1. Angiogenesis Inhibitors and Novel Targeted Agents in Ovarian Cancer Robert L. Coleman, MD Professor & Deputy Chair Vice Chair, Clinical Research Department Gynecologic Oncology & Reproductive Medicine M.D. Anderson Cancer Center

2. Disclosures Research Funding: – OCRF, CPRIT, NCI (P50, N01) – Regeneron, sanofi-aventis, Novartis, Morphotek, Merck, GSK, Esperance, Genentech/Roche – Marcus Foundation Scientific Steering Committee/Advisory: – Regeneron, sanofi-aventis, GSK, Esperance, Boehinger- Ingleheim, Genentech/Roche, Morphotek/Eisai, Merck, Nektar, Endocyte, Medimmune, AstraZeneca

3. Today’s Focus New therapeutics update – Angiogenesis targeting – FR-alpha targeting – Rare ovarian tumors

4. Today’s Focus New therapeutics update – Angiogenesis targeting – FR-alpha targeting – Rare ovarian tumors

5. Cancer is a Disease of Tissues Joyce JA, et al. Nat Rev Cancer. 2009;9(4):239-252.

6. AURELIA: A randomized phase III trial evaluating bevacizumab plus chemotherapy for platinum-resistant recurrent ovarian cancer Recurrent EOC Platinum resistant ≤ 2 prior therapies No clinical or radiologic evidence of bowel involvement Non-Platinum Chemotherapy RANDOMIZERANDOMIZE Non-Platinum Chemotherapy + Bevacizumab 15 mg/kg Chemotherapy Options Paclitaxel 80 mg/m 2 d 1,8,15, 22 q28 Topotecan 4 mg/m 2 d 1, 8,15 q28 or Topotecan 1.25 mg/m 2 d 1-5 q21 PLD 40 mg/m 2 d 1 q28 Stratified chemotherapy PFI (< 3 vs 3-6 mo) prior anti-angiogenesis Treat to progression N = 361 Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

7. Baseline Characteristics CT = chemotherapy; ECOG PS = Eastern Cooperative Oncology Group performance status; PFI = platinum-free interval a Stratification factor. b From last platinum to subsequent PD Characteristic, n (%) CT (N=182) BEV + CT (N=179) Median age, years6162 (range) (25 ‒ 84)(25 ‒ 80) Origin of cancer: Ovary157 (86)167 (93) Serous at diagnosis152 (84)156 (87) Histologic grade at diagnosis 19 (5)10 (6) 2/3153 (84)147 (82) Prior anti-angiogenic therapy a 14 (8)12 (7) Two prior chemotherapy regimens78 (43)72 (40) PFI <3 months a,b 46 (25)50 (28) ECOG PS 099 (54)107 (60) 1/280 (44)70 (39) Measurable disease144 (79)143 (80) Ascites54 (30)59 (33)

8. Baseline Characteristics CT = chemotherapy; ECOG PS = Eastern Cooperative Oncology Group performance status; PFI = platinum-free interval a Stratification factor. b From last platinum to subsequent PD Characteristic, n (%) CT (N=182) BEV + CT (N=179) Median age, years6162 (range) (25 ‒ 84)(25 ‒ 80) Origin of cancer: Ovary157 (86)167 (93) Serous at diagnosis152 (84)156 (87) Histologic grade at diagnosis 19 (5)10 (6) 2/3153 (84)147 (82) Prior anti-angiogenic therapy a 14 (8)12 (7) Two prior chemotherapy regimens78 (43)72 (40) PFI <3 months a,b 46 (25)50 (28) ECOG PS 099 (54)107 (60) 1/280 (44)70 (39) Measurable disease144 (79)143 (80) Ascites54 (30)59 (33)

9. Summary of Overall Response Rates  a Two-sided chi-square test with Schouten correction p=0.001 a p<0.001 a Patients (%)

10. AURELIA Progression-Free Survival 1.0 0.8 0.6 0.4 0.2 0.0 612 Time (months) Estimated Probability 183024 1829337 811 00 20 17914088 1841 1 49 0 BEV + CT CT Number at risk Events, n (%) Median PFS, months (95% CI) 166 (91%) 3.4 (2.2-3.7) 135 (75%) CT (n = 182) BEV + CT (n = 179) 6.7 (5.7-7.9) HR (unadjusted) (95% CI) Log-rnak P -value (2-sided, unadjusted) 0.48 (0.38-0.60) < 0.001 3.46.7 Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

11. AURELIA: QoL

12. OS: ITT population  Data cut-off: 25 January 2013. Median duration of follow-up: 27.4 months in both arms  ITT = intent to treat  a 2-sided log-rank, unadjusted Estimated probability CT BEV + CT No. at risk: CT (N=182) BEV + CT (N=179) Events, n (%) 136 (75)128 (72) Median OS, months (95% CI) 13.3 (11.9‒16.4) 16.6 (13.7‒19.0) HR (unadjusted) (95% CI) 0.85 (0.66‒1.08) p=0.174 a 1821309863291210 17914810675391310 06121824303642 Time (months) 1.00 0.75 0.50 0.25 0

13. Subgroup No. of events/No. of patients Median OS, months HR (95% CI) a BEV + CT better CT better CTBEV + CT All patients264/36113.316.60.85 (0.66–1.08) Age, years<65 ≥65 178/228 86/133 12.9 16.7 14.7 18.3 0.82 (0.61–1.10) 0.95 (0.62–1.46) PFI, months b <3 3‒6 79/97 181/258 11.9 15.7 11.1 18.3 1.02 (0.65–1.58) 0.78 (0.58–1.05) Measurable disease, cm <1 1‒<5 ≥5 58/75 74/125 132/161 13.0 20.2 11.3 18.3 17.4 14.3 0.75 (0.45–1.27) 1.06 (0.67–1.68) 0.72 (0.51–1.01) AscitesYes No 98/113 166/248 7.9 17.0 11.7 19.3 0.67 (0.45–1.00) 0.86 (0.63–1.16) ChemotherapyPaclitaxel PLD Topotecan 77/115 100/126 87/120 13.2 14.1 13.3 22.4 13.7 13.8 0.65 (0.42–1.02) 0.91 (0.62–1.36) 1.09 (0.72–1.67) Exploratory Subgroup Analysis Of OS a Unstratified. b Missing N=3 0.20.30.512345

14. Paclitaxel Cohort: OS Overall survival (%) 75 50 25 0 06121824303642 100 CT BEV + CT No. at risk: 554032221330 605243341941 Time (months) CT (N=55) BEV + CT (N=60) Events, n (%)41 (75)36 (60) Median OS, months (95% CI) 13.2 (8.2 ‒ 19.7) 22.4 (16.7 ‒ 26.7) HR (unadjusted) (95% CI) 0.65 (0.42 ‒ 1.02)

15.  PFS, was significantly improved with bevacizumab  OS HR was 0.85 (95% CI 0.66 ‒ 1.08) (ITT population)  Median OS: 16.6 months (BEV + CT) vs 13.3 months (CT)  Interpretation of OS is complicated by bevacizumab crossover (40%) and the lack of information on post-progression therapy  Exploratory subgroup analyses suggested:  Generally consistent effects on OS  More pronounced OS treatment effect in the weekly paclitaxel subgroup Conclusions

16.  After blockade of the VEGF pathway, there is a compensatory upregulation of FGF and PDGF Casanovas O, et al. Cancer Cell. 2005;8(4):299-309. Beyond VEGF: FGF and PDGF Expression in Ovarian Cancer

17. Nintedanib (BIBF 1120): A Triple Angiokinase* Inhibitor *Angiokinase refers to tyrosine receptor kinases involved in promoting angiogenesis. Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782. Stopfer P, et al. Ann Oncol. 2008;19(S8):Abstract 478P. Endothelial cells (VEGFRs, FGFRs) Pericytes (PDGFRs) Smooth muscle cells (FGFRs, PDGFRs) VEGFs FGFs PDGFs StimulationLigandsCell types (proliferation, survival) Nintedanib blocks three critical factors involved in angiogenesis

18. AGO-OVAR-12 Stratification variables: FIGO stage: II/III vs IV residual tumor: 0 cm vs >0 cm (no macroscopic vs macroscopic Paclitaxel 175 mg/m² Carboplatin AUC 5/6 Paclitaxel 175 mg/m² Arm A Arm B Placebo po BID BIBF 1120 a 200 mg po bid Front-line EOC, PP or FT cancer Stage IIB-IV Primary max. surgery N = 1366 Front-line EOC, PP or FT cancer Stage IIB-IV Primary max. surgery N = 1366 Primary endpoint: PFS 2 years National Institutes of Health. Available at: http://clinicaltrials.gov/show/NCT01015118. Accessed: February 12, 2013.

19. AGO Study Group GCIG Intergroup Study AGO-OVAR 12 /LUME-Ovar 1 AdB 2013 Primary Endpoint: Progression-Free Survival RECIST 1.1 and CA-125 in conjunction with Clinical MBO Criteria Time from randomization (months) 455 381 25716876300 911761 542352160 17 10 TC + Nintedanib (n=911) TC + Placebo (n=455) Events, n (%)486 (53.3)266 (58.5) Median, months17.316.6 HR* (95% CI)0.84 (0.72, 0.98) p value0.0239 All patients (N=1366) – Cut-off date: 29 April 2013 *Stratified for macroscopic residual postoperative tumour, FIGO stage and carboplatin dose

20. AGO Study Group GCIG Intergroup Study AGO-OVAR 12 /LUME-Ovar 1 AdB 2013 Exploratory Subgroup Analysis “ICON 7 defined low-risk patients subgroup” (FIGO II or FIGO III and ≤ 1cm residual postoperative tumor) Patients at risk Estimated percentage alive and progression-free Time from randomization (months) Placebo 283 248 18612352 20 Nintedanib 55647838027012490 TC + Nintedanib (n=556) TC + Placebo (n=283) Events, n (%)234(42.1)149(52.7) Median, months27.120.8 HR (95% CI)0.74 (0.61, 0.91) Median PFS difference: + 6.3 months

22. Presented by Monk BJ at the European Society of Gynecologic Oncology 2013 Trebananib (AMG 386) – Peptibody That Binds and Neutralizes Ang1 and Ang2 Trebananib is an investigational recombinant peptide-Fc fusion protein (peptibody) In clinical studies trebananib has shown: Single-agent activity in relapsed ovarian cancer in a phase 1 study 1 Prolongation of PFS in a randomized phase 2 study in combination with paclitaxel in recurrent ovarian cancer 2 1.Herbst RS, et al. J Clin Oncol. 2009;27:3557 ‒ 3565. 2.Karlan BY, et al. J Clin Oncol. 2012;30:362 ‒ 371.

23. Presented by Monk BJ at the European Society of Gynecologic Oncology 2013 TRINOVA-1: Trial Design EOC = epithelial ovarian cancer including primary peritoneal, or fallopian tube cancer; PD = progressive disease Stratification factors Platinum-free interval (PFI) (≤ 6 vs. > 6 months) Measurable disease (Yes/No) Region (North America, Western Europe/Australia, Rest of World) Recurrent EOC ≤ 3 prior anticancer regimens Evaluable or measurable disease GOG Performance Status of 0 or 1 PFI < 12 months Treat to PD/toxicity Weekly Paclitaxel + Trebananib Weekly Paclitaxel + Placebo R 1:1 Paclitaxel 80 mg/m 2 IV on days 1, 8, 15 Q4W Trebananib 15 mg/kg IV QW ClinicalTrials.gov Identifier: NCT01204749

24. TRINOVA-1: Demographics Paclitaxel + Placebo N = 458 Paclitaxel + Trebananib N = 461 Histologic grade, n (%) Well differentiated Moderately differentiated Poorly differentiated Unknown 31 (7) 84 (18) 256 (56) 87 (19) 24 (5) 69 (15) 274 (59) 94 (20) Prior lines of therapy, n (%)* 1 2 3 172 (38) 172 (38) 114 (25) 190 (41) 174 (38) 94 (20) Platinum-free interval, n (%) †  6 months > 6 months 245 (53) 212 (46) 235 (51) 223 (48) Measureable disease at baseline, n (%) 433 (95)435 (94) Region, n (%) North America Western Europe/Australia Rest of the world 91 (20) 189 (41) 178 (39) 93 (20) 193 (42) 175 (38) *Three patients had 4 or unknown lines of prior therapy (protocol deviation); † Four patients were “refractory” (protocol deviation)

25. Presented by Monk BJ at the European Society of Gynecologic Oncology 2013 TRINOVA-1: PFS Primary Analysis Pac + Placebo (n = 458) Pac + Trebananib (n = 461) Events, n (%)361 (79)310 (67) Median PFS, months5.47.2 HR = 0.66 (95% CI, 0.57–0.77) P (stratified log rank) < 0.001

26. Presented by Monk BJ at the European Society of Gynecologic Oncology 2013 TRINOVA-1: Overall Survival (Interim Analysis) Pac + Placebo (n = 458) Pac + Trebananib (n = 461) Events, n (%)163 (36)150 (33) Median OS, months17.319.0 HR = 0.86 (95% CI, 0.69–1.08) P (stratified log rank) = 0.19

27. TRINOVA-3 Available at: http://clinicaltrials.gov/ct2/show/NCT01493505. Accessed Feb 2014. Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer Post operative Stage III, IV Neoadjuvant Carboplatin AUC 5-6 IV d 1 Paclitaxel 175 mg/m 2 IV d 1 Trebananib (AMG 386) weekly Carboplatin AUC 5-6 IV d 1 Paclitaxel 175 mg/m 2 IV d 1 Trebananib (AMG 386) weekly Carboplatin AUC 5-6 IV d 1 Paclitaxel 175 mg/m 2 IV d 1 Placebo weekly Carboplatin AUC 5-6 IV d 1 Paclitaxel 175 mg/m 2 IV d 1 Placebo weekly N = 1000 (rev) Weekly Placebo x 18 months Maintenance Trebananib x 18 months R (2:1) R (2:1)

28. Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: Results of the ICON6 trial. An academic sponsored GCIG trial Ledermann JA, Perren T, Raja FA, Embleton AC, Rustin GJS, Jayson G, Kaye SB, Swart AM, Vaughan M, Hirte H on behalf of the ICON 6 Collaborators (NCRN, NCIC-CTG, ANZGOG, GEICO)

29. ICON6: Cediranib with platinum-based chemotherapy in ‘platinum-sensitive’ relapsed ovarian cancer Cediranib targets: VEGFR-1/2/3 6 Cycles platinum-based Chemotherapy  Carboplatin/paclitaxel  Carboplatin/gemcitabine  Single agent platinum Maintenance phase Study schema Treatment continued to 18 months or until progression (>18 for patients continuing to benefit) Continue placebo Switch to placebo Maintenance cediranib Chemotherapy + cediranib Chemotherapy + placebo Arm A (Chemo only) Arm B (Concurrent) Arm C (Maintenance) Chemotherapy + cediranib Relapse > 6 months after completion of first line platinum-based chemotherapy Randomise 2 : 3 : 3

30. Chemo. Maint. Chemotherapy Maintenance Restricted mean survival time increases by 3.1 months with maintenance treatment Chemo.Maint. PFS events, n (%)112 (94.9)139 (84.8) Median, months8.711.1 Log-rank testp=0.00001 HR (95% CI)0.57 (0.45 – 0.74) Test for non-proportionality p=0.024 Restricted means, months9.412.5 Progression-free survival – arms A vs. C

31. Chemo.Conc.Maint. PFS events, n (%)112 (94.9)152 (87.4)139 (84.8) Median, months8.710.111.1 Log-rank test (trend)p=0.0003 HR vs. Chemo only (95% CI) 0.67 (0.53–0.87) 0.57 (0.44–0.74) Restricted means, months9.411.412.5 Progression-free survival – all three arms Conc. Maint. Chemo. Concurrent Chemotherapy Maintenance

32. Chemo.Maint. OS events, n (%)63 (53.3)75 (45.7) Median, months20.326.3 Log-rank testp=0.042 HR (95% CI)0.70 (0.51 – 0.99) Test for non-proportionality p=0.0042 Restricted means, months17.620.3 Restricted mean survival time increases by 2.7 months with maintenance treatment (over two years) Overall survival Chemo. Maint. Chemotherapy Maintenance

33. Angiogenesis as a Target: Ovarian 1.Burger RA et al. N Engl J Med. 2011;365:2473 ‒ 2483. 2.Perren TJ et al. N Engl J Med. 2011;365:2484 ‒ 2496. 3.du Bois A et al. J Clin Oncol. 2013;31(18suppl):LBA5503. 4.du Bois A et al. LBA ESGO 2013 Liverpool, UK 5.Pujade-Lauraine E et al. J Clin Oncol. 2012;30(18suppl):LBA5002. 6.Monk BJ, et all., LBA ESGO, Liverpool, UK 7.Aghajanian C et al. J Clin Oncol. 2012;30:2039 ‒ 2045. 8.Ledermann JA et al. Eur J Cancer. 2013;49(suppl):LBA StudyAgentSettingHR-PFS (95% CI) HR-OS (95% CI) GOG 218 1 BevacizumabFront-line/Maintenance0.72 (0.63-0.82)0.89 (0.75-1.04) ICON7 2 BevacizumabFront-line/Maintenance0.81 (0.70-0.94)0.99 (0.85-1.14) AGO-OVAR12 3 NintedanibFront-line/Maintenance0.84 (0.72-0.98)Neg AGO-OVAR16 4 Pazopanib Primary Maintenance0.77 (0.64-0.91)0.99 (0.75-1.32) AURELIA 5 Bevacizumab Recurrence, Platinum- resistant, 1-2 priors 0.48 (0.38-0.60)0.85 (0.66-1.08) TRINOVA-1 6 Trebananib Recurrence, Platinum- resistant/sensitive, 1-3 priors 0.66 (0.57-0.77)0.86 (0.69-1.08) OCEANS 7 Bevacizumab Recurrent, Platinum-sensitive, 1 prior 0.53 (0.41-0.70)0.96 (0.76-1.21) ICON6 8 Cediranib Recurrent, Platinum-sensitive, 1 prior 0.57 (0.44-0.74)0.70 (0.51-0.99)

34. Bottom Line…  Anti-angiogenesis agents in ovarian cancer –PFS appears to be enhanced by biological targeting –The menu of available agents is expanding –Toxicity and impact of therapy is needed to adjudicate use  Intervention is extending post treatment life expectancy  Better and selected therapy is needed for OS

35. Today’s Focus New therapeutics update – Angiogenesis targeting – FR-alpha targeting – Rare ovarian tumors

36. Folate Metabolism: MoA Vergote, Marth, Coleman. Cancer Met Rev 2014 Increases DNA synthesis Inhibits apoptosis Increases anoikis Increases cell motility

37. Folate Receptor Expression

38. Utilizing the Folate Receptor: EC145  Folate-Vinca conjugate  Relevant for imaging targeting and therapy

39. EC145: Novel Folate Receptor Targeted Therapeutic  Randomized Phase II, Platinum-resistant ovarian  Prior therapy: no more than 2 priors  Regimen: –PLD 50 mg/m 2 IBW q 28 days –PLD 50 mg/m 2 IBW q 28 days + EC145 2.5 mg weeks 1 and 3 (cycle: 28 days)  Toxicity similar in both arms: total AEs, SAEs, TETs Naumann W, et al. J Clin Oncol (2013) ArmPFSHRP PLD11.7 wks-- PLD+EC14524.0 wks0.4970.014

40. PROCEED: Randomized Phase III PLD +/- EC145 (Vintafolide) in Platinum-Resistant Ovarian Cancer Platinum resistant ovarian cancer patients (failed first or second platinum therapy <6 months) 2:1 EC145 (vintafolide) + PLD PLD + placebo Receptor scan 50 mg/m 2 (IBW) every 28 days N = 640 patients Primary endpoint: PFS Co-primary analysis ─ EC20 (++/+): 85% power to detect HR = 0.70 ─ EC20 (++): 85% power to detect HR = 0.56 Secondary endpoints ─ OS (no crossover) ─ ORR ─ Duration of Response ─ Quality of Life Assessment EC145 = 2. 5mg TIW weeks 1, 3 PLD = 50 mg/m 2 (IBW) every 28 days

41. Farletuzumab: Pre-Clinical Data   Humanized MoAb to FR    Mechanism: – –Blocks Lyn kinase phosphorylation – –Induces cytotoxicity via ADCC & CDC   Active in xenograft model   Favorable toxicity profile in primate studies

42. Farletuzumab Phase 2: Design Patients with EOC experiencing first platinum sensitive relapse After first remission of 6-18 months duration Evaluable disease by CA125 Asymptomatic relapse Single agent Farletuzumab Until progression Symptomatic relapse Combination Therapy: Original Carbo/Taxane regimen Plus farletuzumab 6 cycles Farletuzumab maintenance Rx For responders Single Agent ORR Compare lengths of first and second remissions Combination ORR Armstrong, et al. Gynecol Oncol (2013) 129:452

43. Target Lesion Response by RECIST (Combination Therapy) Best Response  CR = 7%  PR = 63%  SD = 23%  PD = 7% ORR = 70% Patient Benefit 93% Armstrong, et al. Gynecol Oncol (2013) 129:452

44. 44 Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence EOC in first relapse> 6months or < 24 months Randomize 1:1:1 6 Cycles Carboplatin & Taxane Plus: Farletuzumab 1.25 mg/kg N =300 Farletuzumab 2.5 mg/kg N=300 Placebo (Saline) N=300 Single Agent Maintenance Key Secondary Endpoint: Overall Survival Primary Endpoint: Progression-Free Survival Primary endpoint: PFS (each Farletuzumab arm vs control 2 sided 0.05 level, power 95% Median PFS control group 12 months HR: 0.70, 43% improvement to 17.1 months* *accrual was increased from 900 to 1080 to account for non-progression based discontinuation

45. 45 Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence Strata - characteristics Parameter Placebo + Carboplatin/ Taxane (N= 364) FAR 1.25 mg/kg + Carboplatin/ Taxane (N= 370) FAR 2.5 mg/kg + Carboplatin/ Taxane (N= 366) Total FAR (N= 736) Length of first remission n (%) 6 – <12 months194 (53.3)196 (53.0)193 (52.7)389 (52.9) 12 – <18 months108 (29.7)112 (30.3)111 (30.3)223 (30.3) 18 – 24 months62 (17.0)62 (16.8)62 (16.9)124 (16.8) Route of administration for first-line therapy n (%) Intraperitoneal26 (7.1)28 (7.6)26 (7.1)54 (7.3) Intravenous338 (92.9)342 (92.4)340 (92.9)682 (92.7) Geographic region n (%) North America and Western Europe 183 (50.3)186 (50.3)185 (50.5)371 (50.4) Other Countries181 (49.7)184 (49.7)181 (49.5)365 (49.6) Planned taxane therapy n (%) Paclitaxel294 (80.8)298 (80.5)296 (80.9)594 (80.7) Docetaxel70 (19.2)72 (19.5)70 (19.1)142 (19.3)

46. 46 Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence Progression Free Survival (ITT)

47. 47 Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence Overall Survival (ITT) (2013 April Update)

48. 48  Neither FAR dose met the study’s primary PFS endpoint in the ITT population  Most commonly reported adverse events across arms were those known to be associated with the study chemotherapy agents  Higher dose and exposure of FAR seems to be correlated with PFS improvement  Hypotheses:  CA125 may inhibit the potential ADCC effect of FAR  Hence, FAR in adequate dosing may have a potential effect in lower CA125 populations Farletuzumab Phase 3 in Platinum Sensitive Ovarian Cancer First Recurrence Conclusions

49. Today’s Focus New therapeutics update – Angiogenesis targeting – FR-alpha targeting – Rare ovarian tumors

50. Relevant Mutations in Ovarian Cancer

51. GOG 239: AZD6244 (Selumetinib)   Phase II   Recurrent low-grade serous carcinoma of the ovary – –Central pathology review for eligibility   AZD6244 (ARRY-142886) small molecule inhibitor of the MEK-1/2 – –68% of low-grade serous tumors have mutations in BRAF or KRAS genes

52. GOG 239: Results †Three patients remain on study therapy (after receiving 20, 33, and 54 cycles). 1 2 3 4 5 6 7 10 12 13 15 15+ 14 Duration of Therapy Response

53. MILO: MEKi vs Chemotherapy

54. GOG-281: Randomized Phase II/III Recurrent Low-Grade Serous Carcinoma Measurable Disease Measurable Disease Primary Endpoint: PFS (futility assessment) Primary Endpoint: PFS (futility assessment) N=250 (Global) N=250 (Global) Translational endpoints: Pathway aberration, Seq Translational endpoints: Pathway aberration, Seq Trametinib (MEKi) Trametinib (MEKi) Physician’s Choice Hormone or Chemo Physician’s Choice Hormone or Chemo Activated: 2-26-2014

55. Example: Studies with Companion Diagnostics  HRD (Rad51c,d)  FR-  Etarfolatide (EC- 20)  BRAFv600E (D, K)  K-ras mutation (G12V)  PIK3CA/Akt/PTEN  IGF-1R expression  EGFR catalytic domain mutation  UGT 1A1*28 homozygosity  Her2-neu copy number

56. Selected Therapy Based on Biology Option 1 Option 2 Options 3, 4 Options 5, 6

57. Novel Drug Development: Ovarian  Many new agents being explored based on molecular profiling  Challenges: –How can we improve OS? »Post-progression survivorship is long and increasing »Are there better measures of treatment effect? –What is the best strategy to meet individualization of care? –How do we identify, prevent, avoid, and overcome drug-resistance? –How can therapy be optimized while reducing off/on- target toxicity?

58. Thank You! Two great virtues: – Patience – Wisdom