angiogenesis inhibitors and novel targeted agents in ovarian cancer

Angiogenesis Inhibitors and Novel Targeted Agents in Ovarian Cancer

Robert L. Coleman, MDProfessor & Deputy Chair

Vice Chair, Clinical ResearchDepartment Gynecologic Oncology & Reproductive Medicine

M.D. Anderson Cancer Center

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

Today’s Focus

• New therapeutics update– Angiogenesis targeting– FR-alpha targeting– Rare ovarian tumors

Today’s Focus

• New therapeutics update– Angiogenesis targeting– FR-alpha targeting– Rare ovarian tumors

Cancer is a Disease of Tissues

Joyce JA, et al. Nat Rev Cancer. 2009;9(4):239-252.

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

RANDOMIZE

Non-Platinum Chemotherapy + Bevacizumab 15 mg/kg

Chemotherapy Options• Paclitaxel 80 mg/m2 d 1,8,15, 22 q28• Topotecan 4 mg/m2 d 1, 8 ,15 q28 or • Topotecan 1.25 mg/m2 d 1-5 q21• PLD 40 mg/m2 d 1 q28

Stratifiedchemotherapy

PFI (< 3 vs 3-6 mo)prior anti-angiogenesis

Treat to progression

Treat to progressionN = 361

Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

Baseline Characteristics

CT = chemotherapy; ECOG PS = Eastern Cooperative Oncology Group performance status; PFI = platinum-free intervalaStratification factor. bFrom last platinum to subsequent PD

Characteristic, n (%)CT

(N=182)BEV + CT

(N=179)Median age, years 61 62 (range) (25‒84) (25‒80)Origin of cancer: Ovary 157 (86) 167 (93)Serous at diagnosis 152 (84) 156 (87)Histologic grade at diagnosis 1 9 (5) 10 (6) 2/3 153 (84) 147 (82)Prior anti-angiogenic therapya 14 (8) 12 (7)Two prior chemotherapy regimens 78 (43) 72 (40)PFI <3 monthsa,b 46 (25) 50 (28)ECOG PS

0 99 (54) 107 (60)1/2 80 (44) 70 (39)

Measurable disease 144 (79) 143 (80)Ascites 54 (30) 59 (33)

Baseline Characteristics

CT = chemotherapy; ECOG PS = Eastern Cooperative Oncology Group performance status; PFI = platinum-free intervalaStratification factor. bFrom last platinum to subsequent PD

Characteristic, n (%)CT

(N=182)BEV + CT

(N=179)Median age, years 61 62 (range) (25‒84) (25‒80)Origin of cancer: Ovary 157 (86) 167 (93)Serous at diagnosis 152 (84) 156 (87)Histologic grade at diagnosis 1 9 (5) 10 (6) 2/3 153 (84) 147 (82)Prior anti-angiogenic therapya 14 (8) 12 (7)Two prior chemotherapy regimens 78 (43) 72 (40)PFI <3 monthsa,b 46 (25) 50 (28)ECOG PS

0 99 (54) 107 (60)1/2 80 (44) 70 (39)

Measurable disease 144 (79) 143 (80)Ascites 54 (30) 59 (33)

Summary of Overall Response Rates

Responders (RECIST and/or CA-125) (n=350)

RECIST responders (n=287) CA-125 responders (n=297)05

101520253035404550

12.6 11.8 11.6

30.927.3

31.8

CT BEV + CT

aTwo-sided chi-square test with Schouten correction

p=0.001ap<0.001a p<0.001a

Patie

nts (

%)

AURELIA Progression-Free Survival

1.0

0.8

0.6

0.4

0.2

0.06 12

Time (months)

Est

imat

ed P

roba

bilit

y

18 3024

182 93 37 8 1 1 0 020179 140 88 18 4 1 149

0

BEV + CTCTNumber 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

3.4 6.7

Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

AURELIA: QoL

OS: ITT population

Data cut-off: 25 January 2013. Median duration of follow-up: 27.4 months in both armsITT = intent to treata2-sided log-rank, unadjusted

Est

imat

ed p

roba

bilit

y

CTBEV + 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=0.174a

182 130 98 63 29 12 1 0179 148 106 75 39 13 1 0

0 6 12 18 24 30 36 42Time (months)

1.00

0.75

0.50

0.25

0

Subgroup

No. of events/No. of

patients

Median OS, months

HR (95% CI)aBEV + CT

betterCT

better CT BEV + CT

All patients 264/361 13.3 16.6 0.85 (0.66–1.08)

Age, years <65 ≥65

178/22886/133

12.916.7

14.718.3

0.82 (0.61–1.10)0.95 (0.62–1.46)

PFI, monthsb <33‒6

79/97181/258

11.915.7

11.118.3

1.02 (0.65–1.58)0.78 (0.58–1.05)

Measurable disease, cm

<11‒<5≥5

58/7574/125

132/161

13.020.211.3

18.317.414.3

0.75 (0.45–1.27)1.06 (0.67–1.68)0.72 (0.51–1.01)

Ascites YesNo

98/113166/248

7.917.0

11.719.3

0.67 (0.45–1.00)0.86 (0.63–1.16)

Chemotherapy PaclitaxelPLDTopotecan

77/115100/12687/120

13.214.113.3

22.413.713.8

0.65 (0.42–1.02)0.91 (0.62–1.36)1.09 (0.72–1.67)

Exploratory Subgroup Analysis Of OS

aUnstratified. bMissing N=3

0.2 0.3 0.5 1 2 3 4 5

Paclitaxel Cohort: OSO

vera

ll su

rviv

al (%

) 75

50

25

00 6 12 18 24 30 36 42

100

CTBEV + CT

No. at risk:55 40 32 22 13 3 060 52 43 34 19 4 1

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)

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

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

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

StimulationLigands Cell types (proliferation, survival)

Nintedanib blocks three critical factors involved in angiogenesis

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

Carboplatin AUC 5/6

Paclitaxel 175 mg/m²

Arm

A

Arm B

Placebo po BID

BIBF 1120a 200 mg po bid

Front-line EOC, PP or FT cancer

• Stage IIB-IV• Primary

max. surgery

• N = 1366Primary endpoint: PFS

2 years

2:1

National Institutes of Health. Available at: http://clinicaltrials.gov/show/NCT01015118. Accessed: February 12, 2013.

AGOStudy Group

GCIG Intergroup Study AGO-OVAR 12 /LUME-Ovar 1

AdB 2013

Primary Endpoint: Progression-Free SurvivalRECIST 1.1 and CA-125 in conjunction with Clinical MBO Criteria

0 6 12 18 24 30 36 420

0.5

1

Time from randomization (months)

455 381 257 168 76 3 0 0

911 761 542 352 160 17 1 0

TC +Nintedanib

(n=911)

TC +Placebo(n=455)

Events, n (%) 486 (53.3) 266 (58.5)

Median, months 17.3 16.6

HR* (95% CI) 0.84 (0.72, 0.98)

p value 0.0239

All patients (N=1366) – Cut-off date: 29 April 2013

*Stratified for macroscopic residual postoperative tumour, FIGO stage and carboplatin dose

AGOStudy 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

Estim

ated

per

cent

age

aliv

e a

nd p

rogr

essi

on-fr

ee

Time from randomization (months)

Placebo 283 248 186 123 52 2 0

Nintedanib 556 478 380 270 124 9 0

TC +Nintedanib

(n=556)

TC +Placebo(n=283)

Events, n (%) 234(42.1) 149(52.7)

Median, months 27.1 20.8

HR (95% CI) 0.74 (0.61, 0.91)

0 6 12 18 24 30 36 420

0.5

1

Median PFS difference: + 6.3 months

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 study1

• Prolongation of PFS in a randomized phase 2 study in combination with paclitaxel in recurrent ovarian cancer2

1. Herbst RS, et al. J Clin Oncol. 2009;27:3557‒3565.2. Karlan BY, et al. J Clin Oncol. 2012;30:362‒371.

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

Treat to PD/toxicity

Weekly Paclitaxel+

Trebananib

Weekly Paclitaxel+

PlaceboR

1:1

Paclitaxel 80 mg/m2 IV on days 1, 8, 15 Q4WTrebananib 15 mg/kg IV QW

ClinicalTrials.gov Identifier: NCT01204749

TRINOVA-1: DemographicsPaclitaxel +

PlaceboN = 458

Paclitaxel + Trebananib

N = 461Histologic grade, n (%)

Well differentiatedModerately differentiatedPoorly differentiatedUnknown

31 (7)84 (18)

256 (56)87 (19)

24 (5)69 (15)

274 (59)94 (20)

Prior lines of therapy, n (%)*123

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 AmericaWestern Europe/AustraliaRest 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)

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, months 5.4 7.2

HR = 0.66 (95% CI, 0.57–0.77)P (stratified log rank) < 0.001

Eve

nt-fr

ee P

roba

bilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Study Month0 3 6 9 12 15 18 21 22

Patients at risk:

461458

356310

176132

10568

5024

2210

142

30

10

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, months 17.3 19.0

HR = 0.86 (95% CI, 0.69–1.08)P (stratified log rank) = 0.19

Eve

nt-fr

ee P

roba

bilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Study Month0 3 6 9 12 15 18 21 24 27

Patients at risk:

461458

430434

342346

242234

163160

10899

6546

2818

63

TRINOVA-3

Available at: http://clinicaltrials.gov/ct2/show/NCT01493505. Accessed Feb 2014.

Previously untreatedepithelial ovarian, primary peritoneal, or fallopian tube cancer

• Post operative • Stage III, IV• Neoadjuvant Carboplatin AUC 5-6 IV d 1

Paclitaxel 175 mg/m2 IV d 1Trebananib (AMG 386)

weekly

Carboplatin AUC 5-6 IV d 1Paclitaxel 175 mg/m2 IV d 1

Placebo weekly

N = 1000 (rev)

Weekly Placebo

x 18 months

Maintenance

Trebananib x 18 m

onths

R(2:1)

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)

ICON6: Cediranib with platinum-based chemotherapy in ‘platinum-sensitive’ relapsed ovarian cancer• Cediranib targets: VEGFR-1/2/3

6 Cycles platinum-basedChemotherapy 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)

Continueplacebo

Switch toplacebo

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

Randomise2 : 3 : 3

0.00

0.25

0.50

0.75

1.00

164 148 65 21 7 118 90 24 8 3

.

0 3 6 9 12 15 18 21 24Months

Chemo.Maint.

Chemotherapy

Maintenance

Restricted mean survival time increases by3.1 months with maintenance treatment

Chemo. Maint.PFS events, n (%) 112 (94.9) 139 (84.8)

Median, months 8.7 11.1

Log-rank test p=0.00001

HR (95% CI) 0.57 (0.45 – 0.74)

Test for non-proportionality p=0.024

Restricted means, months 9.4 12.5

Progression-free survival – arms A vs. C

0.00

0.25

0.50

0.75

1.00

164 148 65 21 7 174 152 53 20 12 118 90 24 8 3

.

0 3 6 9 12 15 18 21 24Months

Chemo. Conc. Maint.PFS events, n (%) 112 (94.9) 152 (87.4) 139 (84.8)

Median, months 8.7 10.1 11.1

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, months 9.4 11.4 12.5

Progression-free survival – all three arms

Conc.Maint.

Chemo.

Concurrent

Chemotherapy

Maintenance

0.00

0.25

0.50

0.75

1.00

164 159 139 89 48 2222 118 106 89 46 27 1111

.

0 6 12 18 24 30Months

Chemo. Maint.OS events, n (%) 63 (53.3) 75 (45.7)

Median, months 20.3 26.3

Log-rank test p=0.042

HR (95% CI) 0.70 (0.51 – 0.99)

Test for non-proportionality p=0.0042

Restricted means, months 17.6 20.3

Restricted mean survival time increases by 2.7 months with maintenance treatment (over two years)

Overall survival

Chemo.Maint.

Chemotherapy

Maintenance

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, UK7. Aghajanian C et al. J Clin Oncol. 2012;30:2039‒2045.8. Ledermann JA et al . Eur J Cancer. 2013;49(suppl):LBA

Study Agent Setting HR-PFS (95% CI)

HR-OS (95% CI)

GOG 2181 Bevacizumab Front-line/Maintenance 0.72 (0.63-0.82) 0.89 (0.75-1.04)

ICON72 Bevacizumab Front-line/Maintenance 0.81 (0.70-0.94) 0.99 (0.85-1.14)

AGO-OVAR123 Nintedanib Front-line/Maintenance 0.84 (0.72-0.98) Neg

AGO-OVAR164 Pazopanib Primary Maintenance 0.77 (0.64-0.91) 0.99 (0.75-1.32)

AURELIA5 Bevacizumab Recurrence, Platinum-resistant, 1-2 priors 0.48 (0.38-0.60) 0.85 (0.66-1.08)

TRINOVA-16 Trebananib Recurrence, Platinum-resistant/sensitive, 1-3 priors 0.66 (0.57-0.77) 0.86 (0.69-1.08)

OCEANS7 Bevacizumab Recurrent, Platinum-sensitive, 1 prior 0.53 (0.41-0.70) 0.96 (0.76-1.21)

ICON68 Cediranib Recurrent, Platinum-sensitive, 1 prior 0.57 (0.44-0.74) 0.70 (0.51-0.99)

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

Today’s Focus

• New therapeutics update– Angiogenesis targeting– FR-alpha targeting– Rare ovarian tumors

Folate Metabolism: MoA

Vergote, Marth, Coleman. Cancer Met Rev 2014

Increases DNA synthesisInhibits apoptosisIncreases anoikisIncreases cell motility

Folate Receptor Expression

Utilizing the Folate Receptor: EC145

Folate-Vinca conjugate

Relevant for imaging targeting and therapy

EC145: Novel Folate Receptor Targeted Therapeutic

Randomized Phase II, Platinum-resistant ovarian Prior therapy: no more than 2 priors Regimen:

– PLD 50 mg/m2 IBW q 28 days– PLD 50 mg/m2 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)

Arm PFS HR PPLD 11.7 wks - -PLD+EC145 24.0 wks 0.497 0.014

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/m2 (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, 3PLD = 50 mg/m2 (IBW) every 28 days

Farletuzumab: Pre-Clinical Data Humanized MoAb to FRa Mechanism:

– Blocks Lyn kinase phosphorylation

– Induces cytotoxicity via ADCC & CDC

Active in xenograft model Favorable toxicity profile in

primate studiesNucleus

Cell transformation& proliferation

Cell stasis &suppressed proliferation

antibody mediated cytoxicity via

ADCC and CDC

Lyn kinase

over-expressed folate receptor alpha

Farletuzumab Phase 2: DesignPatients 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 farletuzumab6 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

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

Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence

EOC in first relapse> 6months or < 24 months

Randomize 1:1:1

6 CyclesCarboplatin &Taxane Plus:

Farletuzumab1.25 mg/kg

N =300

Farletuzumab2.5 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

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 months 194 (53.3) 196 (53.0) 193 (52.7) 389 (52.9) 12 – <18 months 108 (29.7) 112 (30.3) 111 (30.3) 223 (30.3) 18 – 24 months 62 (17.0) 62 (16.8) 62 (16.9) 124 (16.8)         Route of administration for first-line therapy n (%)

Intraperitoneal 26 (7.1) 28 (7.6) 26 (7.1) 54 (7.3) Intravenous 338 (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 Countries 181 (49.7) 184 (49.7) 181 (49.5) 365 (49.6)         Planned taxane therapy n (%)        

Paclitaxel 294 (80.8) 298 (80.5) 296 (80.9) 594 (80.7) Docetaxel 70 (19.2) 72 (19.5) 70 (19.1) 142 (19.3)

46

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

47

Farletuzumab Phase 3 in platin-sensitive ovarian cancer first

recurrence Overall Survival (ITT) (2013 April Update)

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

Today’s Focus

• New therapeutics update– Angiogenesis targeting– FR-alpha targeting– Rare ovarian tumors

Relevant Mutations in Ovarian Cancer

High Grade Serous Low Grade Serous CCC Endometrioid Mucinous0

10

20

30

40

50

60

70

80P53 Kras BRAF PIK3CA PTEN CTNNB

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

GOG 239: Results

† Three patients remain on study therapy (after receiving 20, 33, and 54 cycles).

CR: 2%

PR: 14%

SD: 65%

Prog:15%

0

10

20

30

40

50

60

1 2 3 4 5 6 7 10 12 13 15 15+14

Duration of TherapyResponse

MILO: MEKi vs Chemotherapy

GOG-281: Randomized Phase II/III

Recurrent Low-Grade Serous Carcinoma• Measurable Disease• Primary Endpoint: PFS (futility assessment)• N=250 (Global)• Translational endpoints: Pathway aberration, Seq

Trametinib(MEKi)

Physician’s ChoiceHormone or Chemo

Activated: 2-26-2014

Example: Studies with Companion Diagnostics

HRD (Rad51c,d)

FR-a: 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

Selected Therapy Based on Biology

Option 1

Option 2Options 3, 4

Options 5, 6

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?

Thank You!

Two great virtues:– Patience– Wisdom