Slide 1: Ovarian Cancer: New Horizons and Treatments
Ovarian Cancer: New Horizons and Treatments Premal H. Thaker Associate Professor Gynecologic Oncology Washington University School of Medicine
Slide 2: Disclosure
Disclosure Advisory Board: Celsion, Genentech, Iovance Speaker’s bureau: Tesaro and Merck Institutional Grant: Merck and Tesaro
Slide 3: Objectives
Objectives Symptoms and Diagnosis Standard of care therapy: surgery and neoadjuvant chemotherapy Novel therapies – Immunotherapy – PARP inhibitors – Anti-angiogenic
Slide 4: 2018 US Estimates
2018 US Estimates * Women New Cases Deaths 852,630 282,500 30% Breast 25%Lung & bronchus 12% Lung & bronchus 14%Breast 8%Colon & rectum 8%Colon & rectum 7% Uterine corpus 7% Pancreas 5%Thyroid 5% Ovary 4% Non-Hodgkin 4% Leukemia 4% Melanoma of skin 4% Uterine corpus 3%Ovary 3% Non-Hodgkin lymphoma 3
Slide 5: Epidemiology
Epidemiology 239,000 new incidence annually worldwide. Incidence stable since 1970s Median age at diagnosis 63 Fourth commonest cause of cancer death in women in developed countries >60% of women diagnosed with Stage III/IV – symptoms of abdominal pain, bloating, distension, constipation, back pain
Slide 6: Stage at diagnosis
Stage at diagnosis Stage I Confined to the Ovary IA Growth limited to one ovary, no ascites, capsule intact, no surface tumor extension IB Same as IA but involves both ovaries IC IA or IB but with positive washings or ruptured capsule Stage II Extends to True Pelvis IIA Involves fallopian tube or ut
Slide 7: US 5 Yr Relative Survival Rates (%) from 2007-2013
US 5 Yr Relative Survival Rates (%) from 2007-2013 All subtypes Serous Endometrioid Mucinous Clear Cell All stages 47 44 82 69 67 Localized 93 90 98 93 90 Regional 74 75 87 81 74 Distant 30 35 48 18 26 American Cancer Facts & Figures 2018
Slide 8: Ovarian Cancer Risk Factors
Ovarian Cancer Risk Factors 50 years of age or older Other potential risk factors Familial factors – Early menarche (younger than 12 – Family history of breast, ovarian, years of age) endometrial or colon cancers – Late menopause (older than 52 – Personal history of breast or colon years of age) can
Slide 9: Ovarian Cancer and Early Detection
Ovarian Cancer and Early Detection Certain factors may reduce a woman's risk of developing ovarian cancer : – Taking birth control pills for more than 5 years – Breastfeeding – Pregnancy – A hysterectomy or a tubal ligation
Slide 10: Lifetime Risk of Cancers Associated With Specific Genes
Lifetime Risk of Cancers Associated With Specific Genes Cancer, % BRCA1 BRCA2 MMR* Breast 35-60 30-55 0 Ovarian 35-45 15-25 6-20 Endometrial 0 0 40-60 *MMR (mismatch repair) = HNPCC. Chen S, et al. J Clin Oncol. 2007:25:1329-1333. Aarnio M, et al. Int J Cancer. 1999:81:214-218.
Slide 11: Ovarian Ca Screening for general population: PLCO trial
Ovarian Ca Screening for general population: PLCO trial 68557 participants 55-74yo w/o prior hx of oophorectomy annual Ca125 for 6 years and TVUS for 4 years in intervention grp Median f/u:12.4 years Results: – Similar detection rate (5.7 v 4.7 per 10000 person-yrs), HR 1.21 CI:0.99-1.48 – <60% of o
Slide 12: Treatment Landscape Overview for Advanced Ovarian Cancer
Treatment Landscape Overview for Advanced Ovarian Cancer Surgical goal is complete cytoreduction of all macroscopic visible disease1 Standard adjuvant chemotherapy is an IV or IP taxane/platinum combination1 Despite optimal upfront surgery and adjuvant chemotherapy, approximately 80% of patients wil
Slide 13: Surgical Cytoreduction
Surgical Cytoreduction
Slide 14: Adequate Surgery is Vital in Treating Ovarian Cancer
Adequate Surgery is Vital in Treating Ovarian Cancer Maximal effort at primary cytoreduction – Goal is R0 (complete resection = optimal) – Imaging and perhaps laparoscopy to assess feasibility – Decision requires gynecologic oncology input 3 cycles of neoadjuvant chemotherapy and interval debulking
Slide 15: % Overall Survival
3 z < a 2 5 2 2 &? z % Overall Survival HR__(95%C1) 1-10 mmvs.Omm: 2.52 (2.26;2.81) >10mmvs.1-10mm; —1,36(1.24;1,50) log-rank: p< 0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) N = 3126 pts HR. 95%C! 1-10 mmvs. 0mm: 2.70(2.37; 3.07} >10 mm vs. 1-10 mm: 1.34 (1.21; 1.49) log-ran
Slide 16: Laparoscopic Predictive Index
Laparoscopic Predictive Index Nick, A. M. et al. (2015) A framework for a personalized surgical approach to ovarian cancer Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.26
Slide 17: Chemotherapy vs Surgery?
Chemotherapy vs Surgery?
Slide 18: Design of 2 Phase III Trials Addressing NACT
Design of 2 Phase III Trials Addressing NACT
Slide 19: ASCO & SGO Guidelines
Algorithm for the clinical evaluation and treatment of women with suspected stage IIIC or IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. ASCO & SGO Guidelines August 2016 Alexi A. Wright et al. JCO doi:10.1200/JCO.2016.68.6907
Slide 20: NACT Trends
n=114 n= 157 n=128 n=116 n=131 n=129 n=113 n=178 n=62 n=45 n=52 PCS PCS + IP/IV PCS + IP/IV NACT NACT a 3s £2 i= ®o s & a = o i= 2 = i=) Q ° co a Proportion of Patients (%) 2004 2005 2006 2007 2008 2009 2010 2011 2004 2005 2006 2007 2008 2009 2010 2011 Year of Diagnosis Year of Diagnosis Fig 1. (A)
Slide 21: Standard of Care Therapy
STANDARD OF CARE THERAPY
Slide 22: Chemotherapy choices: intraperitoneal therapy improves OS, but toxicity is increased
Chemotherapy choices: intraperitoneal therapy improves OS, but toxicity is increased
Slide 23: GOG 252: PFS optimal stages II & III
GOG 252: PFS optimal stages II & III
Slide 24: Angiogenesis
ANGIOGENESIS
Slide 25: Maintenance therapy results from past frontline studies
Maintenance therapy results from past/old frontline studies: positive,modest (218, ICON7, Pazopanib) Anti-vascular therapy as maintenance in Front Line EOC Therapy Presented By Paul Sabbatini, MD at 2013 ASCO Annual Meeting
Slide 26: Cediranib
Cediranib • Angiogenesis Inhibitor – a potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases and has some c-Kit and PDGF activity • Oral • Similar Side Effects of Olaparib – Fatigue, nausea, diarrhea, hypertension
Slide 27: Rationale for combination of olaparib and cediranib
Rationale for combination of olaparib and cediranib Effect of ced/olap on cell invasion: PARP-inhibitors and anti-angiogenics with known activity in ovarian cancer Pre-clinical data suggesting potential synergy between PARPi and anti-angiogenics Effect of ced/olap on microvascular cell tube organiza
Slide 28: Overall Survival and Updated PFS results from a randomized phase 2 trial
Overall Survival and Updated PFS results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum sensitive ovarian cancer Liu et al. Abst 5535 ASCO 2017
Slide 29: Phase 2 trial olaparib and cediranib: patient characteristics
Phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum sensitive ovarian cancer Patient Characteristics:
Slide 30: Phase 2 trial olaparib and cediranib: overall survival
Phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum sensitive ovarian cancer Median OS 33.3 vs. 44.2 Median OS 40.1 vs. 44.2 Median OS 23.0 vs. 37.8 HR 0.64 HR 0.79 HR 0.48 (95% CI 0.36-1.11; p=0.11) (95% CI 0.38-1.67; p=0.55) (95% CI 0.21-1
Slide 31: PARP Inhibitors
Caco ae PARP INHIBITORS
Slide 32: BRCA 1 and BRCA 2 Pathway
BRCA 1 and BRCA 2 Pathway Homologous recombination pathway: repair of double-stranded DNA tumors with BRCA mutations cannot repair DNA as well; tend to be more responsive to chemo, ionizing radiation, and PARP inhibitors
Slide 33: Combining PARP inhibitors with anti-angiogenic therapy
Combining PARP inhibitors with anti-angiogenic therapy Platine, Avastin and OLAparib in 1st Line (PAOLA-1) Combining olaparib with bevacizumab ClinicalTrials.gov Identifier: NCT02477644 | ee
Slide 34: PARP Inhibitor Summary: Indications and Efficacy
PARP Inhibitor Summary: Indications and Efficacy Olaparib Rucaparib Niraparib Monotherapy for somatic or Monotherapy for gBRCA+ patients Maintenance for recurrent OC in gBRCA+ patients with ≥2 prior Current Label with 3+ prior lines of therapy response to treatment regimens (4L induction) (2L+ PS ma
Slide 35: Immunotherapy
Role of the Immune System in Controlling Cancer Not designed to fight cancer — IMMUNOTHERAPY
Slide 36: The immune system can recognize tumors and mount an active immune response
The immune system can recognize tumors and mount an active immune response
Slide 37: Role of Immune Cells in Ovarian Cancer
Role of Immune Cells in Ovarian Cancer • OC is an immunogenic tumour1-4 – Strong immunosuppressive environment present in OC – Spontaneous antitumor immune response can be detected in the form of tumor-reactive T cells and antibodies • Analyses of OC patient samples showed presence of intratumoral T
Slide 38: The correlation between TILS and survival is supported by multiple studies
The correlation between TILS and survival is supported by multiple studies
Slide 39: PD-L1 expression may represent a tumor resistance mechanism to TILS in OC
PD-L1 expression may represent a tumor resistance mechanism to TILS in OC
Slide 40: Rationale for targeting PD-L1 in OC
Rationale for targeting PD-L1 in OC
Slide 41: Anti-PDL1/PD1 single agent therapy data in OC
Anti-PDL1/PD1 single agent therapy data in OC
Slide 42: Immunogenicity of Chemotherapy
Immunogenicity of Chemotherapy Chemotherapy has been shown to Enhance antigen presentation Enhance immunogenicity (release of adjuvants by cells) Increase susceptibility to immune attack CTL, cytotoxic T lymphocytes; iDCs, inflammatory dendritic cells; TAAs, tumor-associated antigens. Zitvogel L et
Slide 43: IL-12: A Powerful Immune Modulating Agent with Multiple Mechanisms of Action
IL-12: A Powerful Immune Modulating Agent with Multiple Mechanisms of Action Mechanisms of Action 1. NK cell Activation 3. Anti-angiogenesis 2. T cells Activation 4. Treg suppression 4 1 3 2
Slide 44: Modulation of Immune Response by Local Production of IL-12
Modulation of Immune Response by Local Production of a Powerful Immune Modulating Agent, IL-12 Persistent Delivery of IL-12 with a Single Administration of Formulated IL-12 Plasmid PPC Delivery System (Distinct from IV Chemotherapy) (PEG-PEI-Chol) IL-12 Plasmid EGEN-001 Stable Nanoparticles for Loca
Slide 45: GEN-1 Prior Clinical Studies
GEN-1 Prior Clinical Studies
Slide 46: Phase I Trial of GEN-1 + Neoadjuvant Chemo in Newly Diagnosed Ovarian Cancer Patients
PT Phase I Trial of GEN-1 + Neoadjuvant Chemo in Newly Diagnosed Ovarian Cancer Patients (The “OVATION” Trial) Primary Objective: Safety, tolerability, MTD Secondary Objective: Objective Tumor Response Rate, pCR, PFS, OS Translational Research Newly Diagnosed Ovarian Cancer Cohort Number of GEN-1 Ca
Slide 47: OVATION (Protocol 201-14-101) Phase 1 Study Design and Methods
OVATION (Protocol 201-14-101) Phase 1 Study Design and Methods • Standard 3+3 design with approximate 30% dose increments between successive cohorts of patients. Dose levels of GEN-1 in conjunction with standard carboplatin (C) and paclitaxel (T) • Tolerated dose is confirmed when 3-6 patients are t
Slide 48: OVATION Study Population
OVATION (Protocol 201-14-101) Study Population Patients newly diagnosed with EOC were eligible; patients who received prior radiotherapy or chemotherapy to any portion of the abdominal cavity and/or pelvis were excluded. Candidates for neoadjuvant chemotherapy A majority of the patients were Stage I
Slide 49: OVATION Safety Results
OVATION (Protocol 201-14-101) Safety Results The safety evaluation period is based on the first 4 doses of GEN-1 administered to each patient. The DSMB has reviewed data from the first 4 cohorts of patients. To date, 15 patients have been evaluated for safety and no DLTs have been identified. Most c
Slide 50: OVATION Safety Results – Grade and events
OVATION (Protocol 201-14-101) Safety Results – Grade 3 and 4 events Of the 15 patients evaluated for safety, the following Grade 3 and 4 events which can be attributed to GEN-1, in descending order include: – Neutropenia (5) – Leukopenia (2) – Diarrhea (2) – Vomiting (2) – Anemia (1) – Abdominal Pai
Slide 51: Clinical Results
Clinical Results Thaker et al. ASCO 2017
Slide 52: OVATION Summary of Progression Data: As Treated
OVATION Summary of Progression Data: As Treated Current PFS Median – 21.0 months, 95%CI (9.2-24.5) – Assumes all ongoing patients censored February 21, 2018 – Only patients treated according to protocol requirements Cohort Pt ID 1st chemo Date of progression or f/u Time from chemo (d) Time from chem
Slide 53: Phase III NACT Trials
Kehoe et #. 2015 CHORUS Onds et a, 2014 Vergom etal 210 EORTC 55971 (Fagotti's score of 8 to 12) assessed by staging laparoscopy. Stages Ill or IV ovarian cancer based upon imaging or cincs! evidence of peWvic mass with extrapeivic disease; Cé 125 © CEAratio > 25 f less, had to excude gstrontes tng
Slide 54: Phase III NACT Trials
Phase III NACT Trials OVATION PFS 21.0 months
Slide 55: Translational Results
Translational Results Reduction in Immune Suppressive Biomarkers in a Majority of Patients after the Treatment in Cells/mm 3 2400 2000 1600 1200 800 400 20 / 0 Beneficial response % Change g -50 in 60‐80% of patients -100 FOXP3+ FOXP3 IDO‐1+ IDO1 PD‐1+ PD 1 PD‐L1+ PD L1 Increase in the Ratio of CD8+
Slide 56: Conclusion of TR Data
Conclusion of TR Data GEN-1 IP + NAC treatment resulted in immunological changes that are consistent with the ability of GEN-1 to increase local (peritoneal) levels of IL-12 and its downstream anti-cancer cytokines and reduction in VEGF levels with little changes in systemic circulation. The increas
Slide 57: Ovation II: A Phase I/II Study of NACT and GEN-1
Ovation II: A Phase I/II Study of NACT and GEN-1
Slide 58: Conclusion
Conclusion GEN-1 IP can shift the local microenvironment to favor immunostimulation without systemic side effects. Randomized phase I/II Ovation II study will build on GEN- 1 development in the NACT population.
Slide 59: NCER CENTER
NCER CENTER