Update on Novel Therapies for Rare Ovarian Cancers

David M. Gershenson, MD The University of Texas MD Anderson Cancer Center Disclosures

• Research Support: NCI, NRG Oncology • Royalties: Elsevier, UpToDate • Advisory Boards: Clovis • Equity Interests: Johnson & Johnson, Celgene, Pfizer, Biogen, Inc. New Paradigm

• Ovarian cancer is not one but several distinct entities • Advances in understanding heterogeneity: – Pathologic diagnostic criteria – Molecular biology – Hypothesis-generating clinical studies • Establishment of GOG Rare Tumor Committee (2005) with separate clinical trials for specific subtypes • Prior to 2005: – All EOC treated identically – No prospective clinical trials for rare EOC • “One size does not fit all!” MALIGNANT OVARIAN GERM CELL TUMORS: “COMING FULL CIRCLE” Historical Perspective: Pre-1970 Chemotherapy Era

• Available postoperative therapies: external RT, radioisotopes, single-agent AA • Virtually all pts. with advanced disease died

• 5-20% of pts. with “apparent” early stage disease survived BEP Regimen • Cisplatin20 mg/m2 days 1-5 • Etoposide100 mg/m2 days 1-5 • Bleomycin20-30 mg IV weekly Malignant Ovarian GCT: Expected Survival

Stage % Survival I 95+ II 90+ III 75+ IV 75+ Contemporary Management • Current status of management of early-stage GCT in US is schizophrenic: • Children • Less than comprehensive surgical staging • Surveillance • Adults • Comprehensive surgical staging • BEPfor all except: • Stage IA or IB pure dysgerminoma • Stage IA pure immature teratoma, grade 1 • Over past 2 decades, several reports have focused on surveillance (surgery alone) Study No.Pts. Stages Tumor Types Relapse Outcome Bonazziet 22 I, II IT—G1 & G2 2 (9%) Bothsalvaged al. 1994 with surgery (G0) Mitchellet 9 I IT—G2 1 (11%) IT ? Grade al. 1999 Mixed GCT—all Refused further with YST therapy Cushinget 44 I IT—G1,2,3 1 (2%) Salvaged with al. 1999 Mixed GCT—IT + chemo YST Patterson 36 I IT—G0,1,2,3 11 (30%) All salvaged with et al. 2008 Dysg,YST, EC, chemo except 1 Mixed (IT, G2) & 1 (PE)

Mangiliet 19 I IT—G1,2,3 4 (21%) 2 (G0) salvaged al. 2010 with surgery; 2 salvagedwith surgery + chemo

EFS on Low Risk/Surveillance Stratum of AGCT0132 AGCT0132: Low-risk Ovarian EFS/OS • Ovarian 1.00 – 25 patients • 12 events 0.75 74% – 4-yr EFS 52% Outcome Measure – 4-yr OS 96% 0.50 52% EFS Survival E s t i m a e d P r o p on 0.25

0.00 0 1 2 3 4 5 6 7 8 Time (years)

Billmireet al. J ClinOncol2014 MaGICCOG/NRG Trial Low Risk Stratum

Age 0-50 years Surveillance & Chemotherapy if Stage I, All Sites Monitoring Relapse (Stage IA MOGCT) MagICCOG/NRG Trial Intermediate Risk Stratum

Cisplatin33 mg/m2 days 1-3 Etoposide165 mg/m2 days 1-3 Bleomycin15 U/m2 days 1, 8, 15 Age 0-25 All Sites (Stage IC-III MOGCT) R Carboplatin AUC 8.0 day 2 Etoposide165 mg/m2 days 1-3 Bleomycin15 U/m2 days 1, 8, 15 SEX CORD-STROMAL TUMORS; “AN ENIGMATIC SET OF TUMORS” Ovarian Sex Cord-Stromal Tumors

• Rarely involve retroperitoneal lymph nodes • Conventional chemotherapy has only modest activity • Hormonal therapies may be active in granulosacell tumors • Radiotherapy may have limited role • Discovery of FOXL2 mutations and DICER1 mutations has not yet translated into improved therapy

GOG 251 GOG 264 A Randomized Phase II Trial of Paclitaxel and Carboplatin vsBEP for Newly Diagnosed Advanced Stage and Recurrent Chemo-Naïve Sex Cord-Stromal Tumors of the Ovary

Stage III-IV or Recurrent Chemo- Naïve SCST of Ovary

Bleomycin20 U/m2 Carboplatin AUC 6 Etoposide75 mg/m2 d 1-5 Paclitaxel 175 mg/m2 Cisplatin20 mg/m2 d 1-5 X 6 cycles X 4 cycles

Accrual 35/128 A phase II evaluation of enzalutamidefor recurrent sex cord-stromalovarian tumors

Lilian T. Gien, MD MScFRCSC Division of Gynecologic Oncology Sunnybrook Odette Cancer Center, Toronto Clinical Features of Rare EOC Feature Clear Cell Low-Grade Serous Mucinous Incidence 5% 5% 10% Stage Distribution Stages I/II 67% 10% 61% Stages III/IV 33% 90% 39% Biology Aggressive Indolent Aggressive Relative Yes Yes Yes Chemoresistance Outcomes in Early Similar to HGSC Unknown but Similar to HGSC Stage HR = .87 thought to be HR = .87 excellent Outcomes in Median OS = 21 mo Median OS = 101 mo Median OS =15 mo Advanced Stage Worse than HGSC BetterthanHGSC Worse than HGSC HR= 2.2 HR = ? HR = 2.7 CLEAR CELL CARCINOMA Key Pathways & Potential Targets: Clear Cell Carcinoma • Angiogenesis – Bevacizumab, Aflibercept, PX-478 • PI3K/AKT/mTOR(PTEN loss, 40%; PIK3CA mutation, 33%; AKT2 amplification, 14%) – Everolimus, Temsirolimus, and several others • IL-6/STAT3/HIF (IL-6 expression, 49%) – Siltuximab, Ruxolitinib, Panobinostat, Sunitinib • c-MET – Tivantinib, Cabozantanib • MAPK (5% KRAS mutations), HER-2/neu(14% amplification), apoptotic regulators (HNF1β upregulation, ~100%) – Selumetinib, Trametinib, Traztuzumab, Navitoclax • Loss of BAF250a (50% ARID1A mutations) – Dasatinib • PD-1 and PD-L1 NRG Trials Clear Cell Carcinoma

• GOG 268: mTOR – Phase II study of paclitaxel/carboplatin + Temsirolimus(concomitant + maintenance) – Newly diagnosed stage III and IV – 90 pts. – Awaiting analysis • GOG 254: VEGF – Phase II study of Sunitinib – Recurrent, measurable disease – 35 pts. – ORR = 7% • GOG 283: BAF250a (ARID1A) – Phase II study of Dasatinib – Recurrent, measurable disease • GY-001: MET – Phase II study of Cabozantinib – Recurrent, measurable disease MUCINOUS CARCINOMA: “SURPRISING RARITY” Key Pathways & Potential Targets: Mucinous Carcinoma • Angiogenesis pathway – Bevacizumab, Aflibercept, AMG 386, etc. • HER-2/neu(20%) – Traztuzumab • MAPK (RAS mutation, 40-50%) – Selumetinib, Trametinib, many others • Src – Dasatinib GOG 241 A Randomized Phase III Trial of Capecitabine/Oxaliplatin vs. Paclitaxel/Carboplatin +/-Bevacizumabin Patients with Previously Untreated Mucinous Ovarian Cancer Stage II-IV or Recurrent Stage I Mucinous Carcinoma of Ovary (N = 332)

Carboplatin AUC 5/6 Oxaliplatin130 mg/m2 Paclitaxel 175 mg/m2 Capecitabine850 mg/m2 bd X 6 cycles X 6 cycles

Bevacizumab Bevacizumab No No 15 mg/kg 15 mg/kg Bevacizumab Bevacizumab Q. 3 wk. X 6 Q. 3 wk. X 6 Pathology of Advanced Stage Mucinous Carcinoma • Review of 3435 pts in international randomized phase III trial • 41 cases with adequate pathology material – 12 (29%) considered primary – 29 (71%) considered metastatic

Zainoet al. Cancer 2011 GOG 241 LOW-GRADE SEROUS TUMORS LGSC is Relatively Chemoresistant

RPPA Analysis

Up-regulation of p-Akt

Down-regulation of Chk1

Down-regulation of p-ERK1/2 MEKiinteracts with PARPisynergistically Impact of Age in LGSC Mutational Status in LGSC Key Pathways & Potential Targets: Low-Grade Serous Carcinoma • MAP Kinase pathway (20-40% KRAS, 5% BRAF) – MEKi, BRAFi • IGFR-1 – AMG 479, BMS-536942, MK-0646 • Angiogenesis pathway – Bevacizumab, Aflibercept, AMG 386, etc. • PI3K/AKT/mTORpathway – Everolimus, Temsirolimus, and several others • ER – Aromatase inhibitors, Tamoxifen, Leuprolideacetate, etc.

Angiogenesis and Low-Grade Serous Carcinoma of the Ovary • 17 ptstreated with • 21 ptstreated with bevacizumab bevacizumab – 10 with ovarian LGSC • 20 with bev+ chemo – 3with PPC LGSC and 1 with bevalone – 4with SBT • RR = 41% • 15 with bev+ chemo • SD = 18% and 2 with bevalone • RR = 40% • SD = 33%

Grisham et al. Schmeleret al. Cancer 2014 ASCO 2010 GOG 239 Assessments N = 250 patients Clinical: Primary endpoint: PFS GOG 281 Trial Schema • At screening day 1 of each Secondary endpoints: cycle • Adverse effects • Following disease • Objective response Prospective CT-Guided progression, ptswill be followed every 12 wk • Overall survival Pathology Review FNA/Core Bx • Molecular analyses CT Scans: • Quality of Life Screening, then every 8 wk R until disease progression

Arm B = Experimental Arm Arm A = Control Arm Trametinib2 mg podaily Investigators Choice of following: continuous treatment • Letrozole2.5 mg poqdcontinuously For each arm, 1 cycle = 28 days • Tamoxifen20 mg pobid continuously • Paclitaxel 80 mg/m2 IV over 1 hron day 1 q. 7d, 3 wkson, 1 wkoff • PegylatedLiposomal Doxorubicin 40 or 50 mg/m2 IV over 1 hron day 1 q. 28d • Topotecan4.0 mg/m2 over 30 min on days 1, 8 and 15 of a 28 day cycle For each arm, 1 cycle = 28 days

Progression

Crossover to Trametinib Off Study SMALL CELL CARCINOMA HYPERCALCEMICTYPE (SCCOHT): “EPIPHANY IN THE MAKING”

SMARCA4 Mutations in SCCOHT Conclusions

• Multiple challenges associated with rare ovarian cancer trials • Considerable progress in study of rare ovarian cancers over past decade • Need to continue to focus on improving outcomes for women with rare ovarian cancers: networks, registries, novel trial designs, etc. • All rare ovarian cancers are not created equal: Feasibility