New Treatment Options for Uterine Cancer

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 s tage 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 R ecurrence 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 S ome evidence in favor of chemotherapy, but its use is still under investigation

17. New ways …

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

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

20. Treatment of advanced stage endometrial cancer

21. 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 )

22. 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

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

24. 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 ( b lueprint in the body) Immune cells fight infection and disease

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

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

27. 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

28. 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

29. 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

30. Progression free survival (PFS) was better with chemo plus Trastuzumab PFS was 8.0 months CHEMO alone PFS was 12.9 months CHEMO + Trastuzumab p=0.005

31. 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 p=0.015 p=0.004

32. Overall Survival better: chemo plus trastuzumab HR 0.581, 90% CI 0.339-0.994, p=0.0462 O ver 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)

33. 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 ]

34. 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) Objective response rate (complete response + partial response), n (%) 44 (40.7) 36 (38.3) b 7 (63.6) 95% CI c 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+)  a The MSI or MMR status was not available for 3 patients; b As found in the United States Prescribing Information; c 95% CIs were calculated with the Clopper-Pearson method; d Duration of response was estimated with the Kaplan-Meier method. Makker V et al, ESMO 2019

35. 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

36. 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

37. 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)

38. Looking to the future

39. 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 R ecurrent measurable OR E valuable 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

40. [ NCT03884101 | LEAP-001 ]

41. Thank you!