Pharmacological Treatment of Advanced, Persistent or Metastatic Endometrial Cancer: State of the Art and Perspectives of Clinical Research for the Special Issue “Diagnosis and Management of Endometrial Cancer”

Abstract

Patients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment frequently with unsatisfactory clinical outcomes. The purpose of this paper was to review the results obtained with chemotherapy, hormonal therapy, biological agents and immune checkpoint inhibitors in this clinical setting. The combination of carboplatin (CBDCA) + paclitaxel (PTX) is the standard first-line chemotherapy capable of achieving objective response rates (ORRs) of 43–62%, a median progression-free survival (PFS) of 5.3–15 months and a median overall survival (OS) of 13.2–37.0 months, respectively, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with m-TOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Disappointing ORRs have been associated with epidermal growth factor receptor (EGFR) inhibitors, HER-2 inhibitors and multi-tyrosine kinase inhibitors used as single agents, and clinical trials evaluating the addition of bevacizumab to CBDCA + PTX have reported conflicting results. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient (-d) EC. In a recent study, the combination of lenvatinib + pembrolizumab produced a 24-week response rate of 38% in patients with highly pretreated EC, ranging from 64% in patients with MSI-H/MMR-d to 36% in those with microsatellite stable/MMR-proficient tumors. Four trials are currently investigating the addition of immune checkpoint inhibitors to PTX + CBDCA in primary advanced or recurrent EC, and two trials are comparing pembrolizumab + lenvatinib versus either CBDCA + PTX as a first-line treatment of advanced or recurrent EC or versus single-agent chemotherapy in advanced, recurrent or metastatic EC after one prior platinum-based chemotherapy.

Trabectedin and lurbinectedin: Mechanisms of action, clinical impact, and future perspectives in uterine and soft tissue sarcoma, ovarian carcinoma, and endometrial carcinoma

“…Transient severe anemia, neutropenia, and thrombocytopenia occurred in 31.6%, 78.9%, and 15.8%, of the patients, respectively. These results compared favorably with those previously observed with several drugs tested in the second-line setting and were similar to those reported with the combination of lenvatinib + pembrolizumab ( 80 , 81 ). In fact, DOX 40 mg/m 2 + lurbinectedin 2.0 mg and lenvatinib 20 mg daily + pembrolizumab 200 mg q3wk achieved the objective response rates of 42.1% and 38.3%, respectively ( 31 , 82 )…”

Integrated multi-omics analyses and functional validation reveal TTK as a novel EMT activator for endometrial cancer

“…ECs represent very serious health challenges, and new biomarkers are required to allow for early detection, as well as new approaches to improve the sensitivity of chemotherapeutic agents, which could significantly enhance the opportunities for successful cancer treatment and favor a higher chance of cure, survival, and quality of life for patients [ 3 ]. Increasing evidence suggests that CTAs play a crucial role in tumorigenesis and progression.…”

“…Current standard first-line chemotherapy for EC relies heavily on the combination of carboplatin and paclitaxel. It can achieve remission ratios of 43–62% [ 3 ], which implies that 40–60% of individuals continue to demonstrate chemoresistance, significantly decreasing their survival. Resistance to chemotherapeutic medicines necessitates the development of novel methods for enhancing their sensitivity.…”

Effectiveness and safety of PD-1/PD-L1 inhibitors in advanced or recurrent endometrial cancer: a systematic review and meta-analysis

“…Treatment of advanced or recurrent endometrial cancer is unsatisfactory and options are limited (Brooks et al, 2019). At present, the conservative treatment of advanced or recurrent endometrial cancer is hormone therapy and paclitaxel plus carboplatin chemotherapy, and the response rate is low (Gadducci and Cosio, 2021). Therefore, identifying new treatments to address advanced or recurrent endometrial cancer has become important.…”