Dr. Jennifer Mueller, gynecologic cancer surgeon at Memorial Sloan Kettering Cancer Center, will share research updates on uterine/endometrial cancer and other new developments in treatment and surgery.

1. New treatments for endometrial
cancer
A 2020 research update
Jennifer Mueller, MD, FACOG
Assistant Attending, Department of Surgery
Memorial Sloan Kettering Cancer Center

2. •Background facts on endometrial cancer
• Brief review
•Treatment strategies and research updates
• Early stage disease
• Advanced stage and recurrent disease
• Highlights from the Society of Gynecologic Oncology 2020 Conference
•Future directions
• Clinical trials that are ongoing

3. Endometrial cancer basics

4. Endometrial Cancer
• Most common gynecologic cancer
• Arises in the lining of the uterus
• Over 65,000 new cases in 2020
SEER.cancer.gov/statfacts/
Cancer.gov/images

5. Endometrial cancer incidence is increasing
SEER.cancer.gov/statfacts/

6. Endometrial cancer most frequently
diagnosed in women aged 55-64
SEER.cancer.gov/statfacts/

7. Two thirds of women will present with stage I
SEER.cancer.gov/statfacts/

8. Patients with stage I endometrial cancer have
an excellent prognosis
SEER.cancer.gov/statfacts/

9. Treating endometrial cancer
• Surgery is the mainstay of treatment
• Surgery provides staging information
• Guides next steps in treatment

10. 10
We used to remove all the lymph nodes.

11. 11
Now we remove the lymph node that matters.
Sentinel Lymph Node Mapping

12. Treatment of early stage endometrial cancer

13. Determining treatment after surgery
• Are there risk factors for recurrence?
• Age
• Grade of the tumor cells (low grade versus high grade)
• Invasion into uterine wall (inner versus outer half)
• Lymphovascular invasion (present or absent)
• Stage of the cancer (where it has spread)
• Will offering treatment after surgery improve outcome?
• Goal of treatment: to reduce the risk of cancer ever coming back

14. Cell types in endometrial cancer
• ‘Low grade’ cell types
• Endometrioid, grade 1 and 2
• ‘High grade’ cell types
• Endometrioid, grade 3
• Serous
• Undifferentiated
• Clear Cell
• Carcinosarcoma
• Mixed cell types

15. Grade is different from Stage
https://www.foundationforwomenscancer.org/

16. General guidelines for treatment after surgery
(early stage)
• “Low-risk”
• Low grade, <50% uterine wall invasion, no lymphovascular invasion
• No additional treatment
• “Intermediate-risk”
• Low grade, ≥50% uterine wall invasion, no lymphovascular invasion
• Vaginal radiation
• “High intermediate risk”
• (1) endometrioid grade 3, <50% uterine wall invasion (2) low grade with lymphovascular invasion
• Recurrence risk ~25% without treatment after surgery
• Vaginal radiation, sometimes pelvic radiation
• Uncertain benefit to chemotherapy
• “High risk”
• (1) endometrioid grade 3 with ≥50% uterine wall invasion, (2) cervix involved, (3) non-endometrioid cell types
• Pelvic radiation
• Some evidence in favor of chemotherapy, but its use is still under investigation

18. New ways…
Next
Generation
Sequencing
All
endometrial
cancers
TCGA
GroupsMolecular
Subtypes
• Clinical Trials
• Targeted and
Immune
therapies
PERSONALIZED
MEDICINE
• Her2/neu
• MSI-High
• Targetable
mutations
Molecular
features

19. The Cancer Genome Atlas
Nature. 2013;497(7447):67-73
The Cancer Genome Atlas Research Network 2013
Endometrioid and serous type endometrial cancers (373 tumors studied)
Identified four distinct molecular subgroups with different recurrent gene mutations

20. PORTEC-4
Does integrating molecular features into treatment decisions
improve outcomes?

21. Treatment of advanced stage endometrial
cancer

22. General guidelines for treatment
• Advanced stage (high risk for recurrence)
• Chemotherapy (carboplatin and paclitaxel)
• Radiation
• Combination of chemotherapy and radiation
• Immune and targeted therapies (herceptin, bevacizumab)
• Recurrent cancer (any stage at initial diagnosis)
• Site of recurrence (single or multiple spots) and prior radiation treatment matters
• Surgery
• Chemotherapy
• Radiation
• Hormonal treatment
• Immune and targeted therapies (pembrolizumab, herceptin, lenvatinib)

23. Anti-Angiogenic Drugs
• Blocks cancers from growing new blood vessels
• Can help slow or stop cancer growth
• Response rate 10-20% (monotherapy)
• Example: Bevacizumab, Lenvatinib
www.scienceofcrc.org

24. Hormonal treatments
• Progestins – slows down growth of endometrial cancer cells
• Examples: Medroxyprogesterone and Megestrol acetate
• Tamoxifen – ANTI estrogen, starves cancer cells
• Aromatase inhibitors – blocks estrogen in the body
• Examples: Letrozole, Exemestane, Anastrazole
• Response rates range 10-30%

25. Using the immune system to treat cancer
http://cellcartoons.net/lymphocytes/ https://www.verywellhealth.com/t-cells-2252171
Cancer
Cell
T Cells
T
T
T
T
T
T
T
Mutations in DNA (blueprint in the body)
Immune cells fight infection and disease

26. Microsatellite instability (“MSI”)
https://apnews.com/0bd3ece513a5498f8b6219af63d3acd6

27. How immune checkpoint blockers work
Pembrolizumab (brand name Keytruda)
https://www.keytrudahcp.com/mechanism-of-action/

28. Trastuzumab (Herceptin)
Monoclonal antibody
• Binds Her2/neu receptor on the surface of cancer cells
• Blocks the signal from Her2/neu telling the cell “grow and divide”
• May also tell the immune system to destroy the cancer cell

29. Serous endometrial cancer
(papillary serous type)
• Less common endometrial cancer type (<10%)
• More common to present in advanced stage
• Does not respond as well to chemotherapy or radiation
• Outcomes are not as favorable (even in early stage)
• Unique feature: 45-60% over-express Her2/neu protein
• If made in larger than normal amounts, cancer cells may grow more quickly

31. Serous
Endometrial
Cancer
Her2+
(61 patients)
CHEMO plus Trastuzumab
Followed by
Trastuzumab maintenance
CHEMO
X 6 cycles
(carbo/taxol)
Randomization
1:1
Advanced Stage (3 & 4) OR
Recurrent Visible Cancer

32. Progression free survival (PFS) was better with
chemo plus Trastuzumab
PFS was 8.0 months CHEMO alone
PFS was 12.9 months CHEMO + Trastuzumab
28 6 5 5 5 5 4 1
30 19 9 7 5 2 0
0 12 24 36 48 60 72 84
Months since on-treatment date
0.0
0.2
0.4
0.6
0.8
1.0
Proportionprogression-free
No
Yes
YesNoTrastuzumab
PFS vs Trastuzumab, All Eligible Subjects
With Number of Subjects at Risk
28 6 5 5 5 5 4 1
30 19 9 7 5 2 0
0 12 24 36 48 60 72 84
Months since on-treatment date
0.0
0.2
0.4
0.6
0.8
1.0
Proportionprogression-free
No
Yes
YesNoTrastuzumab
● Censored
PFS vs Trastuzumab, All Eligible Subjects
With Number of Subjects at Risk
p=0.005

33. Advanced stage benefit more than recurrent cancer (PFS)
• 9.3 months (Chemo) versus 17.7 months
(Chemo + Trastuzumab) stage III-IV patients
undergoing primary treatment
• 7.0 months (Chemo) versus 9.2 months
(Chemo + Trastuzumab) patients with
recurrent disease
20 6 5 5 5 5 4 1
21 16 9 7 5 2 0
0 12 24 36 48 60 72 84
Months since on-treatment date
0.0
0.2
0.4
0.6
0.8
1.0
Proportionprogression-free
No
Yes
YesNoTrastuzumab
PFS vs Trastuzumab, Advanced USPC
With Number of Subjects at Risk
20 6 5 5 5 5 4 1
21 16 9 7 5 2 0
0 12 24 36 48 60 72 84
Months since on-treatment date
0.0
0.2
0.4
0.6
0.8
1.0
Proportionprogression-free
No
Yes
YesNoTrastuzumab
● Censored
PFS vs Trastuzumab, Advanced USPC
With Number of Subjects at Risk
8 8 5 0
9 8 7 6 3 1 1 0
0 3 6 9 12 15 18 21 24
Months since on-treatment date
0.0
0.2
0.4
0.6
0.8
1.0
Proportionprogression-free
No
Yes
YesNoTrastuzumab
PFS vs Trastuzumab, Recurrent USPC
With Number of Subjects at Risk
p=0.015
p=0.004

34. 28 23 15 6 5 5 4 1
30 28 21 10 7 4 0
0 12 24 36 48 60 72 84
Months from on-treatment date
0.0
0.2
0.4
0.6
0.8
1.0
ProportionAlive
No
Yes
YesNoTrastuzumab
Overall Survival vs Trastuzumab, All Evaluable Subjects
With Number of Subjects at Risk
28 23 15 6 5 5 4 1
30 28 21 10 7 4 0
0 12 24 36 48 60 72 84
Months from on-treatment date
0.0
0.2
0.4
0.6
0.8
1.0
ProportionAlive
No
Yes
YesNoTrastuzumab
● Censored
Overall Survival vs Trastuzumab, All Evaluable Subjects
With Number of Subjects at Risk
Overall Survival better: chemo plus trastuzumab
HR 0.581, 90% CI 0.339-
0.994, p=0.0462
• Over 87 months of follow up
• Overall survival significantly higher in the trastuzumab arm
• 24.4 mos (Chemo) vs 29.6 mos (Chemo + Trastuzumab)
• Benefit highest for advanced stage patients (no benefit in recurrent cancer group alone)

36. Lenvatinib and Pembrolizumab Combination
Phase 2 (expansion from phase 1b)
Endometrial cancer cohort
Recurrent
Endometrial
Cancer
(108 patients)
Pembrolizumab
(IV every 3 weeks)
+
Lenvatinib
(daily)
2 or fewer prior lines of treatment
Measurable disease
[ NCT02501096 | Study 111/KEYNOTE-146 ]

37. Tumor Response (Independent Imaging Review; RECIST version 1.1)
Response Category
Total
(n = 108)a
Not MSI-H
or dMMR
(n = 94)
MSI-H/dMMR
(n = 11)
Best overall response, n (%)
Complete response 11 (10.2) 10 (10.6) 1 (9.1)
Partial response 33 (30.6) 26 (27.7) 6 (54.5)
Stable disease 42 (38.9) 38 (40.4) 3 (27.3)
Progressive disease 14 (13.0) 12 (12.8) 1 (9.1)
Not evaluable 8 (7.4) 8 (8.5) 0
Objective response rate (complete response +
partial response), n (%)
44 (40.7) 36 (38.3)b 7 (63.6)
95% CIc 31.4, 50.6 28.5, 48.9 30.8, 89.1
Duration of response (months), median (range)d 14.8
(1.2+, 35.6+)
NE
(1.2+, 33.1+)
NE
(2.1+, 35.6+)
aThe MSI or MMR status was not available for 3 patients; bAs found in the United States Prescribing Information; c95% CIs
were calculated with the Clopper-Pearson method; dDuration of response was estimated with the Kaplan-Meier method.
Makker V et al, ESMO 2019

38. Percentage Change in Sum of Diameters of Target Lesions at Postbaseline Nadir
(Independent Imaging Review; RECIST version 1.1)
n = the number of previously treated not MSI-H or dMMR patients with both baseline and at least 1 postbaseline target
lesion assessment.
Maximum tumor shrinkage
• >0% = 72/84 (85.7%)
• ≥50% = 26/84 (31.0%)
• ≥75% = 13/84 (15.5%)
Makker V et al, ESMO 2019

39. Accelerated Approval
• The FDA, the Australian Therapeutic
Goods Administration, and Health
Canada granted simultaneous review
decisions in all 3 countries on
September 17, 2019
• Lenvatinib plus pembrolizumab was
granted accelerated approval for the
treatment of advanced endometrial
carcinoma that is not MSI-High or
mismatch repair deficient
• Patients must have had disease
progression following prior systemic
therapy and must not be candidates
for curative surgery or radiation

41. NCCN Compendium 1 or 2A
Cytotoxics
• Carboplatin/paclitaxel
• Carboplatin/paclitaxel/trastuzumab (HER2+
stage III/IV or recurrent serous carcinomas)
• Carboplatin/docetaxel
• Cisplatin/doxorubicin/paclitaxel
• Carboplatin/paclitaxel/bevacizumab
• Carboplatin
• Cisplatin
• Paclitaxel
• Doxorubicin
• Liposomal doxorubicin
• Topotecan
Targeted Agents
• Progestins
• Tamoxifen
• Aromatase inhibitors
• Megestrol/tamoxifen (alternating)
• Letrozole/Everolimus (endometrioid)
• Bevacizumab
• Temsirolimus
• Lenvatinib/Pembrolizumab (MMR-p/MSS)
Immunotherapy
• Pembrolizumab (MMR-d/MSI-H)

42. Looking to the future

53. NRG-GY018
• Randomized Phase III study of carboplatin + paclitaxel + placebo vs
carboplatin + paclitaxel + pembrolizumab in stage III/IV or recurrent
endometrial cancer
Stage III & IV OR
Recurrent measurable OR
Evaluable
Mismatch repair status
R
A
N
D
O
M
I
Z
E
Carboplatin/paclitaxel/placebo
+ 12 mo placebo maintenance
Carboplatin/paclitaxel/pembrolizumab
+ 12 mo pembrolizumab maintenance
Stratification factors: MMR status, PS, measurable disease status
Clinicaltrials.gov; NCT02549209

54. [ NCT03884101 | LEAP-001 ]

56. Thank you!