In patients with advanced endometrial cancer, the standard first-line therapy consists of chemotherapy with paclitaxel plus carboplatin. Results of the phase 3 NRG-GY018 trial, recently published in The New England Journal of Medicine, show that the addition of pembrolizumab to this regimen increases progression-free survival in patients with advanced or recurrent endometrial cancer, regardless of the tumour mismatch-repair status. These results highlight the potential of pembrolizumab as a promising addition to the existing treatment options for patients with advanced or recurrent endometrial cancer.
Endometrial cancer is one of the few malignant conditions for which both incidence and mortality are currently rising. By 2040, it is anticipated to become the third most prevalent cancer and the fourth leading cause of cancer-related deaths among women. In patients with advanced endometrial cancer, the standard first-line therapy consists of chemotherapy with paclitaxel plus carboplatin. However, the potential benefit of incorporating pembrolizumab into this treatment regimen remains unclear. The combination of pembrolizumab and chemotherapy resulted in clinically significant improvements in progression-free (PFS) and overall survival (OS) in patients with multiple types of solid tumours. Additionally, monotherapy with pembrolizumab has shown to be efficient as second-line therapy and beyond in patients with mismatch repair-deficient (dMMR) endometrial cancer with high microsatellite instability. Based on these encouraging results, this clinical trial evaluated whether the addition of pembrolizumab can further improve the management of advanced endometrial cancer, offering new hope and potential benefits for these patients.
The phase 3 NRG-GY018 trial was conducted at 395 sites in four countries (the United States, Canada, Japan, and South Korea) and enrolled 816 patients with newly diagnosed measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer. In total, 816 patients were randomly assigned (1:1) to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. The primary outcome was PFS in the two cohorts.
The follow-up period had a median duration of 12 months for the dMMR cohort and 7.9 months for the pMMR cohort. In the analysis, conducted at the 12-month landmark in patients with dMMR, the estimated PFS was reported at 74% for the pembrolizumab group, as compared to 38% in the control arm. This translates into a significant 70% reduction in the risk of disease progression or death with the use of pembrolizumab (HR[95% CI]: 0.30[0.19-0.48]; p<0.001). Among patients with pMMR, the median PFS mounted to 13.1 months with pembrolizumab as compared to 8.7 months with placebo, resulting in a 46% reduced risk of disease progression or death with pembrolizumab (HR[95% CI]: 0.54[0.41-0.71]; p<0.001). The incidence of grade ≥3 events was expectedly slightly higher when pembrolizumab was combined with chemotherapy (63.3% vs. 47.2% in the dMMR cohort, 55.1% vs. 45.3% in the pMMR cohort, respectively).
In conclusion, the addition of pembrolizumab to standard chemotherapy significantly improves the PFS compared to chemotherapy alone in patients with advanced or recurrent endometrial cancer, regardless of the tumour mismatch-repair status.
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