Q&A: Promising treatment, diagnosis approaches for endometrial cancer
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Key takeaways:
- FDA drug approvals have led to significant advancement in endometrial cancer treatment.
- Stage and histology remain primary factors for guiding treatment decisions at the time of endometrial cancer diagnosis.
Despite the incidence of endometrial cancer diagnosis increasing annually, several promising approaches for treatment and diagnosis of endometrial cancer have been approved or are in development.
The FDA has approved anti-PD-1 antibodies, which include pembrolizumab (Keytruda; Merck), durvalumab (Imfinzi, AstraZeneca) and dostarlimab (Jemperli, GSK), as well as several others under development, for distinct immunotherapy and chemotherapies in endometrial cancer treatment.
Healio spoke with Jessica D. St. Laurent, MD, an endometrial cancer expert in the department of obstetrics and gynecology at Brigham and Women's Hospital, about ongoing trials, precision medicine and antibody-based therapeutics and how they will affect the future of endometrial cancer.
Healio: Have there been any exciting or important approvals in endometrial cancer?
St. Laurent: Recent months have marked a significant advancement in endometrial cancer treatment. Three new approvals, each offering distinct combinations of immunotherapy and chemotherapy, have reshaped the therapeutic landscape for recurrent or advanced (stage III/stage IV) endometrial carcinoma.
In June, the FDA approved pembrolizumab (anti-PD-1 antibody) 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 a significant improvement in PFS observed in the GY018 clinical trial.
Another June approval granted the combination of durvalumab (anti-PD-L1 antibody) with carboplatin, paclitaxel and durvalumab maintenance for patients with mismatch repair-deficient (dMMR) tumors. This approval was supported by improved PFS demonstrated in the DUO-E study.
Finally, in August, the regimen of carboplatin, paclitaxel and dostarlimab (anti-PD-1 antibody) followed by dostarlimab maintenance was approved for patients with dMMR endometrial carcinoma based on improvements in both PFS and OS.
Collectively, 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.
Healio: Are there any therapies that will be coming through the pipeline?
St. Laurent: In addition to the recent phase III trials including PD-1/L1 approvals, several promising approaches for endometrial cancer are under development. Related trials have explored the combination of poly(ADP)-ribose polymerase (PARP) inhibitors with chemotherapy and PD-1/L1 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 a 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.
Healio: Are there treatment gaps?
St. Laurent: Despite the recent approvals and promising new therapeutics, the incidence of endometrial cancer continues to rise annually, and we lack effective early detection strategies. 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.
Healio: What does the future of treatment in endometrial cancer look like?
St. Laurent: We are increasingly incorporating individual patient molecular characteristics into our 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. 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.
Healio: What is the role of precision medicine?
St. Laurent: The molecular features described above are a starting point for personalized medicine for endometrial cancer. Right now, MMR testing is the most important clinically utilized molecular endometrial cancer feature for personalizing treatment. As we use the TCGA categories and other molecular features to select treatments in clinical trials, I anticipate these will be widely used in clinical practice.
Healio: How does stage and histology impact treatment?
St. Laurent: In the initial years following the publication of studies highlighting differences in survival and presentation of endometrial cancer based on molecular features, it appeared that these features might be more predictive of patient outcomes than stage, histology and tumor grade. However, larger studies have demonstrated that while molecular features are important to consider, they may not completely replace traditional factors like stage and histology.
Currently, in clinical practice, with the exception of determining the eligibility for immunotherapy, stage and histology remain the primary factors used to guide treatment decisions at the time of endometrial cancer diagnosis.
Healio: Do any fertility preservation options exist for patients with endometrial cancer?
St. Laurent: For patients with early stage, grade I endometrial carcinoma, uterine preservation can be an option. We utilize progesterone via intrauterine device or orally under the direction of a gynecologic oncologist. Patients are advised that they will need completion surgery with hysterectomy after the completion of childbearing.
Healio: How do you approach recurrent disease?
St. Laurent: For patients with recurrent endometrial carcinoma, I prefer to have all available information when discussing treatment options. This includes recent imaging studies, such as CT chest/abdomen/pelvis or a PET-CT, depending on the clinical situation. Additionally, I value a recent biopsy and targeted next-generation sequencing to assess MMR immunohistochemistry, estrogen/progesterone receptor testing, and HER2 status. Based on this comprehensive information, we can consider appropriate treatment options. If patients have multiple sites of disease and have not received prior systemic treatment, I often initiate chemotherapy in combination with PD-1 or PD-L1 blockade.
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