Targeted Molecular Therapy Gynaecological Cancer Where are we now?

Targeted Molecular Therapy Gynaecological Cancer Where are we now? 0 T O M D E G R E V E S U B - S P E C I A LT Y F E L L O W G Y N A E C O L O G I C A L O N C O L O G Y U N I V E R S I T Y O F P R E T O R I A Q U E E N S L A N D C E N T R E F O R G Y N A E C O L O G I C A L C A N C E R S A S G O M E E T I N G 2 5 TH O F S E P T E M B E R 2 0 1 6

History of Systemic Cancer Treatment 1940 s - chemotherapy agents identified Nitrogen Mustard (Mustard gas) Lymphoma s (Goodman & Gilman) Anti-Folates (Methotrexate) Acute lymphoblastic leukemia (Farber) Toxin agents interfering with all rapidly dividing cells Often accidentally discovered 1969 - Hormonal therapy ICI46474 (Tamoxifen) trialed in breast cancer patients (Cole) 1998 Targeted Molecular therapy Tyrosine Kinase Inhibitors (Gleevec, Glivec ) Chronic Myelogenous Leukemia Interfering with specific targeted molecules, rather than interfering with all rapidly dividing cells (Chemotherapy)

Try to keep it simple. VEGF-Trap Avastin HER2 Pazopanib (Votrient ) PARP Adoptive Cell Therapy WEE1 Tyrosine Kinase PI3K/AKT/m-TOR-signaling pathway mtor Checkpoint Inhibitors & Immune Modulators VEGF Cediranib (Recentin )

Epithelial Ovarian Cancer 0

Introduction Since 1996 with the addition of paclitaxel (GOG-111), limited advances have been made in the treatment of Ovarian Cancer Toxicity has improved with carboplatin compared to cisplatin (AGO - 2000) Decreased surgical morbidity with NACT, without improved PFS or OS (Vergote, et al - 2010) Increased PFS and OS with intra-peritoneal chemotherapy, at increased toxicity (GOG-172 2006) Increased PFS and OS with dose-dense treatment (JGOG 3016-2013) However survival rates over the past 20 years have only increased modestly It appears that a therapeutic ceiling has been reached with chemotherapy agents

Molecular Pathways Targets - EOC Tumour Angiogenesis PARP Inhibitors Interfering with Cell-Cycle checkpoints Folate receptors Inhibiting Insuline-Like Growth Factor (IGF) Immunotherapies

Tumour Angiogenesis

Tumour Angiogenesis Once a tumour exceeds >1mm it cannot receive adequate nutrients or oxygen from surrounding tissues. Tumour cells induce angiogenic response through VEGF pathways New blood vessels with promote growth and facilitate potential spread Angiogenesis

Tumour Angiogenesis - Inhibitors Anti-VEGF Bevacizumab (Avastin ) FDA approved (platinum resistant, recurrent EOC) EMA approval (first-line and recurrent EOC) Aflibercept (Zaltrap ) Tyrosine kinase inhibitors Cediranib (Recentin ) Pazopanib (Votrient ) Nintedanib (Ofev, Vargatef ) Angiopoietin inhibitor Trebananib (AMG 386) Angiogenesis

Bevacizumab Monoclonal antibody, binds to VEGF-receptor ligand VEGF-A Angiogenesis

Bevacizumab First line treatment Addition to carboplatin/paclitaxel as first line treatment and/or maintenance (12-15 months) GOG218 ICON7 Burger, et al. N Engl J Med 2011, Perren, et al. N Engl J Med 2011 Angiogenesis

Bevacizumab First line treatment GOG-218 (2011) ICON7 (2011) N Characteristics PFS P-value OS P- value 1,873 Stage III-IV 14.1 v.s 10.3 months <0.0001 39.7 v.s. 39.3 months 1,528 Stage I-IV 19.0 v.s. 17.3 months 0.004 45.5 v.s. 44.6 months NS NS GOG218 ICON7 Angiogenesis

Bevacizumab First line treatment High risk patients ICON7 (2011/2013) N Characteristics PFS P- value 502 Stage III-IV, Suboptimal debulking (>1cm residual) 16 v.s. 10.5 months 0.0002 39.7 v.s. 30.3 months OS P- value 0.03 Angiogenesis

Ongoing trials First line therapy ICON 8B Dose-dense chemotherapy and bevacizumab, High risk stage III-IV GOG 252 Preliminary results* Stage II-III, Optimal cytoreduction, n=1560 Increased toxicity in IP arms *Walker J et al. SGO 2016 Angiogenesis

Bevacizumab Recurrent disease Chemotherapy with bevacizumab in relapsed disease N Characteristics PFS P-value OS P-value OCEANS 484 Platinum-sensitive 12.4 v.s. 8.4 months <0.0001 33.4 v.s. 33.7 months NS AURELIA 361 Platinum-resistant 6.7 v.s. 3.4 months <0.0001 16.6 v.s. 13.3 months NS OCEANS AURELIA OS could be influenced by high crossover rate to bevacizumab maintenance at progression of disease Angiogenesis

Bevacizumab GI perforations Cannistra, et al.* Phase II trial, (n=44) Partial response rate of 15.9% GI perforation rate of 11.4% Highest rate in patients received 3 prior lines Premature termination of trial Subsequent trials: GOG-218 (n=1,873) 2.6-2.8% ICON7 (n=1,528) 1% OCEANS (n=484) 0.8% AURELIA (n=361) 2.2% *Cannistra, et al. J Clin Oncol 2007 Angiogenesis

Aflibercept Heterodimeric molecule, VEGF receptors 1-2 domains VEGF-Trap Decoy receptor for VEGF Coleman, et al. Phase II trial, recurrent disease (n=46) Aflibercept with docetaxel 54% objective response Gotlieb, et al. Significantly extends time to ascites drainage (55.1 v.s. 23.3 days) No OS benefit More grade 3-4 toxicity Angiogenesis

Cediranib Tyrosine kinase inhibitors Oral agent targeting VEGF 1, 2, 3 and c-kit ICON 6 (n=456), Phase III, Platinum sensitive recurrent EOC, Cediranib during and as maintenance (18 months) with platinum based chemotherapy* PFS benefit 11.4 v.s. 9.4 months (p=0.002) OS benefit 20.3 v.s. 17.6 months (p=0.04) Toxicity increased, but tolerable Pazopanib Oral agent targeting VEGF-, FGF-, PDGF-receptors and c-kit AGO-OVAR16 study (n=940), Phase II, 2 year maintenance therapy in first line setting (after completion of >5 cycles adjuvant chemotherapy)^ PFS benefit 17.9 v.s. 12.3 months (p=0.002) No difference in OS Increased Grade 3/4 Toxicity, 33% discontinued *Raja, et al. Br J Cancer 2011, ^Du Bois, et al. J Clin Oncol Off J Am Soc Clin Oncol 2014 Angiogenesis

Tyrosine kinase inhibitors Nintedanib Targeting VEGF-, FGF- and PDGF-receptors AGO-OVAR12, Double-blind Phase III, first line treatment with adjuvant chemotherapy (Carboplatin/Paclitaxel)* PFS benefit 18.3 v.s. 16.6 months (p=0.02) PFS in low risk patients 27.1 v.s. 20.8 months *Kristensen, et al. J Clin Oncol Off J Am Soc Clin Oncol 2011 Angiogenesis

Angiopoietins Inhibitor Trebananib (AMG 386) Targeting angiopoietin 1 and 2 TRINOVA-1, Phase III study (n=919), Recurrent EOC treated with trebananib and paclitaxel* PFS benefit 7.2 v.s. 5.4 months (p=<0.001) OS non-significant benefit 19.0 v.s. 17.3 months (p=0.19) *Monk, et al. Lancet Oncol 2014 Angiogenesis

Poly(adenosine diphosphate [ADP]-Ribose) Polymerase Inhibitors

PARP-Inhibitors PARP enzymes play role in DNA repair Inhibition causes single-strand DNA breaks, repaired by homologous recombination BRCA 1/2 Mutation-associated cancers, defective HR. Leading to double-strand DNA break during replication and subsequently cell death BRCA PARP-Inhibitors

Breast Cancer Tumour Suppressor Gene (BRCA) Mutation Carriers PARP Inhibition in the setting of defective BRCA protein leads to cell death BRCA 1 40% lifetime risk ovarian cancer BRCA 2 11% lifetime risk ovarian cancer 30-50% EOC harbor HR deficiency Orally available & Well Tolerated PARP Inhibitors Olaparib FDA approved (recurrent EOC, BRCA mutation and 3 prior chemotherapy regimes) EMA approval (recurrent EOC, platinum sensitive and BRCA mutation) Niraparib Talazoparib Veliparib rucaparib PARP-Inhibitors

PARP First Line Therapy Limited data available Ongoing trials: GOG 9923 Phase III, veliparib with carboplatin, paclitaxel and bevacizumab. SOLO1 Phase III, olaparib as maintenance (24 months) after first line carboplatin/paclitaxel, BRCA mutation PARP-Inhibitors

Monotherapy Recurrent EOC Olaparib maintenance after platinum based chemotherapy for platinum-sensitive EOC. Randomized, Phase II* Pre-planned sub-analysis in BRCA group No benefit of OS. However high cross-over to olaparib once relapsed *Study 19. Ledermann, et al. N Eng J Med 2012/Lancet Oncol 2014 PARP-Inhibitors

Ongoing trials PARP inhibitors Recurrent EOC ARIEL3 rucaparib, Phase III SOLO2 olaparib, Phase III NOVA niriparib, Phase III PARP-Inhibitors

Combination therapy Recurrent EOC PARPi could sensitize cells to DNA damage secondary to chemotherapy or angiogenesis inhibitors Phase II, Platinum sensitive EOC, BRCA* Olaparib combination with Carbo/Taxel, followed by olaparib maintenance v.s. chemotherapy alone Improved PFS 12.2 v.s. 9.6 months (p=0.0012) Phase II, Platinum sensitive EOC, BRCA^ Olaparib with cediranib (VEGF inhibitor) v.s. olaparib alone Improved PFS 17.7 v.s. 9 months (p=0.005) *Study 41. Oza, at al. Lancet Oncol 2015, ^Lui, et al. Lancet Oncol 2014 PARP-Inhibitors

Type-1 EOC Histology

Low-Grade Serous Carcinoma of the Ovary More indolent course, however extreme poor response rates to chemotherapy (Response rates ± 4%) Desperate need for new treatment modalities MEK-inhibitors GOG Phase II, Selumetinib in recurrent LGSC* 15% response rate, 65% stable disease MILO trial, Phase III, MEK162 with chemotherapy in recurrent/persistent LGSC - Interim analysis: Failed improvement of PFS *Farley, et al. Lancet Oncol. 2013

Clear-Cell Carcinoma of the Ovary Poor responses to chemotherapy 35% clear-cell ovarian cancer have PIK3CA mutation, susceptible for PI3K/AKT/m-TOR inhibitors mtor Inhibitor is being investigated Phase II, temsirolimus added to first-line chemotherapy Currently ongoing

Immunotherapy Immune system has prominent role in modifying clinical course of disease Anti-Cancer immune responses Infiltrating T-Cells (TILs) in ovarian cancer cells - Associated with improved survival* Manipulate the hosts cancer immune response to cause immune-mediated tumour rejection Immunotherapies have been FDA approved (Prostate cancer, Melanoma, Lymphoma) *Zhang, et al. N Engl J Med 2003

Immunotherapy Categories Monoclonal Antibodies Anti-angiogenic agents (Bevacizumab) Checkpoint Inhibitors & Immune Modulators Enhance pre-existing anti-cancer immune response Therapeutic Vaccines Teach immune system to recognize & target tumour cells, including memory Adoptive Cell Therapy Genetically modified immune cells, re-introduced into the patient with the goal of improving the immune system s anti-cancer response Oncolytic Viruses Modified virus that can cause tumour cells to self-destruct or Generating a greater immune responses

Targeted Therapy in Ovarian Cancer - Summary VEGF inhibitors Bevacizumab active in first-line and recurrent EOC (platinum sensitive and resistant) Only OS benefit in high-risk patients (post-hoc analysis) PARP inhibitors Active in EOC, specifically BRCA mutations Evidence for PFS benefit in recurrent disease Timing remains unclear Immunotherapy Promising New Kid on the Block

Cervix Cancer 0

Cervix Cancer - Introduction 4 th most common cause of cancer-related death globally Early stage disease often curable Advanced, recurrent or persistent disease often incurable Cisplatin based chemotherapy most patent However, Response rate 20-36% and Survival < 1 year* *Monk, et al. J Clin Oncol 2009. GLOBOCAN 2012

Target Pathways Cervix Cancer Angiogenesis Inhibitors Bevacizumab PARP- inhibitor Velaparib Immunotherapy Therapeutic Vaccines Immune Checkpoint Inhibitors Adaptive Cell Therapy

Bevacizumab Cervix Cancer GOG 240 Phase III (n=452), chemo-naïve patients *Tewari, et al. NEJM 2014

Bevacizumab GOG240 Significant improved PFS and OS PFS OS *Tewari, et al. NEJM 2014

Cervix Cancer - PARP inhibitor Role is Unclear Cell lines of cisplatin resistant cervix cancer has found to be PARP inhibitor sensitive* GOG-76HH - Phase I/II, advanced/recurrent/persistent cervix cancer, velaparib with cisplatin and paclitaxel (n=34) Overall response rate 34% Ongoing, Phase I/II trials investigating velaparib with topotecan or cisplatin/carbotaxel in advanced/recurrent cervix cancer. *Michels, at al. Cancer Res. 2013

Immunotherapy Cervix Cancer Therapeutic Vaccines Cell-mediated immunity against HPV-infected cells (Cancer cells) Phase I, ADXS11-001, pre-treated advanced/recurrent disease (n=15)* - 61.5% clinical response rate Phase II, ADXS11-001 with/without cisplatin, recurrent disease (n=110)^ - Response rate 43%, No added benefit of Cisplatin Ongoing, Phase II (GOG265) Immune Checkpoint Inhibitors Two ongoing phase II studies, PD-1 and CTLA-4 inhibitors Adaptive Cell Therapy HPV - tumour infiltrating lymphocytes with chemotherapy (n=9) # - 3 patients with clinical response, lasting 15-22 months *Maciag, et al. Vaccine 2009, ^Basu, et al. J Clin Oncol 2014, # Stevanovic, et al. J Clin Oncol 2015

Endometrial Cancer

Target Pathways Endometrial Cancer Hormonal Therapy Angiogenesis Inhibitors Bevacizumab Aflibercept Tyrosine Kinase Inhibitors PI3K pathway mtor inhibitors HER2 inhibitors Metformin Immunotherapy

Hormonal Therapy Endometrial Cancer Sole approved targeted therapy Progesterone therapy Response rate 22%* Low-grade and PR-receptor positive tumours Aromatase Inhibitors & Tamoxifen Response rates ±10%^ Cochrane review: No improved survival in advanced endometrial cancer # Large randomized trials are required *Wright, et al. Lancet 2012, ^Thigpen, et al. J Clin Oncol 2001, # Koka, et al. Cochrane Database Syst Rev 2010

Bevacizumab Advanced/Recurrent Endometrial cancer Phase II, Advanced or Recurrent endometrial cancer (Type 1 & 2) Carboplatin/Paclitaxel +/- bevacizumab (n=66) Increased PFS 13 v.s. 8.7 months (p=0.036) *Lorusso, et al. ASCO 2015

Future Perspective Targeted Therapy 0

Future perspectives Predictive biomarkers (genomic signatures) Bevacizumab (Gourley, et al) PARP-inhibitor (on-going ARIEL2) Combination of Targeted therapies with/without chemotherapy Immunotherapies are promising