEYNOTE-177 trial, in which Keytruda monotherapy significantly reduced the risk of disease progression or death by 40% ( hazard ratio, HR=0.60 [ 95% CI, 0.45-0.80 ]; p=0.0002 ) compared with chemotherapy ( investigator’s choice: mFOLFOX6 [ Oxaliplatin, Leucovorin and Fluorouracil ( FU ) ] with or without Bevacizumab or Cetuximab; or FOLFIRI [ Irinotecan, Leucovorin and FU ] with or without Bevacizumab or Cetuximab ).
Treatment with Keytruda also more than doubled median progression-free survival ( PFS ) compared with chemotherapy ( 16.5 months [ 95% CI, 5.4-32.4 ] versus 8.2 months [ 95% CI, 6.1-10.2 ] ).
There was a lower incidence of grade greater than or equal to 3 treatment-related adverse events ( TRAEs ) with Keytruda compared with chemotherapy ( 22% versus 66% ), and no new toxicities were observed.
KEYNOTE-177 is a multi-center, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated metastatic MSI-H or dMMR colorectal cancer.
Microsatellite instability ( MSI ) or mismatch repair ( MMR ) tumor status was determined locally using polymerase chain reaction or immunohistochemistry, respectively.
Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.
Patients were randomized 1:1 to receive Keytruda ( 200 mg intravenously ) every three weeks or investigator’s choice of the following chemotherapy regimens given intravenously every two weeks:
mFOLFOX6 ( Oxaliplatin, Leucovorin and FU ) or mFOLFOX6 in combination with either Bevacizumab or Cetuximab: Oxaliplatin 85 mg/m2, Leucovorin 400 mg/m2 ( or Levoleucovorin 200 mg/m2 ), and FU 400 mg/m2 bolus on day 1, then FU 2,400 mg/m2 over 46-48 hours; plus Bevacizumab 5 mg/kg on day 1 or Cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly;
FOLFIRI ( Irinotecan, Leucovorin, and FU ) or FOLFIRI in combination with either Bevacizumab or Cetuximab: Irinotecan 180 mg/m2, Leucovorin 400 mg/m2 ( or Levoleucovorin 200 mg/m2 ), and FU 400 mg/m2 bolus on day 1, then FU 2,400 mg/m2 over 46-48 hours; plus Bevacizumab 5 mg/kg on day 1 or Cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.
Treatment with Keytruda or chemotherapy continued until RECIST v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity.
Patients treated with Keytruda without disease progression could be treated for up to 24 months.
Assessment of tumor status was performed every nine weeks.
Patients randomized to chemotherapy were offered Keytruda at the time of disease progression. The main efficacy outcome measure was progression-free survival as assessed by blinded independent central review ( BICR ) according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ, and overall survival ( OS ). Additional efficacy outcome measures were objective response rate ( ORR ) and duration of response ( DOR ).
In this trial, Keytruda monotherapy significantly reduced the risk of disease progression or death from any cause by 40% ( HR=0.60 [ 95% CI, 0.45-0.80 ]; p=0.0002 ) and has shown a median progression-free srvival of 16.5 months ( 95% CI, 5.4-32.4 ) compared with 8.2 months ( 95% CI, 6.1-10.2 ) for patients treated with chemotherapy. For progression-free survival, in the Keytruda arm, there were 82 patients ( 54% ) with an event versus 113 patients ( 73% ) in the chemotherapy arm.
Overall survival analysis is ongoing.
For patients treated with Keytruda, the ORR was 44% ( 95% CI, 35.8-52.0 ), with a complete response rate of 11% and a partial response rate of 33%.
For patients treated with chemotherapy, the ORR was 33% ( 95% CI, 25.8-41.1 ), with a complete response rate of 4% and a partial response rate of 29%.
Median DOR was not reached ( range, 2.3+ to 41.4+ ) with Keytruda versus 10.6 months ( range, 2.8 to 37.5+ ) with chemotherapy.
Based on 67 patients with a response in the Keytruda arm and 51 patients with a response in the chemotherapy arm, 85% in the Keytruda arm had a duration of response greater than or equal to 12 months versus 44% in the chemotherapy arm.
Among the 153 patients with MSI-H or dMMR colorectal cancer treated with Keytruda, the median duration of exposure to Keytruda was 11.1 months ( range, 1 day to 30.6 months ).
Adverse reactions occurring in patients with MSI-H or dMMR colorectal cancer were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer treated with as a Keytruda single agent.
Pembrolizumab is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells.
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Microsatellite instability ( or MSI ) is defined by the National Cancer Institute ( NCI ) as a change that occurs in the DNA of certain cells, such as tumor cells, in which the number of microsatellite repeats ( short, repeated sequences of DNA ) is different from the number of repeats that was in the DNA when it was inherited.
The cause of MSI may be a defect in the ability to repair mistakes made when DNA is copied in the cell. This defect is also referred to as mismatch repair deficiency ( dMMR ).
Colorectal cancer often begins with growths on the inner lining of the colon or rectum called polyps, which can change into cancer over time.
Colorectal cancer is the third most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide.
Worldwide, it is estimated there were more than 1,930,000 new cases of colorectal cancer in 2020. In Europe, it is estimated there were nearly 520,000 new cases of colorectal cancer.
It is estimated approximately 4-20% of colorectal cancer patients ( inclusive of all stages of disease ) have tumors that score as either MSI-H or dMMR when testing is performed. ( Xagena )
Source: Merck ( MSD ), 2021