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.