Slide 1: Ovarian Cancer: New Horizons and Treatments
Ovarian Cancer: New Horizons and Treatments Premal H. Thaker, M.D. Director of Gynecological Oncology Clinical Research Professor in Gynecologic Oncology Washington University School of Medicine
Slide 2: Disclosure
Disclosure Advisory Board: Celsion, Genentech, Iovance, Eisai, Stryker, Genelux, Unleash Oncolytics, Immunogen, Tesaro, Astra Zeneca, Merck Speaker’s bureau: Tesaro and Merck Institutional Grant: Merck and Tesaro 2
Slide 3: Objectives
Objectives Symptoms and Diagnosis Standard of care therapy: surgery and neoadjuvant chemotherapy Novel therapies – Anti-angiogenic – PARP inhibitors – Immunotherapy 3
Slide 4: 2019 US Estimates
2019 US Estimates * Women New Cases Deaths 891,480 285,210 30% Breast 23% Lung & bronchus 13% Lung & bronchus 15% Breast 7% Colon & rectum 8% Colon & rectum 7% Uterine corpus 8% Pancreas 5% Melanoma 5% Ovary 4% Non-Hodgkin lymphoma 4% Uterine corpus 4% Thyroid 4% Liver & bile duct 2.5% Ovary 3% Non-
Slide 5: 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 5 American Cancer Facts & Figures 2018
Slide 6: Epithelial Ovarian Cancer Subtypes Are Associated With Different Mutations and Molecular Aberrations
Epithelial Ovarian Cancer Subtypes Are Associated With Different Mutations and Molecular Aberrations Epithelial ovarian cancer can be characterized as a heterogeneous disease, not only histologically, but through identification of distinct molecular pathway alterations Epithelial High-grade Low-grad
Slide 7: 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. 7 Aarnio M, et al. Int J Cancer. 1999:81:214-218.
Slide 8: 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 9: Surgical Cytoreduction
Surgical Cytoreduction 9
Slide 10: 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 11: The Impact of Optimal Debulking
11 ct F 3 2 i 3 2 & zg ‘% Overall Survival The Impact of Optimal Debulking 1-10 mm vs.Omm: 2.52 (2.2 210mmys.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 1-10 mmvs. 0mm: 2.70 (2.37; 3.07) >10.mm vs. 1-10 mm: 1.34(1.21; 1.
Slide 12: 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 12
Slide 13: Chemotherapy vs Surgery?
CHEMOTHERAPY VS SURGERY?
Slide 14: Design of Phase III Trials Addressing NACT
Design of 2 Phase III Trials Addressing NACT 14
Slide 15: Algorithm for the clinical evaluation and treatment of suspected stage IIIC or IV ovarian cancer
ASCO & SGO Guidelines August 2016 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. 15 Alexi A. Wright et al. JCO doi:10.1200/JCO.2016.68.6907
Slide 16: NACT Trends
NACT Trends n=114 n=157 n=128 n=116 n=131 n=129 n=113 n=178 60 n=85 n=56 n=71 ——Pcs ——Pcs ----—PCS + IP/V —--—PCS+IP/IV NACT NACT Proportion of Patients (%) x 2 - = o = 3 a ‘S = BS) = S a 2 a 2004 2005 2006 2007 2008 2009 2010 2011 2004 2005 2006 2007 2008 2009 2010 2011 Year of Diagnosis Year of Di
Slide 17: Standard of Care Therapy
STANDARD OF CARE THERAPY
Slide 18: Chemotherapy choices: intraperitoneal therapy improves OS, but toxicity is increased
Chemotherapy choices: intraperitoneal therapy improves OS, but toxicity is increased 18
Slide 19: Addition of HIPEC to Interval Cytoreductive Surgery Improves Outcomes in Advanced Ovarian Cancer
Addition of HIPEC to Interval Cytoreductive Surgery Improves Outcomes in Advanced Ovarian Cancer Intraperitoneal chemotherapy during surgery delivered under hyperthermic conditions is termed HIPEC – Hyperthermia increases penetration of chemotherapy at the peritoneal surface and is thought to increa
Slide 20: GOG 252: PFS optimal stages II & III
GOG 252: PFS optimal stages II & III 20
Slide 21: Immunotherapy
(t) Initiation Mutational load TNA quantity Viral mimicry Danger signals Immature cancer, cell: TME *-Cancer cell [x) Regulation Co-inhibitory ligands Immunosuppressive factors Metabolic competition Lactate secretion Clonal expansion Lymphoid organ (t) Execution Antigen presentation IFNGR signaling
Slide 22: IL-12: A Powerful Immune-Modulating Agent
IL-12: A Powerful Immune-Modulating Agent Interleukin 12 Can Induce Anti-cancer Immunity Through Multiple Mechanisms 1 Stimulates the proliferation of CD-8 positive Activation/Proliferation T-cells and natural killer (NK) cells and their cytotoxic activity against the tumor 2 Shifts the differentiat
Slide 23: Clinical Experience with rhIL-12
Clinical Experience with rhIL-12 Hurteau et al. – GOG trial of recombinant human IL-12 in recurrent platinum resistant or refractory ovarian cancer – rhIL-12 250 ng/kg IV bolus on D#1 followed by a 2 week rest period, with subsequent daily dosing x 5 days – 26 evaluable patients with median of 2 cyc
Slide 24: GEN-1: Designed for IP Administration
GEN-1: Designed for IP Administration PEI IL-12 Expression PEG Vector Cholesterol CMV Immune Agent GEN-1 PEG-PEI-Chol (PPC) (IP Delivery System) Nanoparticles ~150 nm Plasmid vector encoding the p35 and p40 subunits of human IL-12 gene Synthetic lipopolymer GEN-1 delivery system GEN-1 intraperitonea
Slide 25: GEN-1 Design Concepts
GEN-1 Design Concepts PEI condenses DNA into nanoparticle to escape endosomes Cholesterol is designed to IP catheter facilitate uptake by cellular (SC) membrane PEG improves in vivo stability (weekly dosing) GEN-1 Peritoneal Mets (Ovarian/Primary) 25
Slide 26: Rationale for GEN-1 in Newly Diagnosed Ovarian Cancer Patients
Rationale for GEN-1 in Newly Diagnosed Ovarian Cancer Patients Relatively healthier immune system than recurrent population – Tumor and immune system naïve to any cancer therapy Accessibility to primary tumor tissue for translational studies – Neoadjuvant population allows for examining tissue befor
Slide 27: Phase I Study Design
27 Newly Diagnosed EOC Cancer Tumor Tissue Phase | Study Design +— Catheter Treatment Days | Standard Neoadjuvant Chemotherapy (C) AUC of 6 mg/mL min IV q 3 weeks and (T) 80 mg/m IV weekly treatments + 8 weekly cycles of GEN-1 IP starting at a dose of 36 mg/m? GEN-1 planned increments: 36, 47, 61, a
Slide 28: Study Endpoints
Study Endpoints Primary Objectives: To determine safety, feasibility, and dose in targeted patient population Secondary Objectives: pathological CR, PFS Translational Objectives: IFN-y, IL-12, VEGF, and tumor-specific T-cell response of CD4+ and CD8+ 28
Slide 29: Study Population
Study Population Performance Baseline CA- Patients Dates of C1D1 Age (yrs.) Histology Stage Status 125 (U/mL) IIIC: 0: 34% Range: 05Oct2015 – Median: 63 Serous: 95% Median: 565 18 (ITT) 67% 1:55% 17May2017 Range: 48-79 Clear Cell: 5% Range: 78 - 2252 IV: 33% 2:11% IIIC: 0: 36% 14 (Per Range: 05Oct20
Slide 30: Results: Safety (n=15)
Results: Safety (n=15) Most Common AEs Total Grade 1 & Grade 2 Grade 3 Grade 4 Grade 5 Attributed to GEN-1 (n, %) (n,%) (n,%) (n, %) (n, %) Nausea 9, 60% 9, 60% 0, 0% 0, 0% 0, 0% Abdominal Pain/ Cramping 6, 40% 5, 33% 1, 6% 0, 0% 0, 0% Fatigue 6, 40% 6, 40% 0, 0% 0, 0% 0, 0% Vomiting 6, 40% 5, 33% 1
Slide 31: Response Data
Response Data Response Total 36 mg/m2 47 mg/m2 61 mg/m2 79 mg/m2 CR 2 1 0 0 1 RECIST (Prior to IDS) PR 10 0 3 3 4 (n=14) SD 2 2 0 0 0 R0 9 2 0 2 5 Debulking Status R1 3 1 2 0 0 (n=14) R2 2 0 1 1 0 cPR 1 1 0 0 0 Pathologic Response Micro 8 1 2 1 4 (n=14) Macro 5 1 1 2 1 31
Slide 32: OVATION 1 Study: Improved Progression-Free Survival with GEN-1
OVATION 1 Study: Improved Progression-Free Survival with GEN-1 Improvements vs Historic Outcomes in Comparable Patient Populations Historical Estimated PFS* (Vergote, Kehoe) 12 months OVATION 1 – ITT 17 months Final Median PFS Per OVATION 1 Protocol 21 months Similar Baseline Patient Characteristics
Slide 33: Decrease in Immunosuppressive Markers in the TME Post GEN-1/NACT
Decrease in Immunosuppressive Markers in the TME Post GEN-1/NACT 40% FoxP3 IDO-1 PD-1 PD-L1 20% 0% -20% -40% -60% -80% Figure 1. Changes in immunosuppressive markers in response to low and high doses of GEN-1. Low doses (n=4) High doses (n=8) * Data in Figures 1 and 2 from 12 patients treated per pr
Slide 34: Increase in the Ratio of Immune Activating Cells to Immune Suppressive Cells in the TME
Increase in the Ratio of Immune Activating Cells to Immune Suppressive Cells in the TME 4.50 4.00 CD4 CD8 3.50 3.00 2.50 2.00 1.50 1.00 0.50 0.00 FoxP3 IDO-1 PD-1 PD-L1 Figure 2. Changes in the ratios of CD4+ and CD8+ T cells to immunosuppressive markers presented as post-treatment ratio to pretreat
Slide 35: Increase in CD8+/CD4+ in Tumor Post GEN-1 / NAC Treatment
Increase in CD8+/CD4+ in Tumor Post GEN-1 / NAC Treatment Ratio of CD8+/CD4+ T cells increased nearly 500% 4.0 CD8+/CD4+ 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Pre Post 35
Slide 36: Increases in Dendritic and TEM Cells population GEN-1 / NAC
Increases in Dendritic and TEM Cells population GEN-1 / NAC 14.0 Myeloid Dendritic Cells 12.0 Effector Memory T Cells 10.0 % Total Cells 8.0 6.0 4.0 2.0 0.0 Pretreatment Post-treatment 36
Slide 37: Summary of TR Findings
Summary of TR Findings 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 effect. The increase
Slide 38: Conclusions
Conclusions Adding GEN-1 to doublet treatment is safe and appears to be active in EOC patients receiving neoadjuvant chemotherapy. Dose limiting toxicity was not reached. GEN-1 appears to change the tumor microenvironment. OVATION 2 is extending the results of the phase I OVATION trial. 38
Slide 39: OVATION 2
OVATION 2 Ovarian Cancer Patients Primary Endpoint Secondary Endpoint (FIGO IIIC & IV) Progression Clinical Response, Pathological Response, Up to 130 patients Free Survival Surgical Response, Safety, Biological 12 patients in Phase I Run-in (100 mg/m²); Up to 118 patients in Phase II Randomized 1:1
Slide 40: Maintenance Therapy
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Slide 41: FDA-Approved Options for 1L Maintenance Therapy: Bevacizumab and Olaparib
FDA-Approved Options for 1L Maintenance Therapy: Bevacizumab and Olaparib Registrational Biomarker Testing Drug Indication Recommended Dosing Clinical Trial(s) Required? 15 mg/kg IV q3w in Bevacizumab in combination with combination with carboplatin and paclitaxel, followed carboplatin and paclitaxe
Slide 42: Select Phase 2/3 Studies on 1L Maintenance Therapy in Ovarian Cancer
Select Phase 2/3 Studies on 1L Maintenance Therapy in Ovarian Cancer Specific Study NCT Primary Est. Primary Ph Description Biomarker Name Identifier Endpoint(s) Completion Date Status Required? VELIA / Carboplatin/paclitaxel + veliparib NCT02470585 3 No PFS Apr 2019 GOG-3005 Followed by maintenance
Slide 43: Study Designs of Key PARPi Maintenance Therapy Trials in Recurrent Ovarian Cancer
Study Designs of Key PARPi Maintenance Therapy Trials in Recurrent Ovarian Cancer NOVA1,2 Study 193,4 SOLO-25,6 ARIEL37,8 (NCT01847274) (NCT00753545) (NCT01874353) (NCT01968213) N 553 265 295 564 Phase 3 2 3 3 Design Randomized, placebo-controlled, and with patients who have received ≥2 previous cou
Slide 44: Conclusion
Conclusion Molecular and immunotherapeutic targeted therapies in combination with chemotherapy for upfront treatment 44