Ovarian Cancer: Future Therapies and Clinical Trials S. Diane Yamada, M.D. Joseph Bolivar DeLee Professor Department of Obstetrics and Gynecology Section Chief, Gynecologic Oncology University of Chicago Medicine
Disclosures
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Off label use of a product in the context of a research study
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Outline •
Future therapies
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– Prevention – Immunotherapy – Drug repurposing Clinical trials – – – –
Up front and maintenance therapy options Tumor stratification Platinum sensitive/resistant disease How to stay healthy
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Timing of Investigational Therapies
Platinum sensitive Stage I-IV ovarian/FT cancer
Taxane/platinum chemotherapy
M1
Recurrence
M2
Platinum resistant
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Timing of Investigational Therapies
Prevention Platinum sensitive Stage I-IV ovarian/FT cancer
Taxane/platinum chemotherapy
M1
Recurrence
M2
Platinum resistant
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Genomic Instability Mutually exclusive events
2010
Mixed Endometrioid 3% 3% Clear cell 6%
BRCA1 Germline 8%
Carcinosarcoma 6%
Other 34%
BRCA2 Germline 6% BRCA1 Somatic BRCA2 3% Somatic 3% BRCA1 Methylation 11%
Serous 82%
MMR Germline 2%
CCNE1 Amplification 15%
Homologous recombination (HR) proficient
EMSY Amplification 6% PTEN Loss Other HRD 5% 7%
Homologous recombination (HR) deficient
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Fallopian Tube Cancer
Serial sectioning-fallopian tube
Domcheck Breast Cancer Res Treat 2010 7 Manchanda BJOG 2011 Yates Cancer Prev Res 2011 Callahan J Clin Oncol 2007 Sherman ME J Clin Oncol 2014
New Ovarian Cancer Dream Team Announced; $6M Grant Over 3 Years Will Focus on DNA Repair Therapies April 20, 2015 — Stand Up To Cancer (SU2C), Ovarian Cancer Research Fund (OCRF), Ovarian Cancer National Alliance (OCNA), and National Ovarian Cancer Coalition (NOCC), along with the American Association for Cancer Research (AACR), Scientific Partner to SU2C, announced today the formation of a Dream Team devoted to ovarian cancer research at the AACR Annual Meeting 2015, held here April 18-22. + More WISDOM study: RRSO vs salpingectomy with delayed oophorectomy Outcome measure: sexual function, psychosocial well being 8
Timing of Investigational Therapies
Prevention Platinum sensitive Stage I-IV ovarian/FT cancer
Taxane/platinum chemotherapy
M1
Recurrence
M2
Platinum resistant
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IV Chemotherapy Regimens Regimen
Intraperitoneal (GOG 172)
Dose Dense (JGOG) Stage II-IV
Low dose weekly (MITO-7)
Every 3 weeks (GOG 172, JGOG)
Paclitaxel
135 mg/m2 IV Day 1 60 mg/m2 IP Day 8
80 mg/m2 Day 1, 8, 15
60 mg/m2 Day 1, 8, 15
175 -180 mg/m2 Day 1
Carboplatin
100 mg/m2 IP Day 1 (Cisplatin)
AUC 6 Day 1
AUC 2 Day 1, 8, 15
AUC 5-6 Day 1
Overall Survival
65.6 mos
100.5 mos
Neuropathy > Grade 3
19%
7%
0%
2-6%
Neutropenia Grade 3-4
76%
92%
42%
50-88%
Thrombocytopenia
12%
44%
1%
7-38%
49.7, 62.2 mos
Toxicity
Grade 3-4
Katsumata N Lancet Oncol 2009 374:1331-38 Pignata S et al. Lancet Oncol 2014 15:396-405 Armstrong DA et al. N Engl J Med 2006 354:34-43
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Targeting Angiogenesis •
One of the most prolific arenas of drug development
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Dozens are in development – Approaches: ligand, receptor, signal, and regulators – Targets: endothelial cells, tumor cells, pericytes, immune effectors
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Approved: 16
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Incorporation of Bevacizumab into Frontline Therapy GOG 218
Burger, RA. NEJM 2011
ICON 7
Perren, TJ. NEJM 2011
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PARP Inhibition
Fong PC, et al. N Engl J Med. 2009;361:123.
Audeh MW, et al. Lancet. 2010;76:235. 13
GOG 9923 IV q 3 week Carboplatin Paclitaxel Bevacizumab Stage II-IV Ovarian Fallopian tube Primary peritoneal Cancer
Veliparib IV weekly Carboplatin Paclitaxel Bevacizumab Veliparib IV/IP Paclitaxel (IV) Cisplatin (IP) Paclitaxel (IP) Bevacizumab Veliparib 14
Metformin and Ovarian Cancer Survival Progression-free Survival
Overall Survival
Iris Romero, MD
Romero IL et al. Obstet Gynecol 2012
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Drug “Repurposing”: Metformin Epidemiologic: Metformin/cancer associations in diabetes
Metabolic: Association of obesity and insulin with cancer risk/prognosis
Metformin
and cancer Preclinical: In vitro evidence of anticancer activity
Mechanistic Signaling pathways
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Randomized Phase II Metformin Study Primary endpoint: PFS
Primary Debulking
Stage III/IV Ovarian FT PPC
R A N D O M I Z E
Secondary endpoints: CA125 response, OS
Taxane/platinum Metformin
Metformin maintenance
Taxane/platinum Placebo
Placebo maintenance
Neoadjuvant Chemotherapy/Interval Debulking
Biopsies: Stage III/IV Ovarian FT PPC
R A N D O M I Z E
Taxane/platinum Metformin
Taxane/platinum
Interval debulking surgery
Taxane/platinum Placebo
Interval debulking surgery
Metformin
Metformin maintenance
Taxane/platinum Placebo
Placebo maintenance 2 years
Randomized Phase II Metformin Trial | 17
Tumor Stratification: Low Grade Serous Cancers MILO study: Randomized Phase III Study of MEK 162 vs MD choice chemotherapy in recurrent or persistent low grade serous ovarian cancer
Low grade serous
High grade serous
Mean age (years)
56
63
Mean overall survival (mos)
99
57
RR with platinum or taxane 2% or 4%
80%
Positive for KRAS or BRAF mutation
30% or 50%
2% or 3%
Positive for p53 mutation
25%
55%
Positive for BRCA mutation
4%
22%
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Selumetanib (AZD 6244) in Low Grade Serous Cancers Best Response to Treatment
Patient Disposition (at data lock) Patients (n=52)
Patients (n=52) CR
1 (2%)
Alive
PR
7 (13%)
10 (19%)
Stable disease
34 (65%)
Without progression With progression
22 (42%)
Progressive disease 8 (15%) Indeterminate
2 (4%)
Died From disease
17 (33%)
From neither drug rxn or disease
1 (2%)
Undetermined cause
1 (2%)
Cause pending
1 (2%)
Farley J et al. Lancet Oncol 2013
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Immunotherapy -CTLA-4 blockade: -T cell activation I (Ipilimumab) -PDL-1 blockade: - improved T cell mediated tumor lysis -anti-PD-1 mAb -Phase I PR, 20% (Nivolumab)
NRG GY003: -recurrent/persistent -randomized phase II -Nivolumab +/ipilimumab
Chester C, J ImmunoTher Cancer 2015
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Immunotherapy Approaches •
Dendritic cell vaccines
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Adoptive T cell transfer
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Combination of checkpoint inhibitors
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Combination of targeted agents with immunomodulators
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Intlekofer AM Nature Rev Clin Oncol 2014
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Basket Trials
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Univ. of Chicago Ovarian Cancer Center of Excellence: 2004‐2015 Dr. Tony Montag Dr. Aytek Oto Gynecologic Pathology Radiology Drs. Yamada/Tenney/Lee/Lengyel Clinical Gynecologic Oncology State of the Art Surgery
Improve Early Detection
Dr. Gini Fleming Med Onc
Expert Pathology
Adnexal Masses
Unite Patient Care and Discovery to improve the life of women with ovarian cancer
Find Novel Biomarker
Information for Scientists/ Physicians
Dr. Stacy Lindau Sexuality and Cancer Novel Clinical Trials GOG – Phase I network
Training Scientists & Doctors
Cancer Risk Clinic
Dr. Iris Romero Hereditary Ovarian Cancer Metformin
Dr. Hilary Kenny Research/Drug screening
Understand Biology
Discover New Drugs
Information for Patients/ Families-Sexual Health
Dr. Kim REI - Oncofertility
