Current Evidence-Based Systemic Therapy for Advanced and Recurrent Endometrial Cancer

Abstract

Endometrial cancer (EC) is the most common gynecologic malignancy, with worldwide rising incidence and disease-associated mortality. While most patients with EC are diagnosed with early-stage disease, systemic treatment options for patients with advanced or recurrent EC have historically been limited. EC-focused clinical trials and the ensuing therapeutic landscape have expanded since The Cancer Genome Atlas (TCGA) identified four distinct EC subgroups associated with differential survival. This endeavor revolutionized our understanding of the genomic characterization of EC as well as molecular drivers of this heterogeneous malignancy, leading to precision oncology approaches to therapeutics and advancement in treatment options. This manuscript describes the current status of and recent advancements in therapeutic options for patients with advanced and recurrent EC. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Uterine Neoplasms Version 1.2022 provides detailed recommendations regarding the diagnosis, work-up, and management of EC.

Introduction

Endometrial cancer (EC) is the most common gynecologic cancer in high-income countries, with the highest incidence in North America. (1) Worldwide, the overall incidence has increased by over 130% in the last 30 years, and disease-associated mortality in the US is rising 2.5% annually on average. (2, 3) The worsening mortality rate is pronounced among Black women, for reasons including decreased healthcare access, treatment disparities, and molecular tumor differences. (4, 5)

Obesity, a strong risk factor for EC, accounts for approximately 50% of cases in Europe and the US. (6) Obesity may contribute to EC pathogenesis through insulin resistance and abnormalities of insulin growth factor 1 signaling, resulting in increased cell proliferation, chronic low-grade inflammation, alterations in adipokine physiology, and cellular and vascular perturbations that promote oncogenesis. (7) Excess endogenous or exogenous estrogen exposure from early menarche, late menopause, or tamoxifen exposure also increase EC risk. Individuals with Lynch syndrome and Cowden syndrome have genetic increased risk of EC, and there is emerging data indicating a potential role for BRCA1/2 germline pathogenic variants in the development of high-grade EC. (8, 9)

Recent studies have highlighted the molecular underpinnings of EC and associated outcomes. (10, 11) The Cancer Genome Atlas (TCGA) Research Network has identified the following four widely accepted molecular EC subtypes: POLE ultra-mutated, mismatch repair (MMR)-deficient (MMRd), copy-number low, and copy-number high (CN-H). (10, 11) Each molecular subtype has its own prognostic significance, with the POLE subtype associated with the best and the CN-H subtype with the poorest survival. (12) While histology and stage are currently used to stratify patients for treatment and to predict outcomes, recent studies have found considerable histologic diversity within EC subtypes, underscoring the importance of the molecular classification of all EC tumors. (12) Molecular subtyping has informed significant therapeutic advancements in advanced/recurrent EC, as outlined in this review, and has been increasingly exploited for risk stratification for optimal personalized treatment. The largest cohort of patients with endometrial cancer who have undergone complete molecular characterization was recently presented by investigators at Memorial Sloan Kettering Cancer Center (Figure 1). Although these patients were treated at a specialized referral center and are disproportionately at higher risk than the general endometrial cancer population, Figure 1 depicts the heterogeneity of patients with endometrial cancer.

Figure 1. Endometrial cancer molecular subtypes and histologies.

Molecular subtyping of 1906 endometrial cancers at Memorial Sloan Kettering Cancer Center. All four molecular subtypes consist of varying proportions of endometrial cancer histologies. Results presented at the Society for Gynecologic Oncology Annual Meeting, 2022, by Rios-Doria et al., Phoenix, AZ. (12)

These results are preliminary and will be published in finalized form.

CN-H: copy-number high; CN-L: copy-number low; Dediff.: dedifferentiated; Endo.: endometrioid; FIGO: International Federation of Obstetrics and Gynecology; G1: grade 1; G2: grade 2; G3: grade 3; MSI-H: microsatellite instability high; POLE: polymerase epsilon hypermutated; Undiff.: undifferentiated.

While most patients with EC present with early-stage disease and have favorable prognoses, patients with stage III and IV disease have 5-year survival rates of 48% and 15%, respectively. (1) At diagnosis, approximately 20-30% of ECs are considered high risk based on traditional prognostic factors, including stage, histology, myometrial invasion, and lymphovascular invasion, and are associated with recurrence rates of up to 30%. Systemic therapy for advanced/recurrent EC is the cornerstone of treatment. In this review, we will discuss evidence-based therapeutic options for advanced/recurrent EC and review ongoing investigational therapies that may impact the future treatment landscape. Systemic treatment in advanced/recurrent EC remains palliative; therefore, patient quality of life must be prioritized within the shared decision-making process.

First-line (1L) therapy of newly diagnosed advanced EC

The standard 1L therapy for newly diagnosed advanced/recurrent EC regardless of molecular subtype consists of carboplatin/paclitaxel (TC) chemotherapy with or without primary surgical cytoreduction. Key clinical trials assessing systemic therapy for advanced/recurrent EC are summarized in Table 1. TC was established as the standard 1L regimen based on findings from the phase III, randomized non-inferiority Gynecologic Oncology Group (GOG) 209 trial. TC demonstrated non-inferiority over adriamycin, cisplatin, and paclitaxel (TAP) in patients with stage III/IV or recurrent chemotherapy-naïve EC, with an overall survival (OS) of 37 months versus 41 months, respectively (90% CI: 0.9-1.12). TC was also associated with significantly fewer adverse events (AEs) (p<0.05). (13)

Table 1.

Key clinical trials assessing systemic therapy for advanced/recurrent endometrial cancer.

Trial	Key Inclusion Criteria	Treatment Arms	Endpoint(s)	Key Findings/Conclusion
First-line
GOG 122 PMID: 16330675 Enrollment: 05/1992-02/2000	-Stage III/IV endometrial carcinoma -No prior chemotherapy or radiotherapy -Complete surgical staging -No single site of residual tumor >2cm	Arm 1: Whole-abdominal irradiation (30 Gy in 20 fractions, with 15-Gy boost); n=202 Arm 2: Doxorubicin + cisplatin n=194	Primary -PFS Secondary -OS	-Arm 2 had improved PFS (HR 0.71; 95% CI 0.55-0.91) -Arm 2 had improved OS (HR 0.68; 95% CI 0.52-0.89) -Arm 2 had more grade 3/4 adverse events
GOG 163 PMID: 15277255 Enrollment: 08/12/1996-11/30/1998	-Stage III/IV or recurrent endometrial carcinoma -No prior cytotoxic chemotherapy	Arm 1: Doxorubicin (60mg/m2) + cisplatin (50mg/m2); n=157 Arm 2: Doxorubicin (50mg/m2) + paclitaxel (150mg/m2) + filgrastim; n=160	Primary -ORR Secondary -PFS -OS	-No difference in ORR (OR 1.12; 95% CI 0.69-1.79) -No difference in PFS (HR 1.01; 95% CI 0.8-1.28) -No difference in OS (HR 1.00; 95% CI 0.78-1.27)
GOG 177 PMID: 15169803 Enrollment: 12/28/1998-08/14/2000	-Stage III/IV or recurrent endometrial carcinoma -No prior cytotoxic chemotherapy	Arm 1: Doxorubicin (60mg/m2) + cisplatin (50mg/m2); n=129 Arm 2: Doxorubicin (45mg/m2) + cisplatin (50mg/m2) + paclitaxel (160mg/m2) with filgrastim; n=134	Primary -OS Secondary -PFS -ORR	-Arm 2 had improved PFS (HR 0.60; 95%CI 0.46-0.78) -Arm 2 had improved OS (HR 0.75; 95% CI 0.57-0.988)
GOG 209 PMID: 33078978 Enrollment: 8/25/2003-4/20/2009	-Stage III/IV or recurrent endometrial carcinoma with poor potential for cure by surgery and/or radiation therapy -No prior cytotoxic chemotherapy	Arm 1: Paclitaxel (160mg/m2) + doxorubicin (45mg/m2) + cisplatin (50mg/m2); n=640 Arm 2: carboplatin (AUC 6) + paclitaxel (160mg/m2); n=664	Primary -OS Secondary -PFS -Toxicity -HRQoL	-Arm 2 was not inferior: OS (HR 1.00; 90%CI 0.9-1.12), PFS (HR 1.03; 90% CI 0.93-1.15) -Arm 2 had a more favorable toxicity profile and HRQoL difference
PORTEC 3 PMID: 29449189 Enrollment: 11/26/2006-12/20/2013	-Stage IA or IB grade 3 endometrioid endometrial carcinoma, stage II/III endometrioid endometrial carcinoma, or stage IB-III serous or clear cell endometrial cancer -No prior chemotherapy or radiotherapy	Arm 1: Cisplatin (50mg/m2, 2 cycles) with EBRT followed by carboplatin (AUC 5, 4 cycles); n=330 Arm 2: EBRT; n=330	Primary -OS -FFS Secondary -Rec rate -Toxicity -HRQoL	-No difference in 5-year OS (HR 0.76; 95% CI 0.54-1.06) -Arm 1 had significantly more Grade 3 complications vs Arm 2 (60% vs 12%, p<0.01)
GOG 258 PMID: 31189035 Enrollment: 06/29/2009-07/28/2014	-Stage III/IVA endometrial carcinoma or stage I/II clear cell/serous endometrial carcinoma with positive washings -Complete surgical staging, pelvic/paraaortic LN biopsy or dissection was optional -No single site of residual tumor >2cm	Arm 1: Cisplatin (50mg/m2, 2 cycles) with EBRT followed by carboplatin (AUC 5-6) + paclitaxel (175mg/m2); n=370 Arm 2: Carboplatin (AUC 6) + paclitaxel (175mg/m2); n=360	Primary -RFS Secondary -OS -Toxicity -QOL	-No difference in RFS (HR 0.90; 90% CI 0.74-1.10) -Arm 1 had decreased vaginal recurrences (HR 0.36; 95% CI 0.16-0.82) -Arm 1 had decreased pelvic/paraaortic LN recurrences (HR 0.43; 95% CI 0.28-0.66) -Arm 1 had increased distant recurrences (HR 1.36; 95% CI 1.00-1.86) -Similar incidence of grade 3 or higher toxicity
GOG 261 PMID: 35007153 Enrollment: 8/17/2009-03/24/2014	-Any stage or recurrent uterine or ovarian carcinosarcoma -Prior radiation therapy allowed but must have been discontinued	Arm 1: Paclitaxel (175mg/m2) + carboplatin (AUC 6); n=224 (uterine) Arm 2: Ifosfamide (1.6g/m2)+ mesna + paclitaxel (135mg/m2)+ filgrastim; n=204 (uterine)	Primary -OS Secondary -PFS -AEs -QOL	-Arm 1 was not inferior to Arm 2 -Arm 1 had improved OS (HR 0.87; 90% CI 0.70-1.08) -Arm 1 had improved PFS (HR 0.74; 95% CI 0.58-0.93) -Arm 1 had more hematologic toxicities -Arm 2 had more confusion and genitourinary hemorrhage
GOG 184 PMID: 19108877 Enrollment: 7/3/2000-9/13/2004	-Stage III/IV endometrial carcinoma -No prior chemotherapy or radiotherapy -No single site of residual tumor >2cm	Arm 1: Cisplatin (50mg/m2) + doxorubicin (45mg/m2) + tumor directed radiotherapy; n=288 Arm 2: Cisplatin (50mg/m2) + doxorubicin (45mg/m2) + paclitaxel (160mg/m2) + tumor directed radiotherapy; n=298	Primary -RFS	-Arm 2 did not have improved RFS (p=0.21, one-tail) -Arm 2 was associated with increased toxicity
GOG 86P PMID: 29804638 Enrollment: 9/14/2009-1/9/2012	-Stage III/IV or recurrent endometrial carcinoma -No prior cytotoxic chemotherapy	Arm 1: paclitaxel (175mg/m2) + carboplatin (AUC 6) + bevacizumab (15mg/kg); n=116 Arm 2: paclitaxel (175mg/m2) + carboplatin (AUC 5) + temsirolimus (25mg); n=115 Arm 3: ixabepilone (30mg/m2) + carboplatin (AUC 6) + bevacizumab (15mg/m2); n=118	Primary -PFS1 Secondary -ORR -OS -Safety	-PFS was not significantly increased in any arm compared to historical controls2 -An unplanned analysis of PFS stratified by stage/disease status suggested a benefit for Arm 1 compared to historical controls (HR 0.75, 92% CI 0.58-0.95) -ORR was not significantly increased in any arm compared to historical controls
Subsequent lines
MITO Group End-2 Trial PMID: 31677820 Enrollment: 04/2012-06/2014	-Stage III/IV or recurrent endometrial carcinoma with measurable disease (RECIST 1.1) -Excluded carcinosarcoma -One prior platinum allowed if last treatment > 6 months from study initiation	Arm 1: Carboplatin (AUC 5) + paclitaxel (175mg/m2); n=54 Arm 2: Carboplatin (AUC 5) + paclitaxel (175mg/m2) + bevacizumab (15mg/kg); n=54	Primary -PFS Secondary -OS -ORR	-No difference in PFS (HR 0.84; 95% CI 0.5-1.3) -No difference in OS (HR 0.71; 95% CI 0.31-1.36) -ORR 53% in Arm 1 and 74% in Arm 2 -Arm 2 had increased cardiovascular toxicity and treatment discontinuation
KEYNOTE 775 PMID: 35045221 Enrollment: 06/11/2018-2/3/2020	-Advanced, recurrent, or metastatic endometrial carcinoma with measurable disease (RECIST 1.1) -Excluded carcinosarcoma and sarcoma -At least one prior platinum therapy -Two lines prior platinum allowed if one line was given in neoadjuvant setting -No prior PD-1 or VEGF therapies	Arm 1: Lenvatinib (20mg) + pembrolizumab (200mg); n=411 Arm 2: Physician’s choice of doxorubicin (6omg/m2) or paclitaxel (80mg/m2); n=416	Primary -PFS -OS Secondary -ORR -QOL	-Arm 1 had improved PFS (HR 0.56; 95% C, 0.47-0.66) -Arm 1 had improved OS (HR 0.62; 95% CI 0.51-0.75) -Arm 1 had more grade 3 adverse events vs Arm 2 (88.9% vs 72.7%)

AEs: adverse events; EBRT: External beam pelvic radiotherapy; ECOG: Eastern Cooperative Oncology Group; FFS: Failure free survival; HRQoL: health related quality of life; ORR: objective response rate; OS: overall survival; PFS: progression free survival; PMID: PubMed ID number; QOL: quality of life; RFS: recurrence/relapse free survival; RR: response rate; QOL: quality of life; WHO: World Health Organization.

¹Comparable patients on the PC Arm of trial GOG209 were used as historical controls.

²Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63–1.02), 1.22 (0.96–1.55) and 0.87 (0.68–1.11), respectively.

In patients with newly diagnosed advanced EC, primary surgical cytoreduction is considered when optimal cytoreduction (to <1 cm residual disease), or preferably, complete gross resection (no visible residual disease) is feasible. However, this approach is largely based on retrospective data, and there is limited high-quality evidence for cytoreduction in advanced EC; recommendations are often extrapolated from ovarian cancer (OVCA) literature. Trends in the upfront treatment of advanced EC are changing, and neoadjuvant chemotherapy is now more commonly used than primary surgical cytoreduction for stage IVB endometrial cancer according to a recent analysis of SEER data. A neoadjuvant chemotherapy approach for advanced EC has been associated with less surgical morbidity and no difference in OS compared to primary surgical cytoreduction. (14, 15)

For locally advanced EC, radiation is routinely used with chemotherapy to reduce the risk of pelvic relapse based on the results of two landmark clinical trials—GOG 258 and PORTEC-3—the latter of which demonstrated a survival benefit with chemoradiation (CTRT) over radiation alone (RT) for stage 3 EC (OS, 78.7% vs. 69.8%, respectively; p=0.114).

Recurrent EC

Chemotherapy

Retrospective data suggest platinum re-challenge has diminished efficacy. Platinum sensitivity, defined as a platinum-free interval of >6 months in OVCA, is terminology that has not been prospectively evaluated or validated in EC. A retrospective analysis of patients retreated with TC who recurred >6 months after completion of adjuvant TC showed an overall response rate (ORR) of 50%, median progression-free survival (PFS) of 10 months, and median OS of 27 months. (16) Retrospective studies have found time to recurrence after prior chemotherapy is predictive of survival in EC. The largest of these studies, a pooled analysis of phase III GOG studies (GOG 107, 122, 163, and 177), which assessed second-line (2L) chemotherapy following primary platinum chemotherapy, showed time to progression after primary platinum chemotherapy was the most predictive factor for survival following 2L chemotherapy. Patients with a platinum-free-interval >6 months compared with <6 months had a 30% lower risk for death (HR, 0.70; 95% CI: 0.59-0.84; p<0.01). (17) There is limited evidence for platinum-based combinations versus single-agent chemotherapy in the 2L or beyond. Following frontline TC, the benefit of subsequent chemotherapy is modest, with a median PFS of 3-4 months and OS of 6-12 months. (1)

The anti–vascular endothelial growth factor (VEGF) antibody bevacizumab is also active in advanced EC as monotherapy and has been explored in combination with TC. The randomized, phase II NRG/GOG 86P trial compared 1L TC plus bevacizumab; TC plus temsirolimus; and ixabepilone and carboplatin plus bevacizumab, and found improved median OS with the addition of bevacizumab to TC compared with historic data from GOG 209 (34 vs 23 months, respectively). Improvements in OS with bevacizumab were most robust among patients with a TP53 mutation on next-generation sequencing or p53 overexpression on immunohistochemistry (IHC), with a median OS for TC plus bevacizumab of 30.0 months compared to 14.4 months for TC plus temsirolimus in this TP53-altered subgroup. (18) The MITO Group End-2 trial looked at TC +/− bevacizumab in patients who had progressed >6 months after completion of 1L therapy. Patients in the bevacizumab arm had a higher ORR, median PFS, and OS, although these differences were not statistically significant. (19) At this time, definitive evidence for the addition of bevacizumab to standard chemotherapy is limited.

Options for single-agent chemotherapy are limited and include agents such as liposomal doxorubicin, doxorubicin, cisplatin, topotecan, docetaxel, and paclitaxel, with ORRs ranging from 9.5-15%. (20–25) The National Comprehensive Cancer Network (NCCN) guidelines also include single-agent topotecan, as well as combinations that contain cisplatin, docetaxel, and ifosfamide, all with poor or undocumented efficacy. (21)

Human epidermal growth factor receptor 2 (HER2)

HER2 is emerging as a promising target for the treatment of EC. HER2 is overexpressed in approximately 25-30% of CN-H, serous/serous-like ECs and 13% of carcinosarcomas. When HER2 is overexpressed, tyrosine kinase becomes constitutively activated, leading to dysregulation of DNA transcription through activation of PIK3CA/AKT/mTOR and RAS/RAF/MAPK pathways. Findings from a randomized, phase II trial of TC versus TC plus the monoclonal HER2-targeting antibody trastuzumab in patients with HER2+ stage III/IV or recurrent serous EC demonstrated improved median PFS (12.9 vs 8.0 months, respectively) and OS (29.6 vs 24.4 months, respectively) with TC plus trastuzumab. This benefit was most notable in stage III/IV disease with trastuzumab as part of primary treatment. (26) As a result, TC plus trastuzumab is now a recommended regimen for HER2-overexpressed EC. (27)

Early results of a phase II clinical trial assessing the efficacy and safety of the antibody-drug conjugate (ADC) trastuzumab deruxtecan in HER2-expressing, unresectable, chemotherapy-refractory uterine carcinosarcoma demonstrated a median PFS in IHC HER2 2+/3+ of 6.2 months (95% CI: 4.0-8.8). (28) Trastuzumab deruxtecan is also being investigated in an ongoing phase II study in HER2-expressing endometrial cancer (NCT04482309). Other ADCs currently being investigated in phase I/II studies include HER2-targetting DB-1303 (NCT05150691), folate receptor alpha (FRα)-targeting farletuzumab ecteribulin (NCT04300556), and mirvetuximab soravtansine (IMGN853) monotherapy (NCT03832361) and in combination with pembrolizumab (NCT03835819) (Table 2).

Table 2.

Active/ongoing trials for advanced/recurrent endometrial cancer.

Trial	Study start date	Recruitment status	Treatment arms	Experimental maintenance therapy	Molecular assessment	Estimated enrollment	Primary endpoint(s)
First-line Phase 3 Immunotherapy
MK-3475-C93/KEYNOTE-C93/GOG-3064/ENGOT-en15 (NCT05173987)	February 3, 2022	Recruiting	- Comparator: Carboplatin + paclitaxel - Experimental: Pembrolizumab	Pembrolizumab	MMRd/MSI	N=350 (MMRd only)	PFS, OS
MK-3475-B21/KEYNOTE-B21/ENGOT-en11/GOG-3053 (NCT04634877)	January 10, 2021	Recruiting	- Comparator: Carboplatin + paclitaxel + placebo +/− EBRT +/− VBT1 - Experimental: Carboplatin + paclitaxel + pembrolizumab +/− EBRT +/− VBT1	Pembrolizumab	MMRd/MSI	N=990	DFS, OS
DUO-E (NCT04269200)	May 21, 2020	Recruiting	- Comparator Arm A: Carboplatin + paclitaxel + placebo - Experimental Arm B: Carboplatin + paclitaxel + durvalumab - Experimental Arm C: Carboplatin + paclitaxel + durvalumab + olaparib	- Arm B: Durvalumab - Arm C: Durvalumab + olaparib	MMRd/MSI	N=699	PFS
NRG-GY018 (NCT03914612)	July 16, 2019	Recruiting	- Comparator: Carboplatin + paclitaxel + placebo - Experimental: Carboplatin + paclitaxel + pembrolizumab	Pembrolizumab	MMRd/MSI	N=590 (MMRp) N=220 (MMRd)	PFS
RUBY (NCT03981796)	July 18, 2019	Active, not recruiting	- Comparator: Carboplatin + paclitaxel + placebo - Experimental Part 1: Carboplatin + paclitaxel + dostarlimab - Experimental Part 2: Carboplatin + paclitaxel + dostarlimab + niraparib	- Part 1: Dostarlimab - Part 2: Dostarlimab + niraparib	MMRd/MSI	N=785	PFS, OS
ENGOT-EN9/LEAP-001 (NCT03884101)	April 11, 2019	Active, not recruiting	- Comparator: Carboplatin + paclitaxel - Experimental: Pembrolizumab + lenvatinib	Pembrolizumab	MMRd/MSI	N=875	PFS, OS
AtTEnd (NCT03603184)	October 2, 2018	Active, not recruiting	- Comparator: Carboplatin + paclitaxel + placebo - Experimental: Carboplatin + paclitaxel + atezolizumab	Atezolizumab	MMRd/MSI	N=550	PFS, OS
First-line Phase 3 Non-Immunotherapy
NRG-GY026 (NCT05256225)	August 12, 2022	Recruiting	- Comparator Arm I: Carboplatin + paclitaxel - Experimental Arm II: Carboplatin + paclitaxel + trastuzumab - Experimental Arm III: Carboplatin + paclitaxel + pertuzumab/trastuzumab	- Arm II: Trastuzumab - Arm III: Pertuzumab/ trastuzumab	HER2	N=525 (HER2+ serous carcinoma or carcinosarcoma only)	PFS, OS
XPORT-EC (NCT05611931)	November 1, 2022	Recruiting	- Completed a single line of platinum-based therapy Comparator: Placebo Experimental: Selinexor	Selinexor	TP53 wt	N=220	PFS
Phase 2
DESTINY-PanTumor02 (NCT04482309)	June 16, 2023	Active, not recruiting	Trastuzumab deruxtecan		HER2	N=268	ORR
IMGN853- (NCT03832361)	July 15, 2020	Recruiting	Mirvetuximab soravtansine		FRα	N=50	ORR
18-602 (NCT03835819)	January 2, 2020	Recruiting	Mirvetuximab soravtansine + pembrolizumab		FRα and MMRp	N=35	ORR, PFS
16-322 (NCT02912572)	November 14, 2016	Recruiting	- Avelumab - Avelumab + talazoparib		MSI and/or POLE	N=105	ORR, PFS
18-301 (NCT03675893)	December 24, 2018	Recruiting	Letrozole + abemaciclib		ER-positive	N=40	ORR, PFS
INCMGA 0012-204 (NCT04463771)	January 26, 2021	Recruiting	- Retifanlimab - Retifanlimab + epacadostat - Retifanlimab + pemigatinib - Retifanlimab + INCAGN02385 + INCAGN2390		MSI, POLE, PD-L1, FGFR1/2/3	N=300	ORR
21-447 (NCT05156268)	January 27, 2022	Recruiting	Pembrolizumab + olaparib		p53	N=25	ORR
NRG-GY012 (NCT03660826)	September 4, 2018	Recruiting	- Arm I: Cediranib - Arm II: Olaparib - Arm III: Cediranib + olaparib - Arm IV: Capivasertib + olaparib - Arm V: Durvalumab + olaparib - Arm VI: Cediranib + durvalumab		DNA homologous repair gene mutations	N=168	PFS
NRG-GY025 (NCT05112601)	February 7, 2022	Recruiting	- Experimental Arm I: Ipilimumab + nivolumab - Active comparator Arm II: Nivolumab		MMRd/MSI	N=12	PFS
NU 18G07 (NCT04049227)	August 12, 2019	Recruiting	Abemaciclib + letrozole		MMR, PTEN, cyclin D1, p16, pRB	N=27	Ki-67 expression
ZN-c3-004 (NCT04814108)	June 1, 2021	Recruiting	ZN-c3			N=110	ORR
Phase 1/2
MORAb-202 (NCT04300556)	August 6, 2020	Recruiting	Farletuzumab ecteribulin		FRα	N=55	Dose escalation/ confirmation
DB-1303 (NCT05150691)	January 31, 2022	Recruiting	DB-1303		HER2	N=360	Dose escalation/ confirmation
ZN-c3-001 (NCT04158336)	November 1, 2019	Recruiting	ZN-c3			N=110	Safety/ tolerability, ORR

C: cycles; DFS: disease-free survival; EBRT: external-beam radiation therapy; ER: estrogen receptor; FRα: folate receptor alpha; HER2: human epidermal growth factor receptor 2; MMRd: mismatch repair–deficient; MMRp: mismatch repair–proficient; MSI: microsatellite instability; NCT: National Clinical Trial identification number; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; TP53 wt: TP53 wildtype; VBT: vaginal brachytherapy.

¹The standard of care radiotherapy regimen may include, at the discretion of the investigator, EBRT ≥4500 cGY with variable dose frequency, with or without cisplatin 50 mg/m² IV on days 1 and 29 of EBRT, and/or VBT.

MMRd/microsatellite instability–high/tumor mutational burden–high

Approximately 17-33% of advanced and recurrent ECs are MMRd/MSI-high (MSI-H). (29, 30) In MMRd, MSI-H, and tumor mutational burden–high (TMB-H; >10 mutations/megabase) recurrent EC, the recommended 2L systemic therapy is the anti–programmed cell death protein 1 (PD-1) monoclonal antibody pembrolizumab. (31) Other recommended PD-1/programmed death-ligand 1 (PD-L1) agents for the treatment of MMRd/MSI-H EC include dostarlimab, nivolumab, and avelumab. (32, 33)

The Food and Drug Administration (FDA) approval of pembrolizumab for treatment of MMRd/MSI-H EC was largely based on the findings of the phase II KEYNOTE-158 study in patients with advanced MMRd/MSI-H EC, which demonstrated an ORR of 48% and median PFS of 13 months. (34) In 2021, dostarlimab was granted accelerated FDA approval for MMRd/MSI-H EC based on the results of the phase I/II GARNET study, which demonstrated an ORR of 42% and median PFS of 8.1 months in this setting. (32) The PD-1 inhibitor nivolumab has not yet been granted FDA approval but can be used in MMRd/MSI-H EC based on the results of The National Cancer Institute Molecular Analysis for Therapy Choice trial, which showed a 12-month PFS rate of 46.2% in patients with MMRd EC of endometrioid and carcinosarcoma histologies. (33)

MSI is a clear biomarker for response to immune checkpoint inhibitors in EC. However, the underlying mechanisms leading to MSI vary and include germline (Lynch syndrome) and somatic (Lynch-like) MMR gene alterations and sporadic alterations associated with MLH1 methylation. The effect of the underlying mechanism for MSI on immune checkpoint response is unclear. In a phase II study, pembrolizumab was evaluated in recurrent Lynch, Lynch-like, and sporadic MLH1-methylated EC, demonstrating 3-year PFS and OS rates of 100% in Lynch/Lynch-like patients versus 30% and 43%, respectively, in sporadic MLH1-methylated EC. (35)

In the sporadic MLH1-methylated group, mechanism of resistance to PD-L1 agents was associated with acquired loss of beta-2 microglobulin and JAK3, suggesting a lack of surface HLA-class 1 expression and defective response to induction with type I and II interferons. Higher TMB and greater infiltration of CD-68+ macrophages in EC have been proposed as potential mechanisms of response to immunotherapy. (35, 36) While predictive of immune checkpoint response in other cancers, PD-L1 expression is not predictive of response in EC. (37) The anti–PD-L1 agents avelumab and durvalumab have also shown promise as monotherapy in phase II studies in advanced MMRd/MSI-H EC, with ORRs of 27% (and 47%, respectively. (38, 39)

The benefit of incorporating immunotherapy earlier in the therapeutic course, as 1L treatment, is under investigation. There are several ongoing phase III trials of cytotoxic chemotherapy alone or in combination with poly (ADP-ribose) polymerase (PARP) inhibitors, checkpoint inhibitors, and/or VEGF tyrosine kinase inhibitors (TKIs) in 1L therapy of EC, with pending results (Table 2). Whether combination immune checkpoint blockade is more effective than checkpoint inhibitor monotherapy in MMRd/MSI-H EC is of great interest. The phase II NRG-GY025 (NCT05112601) trial of nivolumab versus nivolumab/ipilimumab in recurrent MMRd EC aims to address this question.

MMR-proficient

Most patients with EC have MMR-proficient (MMRp) tumors, which have limited response to single-agent checkpoint inhibitors (ORR, 3-14%). (32, 37–39) However, recent studies have established the combination of the multikinase inhibitor lenvatinib plus pembrolizumab as an effective 2L treatment option. Findings from the phase Ib/II Study 111/KEYNOTE 146 trial in patients with advanced EC demonstrated an ORR at week 24 (ORR_Wk24) of 38.0%. The ORR_Wk24 was 63.6% for MSI-H tumors (n=11) and 36.2% for microsatellite-stable tumors (n=94). Regardless of MSI status, the median duration of response was 21.2 months, median PFS was 7.4 months, and median OS was 16.7 months in previously treated patients. Responses were seen regardless of PD-L1 expression or histology. (40) These results led to the FDA accelerated approval of lenvatinib plus pembrolizumab for advanced EC that is not MSI-H/MMRd and has progressed following prior systemic therapy.

In the confirmatory phase III Study 309/KEYNOTE775 trial, patients with recurrent EC with measurable disease and one prior platinum-based chemotherapy were enrolled regardless of MMR status. Patients were stratified based on MMR status and randomized 1:1 to lenvatinib plus pembrolizumab or investigator’s choice of doxorubicin or paclitaxel. The median PFS was longer with lenvatinib plus pembrolizumab compared with chemotherapy (MMRp population: 6.6 vs. 3.8 months; p<0.001; overall: 7.2 vs. 3.8 months; p<0.001). The median OS was also longer (MMRp population: 17.4 vs. 12.0 months; p<0.001; overall: 18.3 vs. 11.4 months; p<0.001). PFS and OS analyses in all subtypes, including MMR status, histology, and prior lines of therapy, favored lenvatinib plus pembrolizumab; no substantial differences in health-related quality of life scores were appreciated. (20)

Endocrine therapy

In hormone (estrogen or progesterone)-receptor positive EC, endocrine therapy is a viable treatment option for advanced or recurrent EC. In a translational study of advanced EC tissues from study GOG 119, 40% and 45% of the 45 evaluable tumors were estrogen- and progesterone-receptor positive, respectively. (41) Estrogen and progesterone receptors are typically evaluated with IHC, though timing of when this should be performed is not well established. Current NCCN guidelines recommend hormone receptor testing for stage III, IV, or recurrent endometrioid carcinoma. (21)

Endocrine therapy is generally well tolerated and can be considered in patients with minimal symptoms and low-grade or more indolent disease. A systematic review from 2007 reported that up to 30% of advanced or recurrent ECs respond to endocrine therapy, with the highest response rates in low-grade EC (up to 56% in grade 1/2 endometrioid EC). (42) In the phase II GOG 119 study in advanced EC, alternating tamoxifen and megestrol acetate demonstrated an ORR of 27%, median PFS of 2.7 months, and OS of 14.0 months. (43) Other endocrine therapies include progestational agents alone (medroxyprogesterone acetate or megestrol acetate), aromatase inhibitors, tamoxifen alone, or fulvestrant, a selective estrogen receptor degrader. (21, 44)

Anti-VEGF Therapy

Beyond the combination of bevacizumab with cytotoxic chemotherapy, anti-VEGF therapies have been studied as monotherapy and in combination with other agents in advanced EC. In GOG 229E, bevacizumab monotherapy in previously treated EC was associated with an ORR of 13.5%; and 40.4% of patients were progression-free at 6 months. (45) Lenvatinib monotherapy in a phase II trial in the 2L setting was associated with an ORR of 13.3% and median PFS of 5.6 months. (46)

The NRG-GY012 protocol compared the efficacy of olaparib (PARP inhibitor) monotherapy, cediranib (VEGF receptor TKI) monotherapy, and combination olaparib/cediranib in advanced EC who had received at least one prior line of platinum-based chemotherapy and no more than two prior lines of chemotherapy; median PFS was 2.0, 3.8, and 5.5 months, respectively. (47) Findings from a randomized, phase II trial in recurrent EC demonstrated median PFS for combination nivolumab/cabozantinib (a TKI) and single-agent nivolumab of 5.3, and 1.9 months, respectively. The ORRs were 25% and 16.7%, respectively. (48)

Cell signaling–targeted therapy

Cyclin-dependent kinase inhibitors (CDKis) such as palbociclib and abemaciclib function by selectively inhibiting CDK4 and CDK6, which are crucial for the cell cycle G1/S phase transition. (49) A randomized, phase II trial of letrozole with/without palbociclib (PALEO trial) demonstrated improved PFS with the combination (8.3 vs. 3.0 months; HR, 0.56; p=0.04). (50) Data from a phase II trial in patients with ER+ recurrent EC demonstrated an ORR of 30% and median PFS of 9.1 months with abemaciclib plus letrozole at a median follow-up of 12.5 months. (51) These studies suggest a role for CDK4/6 inhibitors in subsets of advanced ECs, warranting further investigation, which is the subject of ongoing trials (Table 2)

Wee1 Kinase Inhibitors

Wee1 kinase regulates cell-cycle checkpoints of G2/M and S phase. TP53-mutant cancers such as serous EC are often disregulated at the G1/S phase checkpoint, allowing for early S phase entry, rendering them more vulnerable to Wee1 inhibition. Adavosertib is a highly selective inhibitor of Wee1 kinase that in a phase II study in recurrent EC resulted in an ORR of 30%, median PFS of 6.1 months, and median duration of response of 9 months. (52) Additional Wee1 inhibitors are being evaluated in ongoing studies.

Exportin 1 (XPO1) inhibition

Selinexor is an orally available potent inhibitor of XPO1 resulting in retention of tumor suppressor proteins in the nucleus. A phase I open-label study of selinexor with TC in advanced OVCA or EC demonstrated good safety and tolerability. (53 ) A subsequent phase II study of selinexor monotherapy in advanced EC showed a 35% disease control rate. (54) Results of the randomized phase III SIENDO trial of maintenance selinexor vs placebo following response to TC chemotherapy in EC showed the greatest therapeutic benefit in p53 wild-type EC, with a 10-month PFS improvement over placebo. (55) The recently opened phase III XPORT-EC trial (NCT05611931) will evaluate selinexor as maintenance therapy after systemic therapy for p53 wild-type advanced or recurrent EC (Table 2).

Unanswered Questions and Future Directions

Current NCCN guidelines recommend universal testing for MMR proteins in EC to assess for genetic predisposition to Lynch Syndrome and encourage molecular subtyping when available to inform future treatment decisions. (21) While molecular analysis for all ECs is resource intensive, molecular subtyping is considered more predictive of outcomes than other risk stratification criteria in patients with early-stage disease and is anticipated to play an increasing role in adjuvant therapeutic decision making. (56–58)

In advanced and recurrent disease, molecular analysis is essential in informing optimal treatment options, delineating predictive biomarkers, and identifying patients eligible for clinical trials investigating emerging therapeutic options based on molecular drivers of EC subtypes. The refinement of MSI-H/MMRd predictive subgroups (e.g., assessment of mutational thresholds and signatures) may identify patients who do not respond or rapidly progress after an initial response to single-agent immune checkpoint inhibition and who could benefit from novel combination strategies. Clinical studies among larger cohorts of Lynch/Lynch-like patients versus sporadic MSI-H patients treated with immune checkpoint inhibitors are warranted. The potential for response to immunotherapy after prior immunotherapy also warrants investigation, as does delineation of mechanisms of response to checkpoint inhibitors in the minority of responding MMRp ECs.

Conclusions

Our understanding of EC biology has been greatly expanded by modern molecular characterization, which has defined molecularly and clinically distinct EC subtypes. Given the heterogeneity of this malignancy, patients with advanced disease should undergo molecular profiling to optimize treatment strategies and inform clinical trial eligibility. The therapeutic ceiling with traditional chemotherapy has been reached, and we must look to relevant biologic targets to individualize treatment. While surgical resection or radiation therapy may be appropriate for localized disease, advanced EC requires systemic therapy. Ongoing phase III studies evaluating immunotherapeutic approaches will likely change the standard of care for 1L management of EC, which will necessitate refinement of 2L and beyond management. While the incidence and number of deaths from EC has increased worldwide, we must advocate for research to improve the quality of life and outcomes for patients with EC.