For patients with high-risk endometrial cancer, multimodality treatment is typically recommended. Hormone therapy, targeted therapy, and immunotherapy approaches have been utilized in clinical practice. In this interview, ONCOLOGY spoke with Vicky Makker, MD, a medical oncologist who treats patients with gynecologic cancers, including cervical, ovarian, and uterine tumors, about these options, as well as emerging combination therapies that are currently being evaluated in clinical trials.
Q: What is the current standard of care for the treatment of advanced endometrial cancers?
DR. MAKKER: Endometrial cancer is the most common gynecologic cancer in the United States. Alarmingly, the incidence and mortality of this malignancy continue to rise due to several factors. Chief among them is obesity. The National Cancer Institute estimates that more than 63,000 new cases of endometrial cancer and 11,000 related deaths occurred in 2018. Endometrial cancer is usually diagnosed in postmenopausal women. The average age at diagnosis is 62 years, and most women have an early stage of cancer that is confined to the uterus. However, approximately 21% of women have regional spread to pelvic lymph nodes or the surrounding organs, and roughly 9% have distant metastases at the time of diagnosis. The prognosis of endometrial cancer is primarily determined by the stage and histology of the tumor, as well as the presence of adverse risk factors such as lymphovascular invasion, high-grade histology, advanced patient age, and deep myometrial invasion.
The goal of adjuvant therapy in newly diagnosed endometrial cancer is to reduce the risk of disease recurrence and distant metastases, and treatment is guided by surgical stage, tumor histology, and the number of adverse risk factors. High-risk endometrial cancers include those with type II histologies: serous carcinoma, clear cell carcinoma, and carcinosarcoma, regardless of stage; grade 3 deeply invasive endometrial adenocarcinoma; and pathologic stage III or IV disease, regardless of histology. Due to their aggressive nature and the possibility of early metastases, multimodality treatment is typically recommended for high-risk endometrial cancer, even in the setting of early-stage disease.
For women with stage III or IV endometrial cancer that has been surgically resected, we offer chemotherapy with the addition of radiation therapy in appropriate cases. Women with unresectable stage III or IV cancer are largely treated with chemotherapy, and the role of radiotherapy should be individualized based on tumor burden and location of the tumor. Multiagent chemotherapy regimens are considered for patients who require chemotherapy, including carboplatin and paclitaxel; cisplatin with doxorubicin; cisplatin with doxorubicin and paclitaxel; carboplatin and docetaxel; carboplatin, paclitaxel, and bevacizumab; or carboplatin, paclitaxel, and trastuzumab. In most cases, the preferred regimen is carboplatin and paclitaxel; this recommendation is based on the results of the phase III Gynecologic Oncology Group (GOG) 209 trial of paclitaxel and carboplatin vs a three-drug regimen of doxorubicin, cisplatin, and paclitaxel, which found that paclitaxel and carboplatin were noninferior to doxorubicin, cisplatin, and paclitaxel with regards to progression-free and overall survival.
According to The Cancer Genome Atlas Project (TCGA), approximately 25% of serous or serous-like endometrial cancers display human epidermal growth factor receptor 2 (HER2) amplification. A phase II trial of paclitaxel and carboplatin vs paclitaxel, carboplatin, and trastuzumab in stage III/IV or advanced HER2-overexpressing uterine cancers found that the triple combination regimen was associated with an improved median progression-free survival compared with carboplatin and paclitaxel (8 vs 12.6 months); therefore, it can be considered for HER2-amplified serous carcinomas or serous-like carcinomas that are advanced or recurrent. Alternatively, combination carboplatin, paclitaxel, and bevacizumab can also be considered in patients with advanced or recurrent disease. In the randomized phase III GOG-86P trial, bevacizumab combined with carboplatin and paclitaxel chemotherapy in advanced chemotherapy-naive patients resulted in an objective response rate of 59.5%, with a significant improvement in overall survival compared with the historic reference of paclitaxel and carboplatin and the other arms in the trial. If patients cannot receive multiagent chemotherapy or have contraindications to it, single therapy options exist, including carboplatin, cisplatin, docetaxel, doxorubicin, paclitaxel, and topotecan. When single agents are utilized in the first-line setting, responses range from 21% to 36%; in the second-line setting, however, responses fall sharply to between 4% and 27%.
That covers chemotherapy, but there are also other options for the treatment of advanced endometrial cancers. Hormone therapy is one such method, and has been mainly studied in the recurrent or metastatic setting. Responses are generally best in low-grade, well-differentiated endometrioid tumors that often overexpress estrogen or progesterone receptors. There are a myriad of hormonal therapy approaches that have been investigated in small phase II trials, with response rates ranging from 10% to 33% and a median progression-free survival ranging from 1 to 10 months.[6-12] The highest responses are seen with tamoxifen alternating with progestational agents.[10,11] Currently, only megestrol acetate is approved by the US Food and Drug Administration (FDA) for the palliative treatment of advanced endometrial cancers. Other agents that can be utilized include tamoxifen, luteinizing hormone-releasing hormone agonists, and aromatase inhibitors.
Additionally, several classes of targeted therapies have been explored in advanced endometrial cancers. These include agents that target the phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways, as well as angiogenesis inhibitors, epidermal growth factor receptor inhibitors, mitogen-activated protein kinase inhibitors, and HER2-targeting antibodies. However, only a limited benefit has been seen with these agents thus far. Based on preliminary favorable findings for endometrioid histologies, the combination of letrozole, an aromatase inhibitor, and everolimus, an mTOR inhibitor, can be used in advanced, recurrent endometrioid subtype tumors. Bevacizumab, a vascular endothelial growth factor antibody, was evaluated in a phase II monotherapy trial in advanced endometrial cancer and demonstrated a response rate of 14.3%, with 40% of patients being progression free at 6 months. This agent is often used in patients with advanced endometrial cancers.
Finally, we have pembrolizumab, a humanized monoclonal antibody that targets programmed death 1 (PD-1). In 2017, the FDA granted the first tissue/site–agnostic, accelerated approval for pembrolizumab in adult and pediatric patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient solid tumors that have progressed following prior treatment.
Q: The results of the GARNET phase I/II trial on dostarlimab (TSR-042) for endometrial cancer were recently presented at the 2019 Society of Gynecologic Oncology (SGO) Annual Meeting in March. What were the key results, and how do you interpret the findings?
DR. MAKKER: Dostarlimab, or TSR-042, is an investigational anti–PD-1 monoclonal antibody that blocks the PD-1 receptor, preventing ligand binding. The GARNET study—a phase I, multicenter, first-in-human, dose-escalation study with an expansion cohort—assessed the safety and clinical activity of dostarlimab in patients with solid tumors. Participants received 500 mg every 3 weeks for 4 doses, then were titrated up to 1,000 mg every 6 weeks until disease progression occurred. Results from two expansion cohorts were reported: patients with MSI-H endometrial cancer (n = 65) and patients with microsatellite-stable (MSS) endometrial cancer (n = 125). The primary objectives were overall response rate and duration of response, as well as safety and tolerability. Patients with recurrent or advanced endometrial cancers who had progressed after a platinum-containing regimen and had not received prior anti–PD-1 or anti–programmed death ligand 1 therapy were enrolled. Most patients (56%) had received 1 prior line of therapy, while 29% received 2 prior lines, and approximately 15% received ≥ 3 prior lines of therapy.
Seventy percent of patients experienced a treatment-emergent adverse event. The most common all-grade treatment-emergent adverse events that occurred in ≥ 10% of patients included fatigue, diarrhea, and nausea. Only 5.6% of patients had a grade 3 or higher immune-related treatment-emergent adverse event (eg, hyperglycemia, elevated liver function, autoimmune hemolytic anemia, colitis, or an infusion-related reaction). The objective response rate was 49% in the MSI-H patients and 20% in the MSS patients. The responses were durable, and 84% of responders were still on treatment when the results were presented. The median duration of response had not been reached at that time, and the median follow-up was 10 months.
These results are encouraging, and we need to follow along as this study matures. Further investigation of dostarlimab in the front-line setting is planned in combination with chemotherapy later in 2019 (ClinicalTrials.gov identifier: NCT02715284). Overall, though, the findings are consistent with what we have seen from checkpoint inhibitors in the MSI-H patient population. The overall response rate was higher in the MSS population than has been reported with other agents, but this may stem from histologic and molecular phenotypic differences in patient populations across studies.
1. National Institutes of Health—National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Cancer stat facts: uterine cancer. https://seer.cancer.gov/statfacts/html/corp.html. Accessed April 10, 2019.
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3. Cancer Genome Atlas Research Network, Kadoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67-73.
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14. U.S. Food & Drug Administration. FDA approves first cancer treatment for any solid tumor with a specific genetic feature. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm560167.htm. Published May 23, 2017. Accessed April 11, 2019.
15. Oaknin A, Duska LR, Sullivan RJ, et al. Preliminary safety, efficacy, and pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-H and MSS endometrial cancer. Presented at the 50th Annual Meeting of the Society of Gynecologic Oncology; March 19, 2019; Honolulu, HI.
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