Endometrial carcinoma is the sixth most common cancer in women. Its incidence has increased worldwide over the past three decades. Following diagnosis, patients are generally treated initially with surgery. Adjuvant therapy consisting of chemotherapy and possibly (chemo)radiotherapy may subsequently be administered depending on the risk of recurrence.
Previous studies had already demonstrated a benefit of pembrolizumab in patients with advanced endometrial carcinoma, particularly in the dMMR or MSI-H subgroups, or in combination with lenvatinib.
In this study, patients were randomized (1:1) to chemotherapy combined with placebo or pembrolizumab. Chemotherapy was administered for six or seven weekly or three-weekly cycles. This was followed by six additional cycles of pembrolizumab or placebo administered every six weeks.
The analysis showed that the study failed to meet its primary endpoint of disease-free survival. The reason for this remains unclear, particularly because this finding contrasts with the significant progression-free survival benefit observed with the combination of pembrolizumab, carboplatin, and paclitaxel in advanced or recurrent endometrial carcinoma.
Several explanations may account for this discrepancy. Participants in this study had no residual disease after surgery, unlike patients in previous studies. Consequently, biological differences in the induced immune response may exist. This is particularly relevant in moderately immunogenic phenotypes such as pMMR tumors, but less so in highly immunogenic tumors such as dMMR. Furthermore, endometrial carcinoma is a highly heterogeneous disease characterized by mutations that differ between early and advanced stages, potentially influencing immune responses. In addition, research has shown that pMMR endometrial carcinoma is highly heterogeneous, whereas dMMR endometrial carcinoma appears less so. The latter generally seems to be associated with a poorer prognosis, making the impact of pembrolizumab more difficult to demonstrate.
The safety profile was consistent with the known profiles of the individual agents. The addition of pembrolizumab did not exacerbate chemotherapy-related adverse events.
Adding pembrolizumab to adjuvant chemotherapy did not improve disease-free survival. However, subgroup analyses suggest that pembrolizumab may provide a clinically meaningful benefit in disease-free survival among dMMR patients in the curative setting.