CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
ABIM MOC: maximum of 1.00 Medical Knowledge MOC point
Released: October 23, 2023
Expiration: October 22, 2024
Endometrial Cancer Overview
Endometrial cancer is the most common gynecologic malignancy in the United States and other developed nations.1 Unlike most other cancers, the incidence of endometrial cancer is steadily increasing by approximately 1% per year.2
The median age at diagnosis is 63 years, and most patients are diagnosed with early-stage disease.1,3 The prognosis for early-stage endometrial cancer is excellent, with a 5-year overall survival rate ranging from 74% to 91%, although this rate drops dramatically to 20% to 26% for those with metastatic disease.2,4 Until recently, treatment options have been limited for patients with advanced or recurrent disease, and this setting remains an area of active drug development.
TCGA Molecular Classification and Outcomes
Endometrial cancer used to be classified into 2 histologic subtypes: endometrioid (type 1) and nonendometrioid (type 2).5 However, molecular classification data from The Cancer Genome Atlas (TCGA) project in 2013 demonstrated that endometrial cancer is a heterogeneous disease with 4 clinically important molecular subtypes conferring different prognoses.
• POLE ultramutated
• Microsatellite instability–high (MSI-H)
• Copy number low
• Copy number high
Patients with POLE-ultramutated tumors have the best prognosis, followed by those with copy number–low disease, MSI-H disease, and, lastly, copy number–high disease.6
Immune Checkpoint Inhibition: Mechanism of Action
A growing body of evidence suggests that endometrial cancer may be particularly amenable to immunotherapy with immune checkpoint inhibitors (ICIs). Before we discuss that evidence, we will quickly review the mechanism of action for ICIs, with a particular focus on those targeting the PD-1/PD-L1 axis.
In brief, the PD-1/PD-L1 regulatory system attenuates T-cell activity, especially in nonlymphoid—“periphery”—tissues.7 In healthy tissue, this system helps minimize damage from the immune response. However, cancer cells can co-opt this regulatory system by expressing the ligand, PD-L1, which then interacts with the PD-1 receptor expressed on T-cells. This PD-L1/PD-1 interaction negatively regulates T-cell activity, allowing the cancer cells to evade immunosurveillance.
Some ICIs—such as the monoclonal antibodies dostarlimab and pembrolizumab—disrupt the ability of cancer cells to evade immunosurveillance by blocking PD-1, thus restoring the immune system’s ability to recognize and attack cancer cells. Other ICIs block PD-L1 or additional molecules involved in regulating T-cells, such as CTLA-4, LAG3, and TIM3.
Rationale for Using ICIs in Endometrial Cancer
Why is endometrial cancer particularly suitable for immunotherapy with ICIs?
First, the endometrial tumor microenvironment has high levels of PD-L1 and PD-1. Immunohistochemistry studies report that 25% to 100% of endometrial cancers express PD-L1.8,9 PD-1 expression on intraepithelial lymphocytes also was observed on 75% of endometrial cancers.
Second, many endometrial cancers have high levels of immunogenic, tumor-specific neoantigens.5,10 These neoantigens reflect the extensive tumor mutational burden (TMB) present in endometrial cancers that accumulate DNA errors due to either a pathogenic mutation in POLE—which encodes the catalytic subunit of a DNA polymerase important to DNA repair and replication—or mismatch repair deficiency (dMMR). Approximately 5% of patients with endometrial cancer have a POLE mutation, and 25% have dMMR.6 Defects in MMR proteins result in MSI H tumors.11-14 Many of these POLE-ultramutated and dMMR endometrial cancers also have large numbers of tumor infiltrating lymphocytes.
Taken together, these are characteristics of an immunologically “hot” tumor that is amenable to immunotherapy stimulating an antitumor immune response.
High Prevalence of Somatic Mutations in Endometrial Cancer
As I just mentioned, endometrial cancers exhibit high levels of TMB. It is helpful to understand how the extent of somatic mutations in this disease compares with other cancers, especially those—like melanoma—where ICIs have demonstrated overall survival benefit.15
The graph shown here presents data on the median number of somatic mutations (horizontal red lines) across difference cancer types, including cancers of the uterus.16 You can see that uterine cancer has a very high somatic mutation load compared with other gynecologic cancers, although not quite as high as melanoma on the far right.
ICIs in Current Management of Advanced Endometrial Cancer
This schematic provides a nice overview of the management options for endometrial cancer that is newly diagnosed in the early through advanced stages, as well as first- and later line treatment of advanced or recurrent disease. The red boxes highlight where ICI-based regimens are standard options for management.
Please see my other module for a focused review of current standard-of-care management of advanced or recurrent endometrial cancer.
Assessment
Novel Immunotherapy Approaches Under Investigation
Moving on, now we will discuss the rationales for several promising immunotherapy-based approaches under investigation in endometrial cancer. For a more extensive discussion of these and other emerging therapies in endometrial cancer, please see this module from my colleague, Hye Sook Chon, MD.
Rationale for Combining ICIs and PARP Inhibition
One strategy under active clinical investigation is combining ICIs with PARP inhibitors. Recall that PARP inhibitors prevent the PARP enzymes from repairing single-strand breaks in the DNA of cancer cells and that cancer cells with a BRCA1/2 mutation or other homologous recombination repair deficiency are particularly sensitive to PARP inhibition.17 Of interest, PARP inhibitors exhibit some activity in cancers that are BRCA wild-type or homologous recombination repair proficient.
By inhibiting DNA repair, PARP inhibition can increase the mutational burden and thus the neoantigen load of cancer cells.18 PARP inhibition also can increase the amount of cytosolic DNA present, thereby upregulating interferon pathways and PD L1 expression. Preclinical data suggest that PARP inhibition and immune checkpoint inhibition can act synergistically against tumors.
Rationale for Combining ICIs and Anti-VEGF Agents
Another strategy consists of combining ICIs with antiangiogenic agents. This combination already has demonstrated activity and been approved in endometrial cancer. Specifically, the combination of the ICI pembrolizumab with the antiangiogenic agent lenvatinib received regular FDA approval in 2021 for treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient/not MSI-H who had progression following any prior systemic therapy and who are not candidates for curative treatment.19 That said, multiple clinical trials are evaluating this combination in earlier settings or different combinations of ICIs and anti-VEGF agents.
Why combine these 2 drug classes? First, anti-VEGF agents can downregulate VEGF-mediated immunosuppression. Second, anti-VEGF agents can help normalize the microenvironment, thereby enabling activated T-cells to reach the cancer cells.20
Select Ongoing Trials Investigating ICIs Plus PARP Inhibitors and/or VEGF Inhibitors
This table lists some of the ongoing trials investigating ICIs combined with PARP inhibitors and/or antiangiogenic agents.
As I mentioned earlier, the combination of pembrolizumab/lenvatinib is under investigation in the frontline setting in the phase III LEAP-001/ENGOT-EN9 trial (NCT03884101).
In July 2023, results from the initial part of the phase III RUBY trial led to approval of dostarlimab in combination with carboplatin/paclitaxel for treatment of primary advanced or recurrent endometrial cancer that is dMMR/MSI-H.21 RUBY part 2 is comparing dostarlimab plus carboplatin/paclitaxel followed by maintenance with dostarlimab plus niraparib vs placebo plus carboplatin/paclitaxel followed by maintenance placebo in patients with recurrent or advanced endometrial cancer (NCT03981796).22
Combining ICIs With Therapies Targeting FGFR or IDO1
Clinical trials also are investigating combining ICIs with other targeted therapies. One such approach involves combining ICIs with agents that target the FGFR family, which is involved in cell proliferation and angiogenesis.23 Genetic alterations to FGFR1-4 act as oncogenic drivers, and TCGA data indicate that 12.5% of endometrial cancers harbor an FGFR2 alteration. Preclinical data suggest that inhibiting aberrant FGFR reduces cell proliferation and promotes cell death.
A phase II study is evaluating futibatinib, an irreversible inhibitor of FGFR1-4, in combination with pembrolizumab in patients with microsatellite stable metastatic endometrial carcinoma (NCT05036681). Futibatinib received accelerated approval in September 2022 for treatment of intrahepatic cholangiocarcinoma harboring a gene fusion or other rearrangement in FGFR2.24
A second approach involves combining ICIs with agents that target IDO1, which converts tryptophan into kynurenine, a metabolite with immunosuppressive effects.12,25 Decreased levels of tryptophan and increased expression of IDO1 correlate with upregulated PD-L1 expression and an increased number of immunosuppressive cells, including regulatory T-cells and myeloid derived suppressor cells, along with decreased numbers of tumor infiltrated lymphocytes and natural killer cells.
IDO1 is overexpressed in endometrial cancer, especially dMMR tumors. Data from other malignancies suggest that high levels of IDO1 expression and higher ratios of kynurenine:tryptophan correlate with resistance to ICIs.26 Of interest, preclinical data suggest that IDO1 inhibition is not active by itself but acts synergistically when combined with ICIs to augment tumor immunosurveillance and improve survival.
POD1IUM-204, a phase II umbrella trial, is evaluating the anti–PD-1 ICI retifanlimab in combination with other therapies in patients with advanced endometrial cancer that progressed on or after platinum-based chemotherapy (NCT04463771). The trial is recruiting patients with and without prior ICI exposure to evaluate treatment with retifanlimab plus epacadostat, an investigational IDO1 inhibitor, or with retifanlimab plus pemigatinib, an FGFR1-3 inhibitor already approved for FGFR2 fusion–positive cholangiocarcinoma or FGFR1-rearranged myeloid/lymphoid neoplasms.27
Antibody–Drug Conjugates and Immune-Stimulating Antibody Conjugates in Endometrial Cancer
Moving away from ICIs, we will briefly look at a few other immunotherapies, starting with antibody–drug conjugates (ADCs) and immune stimulating antibody conjugates (ISACs).
ADCs are an important class of oncologic therapeutics that combine a tumor targeting antibody with a cell killing cytotoxic drug, also called the payload.28 ISACs consist of monoclonal antibodies and synthetic pattern recognition receptor ligands, which stimulate production of proinflammatory molecules.29
Potential targets of ADCs and ISACs in endometrial cancer include HER2, TROP-2, and folate receptor α (FRα). HER2 is overexpressed in 25% to 30% of serous endometrial cancers.30,31 At ASCO 2023, the phase II DESTINY-PanTumor02 trial reported a high overall response rate of 57.5% in a cohort of patients with endometrial cancer treated with the HER2-directed ADC trastuzumab deruxtecan.32 Also at ASCO 2023, a phase I/II trial reported that 1 of 10 patients with endometrial cancer had durable stable disease when treated with the HER2-directed ISAC BDC 1001.29
Regarding the other potential targets, TROP-2 is overexpressed in the vast majority (>95%) of endometrioid endometrial cancers.33 FRα is highly expressed in approximately 50% of endometrial cancers.34
Select Ongoing Trials Investigating ADCs and ISACs
This table lists a selection of ongoing trials of ADCs and ISACs in endometrial cancer, including the phase II DESTINY-PanTumor02 trial (NCT04482309) and the ongoing phase I/II trial evaluating BDC-1001 (NCT04278144) that I described earlier. Still other trials are evaluating TROP-2–directed ADCs, including datopotamab deruxtecan in the phase II TROPION-PanTumor03 trial (NCT05489211) and sacituzumab govitecan in a phase II trial (NCT04251416).
I am particularly curious to see results from the ongoing phase II trial (NCT03835819) evaluating pembrolizumab plus mirvetuximab sorevtansine. This FRα-directed ADC was granted accelerated FDA approval in November 2022 for the treatment of FRα-positive ovarian cancer.35
I have had patients on early-phase trials for ADCs, and although I have been struck by the excellent responses, the toxicities have been very challenging. Two of my patients died as a result of ADC-related interstitial lung disease after achieving complete responses. This experience underscores the importance of very close monitoring for signs and symptoms of interstitial lung disease because the deterioration is so rapid.
Rationales for Investigating Cancer Vaccines, Adoptive T-Cell Therapy, and Bispecific Antibodies in Endometrial Cancer
Lastly, we will look at the rationales for investigating cancer vaccines, adoptive T-cell therapy, and bispecific antibodies in endometrial cancer. The schematic shown here is a nice depiction of how these different approaches exert their anticancer effects.
Cancer Vaccines
Cancer vaccines can “educate” the immune system to better recognize and eliminate cancer cells or cells that could become cancerous. There are preventive cancer vaccines, such as those used to prevent infection with HPV, which causes several different cancers. There are also therapeutic vaccines, which are designed to spur the immune system into attacking cancer cells.12 Data from patients with early-stage melanoma suggest clinical benefit from the combination of adjuvant pembrolizumab and mRNA 4157, a personalized vaccine.36
Adoptive T-Cell Transfer
Adoptive T-cell transfer involves isolation and reinfusion of T-cells into patients to treat disease. This includes approaches such as engineered CAR T-cell therapy and CAR natural killer therapy, as well as therapies leveraging tumor infiltrating lymphocytes.37 CAR T-cell therapy is now part of the standard of care for multiple hematologic cancers, and there is ongoing interest in using this approach to treat solid tumors.38
Bispecific Antibodies
Bispecific antibodies target 2 epitopes on either the same or different antigens, which can be either on the same cell or on different cells (eg, a T-cell and a tumor cell).39 The FDA has approved multiple bispecific antibodies. Most of these are approved for treatment of hematologic malignancies, but 2 have been approved to treat melanoma or non-small-cell lung cancer with EGFR exon 20 insertions.
Select Ongoing Trials Investigating Cancer Vaccines, Adoptive T-Cell Transfer, and Bispecific Antibodies
These strategies are still in early stages of development in endometrial cancer, and I will highlight only a few examples from this table.
The phase I KEYNOTE-603 trial (NCT03313778) is assessing the safety and immunogenicity of the personalized mRNA-4157 vaccine alone and in combination with pembrolizumab in patients with dMMR, MSI-H, or TMB-high endometrial cancer.
A first-in-human phase I trial (NCT04660929) is evaluating CT-0508, a novel anti-HER2 CAR macrophage therapy, in patients with HER2-overexpresssing tumors.
A phase II trial (NCT05297903) is evaluating the efficacy of and safety of vudalimab (XmAb20717), a PD-1 x CTLA-4 bispecific antibody, in patients with microsatellite stable endometrial cancer.
When to Consider Clinical Trials for Patients With Endometrial Cancer
To conclude our discussion, I would like to share my perspective on when to consider clinical trials for patients with endometrial cancer.
It is important to discuss early in the treatment course what clinical trials are and the different types of clinical trials. Healthcare professionals should discuss this early because clinical trials want the healthiest patients and are very strict on whom they can include. If you wait until late in a patient’s disease course, when their health status has declined and they are heavily pretreated, then you may miss the window of opportunity to enroll the patient on a trial.
I also recommend discussing clinical trials as an option anytime a patient has progression on their current therapy. This does not mean that clinical trials are always the best option, but progression is an opportunity to explore what is available and may benefit the patient. Now that ICIs have moved into standard of care for the frontline setting, we are losing an important treatment option in the recurrent setting. I anticipate that healthcare professionals will likely consider clinical trials earlier with this change in care.
Next-generation sequencing (NGS) is an important tool for helping to determine what therapeutic and clinical trial options may exist for a patient with advanced disease. Insurance companies do not always cover NGS, but the increasing commercialization of NGS platforms has decreased their cost and broadened payment options. For example, my institution works with a company that offers sliding-scale payment options.
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