What’s the Latest in Clear Cell Ovarian Cancer?

The understanding of clear cell ovarian cancer is evolving. If you’re diagnosed with clear cell ovarian cancer and eager for information specific to your subtype, we’ve got you covered! Join Dr. Jubilee Brown, Professor and Director of Gynecologic Oncology at Levine Cancer Institute, as she discusses current treatment options and any promising advances. Come with your questions and leave more informed about your subtype. 

1. What’s the latest in clear cell ovarian cancer? Jubilee Brown MD Professor and Director of Gynecologic Oncology Levine Cancer Institute, Charlotte, NC

2. Disclosures Speakers’ Bureau: Clovis, Eisai Advisory Boards: Caris, Tempus , AstraZeneca, Verastem Consultant/Speaker: Clovis, Caris, Tesaro /GSK Principal Investigator: Tesaro /GSK, Genentech Steering Committee BOUQUET trial Co-Chair NRG Oncology Rare Tumor Committee

3. Objectives To discuss current trials and progress in clear cell carcinomas of the ovary To specify therapy utilized to treat clear cell carcinomas of the ovary

4. Clinical Excellence – and Education

5. Mentorship: Gained and Given

6. ”Good research tells a story” - Anil Sood MD, PhD …and sometimes it takes a while…and a great team - Jubilee Brown MD

7. Overview through Time Prior to 2005: All rare tumors included in Phase II/III trials without regard to histologic subtype 2005: Dr. Gershenson chaired the first Rare Tumor Working Group in the GOG 2010: GCIG endorsed this approach 2011: NCI Clinical Trials Planning Meeting endorsed Working Group - > Full NRG Rare Tumor Committee Hypothesis driven research in rare tumors Novel agents, innovative statistical design, translational research components 2022: NRG Preclinical workshop

8. PROGRESS AND SUCCESS!

9. PROGRESS AND SUCCESS!

10. PROGRESS AND SUCCESS!

11. What are the 3 major groups of ovarian cancer? Pathology

12. What are the 3 major groups of ovarian cancer? Pathology Epithelial Germ cell Sex Cord - Stromal Kurman et al. WHO classification of tumours , 4th ed, vol 6. Lyon: International Agency For Research On Cancer, 2014; Prat et al, Hum Pathol 2018;80:11-27.

13. What are the 3 major groups of ovarian cancer? Pathology Epithelial Germ cell Sex Cord - Stromal Kurman et al. WHO classification of tumours , 4th ed, vol 6. Lyon: International Agency For Research On Cancer, 2014; Prat et al, Hum Pathol 2018;80:11-27.

14. What are the 3 major groups of ovarian cancer? Pathology Epithelial 90% Germ cell Sex Cord - Stromal

15. High Grade Serous Low Grade Serous Mucinous Endometrioid Clear Cell Brenner (Transitional) Mixed Undifferentiated Pathology Epithelial 90% Kurman et al. WHO classification of tumours , 4th ed, vol 6. Lyon: International Agency For Research On Cancer, 2014; Prat et al, Hum Pathol 2018;80:11-27.

16. High Grade Serous Low Grade Serous Mucinous Endometrioid Clear Cell Brenner (Transitional) Mixed Undifferentiated Pathology Epithelial 90%

17. Clear Cell Carcinoma of the Ovary Has distinct histology, epidemiology, molecular biology, and clinical behavior 1-12% in Europe and NA 25% in Japan! Thrombosis and hypercalcemia del Carmen MG et al.Gynecol Oncol. 2012;126:481-90. Japanese gynecologic cancer committee. ActaObstetGynecolJpn 2012

18. Clear Cell Carcinoma of the Ovary Kato N, et al., Mod Pathol . 2006 Jan;19(1):83-9 Courtesy K. Fujiwara ER/PR, WT-1 (-) HNF-1Beta and Napsin +

19. Clear Cell Carcinoma of the Ovary Takano M, et al. Int J Gynecol Cancer. 2010 Dec;20(9):1506-10. ; Takano M, et al. Br J Cancer 2006;94:1369-74 ; Satoh T, et al. J Clin Oncol 2010;28:1727-32 ; Chan JK, et al., Gynecol Oncol. 2008; 109(3):370-6; Goff BA, et al., Gynecol Oncol. 1996;60(3):412; Sugiyama T, et al., Cancer 2000: 88(11):2584 Late 40-50’s Early-stage: More common, good prognosis -Fertility-sparing surgery with staging -Consider treatment for IA since all high grade -Platinum + taxane = standard of care -Japanese studies: >95% OS with observation IA Late stage: Worse prognosis than serous or endometriosis, platinum-resistant

20. Surgical Advances

21. Surgical Approach Preoperative discussion: Fertility Historical approach: Vertical midline incision, pelvic washings, USO for frozen section (avoiding rupture); comprehensive staging Complete versus conservative treatment? Childbearing complete: TAH-BSO, TRS Advanced disease: goal of no visible residual disease MIS now an option – limited study Friedman C, et al. J Pediatr Adolesc Gynecol. 2016 Dec;29(6):e91-e94

22. Fertility Options Usually can spare one ovary/tube and uterus USO leads to elevated FSH, decrease in AMH, OR 4.3 early menopause, risk of infertility [Always] conserve uterus ART: Oocyte cryopreservation, Ovarian tissue cryopreservation, Donor oocytes Ovarian tissue harvested, preserved, reimplanted - restoration of function in 4m, >60 live births reported Oelschlager J Pediatr Adolesc Gynecol 2016; Wallace WHB Fert Steril 2016; Anderson RA Lancet 2015

23. Gershenson DM (2005) JNCI Monographs 34:43-7 Describes USO with conservation of normal contralateral ovary and uterus in patients with limited disease Does not refer to cystectomy - No data Staging is STILL required (but modified…)

24. SCST Does not refer to cystectomy: no data Lymphadenectomy is NOT routinely included Gershenson DM (2005) JNCI Monographs 34:43-7

25. Molecular Biology Informs Clinical Trials PIK3CA mutations present in 40% of CCC Wiegand KC et al N Engl J Med.2010;363:1532-43. Kuo KT,. Am J Pathol. 2009;174:1597-601. Target PI3K/AKT mTOR inhibitors

26. Angiogenesis Inhibitors VEGF targeted agents: bevacizumab, aflibercept VEGF receptor agents: cediranib, ramucirumab Multiple VEGF targets: pazopanib, sunitinib, nintedanib Zand B et al, Targeted Therapy in Gynecological Malignancy, Textbook of Uncommon Cancers, 3rd Edition, Eds: Raghavan D, Brown J, et al, 2017

27. GOG 254 - Sunitinib Chan J et al. Gynecol Oncol. 2018 Aug;150(2):247-252 Phase II Trial of Sunitinib in the treatment of persistent or recurrent clear cell ovarian cancer Oral receptor tyrosine kinase inhibitor: VEGFR, PDGFR, EGFR, and kit-receptor N = 30 patients 6.7% response rate (2/30 pts) PFS = 2.7 months 6m PFS = 16.7% “Minimal Activity”

28. GOG 268 – Temsirolimus /P/C - Temsirolimus A Phase II Evaluation of Temsirolimus in Combination with Carboplatin and Paclitaxel followed by Temsirolimus (CCI-779) Consolidation as First-line Therapy in the Treatment of Stage III-IV Clear Cell Carcinoma of the Ovary n=90 (45 US/Korea, 45 Japan) Primary objective: 12 m PFS; stratified by geography PFS>12 m in 0% of suboptimal patients; 49% optimal US pts 12-month PFS NOT significantly (p > 0.05) better than historical controls No difference in PFS or OS between US/Korea and Japan Farley J (PI)

29. GOG 283 – Dasatanib A Phase II Trial of DCTD-Sponsored Dasatinib In Recurrent/Persistent Ovary, Fallopian Tube, Primary Peritoneal, Endometrial, or Endometriosis-Associated Clear Cell Carcinoma Characterized for the Retention or Loss of BAF250a Expression (40-60% of CCC are ARID1A+, coding for BAF250a) Orally bioavailable multi targeted tyrosine kinase inhibitor (MET) Primary endpoint: 6 m PFS and CR/PR n = 13 patients No responses

30. GY-016: A Phase II Study of MK-3475 (Pembrolizumab) + Epacadostat in Recurrent Clear Cell Carcinoma of the Ovary PD-1 inhibitor and oral IDO-1 inhibitor Primary endpoint: ORR within 7m of entry 14 patients accrued rapidly (9/18-4/19) ORR 21% (95%CI: 5-51%); 3 PRs Median PFS 4.8 m (95% CI: 1.9-9.6 m) OS 18.9 m (95% CI: 1.9-NR) MET CRITERIA FOR 2 STAGE Study closed due to insufficient drug supply Gien L et al, IGCS 2022

31. GY-016: A Phase II Study of MK-3475 (Pembrolizumab) + Epacadostat in Recurrent Clear Cell Carcinoma of the Ovary PD-1 inhibitor and oral IDO-1 inhibitor Primary endpoint: ORR within 7m of entry 14 patients accrued rapidly (9/18-4/19) ORR 21% (95%CI: 5-51%); 3 PRs Median PFS 4.8 m (95% CI: 1.9-9.6 m) OS 18.9 m (95% CI: 1.9-NR) MET CRITERIA FOR 2 STAGE Study closed due to insufficient drug supply Gien L et al, IGCS 2022

32. GY-001 – Phase II Study of Single-Agent Cabozantinib in Patients with Recurrent Clear Cell Ovarian, Primary Peritoneal or Fallopian Tube Cancer (NRG-GY001) Small molecule inhibitor of c-Met and VEGFR2 Cabozantinib 60 mg po daily until progression or toxicity (n=13) Primary endpoint: 6m PFS and CR or PR No responses 23% (3/13/ patients) had PFS > 6m Median PFS 3.6 m; Medial OS 8.1 m 5 thromboembolic events Konstaintinopoulos P, et al. Gynecol Oncol 2018 Jul; 150(1): 9-13

33. Ongoing Trials GY-014: Phase II Study of Tazemetostat in Recurrent/Persistent Endometrioid/Clear Cell Carcinoma of the Ovary, and Recurrent or Persistent Endometrioid Endometrial Adenocarcinoma Anlotinib Combined With Niraparib Dual Therapy in Platinum-resistant Recurrent Ovarian Clear Cell Carcinoma. (CC-ANNIE) Pembrolizumab and Lenvatinib in Clear Cell Ovarian Cancer Study Of Nintedanib Compared To Chemotherapy in Patients With Recurrent Clear Cell Carcinoma Of The Ovary Or Endometrium ( NiCCC ) Etigilimab and Nivolumab for the Treatment of Platinum-Resistant Recurrent Clear Cell Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

34. The Case for Immunotherapy in CCC Ovary I/O in Ovarian Cancer 20 evaluable patients received either 1 or 3 mg/kg nivolumab Best clinical response rate = 15% Clinical benefit rate = 45% 10% durable response rate PD-L1 did not correlate 2 CR’s: 1 serous, 1 clear cell Hamanishi J et al, J Clin Oncol 2015;33(34):4015

35. Biomarkers of Immunotherapy Response in Solid Tumors 487 of 877 TMB high tumors did not express high levels of PD-L1 Assessing multiple markers of immunotherapy sensitivity maximizes identification of patients who may benefit Vanderwalde et al. Cancer Med . (2018)

36. Importance of Comprehensive Molecular Profiling Allows treatment based on genomic drivers of tumorigenesis Dramatic responses in treatment-refractory disease Broad panel testing measures levels of genes or gene products Biomarkers of response prediction and prognosis El Deiry WS et al. CA Cancer J Clinicians 2019

37. 57 yo Recurrent Stage IA CCC Ovary EGFR+ (failed cetuximab on TAPUR); PD-L1+ Pre-nivolumab

38. 57 yo Recurrent Stage IA CCC Ovary EGFR+ (failed cetuximab on TAPUR); PD-L1+ Pre-nivolumab 6 months post-nivolumab

39. Data on CCC Ovary - Caris Mutation % Positive Actionable Drug ARID1A 53.4% Y EZH2 Inh PIK3CA 47.5% Y PI3Kinase Inh TP53 13.4% N - KRAS 11.6% Y MEK Inh PTEN 6.8% Y AKT / mTOR Inh TMB 5.4% Y Immunotherapy ATM 4.8% Y PARP Inh MSI 4.1% Y Immunotherapy PIK3R1 3.1% Y PI3K,AKT,mTOR Inh PIK3CA 2.5% Y mTOR Inh ERBB2 2.5% Y HER2 Inh, mAb MSH6 2.5% Y Insufficient info ERBB3 2.3% Y HER 3 Inh, mAb NF1 2.2% Y PI3K Inh BRCA2, MUTYH 2% each Y PARP Inh MSH2 2% each Y Insufficient info BRAF 2% Y BRAF Inh AKT1 2% each Y AKT/mTOR Inh Up to 1% each: ATRX, CDKN2A, FGFR2, NF2, NRAS, PMS2, TSC2, BAP1, BRIP1, ERCC2, MLH1, PALB2, PTCH1, BRCA1, CCND1/3, EGFR, FGFR3, HRAS, MAP2K1, NOTCH1, PMS1 [Brown et al, SGO 2020]

40. Data on Rare Tumors - Caris Histology Minimum %+ N Ovary - SCST 9.8% 228 Ovary - Germ Cell 20% 52 Ovary - Mucinous 62% 132 Ovary - LG Serous/Endometrioid 28.9% 91 Ovary - Clear Cell 53.4% 367 Ovary - MMMT 7.2% 112 Uterine Sarcoma 40.1% 4670 Vulvar CA 28.7% 166 Neuroendocrine GYN CA 20.6% 103 There ARE targetable mutations in rare tumors You cannot generalize – they are all different! Brown et al, SGO 2020

41. Rare Tumor Profiling Brown et al, SGO 2020

42. Submitted Concept DT2337: A Single-Arm, Phase II Evaluation of Durvalumab and Tremelimumab for Recurrent or Metastatic Ovarian Clear Cell Carcinoma and Endometrial Carcinoma with PPP2R1A Loss-of-function Mutations. (Lin)

43. GOG 3051 - the BOUQUET trial A Phase II, Open-Label, Multicenter, Platform Study Evaluating the Efficacy and Safety of Biomarker-Driven Therapies in Patients With Persistent or Recurrent Rare Epithelial Ovarian Tumors Ipatasertib + Paclitaxel Cobimetinib Trastuzumab Emtansine Atezolizumab + Bevacizumab BRAF, KRAS, NRAS, nF1 PTEN, PIK3CA, AKT ERBB2 NOS

44. GOG 3051 - the BOUQUET trial A Phase II, Open-Label, Multicenter, Platform Study Evaluating the Efficacy and Safety of Biomarker-Driven Therapies in Patients With Persistent or Recurrent Rare Epithelial Ovarian Tumors Ipatasertib + Paclitaxel Cobimetinib Trastuzumab Emtansine Atezolizumab + Bevacizumab BRAF, KRAS, NRAS, nF1 PTEN, PIK3CA, AKT ERBB2 NOS

45. TAKE HOME POINTS - EPITHELIAL Low Grade Serous: KRAS, MEK, Trametinib, GY-019 Mucinous: Accurate diagnosis is difficult Lymphadenectomy not necessary Consider capecitabine and oxaliplatin +/- bevacizumab KRAS - ?Targetable Clinical trials needed – central pathology review Clear Cell: Keep working on it… accrue to GY-014 – tazemetostat AND BOUQUET GOG-3051 FOR ALL!