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  1. Today’s Challenges and Controversies in Recurrent Ovarian Cancer Management Bradley J. Monk, MD, FACS, FACOGDivision of Gynecologic Oncology Department of Obstetrics and Gynecology Chao Family Comprehensive Cancer Center University of California, Irvine Medical Center Orange, California

  2. What is Ovarian Cancer? • 3 types of cancer • Epithelial • Germ cell • Stromal • Epithelial tumors are of mesodermal origin • Same as primary peritoneal cancer • Epithelial cancers related to ovulatory events, which increase mutation frequency • Reduced by OCPs, pregnancy, or lactation

  3. Newly Diagnosed Advanced Ovarian Cancer Courtesy of Robert Bristow, Johns Hopkins.

  4. Ovarian Cancer is a Global Disease International Agency for Research on Cancer (WHO). Courtesy of Dr. Bradley J. Monk.

  5. Ovarian CarcinomaIncidence and Mortality Incidence in US women 21,550 cases in 2009 9th most common cancer 2nd most common gynecologic cancer 1.5% lifetime risk of getting ovarian cancer Mortality in US women 14,600 deaths in 2009 5th most common cause of cancer death Most common cause of death due to gynecologic cancer 1.0% lifetime risk of dying of ovarian cancer American Cancer Society. Available at: http://www.cancer.org/

  6. Cancer in the United States With permission from American Cancer Society. Available at: http://www.cancer.org/

  7. FIGO Stage—Outcomes Abbreviation: IP, Intraperitoneal Gynecologic Oncology Group database (J. Tate Thigpen). Courtesy of Dr. Bradley J. Monk.

  8. Results of TreatmentAdvanced Disease Gynecologic Oncology Group database (J. Tate Thigpen). Courtesy of Dr. Bradley J. Monk.

  9. Results of TreatmentAdvanced Disease Gynecologic Oncology Group database (J. Tate Thigpen). Courtesy of Dr. Bradley J. Monk.

  10. Ovarian Cancer Increasing Survival Rates Barnholtz-Sloan JS, et al. Am J Obstet Gynecol. 2003;189(4):1120-1127.

  11. Approved Drugs inOvarian Cancer 1978 Cisplatin 1989 Carboplatin 1990 Altretamine 1992 Paclitaxel 1996 Topotecan 1999 Liposomal doxorubicin (accelerated) 2005 Liposomal doxorubicin (full) 2006 Gemcitabine (with carboplatin) 2009 Trabectedin (with liposomal doxorubicin EMEA only) 1978 2009

  12. First-line TherapyGlobal Standard Treatment Surgery with maximum cytoreduction effort IV Platinum + Taxane Chemotherapy(Carboplatin + Paclitaxel) x 6 2004 Consensus Statements on the Management of Ovarian Cancer: Final Document of the 3rd International GCIG Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol. 2005;16(suppl 8) viii7–viii12. Courtesy of Dr. Bradley J. Monk.

  13. Maximal Primary Cytoreduction • Meta-analysis: 53 studies (1989–1998) • 81 cohorts (stage III/IV) • N = 6885 patients • Results • Expert centers have high optimal rates • Optimal vs not: 11 mo (50% increase) • Each 10%  in cytoreduction = 5.5%  in survival • Platinum intensity = NS Bristow RE, et al. J Clin Oncol. 2002;20:1248-1259.

  14. Basis for Current StandardSystemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 1111 EORTC-NCIC OV 102 Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial3 GOG Protocol 1584 1. McGuire WP, et al. N Engl J Med .1996;334:1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A, et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF, et al. J Clin Oncol. 2003;21:3194-3200.

  15. Standard of Care—2010 Maximum attempt at surgical cytoreduction Chemotherapy following surgery Regimen of choice Paclitaxel 175 mg/m2/3 h IV + Carboplatin AUC 6–7.5 IV Repeat every 3 wk for 6 cycles 2004 Consensus Statements on the Management of Ovarian Cancer: Final Document of the 3rd International GCIG Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol. 2005;16(suppl 8) viii7–viii12. Courtesy of Dr. Bradley J. Monk.

  16. The Role of AntivascularAgents in the Management of Recurrent Ovarian Cancer Robert A. Burger, MDProfessor, Surgical OncologySection of Gynecologic OncologyDirector, Women’s Cancer CenterFox Chase Cancer CenterPhiladelphia, Pennsylvania

  17. Angiogenesis in Tumor Progression With permission from The Angiogenesis Foundation, Inc; www.angio.org.

  18. Angiogenic Balance   Hanahan & Folkman. Cell. 1996;86:353–364.

  19. Rationale for Targeting VEGF in Treatment of EOC Human tumors VEGF expression and degree of tumor angiogenesis (microvessel density) associated with Ascites formation Malignant progression1-3 Poor prognosis4-7 Abbreviation: EOC, epithelial ovarian cancer. 1. Yoneda J, et al. J Natl Cancer Inst. 1998;90:447-454. 2. Ferrara N. J Mol Med. 1999;77:527-543. 3. Dvorak HF. J Clin Oncol. 2002;20:4368-4380. 4. Gasparini G, et al. Int J Cancer. 1996;69:205-211.5. Hollingsworth HC, et al. Am J Pathol. 1995;147:33-41. 6. Paley PJ, et al. Cancer. 1997;80:98-106.7. Alvarez AA, et al. Clin Cancer Res. 1999;5:587-591.

  20. Rationale for Targeting VEGF in Treatment of EOC Preclinical models of solid tumors Anti-VEGF therapy Slowing of tumor progression1,2 Resolution of malignant effusions2 Synergy with cytotoxic agents3-5 Abbreviation: EOC, epithelial ovarian cancer. 1. Byrne AT, et al. Clin Cancer Res. 2003;9:5721-5728. 2. Mesiano S et al. Am J Pathol. 1998;153:1249-1256. 3. Gorski DH, et al. Cancer Res. 1999;59:3374-3378. 4. Lee CG, et al. Cancer Res. 2000;60:5565-5570. 5. Hu L, et al. Am J Pathol. 2002;161:1917-1924.

  21. Direct Anti-VEGF Antitumor Effect? VEGFRs expressed in multiple solid tumor types: colon,1 breast,2,3 ovary4 In vitro stimulation of breast carcinoma cells with VEGF3leads to Invasion Growth factor signaling Activation of VEGFR-1 on tumor cells by VEGF3 Invasion Activation of MAPK Cell migration 1. Fan F, et al. Oncogene. 2005;24:2647-2653. 2. Wu Y, et al. AACR 2004. Abstract 3005. 3. Price DJ, et al. Cell Growth Differ. 2001;12:129-135. 4. Chen H, et al. Gynecol Oncol. 2004;94:630-635.

  22. Classes of Anti-VEGF Agents Target Ligand (VEGF) VEGFR Pharmacology Large molecules (monoclonal antibodies, soluble receptors) Small molecule inhibitors (“ibs”)

  23. Classes of Anti-VEGF Agents Abbreviations: FGF, fibroblast growth factor; Mab, monoclonal antibody; PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. 1. Presta G, et al. Cancer Res. 1997;57:4593-4599. 2. Holash J, et al. Proc Natl Acad Sci U S A. 2002;99:11393-11398. 3. Hu L, et al. Clin Cancer Res. 2005;11:6966-6971.

  24. Unique Toxicities ofAnti-VEGF Agents Proteinuria Hypertension Mucosal hemorrhage Wound healing Arterial thromboembolism Reversible posterior leukoencephalopathy syndrome (RPLS) GI perforation or fistula

  25. Single-Agent Activity

  26. Single-Agent Anti-VEGF Therapy in EOC/PPC—Phase II Efficacy Results *Trial terminated prematurely. †Trial failed to meet primary endpoint.‡Preliminary analysis. Abbreviations: EOC, epithelial ovarian cancer; PPC, primary peritoneal cancer. 1. Burger RA, et al. J Clin Oncol. 2007;25:5165-5171. 2. Cannistra SA, et al. J Clin Oncol.2007;25:5180-5186. 3. Tew WP, et al. Paper presented at: 43rd ASCO; June 1-5, 2007.

  27. GOG 170-DExploratory Analysis of Prognostic Factors for PFS (Proportional Hazards) GOG performance status >0 vs 0 Hazard ratio 1.491 Wald P value 0.2466 Platinum sensitivity yes vs no Hazard ratio 0.803 Wald P value 0.4702 Age Hazard ratio 1.001 Wald P value 0.9076 Number of prior regimens 2 vs 1 Hazard ratio 0.616 Wald P value 0.1207 Burger RA, et al. J Clin Oncol 2007; 25: 5165-5171.

  28. Single-Agent Anti-VEGF Therapy in EOC/PPC Toxicities—Phase II Trials *Trial terminated prematurely. †Trial failed to meet primary endpoint.‡Preliminary analysis. §Event fatal in 1 case. Abbreviations: EOC, epithelial ovarian cancer; PPC, primary peritoneal cancer. 1. Burger RA, et al. J Clin Oncol. 2007;25:5165-5171. 2. Cannistra SA, et al. J Clin Oncol.2007;25:5180-5186. 3. Tew WP, et al. J Clin Oncol.2007;25 (suppl). Abstract 5508.

  29. Rationale for Combination Anti-VEGF and Cytotoxic Regimens Complementary, independent activity Synergy in preclinical models1 Hypothetical mechanisms Sensitization to apoptosis Reversal of cytotoxic drug resistance Increased access of chemotherapeutic—vascular “normalization”2,3 Positive phase III trials (bevacizumab) in metastatic colorectal,4,5 breast,6 and lung7 cancers 1. Sweeney CJ, et al. Cancer Res. 2001;61:3369-3372. 2. Jain RK. Science. 2005;307:5706:58-62. 3. Wildiers H, et al. Br J Cancer. 2003;88:1979-1986. 4. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2243. 5. Giantonio B, et al. JClin Oncol. 2007;25:1539-1544. 6. Miller K, et al. N Engl J Med. 2007:357:2666-2676. 7. Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

  30. Bevacizumab + Metronomic Cyclophosphamide in Recurrent Ovarian Cancer—Phase II Results Toxicity findings similar to single agent anti-VEGF phase II trials N = 70 GI fistula/perforation: 4 (5.7%) CNS ischemia: 2 (2.9%) Wound healing impairment: 1 Pulmonary hypertension: 2 (2.9%) Treatment related deaths: 3 (4.3%) Efficacy PFS-6 mo: 56% Response rate: 24% (17 PR) Garcia AA, et al. J Clin Oncol. 2008;26:76-82.

  31. GOG 213 Recurrent ovarian and peritoneal primary cancerTFI > 6 mo Surgical candidate? Yes No Randomize Randomize Surgery No surgery Carboplatin,paclitaxel Carboplatin,paclitaxel,bevacizumab To chemotherapyrandomization Maintenancebevacizumab Primary endpoint: Overall survival Secondary endpoints: Progression-free survival, toxicity, quality of life, translational research Abbreviation: TFI, treatment-free interval Slide courtesy of Dr. Robert A. Burger. ClinicalTrials.gov. NCT00565851 PI: Coleman, Activated 12/07

  32. Primary outcome measure: Progression-free survival Secondary outcome measures: objective response, duration of response, overall survival, incidence of GI perforation, safety of bevacizumab + carboplatin/gemcitabine, all adverse events OCEANS—Carboplatin/Gemcitabine ± Bevacizumab in Ovarian Carcinoma(Phase III) Bevacizumab + Carboplatin + Gemcitabine Patients with platinum-sensitive recurrent epithelial ovarian, peritoneal, or fallopian tube carcinoma Placebo + Carboplatin + Gemcitabine (Planned N = 450) Slide courtesy of Dr. Robert A. Burger. ClinicalTrials.gov. NCT00434642

  33. Phase III Frontline OvarianCancer Trials Abbreviations: PFS,progression-free survival; PH-EC, pharmacoeconomics; QOL, quality of life; RR, response rate; TOX, toxicity; TR, translational research. 1. ClincialTrials.gov. NCT00262847.2. ClincialTrials.gov. NCT00483782.

  34. GOG 0218—Frontline CT ± Bev in Recurrent Ovarian Cancer (Phase III) Phase B Phase A CT1  CT + plac 2-6 Arm 1 Plac 7-22 CT1  CT + bev 2-6 Arm 2 Plac 7-22 CT1  CT + bev 2-6 Arm 3 Bev 7-22 Cycles 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Months 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 ClincialTrials.gov. NCT00262847. Slide courtesy of Dr. Robert A. Burger.

  35. Multi-Growth Factor Targeting

  36. The Role of the Platelet-Derived Growth Factor (PDGF) Pathway PDGF/PDGFR recruitment of pericytes1 PDGFR activation  direct effect on endothelial cells2-5 Implicated in resistance to VEGF pathway inhibition6-9 1. Jain & Booth. J Clin Invest. 2003. 2. Beitz, et al. Proc Natl Acad Sci USA. 1991. 3. Risau, et al. Growth Factors. 1992. 4. Oikawa, et al. Biol Pharm Bull. 1994 5. Apte, et al. Clin Cancer Res. 2004. 6. Abramsson, et al. J Clin Invest. 2003; 7. Benjamin. Development. 1998. 8. Bergers, et al. J Clin Invest. 2003. 9. Lu, et al. Am J Obstet Gynecol. 2008.

  37. The Role of FGF in Angiogenesis FGF HGF expression (VSMC) VEGF expression (myocytes, stromal cells, EC) PDGFR expression (EC, VSMC) EC activation Mural cell recruitment Angiogenesis Abbreviations: EC, endothelial cell; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; PDGFR, platelet-derived growth factor receptor; VSMC, vascular smooth muscle cell. Slide courtesy of of Dr Robert A. Burger. Murakami and Simons. Curr Opin Hematol. 2008;15:215–220.

  38. Toxicities Associated with Dual Multi-Pathway Inhibitors Dermatologic toxicity (ie, hand-foot skin reaction, rash/desquamation, skin discoloration) GI toxicity (ie, diarrhea, nausea, abdominal pain, vomiting, dyspepsia, constipation, perforation) Hypertension Fatigue Weight loss Alopecia Anorexia Asthenia Mucositis/stomatitis Altered taste Bleeding events Arterial thrombotic events Myocardial toxicity Hypothyroidism Adrenal toxicity

  39. Phase II Efficacy—Multi-Targeted TKI * Closed due to toxicity ** Secondary Consolidation, Placebo-Controlled 1. Matei D, et al. J Clin Oncol. 2008;26(suppl). Abstr 5537. 2. Friedlander M, et al. J Clin Oncol. 2007; 25(suppl). Abstr 5561. 3. Hirte HW, et al. J Clin Oncol. 2008;26(suppl). Abstr 5521. 4. Matulonis UA, et al. J Clin Oncol 2009; 27: 5601-5606. 5. Ledermann JA, et al. J Clin Oncol. 2009;27(suppl). Abstr 5501.

  40. Patients with platinum-sensitive ovarian cancer Relapsed >6 mo following first-line platinum-based treatment ICON 6 (Second-Line European Trial) 2:3:3 Randomization Platinum-based chemo (± taxane)q 21 days x 6 cycles + placebo Platinum-based chemo (± taxane)q 21 days x 6 cycles + oral cediranib daily during chemo, then 18 mo placebo Measurable disease Platinum-based chemo (± taxane)q 21 days x 6 cycles + oral cediranib during chemo and until progression or 18 mo Slide courtesy of Dr. Robert A. Burger. Planned: phase II (N = 300), phase III (N = 2,000).

  41. Theoretical Pros and Cons ofMulti-Targeting vs Isolating VEGF Pros May more effectively block angiogenesis Potentially reduced likelihood of resistance due to activity of compensatory pathways Benefit of oral vs IV route Cons Benefit of IV vs oral Increased risk of off-target effects

  42. Vascular Disrupting Agents Unlike anti-angiogenesis agents, which inhibit the formation of new blood vessels, vascular disrupting agents destroy the existing vascular structure in a tumor Small molecule flavonoids: DMXAA Microtubulin-destabilizing agents: combretastatin (CA4P, AVE8062) Lippert JW III. Bioorg Med Chem. 2007;15: 605-615. Cai SX. Recent Pat Anticancer Drug Discov.2007;2:79-101. Delmonte A, Sessa C. Expert Opin Investig Drugs. 2009;18:1541-1548.

  43. Summary Rationale for antiangiogenic ovarian cancer therapy Multiple pathways and targets Anti-VEGF drugs Single-agent activity Unique toxicity profile Multi-targeted inhibitors Single-agent activity Expanded toxicity profile Role of vascular disrupting agents Many unanswered questions

  44. The Role of OtherNonvascular Targeted Therapies in the Managementof Recurrent Ovarian Cancer Bradley J. Monk, MD, FACS, FACOGDivision of Gynecologic Oncology Department of Obstetrics and Gynecology Chao Family Comprehensive Cancer Center University of California, Irvine Medical Center Orange, California

  45. Active Nonvascular Targeted Agents in Ovarian Cancer Poly (ADP-ribose) polymerase (PARP) inhibitors Olaparib Antifolates Pemetrexed Farletuzumab (MORAb-003) Mammalian target of rapamycin (mTOR) inhibitors Everolimus Human epidermal growth factor receptor 2 (HER2) inhibitors Trastuzumab Pertuzumab

  46. PARP Inhibitors

  47. Targeting DNA Repair in Oncology—Rationale DNA damage frequently occurs in all cells DNA repair defects lead to increased cancer susceptibility and increased sensitivity to DNA-damaging agents Why is DNA repair a good target? Normal cells have multiple DNA repair pathways but some are lost in cancer cells Inhibiting DNA repair in cancer cells that have impaired repair pathways leads to selective cell killing and an increased therapeutic ratio Novel targeted therapeutic approach Kennedy RD, D’Andrea AD. J Clin Oncol. 2006;24:3799-3808. Courtesy of Dr. Bradley J. Monk.

  48. Types of DNA Damage and Repair O6- alkylguanine Bulky adducts Type of damage Single- strand breaks Double- strand breaks Insertions and deletions Nucleotide- excision repair Recombinational repair Base excision repair Repair pathway Directreversal Mismatch repair NHEJ HR Repair enzymes PARP ATM DNA-PK XP, poly-merases MSH2,MLH1 AGT Hoeijmakers JHJ. Nature.2001;411:366-374. Khanna KK, Jackson SP Nat Genet. 2001;27:247-254. Sanchez-Perez I. Clbl. Transl Oncol. 2006;8:642-646. Courtesy of Dr. Bradley J. Monk

  49. Targeted Killing of Cancer Cells with Defective DNA-Repair Mechanisms Cancer cell with defective repair No repair(no HR pathway) BRCA deficient or deficiency of other HR proteins Cell death Exploits inherent weakness of cancer cells that have defective DNA repair Double-stranded break Normal cell Repair by HR pathway Survival Abbreviation: HR, homologous recombination. Martin SA, et al. Curr Opin Genet Develop.2008;18:80-86. Courtesy of Dr. Bradley J. Monk.