Manejo del Cáncer de endometrio

metastásico o recurrente:
Estado del arte

Prof. Angélica Nogueira-Rodrigues, MD PhD

UFMG, EVA, LAGOG, DOM, Oncoclínicas
Conflictos de interés:
Consultor:
ANVISA (Brazil), Roche, AstraZeneca, MSD, EISAI, Pfizer, GSK, Agenus, Novartis

Investigación científica:
CNPq, FAPEMIG (public research organizations in Brazil)

Entrenamiento educacional:
Roche, AstraZeneca, MSD, GSK, Pfizer, Novartis, Gilead

Acciones en empresas:
DOM Oncologia
Phase 3 RUBY: Dostarlimab Plus Chemotherapy

Mirza NEJM 2023

Mirza NEJM 2023
Primary Endpoint: OS in Overall Population
(33% maturity) 1.0

84.6%
0.8
71.3%
HR, 0.64
Probability of Survival

81.3% Dostarlimab + CP
(95% CI, 0.464–0.870)
0.6 P=0.0021a

56.0%
Placebo + CP
0.4

Received subsequent immunotherapy:

0.2 No. with Median • 34.5% of patients on placebo arm
event, % (95%CI), mo
• 15.5% of patients on dostarlimab arm
Dostarlimab+ CP 26.5 NE (NE–NE)
Placebo+ CP 40.2 NE (23.2–NE)
Censored
0.0 OS maturity 33.4

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Chemotherapy Period
Months from randomization
At Risk(Events)
Dostarlimab + C P 235(3) 224(8) 214(15) 198(25) 190(33) 183(35) 174(42) 169(44) 162(47) 145(53) 110(57) 83(60) 64(62) 45(64) 25(65) 7(65) 2(65) 0(65)
245(0)
Placebo + CP 249(0) 242(3) 237(7) 226(17) 219(22) 203(35) 189(45) 177(57) 162(68) 147(78) 125(88) 88(93) 65(97) 48(98) 33(99) 15(100) 6(100) 1(100) 1(100) 0(100)
Median duration of follow-up 25.38 months.
aP≤0.00177 required to declare statistical significance at first interim analysis.

CP, carboplatin/paclitaxel; HR, hazard ratio; NE, not estimable;OS, overall survival.

ENGOT-EN6-NSGO/GOG-3031/RUBY presented by Mansoor R Mirza

Eskander NEJM 2023
 Westin JCO 2023
Colombo ESMO 2023
ATTEND: Phase III atezolizumab in EC

Colombo ESMO 2023

Atezolizumab Improves PFS in All Comers and MMRd

Colombo ESMO 2023

DUO E: Combination of durvalumab and Olaparib in EC

Westin JCO 2023

 Patient characteristics
Control Durva Durva+Ol Control Durva Durva+Ol
Characteristics Characteristics
(N=241) (N=238) a (N=241) (N=238) a
(N=239) (N=239)

Age, years Median (range) 64 (31–85) 64 (22–84) 63 (27–86) MMR status,*,† Proficient 80 81 80
Geographi Asia 28 29 28 %
c region,* Deficient 20 19 20
Non-Asia 72 71 72
% ‡
PD-L1 status, Positive (TAP score 68 71 63
% ≥1%)
Race, % White 59 57 56 Negative (TAP score 31 26 34
Asian 30 30 29 <1%)
Unknown 1 3 3
Black/AfricanAmerican 4 5 6
§
HRRm status, HRRm 13 11 16
American Indian/Alaska 0 3 3 %
Native
Non-HRRm 55 58 59
Other or not reported 6 5 7
Unknown 32 31 25
Ethnicity, % Not Hispanic or Latino 90 87 86
Hispanic or Latino 8 12 13 Histology type Endometrioid 58 59 64
at diagnosis, Serous 22 24 18
Disease Newly diagnosed* 48 47 48 %
status, % FIGO Stage III 5 7 5 Carcinosarcoma 9 5 8
Mixed, epithelial 5 4 4
FIGO Stage IV 42 40 41
Clear cell 3 2 3
Recurrent* 52 53 52
Undifferentiated 1 2 2
ECOG PS, % (0) Normal Activity 65 66 69
Mucinous or other 2 4 2
(1) Restricted Activity 35 34 31 Previous chemotherapy, % 21 21 23
Measurable disease at baseline, % 82 85 77 Previous radiotherapy, % 29 31 36
Prior surgery, 84 86 87
Shannon N. Westin Content of this presentation
% is copyright and responsibilityof the author. Permission is required for re-use.
 Patient disposition
Control Durva Durva+Ola
(N=241) (N=238) (N=239)

Randomised, n (%) 241 (100) 238 (100) 239 (100)

Received any treatment, n (%) 236 (98) 235 (99) 238 (100)
Carboplatin/paclitaxel 236 (98) 235 (99) 238 (100)
Durvalumab/placebo 236 (98) 235 (99) 238 (100)
Olaparib/placebo 169 (70) 183 (77) 192 (80)
Started maintenance phase, n (%) 169 (70) 183 (77) 192 (80)
Did not receive any treatment, n (%) 5 (2) 3 (1) 1 (<1)
Still receiving treatment at DCO,* n (%) Durvalumab/placebo 42 (18) 71 (30) 94 (39)
Olaparib/placebo 39 (23) 70 (38) 86 (45)
Still ongoing in study at DCO, n (%) 147 (61) 159 (67) 170 (71)
Median (range) duration of treatment, months Durvalumab/placebo† 9.0 (0.2–32.9) 9.9 (0.2–31.7) 13.1 (0.2–33.2)
Olaparib/placebo‡ 5.7 (0.2–28.6) 7.6 (0.4–27.2) 9.2 (0.3–28.7)
Median (range) no. of cycles Carboplatin§ 6 (1–6) 6 (1–6) 6 (1–6)
Paclitaxel§ 6 (1–7) 6 (1–6) 6 (1–7)
Median (range) duration of follow-up, months 16.4 (0.2–32.9) 17.1 (0.2–33.0) 17.5 (0.2–33.4)

Shannon N. Westin Content of this presentation is copyright and responsibilityof the author. Permission is required for re-use.
Subgroup analyses by biomarkers: Mismatch repair

Westin JCO 2023

Subgroup analysis of PFS:DurvavsControl
By stratification factors and biomarker status
HR Durva Control
(95% CI) n/N (%) n/N (%)
All patients 0.68 (0.55–0.86) 139/238 (58.4) 173/241 (71.8)
Newly 0.59 (0.42–0.82) 67/113 (59.3) 81/115 (70.4)
Disease
diagnosedstatus
Recurrent 0.79 (0.58–1.07) 72/125 (57.6) 92/126 (73.0)
disease
MMRstatus
Proficienttumours 0.77 (0.60–0.97) 124/192 (64.6) 148/192 (77.1)
Deficient tumours 0.42 (0.22–0.80) 15/46 (32.6) 25/49 (51.0)
Region
Asia 0.98 (0.65–1.49) 44/68 (64.7) 45/68 (66.2)
Non-Asia 0.59 (0.45–0.76) 95/170 (55.9) 128/173 (74.0)
HRRm status
HRRm 0.57 (0.27–1.13) 12/26 (46.2) 23/32 (71.9)
Non-HRRm 0.72 (0.54–0.97) 85/138(61.6) 96/132(72.7)
Unknown 0.65 (0.43–0.97) 42/74 (56.8) 54/77 (70.1)
PD-L1 expression
Positive(TAP score ≥1%) 0.63 (0.48–0.83) 97/170 (57.1) 114/163(69.9)
Negative (TAPscore <1%) 0.89 (0.59–1.34) 38/61 (62.3) 57/75 (76.0)
Unknown NC (NC–NC) 4/7 (57.1) 2/3 (66.7)
0.12 0.25 0.5 1 2 4
FavoursDurva FavoursControl
Stratification factors(diseasestatus, MMR status, and geographicregion)areperthe randomisationcode.PD-L1 statusin baselinetumourtissue wasdeterminedcentrallyusingVentana
PD-L1 SP263 immunohistochemistryassay.Expressionwasassessed usinga TAP score,calculatedbased on the proportion of the tumourareapopulatedbytumourcellsorimmune cells
with membranous PD-L1 staining.HRRm status was assessed in baselinetumourtissueusingtheFoundationOneCDx NGS assay and includes amutationin any of thesegenes:ATM,
BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. HRRmstatusunknown includespatientsrecruitedinChinawhere
HRR testingwas not performed andpatients with samples that were unavailablefor testing.
Shannon N. Westin Content of this presentation is copyright and responsibilityof the author. Permission is required for re-use.
Subgroup analysis of PFS:Durva+OlavsControl
By stratification factors and biomarker status
HR Durva+Ola Control
(95% CI) n/N (%) n/N (%)
All patients 0.53 (0.42–0.67) 126/239 (52.7) 173/241 (71.8)
Disease status
Newly 0.47 (0.33–0.66) 58/114 (50.9) 81/115 (70.4)
diagnosed
Recurrent
MMRstatus 0.59 (0.43–0.81) 68/125 (54.4) 92/126 (73.0)
disease
Proficienttumours 0.57 (0.44–0.73) 108/191 (56.5) 148/192 (77.1)
Deficient tumours 0.41 (0.21–0.75) 18/48 (37.5) 25/49 (51.0)
Region
Asia 0.68 (0.44–1.06) 37/67 (55.2) 45/68 (66.2)
Non-Asia 0.48 (0.36–0.63) 89/172 (51.7) 128/173 (74.0)
HRRm status
HRRm 0.30 (0.15–0.58) 16/39 (41.0) 23/32 (71.9)
Non-HRRm 0.59 (0.44–0.80) 81/141(57.4) 96/132(72.7)
Unknown 0.57 (0.36–0.89) 29/59 (49.2) 54/77 (70.1)
PD-L1 expression
Positive(TAP score ≥1%) 0.42 (0.31–0.57) 68/150 (45.3) 114/163(69.9)
Negative (TAPscore <1%) 0.80 (0.55–1.16) 55/82 (67.1) 57/75 (76.0)
Unknown NC (NC–NC) 3/7 (42.9) 2/3 (66.7)
0.12 0.25 0.5 1 2 4
FavoursDurva+Ola FavoursControl
Stratification factors(diseasestatus, MMR status, and geographicregion)areperthe randomisationcode.PD-L1 statusin baselinetumourtissue wasdeterminedcentrallyusingVentana
PD-L1 SP263 immunohistochemistryassay.Expressionwasassessed usinga TAP score,calculatedbased on the proportion of the tumourareapopulatedbytumourcellsorimmune cells
with membranous PD-L1 staining.HRRm status was assessed in baselinetumourtissueusingtheFoundationOneCDx NGS assay and includes amutationin any of thesegenes:ATM,
BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. HRRmstatusunknown includespatientsrecruitedinChinawhere
HRR testingwas not performed andpatients with samples that were unavailablefor testing.
Shannon N. Westin Content of this presentation is copyright and responsibilityof the author. Permission is required for re-use.
 RUBY GY018 ATTEND DUO-E MITO END-3
Investigational Durvalumab / Durvalumab +
agent Dostarlimab Pembrolizumab Atezolizumab Olaparib Avelumab
N 494 816 549 718 125
MMRd% 23.9% 27.6% 22.8% 20% 46%
NON-MMRd% 76.1% 72.4% 77.2% 80% 51.2%
EC IV % 31.58% ### 22% 40.9% 28.8%
PFS ITT 11.8 m x 7.9 m ### 10.1 m x 8.9 m 10.2 m x 15.1 m x 9.6 m 9.6 m x 9.9 m
PFS MMRd NR x 7.7 m NR x 7.6 m NR x 6.9 m NR x 31.8 m x 7 m 60% x 35% - 12 m
50% x 13% - 24 m
PFS Non-MMRd 9.9 m x 7.9 m 13.1 m x 8.7 m 9,5 x 9,2m 9.9 m x 15 m x 9.7 m 32% x 42% - 12 m
17% x 21% - 24 m
OS ITT 71.3% x 56% - 24m ### 38,7m x 30,2m NR x NR x 25.9 m NR x 27.4 m
OS MMRd 83.3% x 58.7% - 24m ### NE x 25,7 ### 87% x 79% - 12 m
76% x 55% - 24 m
OS Non-MMRd NR x 29.8 m ### 31,5x28,6 ### 67% x 87% - 12 m
47% x 63% - 24 m
Timeline of Approvals for Second-Line Treatment of Endometrial Cancer

Rubinstein M et al. Gynecol Oncol. 2022;167(3):540-546.

Treatment sequencing in advanced endometrial cancer
KEYNOTE-028
PAT I E N T P O P U L AT I O N :

• Advanced endometrial cancer

• Failure of or inability to receive
standard therapy
CR, PR, or SD
RR 13%
Treat for 24 months
or until progressiona
or intolerable toxicity

• ECOG PS 0 or 1
Pembrolizumab
• ≥1 measurable lesion 10 mg/kg IV, Q2W
• PD-L1 positivity
• No autoimmune disease2 Discontinue
Confirmed PD
pembrolizumab

Frenel JS et al. J Clin Oncol. 2017;35(36):4035-4041.

KEYNOTE-158
PAT I E N T P O P U L AT I O N : Treat for 24 months
or until progressionb or
• Advanced endometrial cancer CR, PR, or SD
intolerable toxicity, withdrawal,
or investigator decision
• MSI-H
• Progression on or intolerance to ≥1
line of standard therapy
Pembrolizumab
200 mg/kg IV Q3W
RR 57%
• ECOG PS 0 or 1
• Provision of tumor sample for
biomarker analysis Confirmed PD
DCR 73% Discontinue
J Clin Oncol 2016 Abstract;
pembrolizumab
• No autoimmune disease2 ASCO 2016 Slides; ClinicalTrials.gov
NCT02054806
O’Malley DM et al. J Clin Oncol. 2022;40(7):752-761.
GARNET TRIAL

Oaknin A et al. JAMA Oncol. 2020;6(11):1766-1772.

KEYNOTE 775
Key eligibility criteria
Primary endpoints
• Advanced, metastatic, or recurrent Lenvatinib
endometrial cancer • PFS by BICR
20 mg PO QD
• Measurable disease by BICR + • Overall survival
Pembrolizumab b
• 1 Prior platinum-based CTa 200 mg IV Q3W
Secondary endpoints
• ECOG PS 0-1
• ORR
• Tissue available for MMR testing
R Treat until progression or • HRQoL
(1:1) unacceptable toxicity
Stratification factors • Pharmacokinetics
MMR status (pMMR vs dMMR) and • Safety
further stratification within pMMR by: Doxorubicin
60 mg/m2 IV Q3W c
• Region (R1: Europe, USA, Canada, or Key exploratory
Australia, New Zealand, and Israel, vs Paclitaxel endpoint
R2: rest of the world) 80 mg/m2 IV QW
• Duration of response
• ECOG PS (0 vs 1) (3 weeks on/1 week off)
• Prior history of pelvic radiation (Y vs N)

aPatients may have received up to 2 prior platinum-based CT regimens if 1 is given in the neoadjuvant or adjuvant treatment setting. bMaximum of 35
doses. c Maximum cumulative dose of 500 mg/m2.
BICR, blinded independent central review; ECOG PS, Eastern Cooperative Oncology Group performance status; HRQoL, health-related quality of life; IV,
intravenous; PFS, progression-free survival; pMMR, mismatch repair-proficient; ORR, objective response rate; PO, per os (by mouth); QD, once daily;
Q3W, every 3 weeks; QW, once weekly.

Makker V et al. N Engl J Med. 2022;386(5):437-448.

KEYNOTE 775-Overall Survival
pMMR All-comers

Makker V et al. J Clin Oncol. Clinical Trial Updates. 2023. DOI: 10.1200/JCO.22.02152.
GOG209: Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall
Survival and Adverse Event Analysis of a Phase III, Randomized, Noninferiority, Open-
Label Trial

CT TAP
ORR (%) 52 52
PFS (mos)* 13.2 13.9

OS (mos) 20.4 22

Miller DS et al. J Clin Oncol. 2020;38(33):3841-3850. Rubinstein M et al. Gynecol Oncol Rep. 2019;28:120-123.
 Distinct Scenarios
• Progression on CT+IO

• Progression on IO, long interval free of CT

• Progression after stopping IO

Rubinstein M et al. Gynecol Oncol. 2022;167(3):540-546.

©️ M R Mirza
Questions:

• Will IO work after IO?

• Will lenva (or another partner) rescue IO efficacy after IO?

©️ M R Mirza
Predictors of
response to
IO
rechallenge? Hinchcliff SGO 2022 et al

OJesina, Nature 497, 67–73 (2013)

Skander RN et al. N Engl J Med. 2023 Mar 27. doi: 10.1056/NEJMoa2302312. Epub ahead of print. Mirza MR et al. N Engl J Med. 2023 Mar 27. doi: 10.1056/NEJMoa2216334.
Makker V et al. J Clin Oncol. 2020 ;38(26):2981-2992.
Endometrial Cancer:Metastatic Recurrent
Front-line, metastatic or
recurrence
LEAP -001 Pembrolizumab (MK-3475) Plus Lenvatinib
(E7080/MK-7902) Versus Chemotherapy for
NCT04865289 Endometrial Carcinoma (ENGOT-en9/MK-7902-001)
DOMENICA 1st line dorstalimab vs chemo in dMMR patients

KNC93 study 1st line dorstalimab1st line pembro vs chemo in dMMR patients

Advanced Recurrent, 2nd line, CPI GOG-3038/POD1UM-204 An Umbrella Study of INCMGA00012 Alone and
pretreated or naive in Combination with Other Therapies in
endometrial PI: Slomovitz NCT04463771 Participants with Advanced or Metastatic
Cancer Co-PI: Moxley Endometrial Cancer Who Have Progressed on
or After Platinum-Based Chemotherapy

Recurrent 2nd line, CPI AFT-50 EndoMap A Phase IB/II Multi-Cohort Study of Targeted
naive Agents With Atezolizumab for Patients With
PI: Slomovitz NCT04486352 Recurrent or Persistent Endometrial Cancer
Co-PI:
Moroney, Alvarez,
Cantillo, Secord, LIu

NCT04463771. Updated December 2, 2022. Accessed May 5, 2023. https://clinicaltrials.gov/ct2/show/NCT04463771

NCT04393285. Updated March 17, 2023. Accessed May 5, 2023. https://clinicaltrials.gov/ct2/show/NCT04393285
NCT04486352. Updated February 10, 2023. Accessed May 5, 2023. https://clinicaltrials.gov/ct2/show/NCT04486352
ESGO/ESTRO/ESP 2021

Concin N., et al. Int J Gynecol Cancer 2021;31:12-39.

 Ongoing Trials – status update

PORTEC-4a

ENGOT-en11/GOG-3053/KEYNOTE-B21: Phase 3 study

of pembrolizumab or placebo in combination with
adjuvant chemotherapy with/without radiotherapy in
patients with newly diagnosed high-risk endometrial
cancer. Trial setting: Stage I-II endometrial
cancer - high-intermediate risk
Study Design: Randomised trial of molecular profile-based versus
recommendations for adjuvant radiotherapy
Sponsor(s): LUMC; funding: Dutch Cancer Society
Planned No. of patients: 500
Current accrual: 80
Other important information: ANZGOG and NCRI UK planning to p
Biomarkers of
special interest
AtTEnd dMMRPFSandOS Subsequentimmunotherapy

Atezolizumab arm 6.2%

PFSdMMR OSdMMR Placebo arm 40.9%

Blue zone dMMR patients:

Red zone dMMR patients: PFS and OS curve plateau
IO + chemo is not sufficient after 24mths → cure?

David SPTan Content of this presentation is copyright and responsibilityof theauthor.Permission is required for re-use.
Hormonal Therapy In Endometrial Cancer

GOG 153 and 119: No prior

hormonal or chemotherapy

Van Weelden WJ et al.. Front Oncol. 2019;9:359.

ENGOT-EN3/NGSO -PALEO

Mirza MR et al. Ann Oncol 2020;31(suppl_4):S1142-S1215.

Subgroup analyses by biomarkers: PD-L1

Westin JCO 2023

Homologous Recombination Defects in EC
Figure 5 Genomic aberrations in HR pathway in 240 TCGA Samples

Classic HR members (Blue square) are abnormal in 22% of cases

ARID1A Red Square) complex is abnormal in 41% of cases
HR defects occur in 48% of cases
Subtype Blue PolE ultramutated
Green MSI
Orange copy number low endometrioid
Red serous

Mutations or homozygous
loss occur in classic HR
• Classic HRD members: 22% pathway members in 22%, in
ARID1A and its binding
• ARID1A: 41% partners in 41% and in
classic and ARID1A binding
• HRD + ARID1A: 48% partners in 48% of EC. Note:
all ultramutators (polE
• HRD, ARID1A, PTEN:
Any 77%
HR Defect ARID1A binding mutant) have HR defects and
the frequency of HR
P=0.006 partners only
Liang H, et al. Genome Res. 2012. aberrations is lower in
Fremond S., et al. Lancet Digit Health 2023;5(2):e71-e82.