Targeted Treatment of Advanced Endometrial Cancer: Focus on Pembrolizumab

Abstract

Endometrial cancer (EC) accounts for 2% of all new cancers. Advanced forms have a poor prognosis with barely 17% 5-year survival. The last few years improved our knowledge of EC with a new molecular classification derived from The Cancer Genome Atlas (TCGA). They are now divided between POLE mutant, Microsatellite Instability High (MSI-H) or deficient in Mismatch Repair System (dMMR), TP53 mutant and no specific molecular profile. Until now, treatments for advanced EC have included conventional platinum-based chemotherapy or hormonotherapy. The revolution in oncology represented by the advent of immune checkpoints inhibitors (ICI) has also led to a major advance in the management of recurrent and metastatic EC. Pembrolizumab, a well-known anti PD-1, has firstly been approved as monotherapy in the second-line setting for dMMR/MSI-H advanced EC. More recently, a combination of lenvatinib with pembrolizumab offered a new effective option in the second line setting irrespectively of the MMR status, giving a new opportunity for these patients who had no actual standard of care before. This combination is currently being evaluated as frontline therapy. Despite exciting results, the main problem in identifying solid biomarkers remains unresolved and further investigations are required. New original combinations of pembrolizumab with other drugs including chemotherapy, poly ADPribose polymerase inhibitors (PARP-i) or tyrosine kinase inhibitors are being tested and promise exciting new therapeutic evolutions in a close future.

Keywords: endometrial cancer; immunotherapy; pembrolizumab; precision medicine.

Figure 1

Molecular classification of EC based on the ProMisE molecular classifier by Kommos et al. This classification is based on several successive biomarker investigations. First, ECs are categorized between MMR proficient and MMR deficient tumors. 25–30% belong to the latter. When pMMR, POLE mutations need to be searched through NGS or PCR. Between 10 and 15% of ECs belong to the POLE mutated subgroup. If samples are pMMR and do not harbor POLE mutations, IHC for p53 allows the distinction between p53-mut group (5–15%) and NSMP group (30–40%).

Figure 2

Schematic of the Leiden molecular classification. All molecular markers are determined for each sample at the same time and not in a stepwise fashion. If a sample present with multiple alterations, it is considered unclassifiable.

Figure 3

Systemic treatment strategies for advanced/metastatic endometrial cancers.