The emerging role of targeted therapy in treatment of epithelial ovarian cancer

1. Nick Reed Glasgow, UK The emerging role of targeted therapy in treatment of epithelial ovarian cancer

2. Changing Paradigms of Ovarian cancer • New management approaches required • Traditional • Surgical management • Adjuvant chemotherapy • Scheduling of treatments • Chronic disease process • Tailoring treatments

3. New ChallengesBecoming a chronic disease? • Changing pattern • More chronic disease process • Many patients reaching 4th 5th or 6th line • Issues of costs and reimbursement • Issues of patient expectation • Need for new drugs and technologies

4. Focus on First-line Therapy • If carboplatin + paclitaxel is current ‘standard of care’, where do we go from here? • Is there a better taxane? • Are 3 drugs better than 2? • Is Neo-Adjuvant chemotherapy better? • Should we treat for longer than 6 cycles? • If so, what with? And for how long? • Is intraperitoneal delivery a better treatment? • Can we utilise biological therapies?

5. Small molecules KIs vs Antibodies • TKIs Small molecules • TKI antibodies (mabs) • EGFR antibodies • VEGFR,AAG and VDAs • PDGFR,FGFR, IGFR • Folate receptor antagonists • HDAC • PARP • SRC • To name but a few

7. Targeting Tumour Metabolism Tennant, Duran and Gottlieb, Nature cancer reviews 2010

8. Pathway Identification by microarray analysis Landen, Birrer and Sood JCO 2008

9. So where do we begin? How do identify candidate targets?

10. Which pathways and signals?Multiple pathways involved

11. Even more complex!!

12. So we begin to identify some of the signals and targets • How do we put this into practice

13. Studies in Ovarian cancers to date, completed not reported • EORTC 55041 Tarceva (Erlotinib) 1st line • ICON 6 Cediranib Rel PtS • ICON 7 Bevacizumab 1st line • GOG 218 Bevacizumab 1st line • BI BIBF1120 BIBF 1120 Maintain

14. Ongoing major trials • AGO OVAR 16 BIBF 1120 1st line • AGO GCIG Pazopanib 1st line • Imclone 3G3 PDGFR Rel • Morphotek Farletuzumab Rel • Phase 2s in SRCs, PARPs, Sorafenib, mTOR • 173 trials listed in NCI Index of studies

15. EGFR signalling pathways

16. Extracellular Intracellular Transactivation P P Src PLCg GAP Grb2 Shc Nck Vav Grb7 Crk PKC Ras Abl JNK PI3KAkt MAPK Proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis Effects of HER1/EGFR Activation

17. Erbitux Herceptin Cell membrane Erlotinib Tyrosine-kinase domain HER1/EGFR HER2 Anti-HER monoclonal antibodies Whilst EGFR commonly demonstrated in OvCa, little clinical activity • Inhibit cell-cycle progression; potentiate apoptosis • Decrease production of angiogenic factors • Recruit natural killer cells to tumours • Enhance receptor internalisation Agus D, et al. Cancer Cell 2002;2:127–37Baselga J. Cancer Cell 2002;2:93–95

18. Adapted from: Harari PM, Huang S-M, Clin Cancer Res 5:323,2000.

19. EORTC 55041 1st major trial • Tarceva Trial Design A randomised, multicentre, phase III study of Tarceva versus observation in patients with no evidence of disease progression after first line, platinum-based chemotherapy for high-risk Stage I and Stages II-IV ovarían epithelial, primary peritoneal, or fallopian tube cancer • Primary Objective • Progression-free survival. • Secondary Objectives • Overall survival. • Toxicity profile. • Quality of life. • Rash (surrogate marker of efficacy).

20. Study design EORTC 55041 First line, platinum-based chemotherapy CR, PR, or SD Screening STUDY ENTRY Randomization TarcevaTM until progression (up to 2 years) Observation until progression 1st results expected 2011

21. Agents Targeting theVEGF Pathway Antibodies inhibiting VEGF receptors Soluble VEGF receptors (VEGF-TRAP) Antibodies inhibiting VEGF(e.g. bevacizumab)  Permeability VEGF Cation channel VEGF receptor-2 Small-molecules inhibiting VEGF receptors (TKIs)(e.g cediranib) – P P– – P – P P– P– – P P– P– P– – P – P Migration, permeability, DNA synthesis, survival Ribozymes (Angiozyme) Angiogenesis Lymphangiogenesis

22. ICON7 Design: 1st Line • Stratification factors: stage, residual disease status, country Carboplatin/ paclitaxel observation 1520 stage IIB-IV patients + poor risk stage 1 Carboplatin/ paclitaxel + bevacizumab bevacizumab Treatment: Carboplatin AUC = 6 Paclitaxel 175 mg/m2 Bevacizumab 7.5 mg/kg (All treatments q 3 weeks) 6 cycles (4.5 months) 12 cycles (7.5 months) 1st report expected ESMO or IGCS 2010

23. GOG 218 : 1st line Carboplatin AUC6 Primary endpoint: OS Secondary endpoint: PFS Arm A Paclitaxel 175 mg/m2 Placebo Carboplatin AUC6 Sub-optimally debulked Stage III/ IV OC N=2000 Arm B Paclitaxel 175 mg/m2 Bevacizumab (15 mg/kg) Placebo Placebo Carboplatin AUC6 Arm C Paclitaxel 175 mg/m2 1:1:1 Randomization Bevacizumab (15 mg/kg) Stratification variables: PS (0-1 vs 2), stage (III vs IV) 15 months* Cycles (q3wk)* * Taxane consolidation therapy prohibited

24. GOG 218: ASCO 2010 1st results • Early release of data • Provisional report of PFS improved in maintenance arm of GOG 218 • Note higher dose than ICON 7 • 15 mg/kg cf 7.5 mg/kg • What is likely impact in US practice this year? • Unlikely to change UK practice

25. Other studies in 1st line • AGO BIBF1120 • AGO/GCIG Pazopanib AGO-Ovar 16

26. BIBF 1120 – mechanism of action • BIBF 1120 is a potent tripleangiokinase inhibitor that simultaneously acts on three receptors involved in the formation of blood vessels1: • vascular endothelial growth factor receptor (VEGFR) • platelet-derived growth factor receptor (PDGFR) • fibroblast growth factor receptor (FGFR) • These growth factors and receptors play an important role in angiogenesis; their inhibition plays a critical role in the prevention of tumour growth and spread2,3 • PGDGF and VEGF are over-expressed and associated with poor prognosis and poor outcome in NSCLC3,4 1. Hilberg F et al. Eur J Cancer 2004;2:50. 2. Hilberg F et al. Manuscript in preparation. 3. Bremnes RM et al. Lung Cancer 2006;51:143-158. 4. Shikada Y et al. Cancer Res 2005; 65:7241–7248.

27. Treatment

28. Pazopanib AGO OVAR 16

29. Relapsed disease - Focus on Current UK/European studies • ICON 6 - Cediranib • Morphotek - Farletuzumab (Folate receptor) • Imclone 3G3 - PDGFR • PARPs • mTOR, HDACs, SRC (AZ), p1k3/akt • IGFR

30. ICON 6 Cediranib

31. Arm B Chemotherapy Plus cediranib during Chemotherapy Arm C Chemotherapy plus cediranib during Chemotherapy Arm A Reference arm 6 cycles of chemotherapy plus Placebo No Progressive disease Placebo Maximum 18 months from randomisation No Progressive disease Placebo Maximum 18 months from randomisation No Progressive disease Maintenance cediranib after chemotherapy Maximum 18 months from randomisation ICON 6 Design schema 2:3:3 RANDOMISATION

32. ICON 6 design • 1st phase completed • Now starting 2nd phase with international collaboration

33. Folate- The role in the cell Transfers 1-carbon chemical units from donor to acceptor molecules Critical to synthesis of nucleotide precursors of DNA Kinetic or proliferative state of cell influences rate of internalization of folate Folate entry proceeds via one of two distinct pathways, RFC and FR

34. Folate Receptor • 1960s: Folate Binding Protein in milk (FBP) • 1970s: FBP in CML cells, kidney, cord serum & folate deficient serum (carcinoma, cirrhosis uraemia & pregnancy) • 1979s: FBP described as a membrane protein • Mid 1980s: membrane localization “endocytosis” defined • Late 1980s: 4 laboratories cloned FR from placenta and malignant cell lines GPI anchor recognized • 1990s: Gene at 11q13, MoAb (Mov18&19) & LK26 molecular studies, transfection, targeting drugs & development of transgenic animals

35. PCFT?

36. MORAb-003: Pre-Clinical Data USAN name: farletuzumab Humanized MAB to Folate Receptor Alpha Blocks phosphorylation by Lyn kinase Active in ADCC assays Active in xenograft model Favorable toxicity profile in primate studies 37

37. Farletuzumab: Bi-modal mechanism of action

38. MORAb-003 (Farletuzumab)Randomized Phase II Trial Accrual Ongoing (Target accrual 126 pts)2:1 Randomization PFS Primary Endpoint Weekly Paclitaxel Plus Farletuzumab 2.5mg/kg IV weekly R A N D O M I Z E Recurrent Platinum- resistant Ovarian cancer Weekly Paclitaxel Plus Placebo

39. MORAb-003 (Farletuzumab)Randomized Phase III Trial Accrual Ongoing (Target accrual 900 pts)1:1:1 Randomization PFS Primary Endpoint Carbo/Taxane Plus Farletuzumab 1.25 mg/kg IV weekly R A N D O M I Z E Recurrent Platinum- sensitive Ovarian cancer Carbo/Taxane Plus Farletuzumab 2.5 mg/kg IV weekly Carbo/Taxane Plus Placebo

41. HR deficient

42. BRCA and PARP Inhibition

43. PARP- AZD 2281 Yap et al ASCO 2008

44. Early data on PARP Yap et al ASCO 2008

45. Horses for coursesExample of different mechanism

46. Challenges with TATs 1 • Does presence of target even matter? • Discordance of Herceptin in breast/ovary tumours • Poor correlation with degree of overexpression of EGFR and response to Iressa • How does one select which biological to incorporate into primary therapy? • Is ‘response’ in phase II necessary? • Combinations of biologicals? • Which correlative studies are best? • QoL? • Pharmacoeconomic?

47. Challenges with TATs 2 • New side effects • Need for extra vigilance • Need to avoid dilution effect too quickly • Different end points and response criteria • RECIST less useful • PET CT. Novel radionuclides • DCE MRI

48. DCE-MRI of a patient treated with 2 x 250 mg of BIBF 1120 in a phase I trial • New ways of predicting and assessing response Before treatment After 4 weeks After 8 weeks

49. The way forward • Continued support of clinical trials • We are only at the beginning • Many of our targeted agents are “dirty” • It has taken 40 years to achieve our level of expertise with current agents • Infancy