Recent advancements in immunotherapy and precision medicine are reshaping the treatment landscape for endometrial cancer, offering new hope for patients with advanced disease. The FDA has recently approved several immunotherapy combinations that have demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS). These approvals, along with ongoing research into novel therapeutic approaches, are paving the way for more personalized and effective treatments.
Immunotherapy Combinations Show Promise
In June, the FDA approved pembrolizumab (Keytruda; Merck) in combination with carboplatin and paclitaxel, followed by pembrolizumab maintenance, for patients with recurrent or advanced endometrial carcinoma, regardless of mismatch repair (MMR) protein expression. This approval was based on the GY018 clinical trial, which demonstrated a significant improvement in PFS.
Also in June, durvalumab (Imfinzi, AstraZeneca) combined with carboplatin, paclitaxel, and durvalumab maintenance was approved for patients with mismatch repair-deficient (dMMR) tumors. The DUO-E study supported this approval, showcasing improved PFS.
August saw the approval of carboplatin, paclitaxel, and dostarlimab (Jemperli, GSK) followed by dostarlimab maintenance for patients with dMMR endometrial carcinoma, based on improvements in both PFS and OS.
According to Jessica D. St. Laurent, MD, an endometrial cancer expert at Brigham and Women's Hospital, these studies provide compelling evidence that blocking the PD-1/PD-L1 axis, particularly in patients with dMMR endometrial cancer, is a promising therapeutic approach.
Novel Therapies in Development
Beyond the recent PD-1/L1 approvals, several other approaches are under development. Trials are exploring the combination of poly(ADP)-ribose polymerase (PARP) inhibitors with chemotherapy and PD-1/L1 inhibitors for recurrent and advanced-stage endometrial cancer. Further studies are necessary to identify the patients who may benefit most from incorporating PARP inhibitors into their treatment regimens.
CDK 4/6 inhibitors in combination with aromatase inhibition is a National Comprehensive Cancer Network-listed regimen that has shown promise in phase 2 trials. Head-to-head comparisons with other endocrine therapies for estrogen and progesterone receptor-positive endometrial carcinoma will be crucial to determine its optimal use.
Antibody-drug conjugates (ADCs) are another promising class of antibody-based therapeutics. Several ongoing studies targeting HER2, folate receptor alpha and other targets have demonstrated significant responses in patients with endometrial cancer. Ongoing trials will be essential to understand the magnitude of benefit and the correct sequence to incorporate this class of therapeutic.
The Role of Precision Medicine
Molecular features are increasingly incorporated into treatment decision-making. NCCN and International Federation of Gynecology and Obstetrics (FIGO) guidelines now recommend a panel of molecular tests at the time of endometrial cancer diagnosis for all histologies and stages of endometrial carcinoma to determine which of four prognostic molecular categories (TCGA categories) an endometrial cancer belongs to at the time of diagnosis. These tests are already being utilized to stratify and predict outcomes in ongoing clinical trials. MMR testing is the most important clinically utilized molecular endometrial cancer feature for personalizing treatment.
Unmet Needs and Future Directions
Despite the recent approvals and promising new therapeutics, the incidence of endometrial cancer continues to rise annually, and effective early detection strategies are lacking. Moreover, there are still critical aspects of endometrial cancer biology that remain elusive; the more we learn about the basic biology, the more we can tailor treatment. Particularly in the setting of endometrial cancer treatment regimens including immunotherapy, a lot of work remains to understand which patients without dMMR will benefit from immunotherapy versus alternative treatments. Within the next 10 years, we will have significantly more molecularly tailored treatment approaches for all patients with endometrial cancer and more refined molecular markers.
