The endometrial cancer treatment landscape is experiencing significant evolution, particularly in the management of mismatch repair-proficient (pMMR) disease, following successful implementation of immunotherapy in mismatch repair-deficient (dMMR) cases.
"An interesting area of research is pMMR endometrial cancer—how do we stratify some of these patients [by] looking at subgroup analyses and figuring out the best strategies?" notes Dr. Ritu Salani, director of gynecologic oncology at UCLA Health.
Immunotherapy Success in dMMR Disease
The treatment paradigm for dMMR endometrial cancer has been firmly established with immunotherapy. Dostarlimab (Jemperli) received two significant approvals in 2023: as monotherapy for recurrent or advanced disease after platinum-based therapy, and in combination with carboplatin and paclitaxel for primary advanced or recurrent dMMR/MSI-H disease.
Clinical data has been compelling, with dostarlimab plus chemotherapy reducing disease progression or death risk by 72% compared to chemotherapy alone in dMMR patients. The GARNET trial demonstrated a 45.4% objective response rate with dostarlimab monotherapy, with over half of responding patients maintaining responses for at least 24 months.
Emerging Strategies for pMMR Disease
For pMMR disease, recent developments have shown promise. The combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) demonstrated improved overall survival with a hazard ratio of 0.70 in advanced disease. The median progression-free survival reached 6.7 months versus 3.8 months with standard chemotherapy.
The phase 3 RUBY trial recently reported that dostarlimab plus chemotherapy followed by dostarlimab/niraparib maintenance significantly improved progression-free survival in pMMR patients compared to chemotherapy alone.
Biomarker-Driven Approaches
Researchers are increasingly recognizing pMMR disease as heterogeneous, requiring more nuanced treatment approaches. Dr. Salani emphasizes the importance of additional biomarkers:
"Looking at the p53 mutation type and particularly HER2, and examining the role of trastuzumab or antibody-drug conjugates like trastuzumab deruxtecan is very interesting," she explains. "There may also be other markers such as TROP2 and FRα."
The SIENDO trial demonstrated promising results for selinexor maintenance therapy in TP53 wild-type disease, with median progression-free survival reaching 27.4 months compared to 5.2 months with placebo.
Future Directions
Multiple clinical trials are exploring novel combinations, including mirvetuximab soravtansine with pembrolizumab in FRα-positive relapsed serous endometrial cancer, and trastuzumab deruxtecan with olaparib in solid tumors.
"We need to continue to improve care for patients if they have disease recurrence," Dr. Salani emphasizes, highlighting the ongoing need for research into optimal treatment sequencing and novel therapeutic approaches for this challenging disease.
