Management of relapsed

endometrial cancer after first-line

chemotherapy
Bradley J. Monk, MD, FACS, FACOG
Florida Cancer Specialists and Research Institute
Medical Director Late-Phase Clinical Research
West Palm Beach, FL 33401
bradley.monk@flcancer.com

Vice President and Member Board of Directors GOG-Foundation

Director GOG-Partners
bmonk@gog.org
 Commercial Interest What was received Role
Acrivon Honorarium Consultant
Adaptimmune Honorarium Consultant
Agenus Honorarium Consultant
Akeso Bio Honorarium Consultant
Amgen Honorarium Consultant
Aravive Honorarium Consultant
AstraZeneca Honorarium Speaker/Consultant
Bayer Honorarium Consultant
Clovis Honorarium Speaker/Consultant
Easai Honorarium Speaker/Consultant
Elevar Honorarium Consultant
EMD Merck Honorarium Consultant
Genmab/Seagen Honorarium Consultant

DECLARATION OF INTERESTS GOG Foundation

Gradalis
Heng Rui
Honorarium
Honorarium
Honrarium
Consultant
Consultant
Consultant
ImmunoGen Honorarium Consultant
Karyopharm Honorarium Consultant
Iovance Honorarium Consultant

Bradley J. Monk, MD Laekna Health Care

Merck
Honorarium
Honorarium
Consultant
Speaker/Consultant
Mersana Honorarium Consultant
Myriad Honorarium Consultant
Novartis Honorarium Consultant
Novocure Honorarium Consultant
OncoC4 Honorarium Consultant
Panavance Honorarium Consultant
Pieris Honorarium Consultant
Pfizer Honorarium Consultant
Puma Honorarium Consultant
Regeneron Honorarium Consultant
Roche/Genentech Honorarium Speaker/Consultant
Sorrento Honorarium Consultant
TESARO/GSK Honorarium Speaker/Consultant
US Oncology Research Honorarium Consultant
VBL Honorarium Consultant
Verastem Honorarium Consultant
Zentalis Honorarium Consultant
 Overview

▪ Updated clinical trial data from recent oncology and

gynecologic oncology conferences

▪ Case-based examples of tailoring therapy for patients

with EC

▪ Managing irAEs

▪ Working within a multidisciplinary team (MDT)

EC, endometrial cancer; irAE, immune-related adverse event.

 Case Study: Presentation

58-year-old woman with a BMI of 42 kg/m2

▪ Has a long history of intermittent vaginal spotting

▪ Ultrasound results:

• Enlarged uterus

• Endometrial thickness of 15 mm

• Multiple polyps

▪ CA-125 level is elevated at 400 U/mL

BMI, body mass index; CA-125, cancer antigen 125.

Case Study: Diagnosis

58-year-old woman with a BMI of 42 kg/m2

▪ Has a long history of intermittent vaginal spotting

▪ Ultrasound results:

• Enlarged uterus

• Endometrial thickness of 15 mm

• Multiple polyps

▪ CA-125 level is elevated at 400 U/mL

Biopsy results: Poorly differentiated grade 3 endometrioid carcinoma

 Molecular Profiling in Newly Diagnosed EC
ProMisE Molecular Classification Algorithm [1]
Recommended molecular
POLE missing
New Sample Unclassifiable profiling in newly
diagnosed EC[2]
▪ MMR status[2] (presence or
MMR IHC absence of MLH1, PMS2,
missing
Unclassifiable MSH2, and MSH6 proteins[3])
POLEmut ▪ POLE status (if feasible)[2]
or if status would influence
p53 IHC adjuvant treatment[3]
missing • May be lower priority for
Unclassifiable
dMMR very low-risk EC[3]
▪ p53 status[2]
▪ ER/PR expression[2]
▪ HER2 amplification[2]
NSMP/p53 wt p53 aberrant
dMMR, mismatch repair deficient; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; mut, mutated; NSMP, no specific molecular profile; pMMR, proficient
MMR; PR, progesterone receptor; TMB-H, tumor mutational burden-high; wt, wild type.
1. Walsh CS, et al. Gynecol Oncol. 2023;168:48-55; 2. NCCN®. Uterine Neoplasms (v1.2024). 2023. Accessed November 30, 2023. https://www.nccn.org/professionals/physician_gls/pdf/uterine .pdf; 3. Berg HG,
et al. Br J Cancer. 2023;128:647-655; 3. Jamieson A, et al. J Natl Compr Canc Netw. 2023;21:210-216.
 Tools for Biomarker Testing in EC

IHC FISH PCR DNA Testing

▪ ER/HR ▪ HER2 amplification ▪ MSI (PCR followed ▪ NGS for MSI, POLE,
by capillary or TMB or for
▪ HER2 amplification
electrophoresis on a comprehensive
▪ MMR proteins DNA sequencer) or genomic profiling
MLH1, MSH2, multiplex PCR
▪ Sanger sequencing
MSH6, and PMS2
▪ MLH1 promoter an option for POLE
▪ p53 methylation testing or other single genes
© Medscape, LLC

FISH, fluorescence in situ hybridization; MSI, microsatellite instability; NGS, next-generation sequencing; PCR, polymerase chain reaction; TMB, tumor mutational burden.
Walsh CS, et al. Gynecol Oncol. 2023;168:48-55.
 Predictive and Prognostic Value of Key Biomarkers
Application of Key Biomarkers in EC

FDA Approved Predictive of

Biomarker Prognostic
Biomarker in EC[1] Response[1]

dMMR (MSI-H) Yes Yes Intermediate[2]

ER+ POLE sits at the

ER/PR No Yes top of the testing
favorable[1]
hierarchy, followed
HER2+ No Yes Unfavorable[1] by dMMR[1]
p53 abnormal
p53 No Yes
unfavorable[1]

POLE No — Favorable[1]

FDA, US Food and Drug Administration; MSI-H, MSI-high.

1. Walsh CS, et al. Gynecol Oncol. 2023;168:48-55; 2. Berg HF, et al. Br J Cancer. 2023;128:647-655.
 Case Study: Hysteroscopy, Biopsy, and Imaging Results

58-year-old woman with grade 3

endometrioid carcinoma on biopsy

PET-CT scanning
found peritoneal
▪ ER/PR positive metastases
▪ dMMR/MSI-H (intact nuclear staining for MSH2 and MSH6
but deficient nuclear staining for MLH1 and PMS2)
▪ p53 wild type
▪ HER2 3+ gastric IHC scoring

PET-CT, positron emission tomography-computed tomography.

Case Study: Diagnosis

Stage IVB, grade 3

endometrioid EC
that is dMMR

LLC
ape,
©Meds c
 Phase 3 Trial of Pembrolizumab Plus Chemotherapy in EC
NRG-GY018 Study Design

Key eligibility criteria (N = 816) Pembrolizumab 200 mg

Pembrolizumab 400 mg
Carboplatin (AUC 5)
▪ Measurable stage III/IVA or (once every 6 weeks for
measurable/nonmeasurable Paclitaxel (175 mg/m²) up to 14 cycles)
stage IVB or recurrent EC (once every 3 weeks for 6 cycles)
(excluding carcinosarcoma)
▪ Known MMR status R
▪ Prior adjuvant chemotherapy 1:1
allowed if completed
≥ 12 months before study Placebo
Carboplatin (AUC 5) Placebo
Outcomes were stratified by (once every 6 weeks for
Paclitaxel (175 mg/m²)
dMMR (n = 225) vs pMMR up to 14 cycles)
(once every 3 weeks for 6 cycles)
(n = 591) status

Primary endpoint: PFS by investigator

Secondary endpoints: Safety, ORR, DOR, OS, PRO/QOL

AUC, area under the curve; DOR, duration of response; IV, intravenous; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PRO, patient-reported outcomes; QOL, quality of life.
Eskander RN, et al. Ann Oncol. 2023;34(2_suppl): Abstract LBA43; Eskander RN, et al. N Engl J Med. 2023;388:2159 -2170.
 Phase 3 Trial of Dostarlimab Plus Chemotherapy in Advanced EC
RUBY/ENGOT-EN6/GOG3031/NSGO Study Design

Dostarlimab 500 mg (n = 245)

Dostarlimab 1000 mg
Carboplatin (AUC 5)
Key eligibility criteria (once every 6 weeks for
Paclitaxel (175 mg/m²) up to 3 years)
▪ Stage III/IV or first recurrent EC (once every 3 weeks for 6 cycles)
(carcinosarcoma, clear cell,
serious, or mixed histology)
R
▪ Low potential for cure by RT or
1:1
surgery alone or combined
▪ No systemic therapy or Placebo (n = 249)
recurrence or PD ≥ 6 months Carboplatin (AUC 5) Placebo
after therapy Paclitaxel (175 mg/m²)
(once every 6 weeks for
up to 3 years)
(once every 3 weeks for 6 cycles)

Primary endpoints: PFS by investigator, OS

Secondary endpoints: PFS by BICR, PFS2, ORR, DOR, DCR, HR-QOL/PRO, safety

BICR, blinded independent central review; DCR, disease control rate; HR-QOL, health-related QOL; PD, progressive disease; RT, radiation therapy.
Mirza MR, et al. Ann Oncol. 2023;34(2_suppl): Abstract 740MO.
 PFS in dMMR Cohorts in the NRG-GY018 and RUBY Trials
RUBY[1] NRG-GY018[2]
dMMR

Pembro + CP

Probability of PFS
(n = 112)
Probability of PFS

Dostarlimab + CP (n = 53)
HR: 0.30
(95% CI: 0.19, 0.48)
HR: 0.28
(95% CI: 0.162, 0.495)
Placebo + CP (n = 65) Placebo + CP
(n = 113)

Months
Months

PFS outcomes in the dMMR cohort were similar in both trials, with a 70% reduction
in the risk of PD or death with pembrolizumab and a 72% reduction with dostarlimab
CP, carboplatin-paclitaxel; pembro, pembrolizumab.
1. Mirza MR, et al. Ann Oncol. 2023;34(2_suppl 2): Abstract 740MO; 2. Eskander RN, et al. N Engl J Med. 2023;388:2159-2170.
Implications
My Perspective

The latest clinical trial data support adding immunotherapy to

chemotherapy for patients with stage IV EC and dMMR. Dostarlimab
FDA approved in July 2034 for advanced and recurrent dMMR cases.

There are no head-to-head data comparing the addition of

dostarlimab vs pembrolizumab to CP in this setting

One consideration for treatment selection is that the RUBY trial

included patients with carcinosarcoma but the NRG-GY018 trial did not
 PFS Benefit by Histology in the RUBY Trial

No. of Events/Patients
Dostarlimab + Placebo +
Histology CP CP HR (95% CI) HR (95% CI)

Endometrioid carcinoma 64/130 89/136 0.65 (0.473, 0.902)

Carcinosarcoma 14/24 18/22 0.56 (0.278, 1.138)

Serous adenocarcinoma 36/55 35/48 0.65 (0.403, 1.035)

Other 21/36 35/43 0.58 (0.335, 0.997)

Dostarlimab + CP Better Placebo + CP Better

Mirza MR, et al. Ann Oncol. 2023;34(2_suppl): Abstract 740MO.

 PFS by Methylation Status in the dMMR Cohort in the NRG-GY018 Trial
Proportion of Patients Alive and Progression Free at Data Cutoff
Methylation Status
Methylation No Methylation Pembro + CP Arm
Median, mo (95% CI) Median, mo (95% CI) Median, mo
Placebo + CP 8.3 (4.4, NR)
(95% CI)
Placebo + CP 7.5 (6.4, 11.3)
No Methylation NR (14.2, NR)
Pembro + CP NR (22.3, NR) Pembro + CP NR (14.2, NR)
HR: 0.307 (95% CI: 0.19, 0.49) P < .0001 HR: 0.263 (95% CI: 0.07, 0.99) P = .0172 Methylation NR (22.3, NR)

100 100 100

90 90 Pembro + CP 90 No Methylation
80 80
(n = 13) 80 (n = 13)
Patients, %

Patients, %
Patients, %

70 70 70
Pembro + CP
60 (n = 83) 60 60
50 50 50
40 40 40 Methylation
30 30 30 (n = 63)
20 20 Placebo + CP 20
Placebo + CP
10 10 (n = 17) 10
(n = 77)
0 0 0
0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Months Months Months
NR, not reached.
Eskander RN, et al. Ann Oncol. 2023;34(2_suppl): Abstract LBA43.
 OS in the dMMR Cohorts of the RUBY and NRG-GY018 Trials

Median duration of follow- OS data for the dMMR cohort

up in the dMMR cohorts are not ripe for NRG-GY018[2]
▪ 24.8 months in RUBY[1] and showed a trend toward
▪ 12 months in NRG-GY018[2] superiority with dostarlimab
in RUBY (HR 0.30)[1]

1. Mirza MR, et al. Ann Oncol. 2023;34(2_suppl): Abstract 740MO; 2. Eskander RN, et al. N Engl J Med. 2023;388:2159 -2170.
 OS in the dMMR Cohorts of the RUBY and NRG-GY018 Trials

Median duration of follow- OS data for the dMMR cohort

up in the dMMR cohorts are not ripe for NRG-GY018[2]
▪ 24.8 months in RUBY[1] and showed a trend toward
▪ 12 months in NRG-GY018[2] superiority with dostarlimab
in RUBY (HR 0.30)[1]

▪ Per updated NCCN guidelines for stage III-IV EC, pembrolizumab/CP and dostarlimab/CP are the
preferred ICI regimens in the primary/adjuvant setting and as first-line therapy for recurrent EC[3]
▪ Pembrolizumab/CP should not be used to treat carcinosarcoma[3]
ICI, immune checkpoint inhibitor.
1. Mirza MR, et al. Ann Oncol. 2023;34(2_suppl): Abstract 740MO; 2. Eskander RN, et al. N Engl J Med. 2023;388:2159 -2170; 3. NCCN®. Uterine Neoplasms (v.1.2024). 2023. Accessed December 3, 2023.
https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf
Case Study: What If the Patient Had pMMR EC?

Patient is a 58-year-old woman

with newly diagnosed stage
IVB endometrioid carcinoma
that is pMMR
 PFS According to Molecular Subgroup in the RUBY Trial

Probability of PFS
Dostarlimab + CP (n = 2) 100%
Probability of PFS

dMMR/MSI-H
100%
POLE mut

Placebo + CP (n = 3)
57.0%
Dostarlimab + CP (n = 39)

Placebo + CP (n = 52) 10.2%

Months Months
Probability of PFS

Probability of PFS
TP53 mut

NSMP
Dostarlimab + CP (n = 47)
Dostarlimab + CP (n = 103)
32.4% 31.0%

Placebo + CP (n = 113)
Placebo + CP (n = 41) 17.8% 20.1%

NA, not available. Months Months

Mirza MR, et al. Ann Oncol. 2023;34(2_suppl): Abstract 740MO.
 Phase 3 Trial of Atezolizumab Plus Chemotherapy in Advanced EC
ATTEND Study Design

Key eligibility criteria (N = 551) Atezolizumab 1200 mg Maintenance

▪ Stage III/IV or newly diagnosed or Carboplatin (AUC 5 or 6) atezolizumab 1200 mg
recurrent EC or carcinosarcoma Paclitaxel (175 mg/m²) until PD
▪ No prior systemic chemotherapy
for recurrence
R
▪ One prior platinum-based regimen 2:1
allowed with platinum-free interval
≥ 6 months
Placebo
Outcomes were stratified by Carboplatin (AUC 5 or 6) Maintenance placebo
pMMR vs dMMR status vs until PD
Paclitaxel (175 mg/m²)
nonevaluable status

Endpoints PFS dMMR IF POSITIVE PFS All IF POSITIVE OS All

(hierarchical order) α (2-sided) 4% α = 4% α (2-sided) 4% α = 4% α (2-sided) 5%
HR 0.5 HR 0.7 HR 0.7
Colombo N, et al. Ann Oncol. 2023;34(2_suppl): Abstract LBA40.
 Phase 3 Trial of Atezolizumab Plus Chemotherapy in Advanced EC
PFS in the dMMR Cohort and in All Comers

PFS in the dMMR Cohort PFS in All Comers

Patients, %
Patients, %

HR 0.74
(95% CI: 0.61, 0.91) P = .0219
HR 0.36
(95% CI: 0.23, 0.57) P = .0005

Months Months

PFS outcomes were significantly improved in the atezolizumab arms overall and in the dMMR
subset, but there was no significant difference between arms in overall OS (HR 0.82)
Colombo N, et al. Ann Oncol. 2023;34(2_suppl): Abstract LBA40.
 Phase 3 Trial of Atezolizumab Plus Chemotherapy in Advanced EC
PFS and OS in the pMMR Cohort
PFS in the pMMR Cohort OS in the pMMR Cohort

77.8%
Patients, %

HR 0.92 77.3% 57.4%

Patients, %
(95% CI: 0.73, 1.16)
39.5% 58.3%

21.3%
30.2% HR 1.00
16.4% (95% CI: 0.74, 1.35

Months Months

PFS and OS benefit with atezolizumab are largely driven by the dMMR population

Colombo N, et al. Ann Oncol. 2023;34(2_suppl): Abstract LBA40.

 Homologous Recombination Repair Deficiency (HRD) in EC

HRD promotes upregulation of PD-1 and PD-L1[1]

Preclinical data show synergy between PARP inhibitors and anti-PD-1/PD-L1 antibodies[2]

HRD is highly prevalent in EC (prevalence varies from 15% to 53%)[3]

HRD appears to be more common in non-endometrioid histology and p53-mutated EC[4,5]

ARID1A, ATM, ATRX, and BRCA1/2 are the most common HRD defects in EC[6]
PTEN is the most common mutation in endometrioid EC, [5] and PTEN loss may promote HRD[7]

The clinical significance of HRD in EC is still being elucidated [3,5]

PARP, poly (ADP-ribose) polymerase; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1.
1. Musacchio L, et al. Cancer Manag Res. 2020;12:6123-6135; 2. Musacchio L, et al. ESMO Open. 2022;7:100536; 3. Corr B, et al. BMJ Med. 2022;1:e000152; 4. de Jonge MM, et al. Clin Cancer Res.
2019;25:1087-1097; 5. Siedel JH, et al. Gynecol Oncol. 2021;160:777-785; 6. Heeke AL, et al. JCO Precis Oncol. 2018:2018:PO.17.00286; 7. Madariaga A, et al. Nat Commun. 2023;14:1452.
 Phase 3 DUO-E/GOG-3041/ENGOT-EN10 Trial of Durvalumab Plus CP in
Advanced EC With Maintenance Durvalumab and Olaparib: Study Design
Key eligibility criteria (N = 718) 6 CYCLES INDUCTION MAINTENANCE
▪ Newly diagnosed stage III/IV Placebo (for durvalumab)
or recurrent EC (excluding Control Placebo (for durvalumab
Carboplatin (AUC 5 or 6) and olaparib)
sarcomas)
Paclitaxel (175 mg/m²)
▪ Known MMR status
▪ No prior systemic
chemotherapy for recurrence Durvalumab 1120 mg
R Durva Durvalumab 1500 mg
▪ Adjuvant chemotherapy 1:1:1
Carboplatin (AUC 5 or 6)
Placebo (for olaparib)
allowed Paclitaxel (175 mg/m²)
if ≥ 12 months from last
treatment to relapse
▪ No prior PARP inhibitor or Durvalumab 1120 mg
Durva + Ola Olaparib 300 mg twice a day
immunotherapy Carboplatin (AUC 5 or 6)
Durvalumab 1500 mg
Paclitaxel (175 mg/m²)

Primary endpoints: PFS by investigator (Durva vs Control and Durva + Ola vs Control)
Secondary endpoints: OS, safety
Exploratory: PFS in Durva + Ola vs Durva, subgroup analyses of PFS
Durva, durvalumab; Ola, olaparib.
Westin SN, et al. Ann Oncol. 2023;34(2_suppl): Abstract LBA41.
 Phase 3 DUO-E/GOG-3041/ENGOT-EN10 Trial
PFS in the Intent-to-Treat Population
100
12 mo Relative to placebo, adding olaparib to
90
61.5% durvalumab resulted in greater PFS than
80
18 mo
48.5% 46.3% durvalumab alone (HR 0.55 vs 0.71)
Patients, %

70
41.1% 37.8%
60

50 21.7%
40
Durva + Ola (n = 239)
30

20
Durva (n = 238)
10 Control (n = 241)
0
0 3 6 9 12 15 18 21 24 27 30 33

Months

Control Durva Durva + Ola

Median PFS, mo 9.6 10.2 15.1
HR (95% CI) vs Control 0.71 (0.57, 0.89); P = .003 0.55 (0.43-0.69); P < .0001
HR (95% CI) vs Durva 0.78 (0.61, 0.99)
Westin SN, et al. Ann Oncol. 2023;34(2_suppl): Abstract LBA41.
 Phase 3 DUO-E/GOG-3041/ENGOT-EN10 Trial
PFS by MMR Status (Prespecified Exploratory Analysis)
PFS in the dMMR Cohort PFS in the pMMR Cohort
(20% of population) (80% of population)
12 mo 18 mo Adding olaparib to durvalumab improved PFS
100
70.0% 62.7% 12 mo
67.9% 67.9% 100
90 59.4% 18 mo
90
80 43.3% 31.7% 80 44.4% 42.0%
Patients, %

70

Patients, %
Durva + Ola (n = 49) 70
60 40.8% 31.3%
60
50
50
20.0%
40
Durva (n = 46) Durva + Ola (n = 191)
40
30 30
Control (n = 48)
20 20 Durva (n = 192)
10 10
0
Control (n = 192)
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Months Months
Control Durva Durva + Ola Control Durva Durva + Ola
Median PFS 7.0 NR 31.8 Median PFS 9.7 9.9 15.0
HR (95% CI) vs Control 0.42 (0.22-0.80) 0.41 (0.21-0.75) HR (95% CI) vs Control 0.77 (0.60-0.97) 0.57 (0.44-0.73)
HR (95% CI) vs Durva 0.97 (0.49-1.98) HR (95% CI) vs Durva 0.76 (0.59-0.99)
Westin SN, et al. Ann Oncol. 2023;34(2_suppl): Abstract LBA41.
 Phase 3 DUO-E/GOG-3041/ENGOT-EN10 Trial
PFS Subgroup Analysis for Durva + Ola vs Control
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 diagnosed 0.47 (0.33, 0.66) 58/114 (50.9) 81/115 (70.4)
Recurrent disease 0.59 (0.43, 0.81) 68/125 (54.4) 92/126 (73.0)
MMR status
Proficient tumours 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 (TAP score <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
Favours Durva + Ola Favours Control

Westin SN, et al. Ann Oncol. 2023;34(2_suppl): Abstract LBA41.

Implications of the Data in pMMR EC

The treatment of pMMR tumors still represents

an unmet need that we need to further explore.
— Dr Monk
 Treat pMMR EC According to Guidelines/FDA Approvals

NCCN guidelines include dostarlimab/CP and pembrolizumab/CP as category 1

regimens for primary therapy, and either is an option for pMMR EC a

NCCN guidelines for systemic therapy do not include atezolizumab/CP or the

durvalumab/olaparib/CP regimen, and more data are needed to confirm efficacy

aPembrolizumab is not recommended for patients with carcinosarcoma.

NCCN®. Uterine Neoplasms (v.1.2024). 2023. Accessed November 30, 2023. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf
 Safety Findings From the NRG-GY018, RUBY, ATTEND, and DUO-E Trials

irAEs in NRG-GY018 dMMR Cohort[1] irAEs in RUBY dMMR Cohort[2]

Grade Placebo + CP (n = 106) Pembro + CP (n = 109) Placebo + CP Dostarlimab + CP
Grade
≥ 10% in Infusion reaction (15), Infusion reaction (15), (n = 65) (n = 53)
any arm hypothyroidism (9) hypothyroidism (13)
irAE, % 38 15
Grade 3 Infusion reaction (3), Infusion reaction (4),
pneumonitis (1), acute pneumonitis (2), acute Most Hypothyroidism (3), Hypothyroidism (11),
kidney injury (2), hepatic kidney injury (2), hepatic common, % rash (2), arthralgia (7), rash (7), arthralgia (6),
failure (0) failure (1) ALT increase (1) ALT increase (6)

AEs in ≥ 20% of Patients in ATTEND[3] Grade ≥ 3 AEs in DUO-E (Chemo + Maintenance)[4]

Placebo + CP (n = 185) Atezolizumab + CP (n = 356) Control Durva Durva + Ola
AEs
Anemia (35), fatigue (41), Anemia (41), fatigue (39), (n = 236) (n = 235) (n = 238)
neutropenia (39), PSN (40), neutropenia (40), PSN (38), ≥ 20% in Neutropenia Neutropenia Neutropenia
nausea (37), alopecia (36), nausea (34), alopecia (32), any arm (23), anemia (22), anemia (27), anemia
thrombocytopenia (27), thrombocytopenia (28), (14) (16) (24)
constipation (27), arthralgia constipation (28), arthralgia
(27), diarrhea (19) (25), diarrhea (21) AESI, % PRCA (0), PRCA (0), PRCA (1),
AIHA (0) AIHA (0.4) AIHA (0.8)
AESI, AE of special interest; AIHA, autoimmune hemolytic anemia; ALT, alanine aminotransferase; PN, peripheral neuropathy; PRCA, pure red cell aplasia; PSN, peripheral sensory neuropathy.
1. Eskander RN, et al. N Engl J Med. 2023;388:2159-2170; 2. Mirza MR, et al. Ann Oncol. 2023;34(2_suppl): Abstract 740MO; 3. Colombo N, et al. Ann Oncol. 2023;34(2_suppl): Abstract LBA40; 4. Westin SN, et
al. Ann Oncol. 2023;34(2_suppl): Abstract LBA41.
 irAEs Can Happen at Any Time and Affect Any Organ System
Encephalitis
Aseptic meningitis Uveitis
▪ Although irAEs most often Hypophysitis

affect the skin, gut, endocrine Thyroiditis

Dry mouth
Mucositis
organs, liver, and lungs, they Hypothyroidism
Hyperthyroidism
can affect any organ Myocarditis
system [1,2]
Pneumonitis Colitis
Enteritis
▪ The onset of most irAEs is
within weeks to months after Hepatitis Rash
Vitiligo
starting an ICI regimen[1] Autoimmune
Diabetes
Pancreatitis
▪ Late-onset of irAEs is Arthralgia
Thrombocytopenia
possible, with the first onset Anemia C

edscape, LL
documented up to 1 year Vasculitis Neuropathy

after discontinuation[1]

©M
1. Haanen JB, et al. Ann Oncol. 2017;28:iv119-iv142; 2. Postow MA, et al. N Engl J Med. 2018;378:158-168.
 General Principles of irAE Management

Be suspicious of any
Refer to ASCO and Consult closely with
unusual symptom and
NCCN guidelines pertinent subspecialists
work up promptly

Grade 1: asymptomatic Grade 2: moderate Grade 3: severe Grade 4:

to mild symptoms symptoms symptoms life-threatening
▪ Monitor closely (no ▪ Consider holding ICI ▪ Stop ICI promptly ▪ Permanently
intervention needed) until improvement to ▪ Start high-dose oral discontinue ICI except
▪ Continue ICI in most grade ≤ 1 steroids with ≥ 4- to for some controlled
cases (except for some ▪ Start oral steroids (0.5- 6-week taper endocrinopathies
cardiac, neurologic, or 1 mg/kg/d prednisone ▪ Consider admitting ▪ Initiate high-dose IV
hematologic toxicities) or equivalent) ▪ If no improvement in steroids in most cases
▪ Investigate as a 48 to 72 hours, may ▪ Hospitalization
potential irAE add another immuno- required (ICU may
suppressive agent be indicated)
▪ ICI rechallenge may
be possible
ASCO, American Society of Clinical Oncology; ICU, intensive care unit.
Schneider BJ, et al. J Clin Oncol. 2021;39:4073-4126; NCCN®. Management of immunotherapy-related toxicities (v3.2023). 2023. Accessed November 21, 2023.
https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf
 Managing irAEs Requires a Multidisciplinary Approach

Engage wider members of the MDT[1,2]

Identify relevant medical subspecialists (beyond
Endocrinologist Oncologist GI Specialist Pulmonologist medical oncologists) who are interested, able,
and willing to assist in managing irAEs

Cardiologist Ophthalmologist Nephrologist Specialty Rely on the team at your institution

Nurse
Beyond the oncologist, NP, and PA, involve the
infusion team, palliative care/symptoms team,
GI team, and others to optimize care

Pharmacist Psychosocial Dermatologist Rheumatologist

Support
GI, gastrointestinal; NP, nurse practitioner; PA, physician assistant.
1. Cheema PK, et al. Curr Oncol. 2022;29:869-880; 2. Cole S, et al. Am Soc Clin Oncol Educ Book. 2019;39:96-104.
Case Study: What If Patient Had Recurrence Without Prior ICI Use?

Patient is a 58-year-old woman with

stage IVB dMMR endometrioid
carcinoma that recurred after
6 cycles of adjuvant CP
 ICI Monotherapy Options for Recurrent EC With dMMR
NCCN Guideline Options for Recurrent EC With dMMR[1] and Supporting Data [3,5,7,9]
ICI (FDA Indication NCCN
Trial (dMMR Cohort) Efficacy Limitations
Y/N) Recommendation[1]
≥ second line, Phase 2 ORR 26.7%, Small cohort,
Avelumab (N)[2]
dMMR (n = 15)[3] PFS6 40.0%[3] single arm [3]
Single arm,
Phase 1 GARNET ORR 43.5% at median
Dostarlimab (Y)[4]a ≥ first line, dMMR immature
(n = 129)[5] follow-up of 16.3 mo[5]
data[5]
≥ second line, Phase 2 NCI-Match Small cohort,
Nivolumab (N)[6] 2 CR in EC[7]
dMMR (n = 13)[7] single arm [7]
ORR 48.0% (14.0%
Pembro (Y)[8]a Phase 2 KEYNOTE-158
≥ first line, dMMR CR), median PFS Single arm [9]
(n = 79)[9]
13.1 mo[9]

All trials reported manageable toxicities consistent with the ICI’s known safety profile [3,5,7,9]
aNCCN preferred first-line regimen (category 1) includes carboplatin and paclitaxel for patients who have not received platinum-based chemotherapy.[1]
CR, complete response; N, no; PFS6, PFS ≥ 6 months; Y, yes.
1. NCCN®. Uterine Neoplasms (v.1.2024). 2023. Accessed December 3, 2023. https://www.nccn.org/professionals/physician_gls/pdf/uterine .pdf; 2. Avelumab [PI]. Approved 2017. Revised September 2023; 3.
Konstantinopoulos PA, et al. J Clin Oncol. 2019;37:2786-2794; 4. Dostarlimab [PI]. Approved 2021. Revised July 2023; 5. Oaknin A, et al. J Immunother Cancer. 2022;10:e003777; 6. Nivolumab [PI]. Approved
2014. Revised October 2023; 7. Azad NS, et al. J Clin Oncol. 2020;38:214-222; 8. Pembrolizumab [PI]. Approved 2014. Revised November 2023; 9. O’Malley DM, et al. J Clin Oncol. 2020;40:752-761.
 Keynote-775: 2L+ Lenvatinib +
Pembrolizumab
Lenvatinib + Pembrolizumab in previously treated advanced endometrial cancer

Key eligibility criteria

• Advanced, metastatic, or recurrent Lenvatinib
endometrial cancer 20 mg PO QD Primary endpoints
• Measurable disease by BICR + • PFS by BICR
• One prior platinum-based CTa Pembrolizumab b • OS
• ECOG PS 0-1 200 mg IV Q3W
Secondary endpoints
• Tissue available for MMR testing
• ORR
R Treat until progression or
unacceptable toxicity • HRQoL
(1:1)
Stratification factors • Pharmacokinetics
MMR status (pMMR vs dMMR) and Doxorubicin • Safety
further stratification within pMMR by: 60 mg/m2 IV Q3Wc Key exploratory endpoint
• Region (1: Europe, USA, Canada, or
Australia, New Zealand, and Israel vs 2: Paclitaxel • Duration of response
rest of the world) 80 mg/m2 IV QW
• ECOG PS (0 vs 1) (3 weeks on/1 week off)
• Prior history of pelvic radiation (Y vs N)

Patients may have received up to 2 prior platinum-based CT regimens if 1 was given in the neoadjuvant or adjuvant treatment setting; bmaximum of 35 doses; cmaximum cumulative dose of 500 mg/m 2
a

Makker, V, et al. SGO March 2023.

 Keynote-775: Baseline Characteristics in pMMR and All-
Comers Lenvatinib Plus Pembrolizumab Chemotherapy
Characteristic
All-Comer Population (n= All-Comer Population (n =
pMMR (n= 346) pMMR (n= 351)
411) 416)
Age, years, median (range) 65 (30-82) 64 (30-82) 66 (35-86) 65 (35-86)
Age , 65 years, No. (%) 171 (49.4) 206 (50.1) 165 (47.0) 204 (49.0)
Race, No. (%)b
White 220 (63.6) 261 (63.5) 212 (60.4) 247 (59.4)
Black or African Americans 15 (4.3) 17 (4.1) 9 (2.6) 14 (3.4)
Asian 74 (21.4) 85 (20.7) 80 (22.8) 92 (22.1)
Geographic region, No. (%)c
Region 1 202 (58.4) 234 (56.9) 204 (58.1) 240 (57.7)
Region 2 144 (41.6) 177 (43.1) 147 (41.9) 176 (42.3)
Mismatch repair status, No. (%)
Mismatch repair–proficient - 346 (84.2) - 351 (84.4)
Mismatch repair–deficient NA 65 (15.8) NA 65 (15.6)
ECOG PS, No. (%)d
0 212 (61.3) 246 (59.9) 207 (59.0) 241 (57.9)
1 133 (38.4) 164 (39.9) 144 (41.0) 175 (42.1)
History of pelvic irradiation, No. (%) 144 (41.6) 176 (42.8) 149 (42.5) 187 (45.0)
Histologic features at initial diagnosis, No. (%)e
Endometrioid carcinoma 189 (54.6) 244 (59.4) 198 (56.4) 254 (61.1)
High-grade 73 (21.1) 94 (22.9) 77 (21.9) 90 (21.6)
Low-grade 50 (14.5) 59 (14.4) 41 (11.7) 54 (13.0)
Not specifiedf 66 (19.1) 91 (22.1) 80 (22.8) 110 (26.4)
Serous carcinoma 99 (28.6) 103 (25.1) 112 (31.9) 115 (27.6)
Clear cell carcinoma 29 (8.4) 30 (7.3) 17 (4.8) 17 (4.1)
Mixed features 18 (5.2) 22 (5.4) 13 (3.7) 16 (3.8)
Makker, V, et al. JCO July 2023.
 pMMR Population All- Comers Population
100 Censored Median OS (95% CI) 100 Censored Median OS (95% CI)

Lenvatinib plus 18.0 months Lenvatinib plus 18.7 months

pem brolizumab (14.9–20.5) pem brolizumab (15.6–21.3)

Patients Who Were Alive (%)

80 12.2 months 80 11.9 months
Chem otherapy Chem otherapy
(11.0–14.1) (10.7–13.3)

HR for death, 0.70 (95% CI, 0.58–0.83) HR for death, 0.65 (95% CI, 0.55–0.77)

60 60

Lenvatinib Plus Lenvatinib Plus

40 Pembrolizumab 40 Pembrolizumab

20 20
Chemotherapy Chemotherapy
0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Time (Months) Time (Months)

No. at risk No. at risk

Lenvatinib Lenvatinib
Plus 346 322 285 242 214 188 171 148 124 95 65 41 20 7 2 Plus 411 383 337 292 258 229 211 186 160 125 91 58 30 10 2
Pembrolizumab Pembrolizumab
Chemotherapy 351 324 267 217 171 138 111 86 71 53 40 21 6 3 1 Chemotherapy 416 378 305 246 196 158 129 104 84 64 49 28 6 3 1

Makker, V, et al. JCO July 2023.

 pMMR Population All-Comers Population

100 Censored Median PFS (95% CI) 100 Censored Median PFS (95% CI)

Patients Without Progression (%)

Lenvatinib plus 6.7 months Lenvatinib plus 7.3 months
pem brolizumab (5.6–7.4) pem brolizumab (5.7–7.6)

80 3.8 months 80 3.8 months

Chem otherapy Chem otherapy
(3.6–5.0) (3.6–4.2)

HR for progression or death, HR for progression or death,

0.60 (95% CI, 0.50–0.72) 0.56 (95% CI, 0.48–0.66)
60 60

40 40
Lenvatinib Plus Lenvatinib Plus
Pembrolizumab Pembrolizumab
20 20
Chemotherapy Chemotherapy
0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Time (Months) Time (Months)

No. at risk No. at risk

Lenvatinib Lenvatinib
Plus 346 265 166 116 80 61 55 43 36 24 18 14 6 4 0 Plus 411 317 203 148 109 87 79 65 57 45 35 23 10 4 0
Pembrolizumab Pembrolizumab
Chemotherapy 351 177 83 38 23 16 12 9 6 4 3 3 1 0 0 Chemotherapy 416 214 95 43 27 19 15 11 8 6 5 5 1 0 0

Makker, V, et al. JCO July 2023.

 Lenvatinib Plus Pembrolizumab for Previously Treated Advanced EC
Phase 3 KEYNOTE-775/Study 309
Final Outcomes in the pMMR Cohort (n = 697)

Lenvatinib +
Outcome Chemotherapya
Pembrolizumab
▪ Patients had measurable
ORR (CR), % 32.4 (5.8) 15.1 (2.6) advanced EC after ≥ 1 line of
platinum-based therapy
Median OS, mo 18.0 12.2
▪ The ORR was more than
Median PFS, mo 6.7 3.8 double in the lenvatinib
pembrolizumab arm than in
Median DOR, mo 9.3 5.7
the chemotherapy arm

TRAE ≥ 3, % 78.8 60.1

a. Physician’s choice of doxorubicin or paclitaxel.

TRAE, treatment-related adverse event.
Makker V, et al. J Clin Oncol. 2023;41:2904-2910.
 Lenvatinib + Pembrolizumab in previously treated advanced endometrial cancer
Adverse events of any cause with incidence of 25%+ among all patients in either treatment arm
Lenvatinib plus Pembrolizumab Chemotherapy
(N - 406) (N = 388)
Event
Any Grade Grade ≥3* Any Grade Grade ≥3*
Any adverse event 405 (99.8) 361 (88.9) 386 (99.5) 282 (72.7)
Hypertension† 260 (64.0) 154 (37.9) 20 (5.2) 9 (2.3)
Hypothyroidism†‡ 233 (57.4) 5 (1.2) 3 (0.8) 0
Diarrhea 220 (54.2) 31 (7.6) 78 (20.1) 8 (2.1)
Nausea 201 (49.5) 14 (3.4) 179 (46.1) 5 (1.3)
Decreased appetite 182 (44.8) 32 (7.9) 82 (21.1) 2 (0.5)
Vomiting 149 (36.7) 11 (2.7) 81 (20.9) 9 (2.3)
Weight decrease 138 (34.0) 42 (10.3) 22 (5.7) 1 (0.3)
Fatigue 134 (33.0) 21 (5.2) 107 (27.6) 12 (3.1)
Arthralgia 124 (30.5) 7 (1.7) 31 (8.0) 0
Proteinuria† 117 (28.8) 22 (5.4) 11 (2.8) 1 (0.3)
Anemia 106 (26.1) 25 (6.2) 189 (48.7) 57 (14.7)
Constipation 105 (25.9) 3 (0.7) 96 (24.7) 2 (0.5)
Urinary tract infection 104 (25.6) 16 (3.9) 39 (10.1) 4 (1.0)
Neutropenia 30 (7.4) 7 (1.7) 131 (33.8) 100 (25.8)
Alopecia 22 (5.4) 0 120 (30.9) 2 (0.5)

Makker, V, et al. NEJM 2022.

 Dose Modification of Lenvatinib When Used With Pembrolizumab
to Treat EC
Recommended Lenvatinib Dose Reductions for Toxicity
Starting dose First reduction Second reduction Third reduction
20 mg once daily 14 mg once daily 10 mg once daily 8 mg once daily

Grade Withhold Until Improved or Resolved (See PI) Permanently Discontinue

▪ ATE, GI perforation, hepatic failure, or
nephrotic syndrome
Any ▪ Proteinuria, QT prolongation, or RPLS
▪ Consider for severe/persistent renal
impairment or hepatotoxicity
2 or 3 ▪ Persistent or intolerable AEs
3 ▪ Cardiac dysfunction or hypertension

3 or 4 ▪ Hepatotoxicity, renal failure/impairment ▪ Fistula formation

4 ▪ Laboratory abnormality ▪ Cardiac dysfunction or hypertension

ATE, arterial thromboembolic events; PI, prescribing information; RPLS, reversible posterior leukoencephalopathy syndrome.
Lenvatinib [PI]. Approved 2015. Revised October 2023.
 Case Study: What If the Patient Had USC Recurrence After ICI Use?

Patient is a 58-year-old woman with

stage IV USC (HER2 3+) whose
disease recurred after primary
therapy with 6 cycles of CP plus an
ICI and maintenance ICI

USC, uterine serous carcinoma.

 Phase 2 Randomized Trial of Trastuzumab Plus CP for Advanced
or Recurrent USC
▪ Eligible patients had HER2-positive (IHC 2+/3+) advanced or recurrent serous carcinoma (N = 58)
▪ The addition of trastuzumab significantly prolonged PFS and OS in patients with advanced USPC
▪ A preliminary analysis found similar rates of toxicity in both treatment arms
▪ Limitations include the small number of patients and the older median patient age in the control arm

PFS in Treatment-Naive Advanced USC PFS in All Eligible Patients

Proportion Progression Free

Proportion Progression Free

HR 0.436 HR 0.462
(90% CI: 0.229, 0.830) (90% CI: 0.279, 0.765)
One-sided P = .015 One-sided P = .005
Trastuzumab + CP

CP Only Trastuzumab + CP
CP Only

Months Months
Fader AN, et al. Clin Cancer Res. 2020;26:3928-3935.
 DESTINY-PanTumor02 Trial of T-DXd in HER2-Positive Tumors
EC Cohort
Confirmed ORR in EC
Phase 2 Open-Label Trial
90 84.6
80 Eligibility (n = 40)
70
57.5 ▪ Locally advanced or metastatic EC
Patients, %

60
47.1 ▪ HER2-positive (IHC 2+/3+)
50
40 ▪ At least 1 systemic treatment or no options
30 (77.5% of patients had ≥ 2 prior lines of
20 therapy)
10
0 Treatment
All IHC3+ IHC2+
(n = 40) (n = 13) (n = 17) ▪ T-DXd 5.4 mg/kg once every 3 weeks
TRAEs
In the EC cohort, median PFS ▪ Grade ≥ 3: 35%
was 11.1 months and median
▪ Two deaths, including one from
OS was 26.0 months
ILD/pneumonitis
ILD, interstitial lung disease; T-DXd, trastuzumab deruxtecan.
Meric-Bernstam F, et al. J Clin Oncol. 2023. doi:10.1200/JCO.23.02005 [Epub ahead of print]
 Implications of the DESTINY-PanTumor02 Trial for EC

T-DXd is an ADC and is not FDA-approved for EC

NCCN guidelines list T-DXd as a second-line option for HER2-positive (IHC 3+/2+) EC[1]

More data are needed to confirm the findings[2]

Study is limited by the small number of EC patients and its single-arm, open-label design

Other ADCs with molecular various targets are being studied in EC

Targeting FRα: luveltamab tazide and farletuzumab ecteribulin[3]; targeting TROP2:
sacituzumab govitecan and SKB264 [3]; targeting HER2: T-Duo[3] and DB-1303[4]

ADC, antibody drug conjugate; FR, folate receptor; T-duo, trastuzumab duocarmazine; TROP2, trophoblast cell surface antigen 2.
1. NCCN®. Uterine Neoplasms (v.1.2024). 2023. Accessed December 3, 2023. https://www.nccn.org/professionals/physician_gls/pdf/uterine .pdf; 2. Meric-Bernstam F, et al. J Clin Oncol. 2023.
doi:10.1200/JCO.23.02005 [Epub ahead of print]; 3. McNamara B, et al. Int J Womens Health. 2023;15:1353-1365; 4. Moore KN, et al. J Clin Oncol. 2023;41(16_suppl): Abstract 3023.
Key Take-Home Points

Patients with dMMR should receive immunotherapy

ICI plus CP in the frontline or single-agent ICI for recurrent EC if ICI naive

Patients with pMMR still require frontline chemotherapy

Many questions remain (eg, should bevacizumab or an ICI be added to CP)

Efficacy of immunotherapy is less robust in pMMR than in dMMR EC

Promising data were reported with a PARP inhibitor plus an ICI in EC with pMMR

In 2-L pMMR ICI naive recurrent EC

Pemrolizumab plus lenvatinib is approved in several countries (including FDA
and EMA) and regions as well as NCCN recomended
 Florida Cancer Specialists: Research and Clinical Trials
Majority of new cancer drugs approved for use in U.S.
were studied in clinical trials with FCS’ participation.
Over 160 highly-trained specialists & staff
Well-established relationships with companies at
forefront of developing new therapies

Research Office 3 Phase 1 Drug

Locations in 21 Counties Development Units

Patients That Have Patients Treated

More than
11,000 Accessed Novel
Therapies Through
the DDU to Date
Per Year on
Clinical Trials

2,700
300
trials available at Patients Enrolled
any given time Since Inception of the
Research Program 600+