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patients or employing any therapeutic products described in this educational activity.

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DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information

to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for

patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by

clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s

product information, and comparison with recommendations of other authorities.

DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational

uses of agents that are not indicated by the FDA. Albert Einstein College of Medicine and IMER do not recommend the use of any agent outside of the labeled

indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Albert Einstein College of Medicine and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestDeborah K. Armstrong, MDDeborah K. Armstrong, MD

Reported a financial interest/relationship or affiliation in the form of: Consultant, Eisai Inc.; Contracted Research, Eisai, Inc., MedImmune, LLC, Roche Pharmaceuticals, Inc.

Learning ObjectivesLearning ObjectivesUpon completion of this activity, Upon completion of this activity,

participants should be better able to:participants should be better able to:

Assess data on recent clinical trials incorporating antiangiogenic agents into the treatment of patients with ovarian cancer

Implement effective toxicity prophylaxis and side-effect management for patients receiving antiangiogenic therapies

Assess optimal dose and schedule when incorporating antiangiogenic agents into the treatment of patients with ovarian cancer

Implement the use of antiangiogenic agents into the treatment paradigm in newly diagnosed, maintenance, or relapse settings

Activity AgendaActivity Agenda Activity Overview (5 mins)

Incorporating Antiangiogenic Therapies Into the Treatment Armamentarium (50 mins)

– Case Study 1: Managing a newly diagnosed ovarian cancer patient

– Case Study 2: Managing a patient in the maintenance setting

– Case Study 3: Managing a patient with recurrent disease (platinum-resistant and platinum-sensitive)

Questions & Answers (5 mins)

Case Study 1: Case Study 1: Managing A Newly Diagnosed Managing A Newly Diagnosed

Ovarian Cancer PatientOvarian Cancer Patient

Case Study 1: Front-Line TherapyCase Study 1: Front-Line Therapy A 52-yr-old small business owner presents with

ascites and an adnexal pelvic mass on exam and CT scan

– Omental cake and ascites seen on CT; CA-125 = 580

Exploratory laparotomy with radical tumor debulking including TAH/BSO, omentectomy, appendectomy, lymphadenectomy

Optimally cytoreduced stage IIIC papillary serousovarian cancer

PS = 0; No significant comorbidities

CT = computed tomography; CA-125 = cancer antigen-125; TAH = total abdominal hysterectomy; BSO = bilateral salpingo-oophorectomy; PS = performance status.

Question 1Question 1

What treatment would you recommend for this patient?

1) IV carboplatin and IV paclitaxel

2) IV platinum and taxane plus bevacizumab

3) IV paclitaxel, IP cisplatin, and IP paclitaxel

4) IP cisplatin, IV paclitaxel, and IP paclitaxel with bevacizumab

Ovarian Cancer: ChemotherapyOvarian Cancer: Chemotherapy

Standard front-line chemotherapy today is paclitaxel 175 mg/m2 plus carboplatin AUC 6–7, q21days for 6 cycles

Result of several studies over last decade

– GOG 111 and OV10 – paclitaxel/cisplatin vs. cyclophosphamide/cisplatin

– GOG 158 and AGO OVAR-3 – carboplatin instead of cisplatin

AUC = area under the curve; GOG = Gynecologic Oncology Group; AGO = Arbeitsgemeinschaft Gynaekologische Onkologie.

NCCN, 2012; McGuire et al, 1996; Piccart et al, 2000; Ozols et al, 2003; du Bois et al, 2003.

GOG 172 SurvivalGOG 172 Survival

IV: 18 mosIP: 24 mosHR: 0.80, p = .05

IV: 50 mosIP: 66 mosHR: 0.75, p = .03

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 12 24 36 48 60

Time (mos on study)

Pro

po

rtio

n P

FS

(%

)

PFS

Rx GroupIVIP

5063

PF Failed Total160142

210205

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 12 24 36 48 60

Time (mos on study)

OS

Rx GroupIVIP

Alive93117

Dead11788

Total210205

PFS = progression-free survival; OS = overall survival.

Armstrong et al, 2006.

JGOG: Dose-Dense Wkly PaclitaxelJGOG: Dose-Dense Wkly Paclitaxel

JGOG = Japanese Gynecologic Oncology Group.Katsumata et al, 2009.

OSOSPFSPFS

VEGF-AVEGF-BPlGF

VEGFR-1

VEGF-AVEGF-CVEGF-DVEGF-E

VEGFR-2

NRP-1

AngiogenesisVasculogenesis

NRP-2

VEGF-CVEGF-D

VEGFR-3

Lymphangiogenesis

NRP-1

NRP-2

The VEGF/VEGF-Receptor AxisThe VEGF/VEGF-Receptor Axis

VEGF = vascular endothelial growth factor. Courtesy of Dr. Bradley Monk.

VEGF Ligand Agents in the ClinicVEGF Ligand Agents in the Clinic

Bevacizumab Aflibercept

Presta et al, 1997 Hu et al, 2005

GOG 218: SchemaGOG 218: Schema

Front-Line EOC, PP, or FT

• Stage III optimal (macroscopic)

• Stage III suboptimal• Stage IV

N = 1,800 (planned)

Front-Line EOC, PP, or FT

• Stage III optimal (macroscopic)

• Stage III suboptimal• Stage IV

N = 1,800 (planned)

Stratification variables – GOG PS – Stage/debulking status

1:1:1

15 mos

P 175 mg/m2

C AUC 6

Placebo

I

Arm

Cytotoxic

(6 cycles)

Maintenance

(16 cycles)

(CP)

C AUC 6

P 175 mg/m2

PlaceboBev 15 mg/kg

II(CP + Bev)

Bev 15 mg/kg

C AUC 6

P 175 mg/m2 III

(CP + Bev)

(Bev)

C = carboplatin; P = paclitaxel; EOC = epithelial ovarian cancer; PP = primary peritoneal; FT = fallopian tube. C = carboplatin; P = paclitaxel; EOC = epithelial ovarian cancer; PP = primary peritoneal; FT = fallopian tube. Burger et al, 2011. Burger et al, 2011.

CP (Arm I)

GOG 218: Investigator-Assessed PFSGOG 218: Investigator-Assessed PFS

+ Bev (Arm II)

+ Bev Bev maintenance (Arm III)

Pro

po

rtio

n P

FS

(%

)

Time (Mos Since Randomization)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 12 24 36

Arm I

CP (n = 625)

Patients with event (n; %)423

(67.7)

Median PFS (mos) 10.3

Stratified analysis HR (95% CI)

One-sided p value (log rank)

Arm III

CP + Bev Bev(n = 623)

360 (57.8)

14.1

0.717

(0.625–0.824)

< .0001a

Arm II

CP + Bev(n = 625)

418 (66.9)

11.2

0.908

(0.759–1.040)

.080a

a p = .0116Burger et al, 2010.

a p = .0116Burger et al, 2010.

GOG 218: OS Analysis GOG 218: OS Analysis At Time of Final PFS Analysis (January 2010)At Time of Final PFS Analysis (January 2010)

Arm I

CP

(n = 625)

Arm II

CP + Bev

(n = 625)

Arm III

CP + Bev Bev

(n = 623)

Patients with events (n; %)

156

(25.0)

150

(24.0)

138

(22.2)

Median (mos) 39.3 38.7 39.7

HRa

(95% CI)

1.036

(0.827–1.297)

0.915

(0.727–1.152)

One-sided

p value.361 .252

Pro

por

tion

Aliv

e (%

)

Time (Mos Since Randomization)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 12 24 36 48

625/625/623 442/432/437 173/162/171 46/39/40No. at risk

aStratified analysis.Burger et al, 2010.

aStratified analysis.Burger et al, 2010.

ICON7: Study DesignICON7: Study Design

Stratification variables – Stage/surgery– Time since surgery

– GCIG group

P 175 mg/m2

C AUC 6a

C AUC 6a

P 175 mg/m2

Arm A

Arm A

Arm A

Arm A

ArmArm BBArmArm BB

12 mos12 mos

Front-Line EOC, PP, or FT

• Stage I/IIA (grade 3) • Stage IIB/C• Stage III• Stage IV

N = 1,520 (planned)

Front-Line EOC, PP, or FT

• Stage I/IIA (grade 3) • Stage IIB/C• Stage III• Stage IV

N = 1,520 (planned)

Bev 7.5 mg/kg

Primary end point:

PFS

Secondary end points:

OS, RR, QOL, safety,

cost-effectiveness,

translational

No IRC present

VaMight vary based on GCIG group.GCIG = Gynecologic Cancer Intergroup; IRC = independent review committee; RR = response rate; QOL = quality of life.Perren et al, 2011.

VaMight vary based on GCIG group.GCIG = Gynecologic Cancer Intergroup; IRC = independent review committee; RR = response rate; QOL = quality of life.Perren et al, 2011.

ICON7 PFS: UpdatedICON7 PFS: Updated

17.4

19.8

Control

Research

Kristensen et al, 2011.

PFS: “High Risk” Subgroup (Ad Hoc Analysis)PFS: “High Risk” Subgroup (Ad Hoc Analysis)

No. At RiskControl 234 205 98 36 14 2Research 231 213 159 56 10 1

No. At RiskControl 234 205 98 36 14 2Research 231 213 159 56 10 1

1.00

0.75

0.50

0.25

0

1.00

0.75

0.50

0.25

0Pro

po

rtio

n A

liv

e W

ith

ou

t P

rog

res

sio

n (

%)

Pro

po

rtio

n A

liv

e W

ith

ou

t P

rog

res

sio

n (

%)

Time (mos)Time (mos)

0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 24 27 30

Control(n = 234)

Research (n = 231)

Events, n (%) 173 (74) 158 (68)Median (mos) 10.5 15.9Log-rank test p < .001HR (95% CI) 0.68 (0.55–0.85)Restricted mean 13.3 16.5

10.5 15.9

ControlResearch

High Risk: Stage IIIC Suboptimal/Stage IV

Kristensen et al, 2011.

Kristensen et al, 2011.

ICON7 OS by Risk GroupsICON7 OS by Risk Groups

GOG 252: Stage II/III Disease: GOG 252: Stage II/III Disease: Small Volume ResidualSmall Volume Residual

Carboplatin AUC = 6 (IV)Paclitaxel 80 mg/m2 (Days 1, 8, 15, 3 hrs)Bevacizumab (C2+ C22) x 21 days

Cisplatin 75 mg/m2 (IP Day 2)Paclitaxel 135 mg/m2 (Day 1, 3 hrs)Paclitaxel 60 mg/m2 (Day 8, IP)Bevacizumab (C2+ C22) x 21 days

EOC Optimal stage III No prior therapy

Phase III PFS primary end point

Open: 27 Jul 2009Closed: November 2011 Accrual: 1,100

I

III

II

Carboplatin AUC = 6 (IP)Paclitaxel 80 mg/m2 (Days 1, 8, 15, 3 hrs)Bevacizumab (C2+ C22) x 21 days

US NIH, 2009a.

Nintedanib (BIBF 1120) – First Triple Nintedanib (BIBF 1120) – First Triple Angiokinase Inhibitor: Mode of Action Angiokinase Inhibitor: Mode of Action

Ligands Cell Type/Receptors

VEGFs

FGFs

PDGFs

Endothelial CellsVEGFRs, FGFRs

PericytesPDGFRs

Smooth Muscle CellsFGFRs, PDGFRs

Stimulation

By Targeting 3 Major Angiogenesis Signalling Pathways, Nintedanib Prevents Further Tumor Growth and Related Tumor Escape Mechanisms

BIB

F 1

120

FGF = fibroblast growth factor; PDGF = platelet-derived growth factor.Hilberg et al, 2008.

Multicenter, Randomized, Double-Blind, Phase III Trial to Investigate the Efficacy and Safety of Nintedanib in Combination With Standard Treatment of Carboplatin and Paclitaxel Compared to Placebo Plus Carboplatin and

Paclitaxel in Patients With Advanced Ovarian Cancer

R

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

C

T

= Nintedanib 2 x 200 mg po qd

= Placebo

≤ 120 wks

C = Carboplatin AUC 5–6 Day 1

T = Paclitaxel 175 mg/m2 (3 hrs) Day 1

q21days / 6 courses

Nintedanib / Placebo- No intake on days of chemotherapy- Dose: 200 mg po bid (combi + mono)- Dose adaptation in case of undue toxicity- Max. duration of 120 wks in non-progressing patients

2

1

SURGERY

N = 1,300

US NIH, 2009b.

AGO-OVAR12: Nintedanib ConsolidationAGO-OVAR12: Nintedanib Consolidation

PFS

(A)OS

Ledermann et al, 2011.

Nintedanib: Phase II PFS and OSNintedanib: Phase II PFS and OSRandomized Phase II Placebo-Controlled Trial of Maintenance Therapy Randomized Phase II Placebo-Controlled Trial of Maintenance Therapy

Using the Oral Triple Angiokinase Inhibitor BIBF 1120 After Using the Oral Triple Angiokinase Inhibitor BIBF 1120 After Chemotherapy for Relapsed Ovarian CancerChemotherapy for Relapsed Ovarian Cancer

OS

TRINOVA-3 (GOG 3001)TRINOVA-3 (GOG 3001)::TC ± AMG 386 as First-Line Therapy of TC ± AMG 386 as First-Line Therapy of

Stage III–IV Ovarian CancerStage III–IV Ovarian Cancer Concurrent Treatment Maintenance Phase

ARM A:AMG 386Paclitaxel

Carboplatin (TC)

ARM B:Placebo

PaclitaxelCarboplatin

Paclitaxel 175 mg/m2 IV q3wksCarboplatin AUC 5 or 6 IV q3wks

for Maximum of 6 cycles+

AMG 386 15 mg/kg IV qwk orAMG 386 Placebo IV qwk

AMG 386 Monotherapy

Until Progression or 18 mos

AMG 386 Placebo Monotherapy

Until Progression or 18 mos

END OF TREATMENT

Progressive disease or unacceptable

toxicity or withdrawal of

consent or death

N = 2,000

Neoadjuvant Chemo +Interval Debulking

Allowed in Both Arms After 3 Courses

US NIH, 2011.

Key TakeawaysKey Takeaways

Bevacizumab with and following chemotherapy improves PFS

Patients with large volume disease may benefit most

Bevacizumab can be given with IP therapy but impact on outcome is unknown

Bevacizumab can be given with dose-dense paclitaxel regimen based on completion of GOG 252 (and 262) without stopping for safety concerns

Case Study 2: Case Study 2: Managing A Patient In The Managing A Patient In The

Maintenance SettingMaintenance Setting

Case Study 2Case Study 2

A 62-yr-old woman comes to you to ask your opinion about maintenance therapy after treatment for ovarian cancer. She had stage IV disease based on thoracic nodal involvement and was treated with 6 cycles of paclitaxel and carboplatin with excellent tolerance. At completion of chemotherapy CA-125 had normalized, CT shows persistent enlarged thoracic nodes up to 1.5 cm but PET shows no uptake in these nodes.

She wants to know if you recommend any further treatment for her at this time.

PET = positron emission tomography.

Clinical Decision QuestionClinical Decision Question

What do you recommend for her at this time?

1) No further therapy

2) Three more cycles of paclitaxel and carboplatin

3) Paclitaxel alone q4wks x 12

4) Bevacizumab

5) Another VEGF targeted agent

Consolidation Therapy: GOG 178Consolidation Therapy: GOG 178

EOC, FT, PPStage III/IVPrior chemo 5–6 cyclesRegister 3–8 wksCCRNeuropathy ≤ grade II

Paclitaxel (3 hrs) 175 mg/m2 q28days x 12

Paclitaxel (3 hrs) 175 mg/m2 q28days x 3

RRAANNDDOOMMIIZZEEN = 450 anticipated

Accrual closed 9/6/01N = 277; 222 with FU54 progression events

End points• PFS• OS

FU = follow-up.Markman et al, 2003.

GOG 178: ConsolidationGOG 178: Consolidation

Unadjusted Log Rankp (1-sided) = .0035

Adjusted Log Rankp (1-sided) = .0023

Markman et al, 2003.

GCIG Intergroup Protocol: GINECOGCIG Intergroup Protocol: GINECO

French/German Study Group

EOC (Stage IIB–IV)All Strata

N = 1,308

Paclitaxel (3 hrs) 175 mg/m2 q21days x 6Carboplatin AUC = 5.0 q21days x 6

Paclitaxel (3 hrs) 175 mg/m2 q21days x 6Carboplatin AUC = 5.0 q21days x 6

RRAANNDDOOMMIIZZEE

Topotecan 1.25 mg/m2 q21days x 4

Pfisterer et al, 1999.

Maintenance Therapy: GOG 212 Maintenance Therapy: GOG 212

EOC, FT, PPStage III/IVPrior chemo 5–8 cyclesRegister 3–8 wksCCRNeuropathy ≤ grade II

PG-Ptx (paclitaxel poliglumex) 135 mg/m2 q28days x 12

Paclitaxel (3 hrs) 135 mg/m2 q28days x 12

RRAANNDDOOMMIIZZEE

N = 1,400 anticipatedPhase III; Superiority Design

End points• PFS• OS

Observation

US NIH, 2005.

EOC, FT, or PP Primary platinum-based therapy (IV, IP, neoadjuvant permitted) CR, PR, or SD after initial therapy Primary end point: PFS Secondary end point: OS (with interim analysis)

AGO-OVAR16: Pazopanib ConsolidationAGO-OVAR16: Pazopanib Consolidation

I Pazopanib 800 mg po qd (2 yrs)

II Placebo po qd (2 yrs)

Estimated Enrollment: 900 Study Start: May 2009 Estimated Completion: March 2013

Primary Rx:Platinum and Taxane

CR = complete response; PR = partial response; SD = stable disease. US NIH, 2009c.

Sorafenib: Study 12007 Sorafenib: Study 12007 (Phase IIb Maintenance)(Phase IIb Maintenance)

Patients with FIGO stage III/IV ovarian epithelial

cancer or PPC who have achieved clinical CR after standard platinum/taxane therapy and cytoreductive

surgery

Sorafenib 400 mg po bid,

continuous dosing

US NIH, 2008.

Placebo 400 mg po bid,

continuous dosing

RR

Estimated Enrollment: 247 Study Start: November 2008 Primary Completion: July 2011 Estimated Study Completion July 2012*

Patients stratified according to the degree of residual disease following initial diagnosis and surgical debulkment Primary objective: PFS Secondary objectives: Abnormal CA-125, OS 1:1 randomization

*This trial is ongoing, but not recruiting participants - status updated April 2012

Key TakeawaysKey Takeaways

Given the high rate of disease recurrence in ovarian cancer, there is impetus to consider consolidation or maintenance therapy

Continuing paclitaxel for 1 year after initial chemotherapy past 6 cycles improves PFS

Bevacizumab with and following chemotherapy improves PFS and OS in some situations

There is no data on using only bevacizumab for maintenance therapy, after chemotherapy

Case Study 3: Case Study 3: Managing A Patient In The Managing A Patient In The

Resistant/Refractory Setting (Platinum-Resistant/Refractory Setting (Platinum-Resistant and Platinum-Sensitive)Resistant and Platinum-Sensitive)

Case Study 3Case Study 3

A 60-yr-old woman with a PMH of HTN presents with extensive pelvic and peritoneal implants, ascites, and large volume disease at the root of the mesentery. A diagnosis of ovarian cancer was made by paracentesis showing papillary serous carcinoma. She was deemed unresectable by a gynecologic oncologist.

Received neoadjuvant paclitaxel and carboplatin x 3 without response

She then received topotecan x 3 without response

She now has persistent ascites requiring paracentesis q5–8days for palliation

CA-125 = 6,916

PS = 1

PMH = past medical history; HTN = hypertension.

CA-125 = 6,516, exam shows marked ascites The patient requires frequent paracenteses wkly PS = 1

Paclitaxel, Carboplatin, and Topotecan Paclitaxel, Carboplatin, and Topotecan Refractory, Platinum-Resistant Ovarian CancerRefractory, Platinum-Resistant Ovarian Cancer

Clinical Decision QuestionClinical Decision Question Based on data presented at ASCO 2012 what

treatment would you recommend for this patient?

1) Pegylated liposomal doxorubicin (PLD, doxil, lipodox)

2) Wkly paclitaxel

3) 1 or 2 with bevacizumab

4) Bevacizumab

5) Gemcitabine, carboplatin

6) Gemcitabine, carboplatin, bevacizumab

Recurrent Ovarian Carcinoma:Recurrent Ovarian Carcinoma: Pegylated Liposomal Doxorubicin Pegylated Liposomal Doxorubicin

Author/Year DosePlatinum-Refractory

(< 6 mos) Response

Platinum-Sensitive

(> 6 mos) Response

Muggia et al, 1997* 50 mg/m2

q3wks

9/35 26% -- --

Gordon et al, 2000 40–50 mg/m2

q4wks

15/82 18% -- --

Gordon et al, 2001 50 mg/m2

q4wks

16/130 12% 31/109 28%

Ferrandina et al, 2008*

40 mg/m2

q4wks

11/70 16% -- --

*Enrolled patients with platinum-refractory and platinum-sensitive disease.

Platinum-Resistant Ovarian Cancer Platinum-Resistant Ovarian Cancer Cytotoxic TherapyCytotoxic Therapy

STUDY* AGENT N RR (%)

126-J Docetaxel 58 22

126-N Wkly Paclitaxel 48 21

126-M Ixabepilone 50 14

126-Q Pemetrexed 48 21

126-R nab-Paclitaxel 47 23

Thresholds: 10%, 25%

*1 prior line.

Randomized Phase II,

NKTR-102*

145 mg/m2 q14days 33 21

145 mg/m2 q21days 31 23

Vergote et al, 2010.

*Median of 3 prior lines.

Bevacizumab Trials: Relapsed EOCBevacizumab Trials: Relapsed EOC

*Burger et al, 2007. **Garcia et al, 2008. ***Cannistra et al, 2007.

GOG 170-D*(N = 62)

NCI 5789**(N = 70)

Genentech Study***(N = 44)

Study Treatment

Single-agent BV 15 mg/kg q3wks

BV 10 mg/kg q2wks + low-dose oral

cyclophos.

Single-agent BV 15 mg/kg

q3wks

Prior Regimens

1 – 21/62 (34%) 2 – 41/62 (62%)

Median = 2Range 1–3

2 – 23/44 (52%)3 – 21/44 (48%)

Platinum-Resistant

42% 40% 100%

Efficacy ORR 21% 24% 16%

6-mos PFS 39% 56% 27%

GIP or Fistula 0 4 (6%) 5 (11%)

GI Perforations With BevacizumabGI Perforations With Bevacizumabin Ovarian Cancerin Ovarian Cancer

Study Gl Perforations

Burger (GOG 170D) 0/62 (0)

Garcia (ASCO, 2005) 2/29 (6.9)

Cannistra (ASCO, 2006) 5/44 (11.4)

Wright (ASCO, 2006) 4/62 (6.5)

Friberg (ASCO, 2006) 2/13 (15.4)

Monk (Gyn Oncol, 2006) 1/32 (3.1)

Wright (Cancer, 2006) 2/23 (8.7)

Bidus (Gyn Oncol, 2006) 0/3 (0)

Penson (ASCO, 2006) 0/30

Total 16/298 (5.4%)

GI = gastrointestinal.Han et al, 2007.

Note: A recent history of bowel obstruction symptoms may be associated with GI perforation

Ovarian Cancer: GOG Trials of Targeted TherapyOvarian Cancer: GOG Trials of Targeted Therapy

Study* Agent Target N RR (%) PFS at

6 Mos (%)

170-C Gefitinib EGFR 27 3.7 14.8

170-D Bevacizumab VEGFA 62 21 40.3

170-E Imatinib bcr-abl/c-kit/PDGFR 56 1.8 16.1

170-F Sorafenib VEGFR/PDGRR/Raf 59 3.4 23.7

170-G Lapatinib EGRR/HER2neu 26 0 7.7

170-H Vorinostat HDAC 27 3.7 7.4

170-I Temsirolimus¥ mTor 54 9.3 24.1

170-J Enzastaurin PKC-beta 27 7.4 11.1

170-K Mifepristone PR 22 4.5 13.6

170-M Dasatinib Scr/bcr-abl/c-kit 34 0 20.6

170-N A6 uPAR 31 0 6.5

170-P AMG-102 HGF (c-met) Suspended after first stage

170-Q EGEN-001 IL-12 First stage accrual in progress

*1–2 priors; ¥1–3 priors.

Thresholds: RR – 10%, 25%; PFS – 15%, 35%

Reference Agent Target N RR (%)

Tew et al, 2007 Aflibercept

(VEGF-TRAP) VEGF

2 mg/kg

215

3.8

4 mg/kg 7.3

Biagi et al, 2011 (NCIC-CTEP)

Sunitinib VEGF/PDGF 30 3.3

Matulonis

et al, 2009

(DFCI-CTEP)

Cediranib VEGF/c-kit 46 17

Buckanovich

et al, 2011

Cabozantinib VEGFR2/c-met 70 24

Friedlander

et al, 2010

Pazopanib VEGFR/PDGFR/c-kit

36 18

Ovarian Cancer: VEGF Targeted Ovarian Cancer: VEGF Targeted TherapyTherapy

Aflibercept for Ascites in Advanced Ovarian Cancer: Aflibercept for Ascites in Advanced Ovarian Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II StudyA Randomized, Double-Blind, Placebo-Controlled Phase II Study

Time to Repeat ParacentesisTime to Repeat Paracentesis

Median 55 vs. 23 days

Fatal GI Perforation:

Aflibercept 3/30

Placebo 1/25

Gotlieb et al, 2011.

Kaplan-Meier curve Waterfall plot

Randomized Phase II Trial of Wkly Paclitaxel Randomized Phase II Trial of Wkly Paclitaxel +/- AMG 386 in Recurrent Ovarian Cancer+/- AMG 386 in Recurrent Ovarian Cancer

EOC, FT, EOC, FT, or PPor PP

N = 161N = 1611–3 Prior 1–3 Prior

LinesLines

Wkly PaclitaxelWkly Paclitaxel

AMG 386 10 mg/kg IV wklyAMG 386 10 mg/kg IV wkly

(n = 53)(n = 53)Wkly PaclitaxelWkly Paclitaxel

AMG 386 3 mg/kg IV wklyAMG 386 3 mg/kg IV wkly

(n = 53)(n = 53)Wkly PaclitaxelWkly Paclitaxel

PlaceboPlacebo

(n = 55)(n = 55)

R

A

N

D

O

MI

Z

E

Paclitaxel 80 mg/m2 IV wkly, 3 wks on/1 wk off

AMG 386AMG 386

10 mg/kg IV10 mg/kg IV

wklywkly

10 mg/kg 3 mg/kg Placebo

*Median PFS (mos) 7.2 5.7 4.6

*HR (Arm A+B vs. placebo) = 0.76 (80% CI, 0.59, 0.98), p = .17Trend Test, p = .037

ORR (CR + PR; %) 37 19 27

PD = progressive disease.Karlan et al, 2012.

PD

TRINOVA-1:TRINOVA-1:Randomized Phase III on AMG 386 in Combination With Randomized Phase III on AMG 386 in Combination With

Paclitaxel in Advanced Recurrent Ovarian CancerPaclitaxel in Advanced Recurrent Ovarian Cancer

US NIH, 2010.

* Blinded.† Radiographic PD, unacceptable toxicity, withdrawal of consent, or death.

SA

FE

TY

F

U

ScreeningEnrollment

Treatment Phase

LO

NG

-TE

RM

FU

FUPhase

RA

ND

OM

IZA

TIO

N

AMG 386 15 mg/kg* IV qwk +Paclitaxel 80 mg/m2 IV qwk

(3 on/1 off)

Placebo* IV qwk +Paclitaxel 80 mg/m2 IV qwk

(3 on/1 off) EN

D O

F T

RE

AT

ME

NT

†

N = 900

Pujade-Lauraine et al, 2012.

Platinum-Resistant OCa

• ≤ 2 prior anticancer regimens

• No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvement

Platinum-Resistant OCa

• ≤ 2 prior anticancer regimens

• No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvement

Treat to PD/toxicity

Treat to PD/toxicity

Treat to PD/toxicity

Treat to PD/toxicity

Investigator’s choice

(without BEV)

Investigator’s choice

(without BEV)

Optional BEV monotherapyc Optional BEV monotherapyc

BEV 15 mg/kg q3wkb

+ chemotherapyBEV 15 mg/kg q3wkb

+ chemotherapy

Chemotherapy

RR

1:1

Stratification Factors • Chemotherapy selected

• Prior antiangiogenic therapy

• Treatment-free interval (< 3 vs. 3–6 months from previous platinum to subsequent PD)

Chemotherapy Options(investigator’s choice)

• Paclitaxel 80 mg/m2 Days 1, 8, 15, & 22 q4wks

• Topotecan 4 mg/m2 Days 1, 8, & 15 q4wks (or 1.25 mg/m2, Days 1–5 q3wks)

• PLD 40 mg/m2 Day 1 q4wks

aEOC, FT, or PP.bOr 10 mg/kg q2wks.c15 mg/kg q3wks, permitted on clear evidence of progression.

AURELIA Trial DesignAURELIA Trial Design

Pujade-Lauraine et al, 2012.

CT (n = 182)

BEV + CT (n = 179)

Events, n (%) 166 (91%) 135 (75%)

Median PFS (mos) (95% CI)

3.4(2.2‒3.7)

6.7(5.7‒7.9)

HR (unadjusted)(95% CI)Log-Rank p Value (2-sided, unadjusted)

0.48 (0.38‒0.60)

< .001

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

Est

ima

ted

Pro

bab

ility

(%

)E

stim

ate

d P

roba

bili

ty (

%)

0 6 12 18 24 300 6 12 18 24 30

Time (mos)Time (mos)

182182 3737 8 8 11 00179179 8888 1818 11 00

CTCTBEV + CTBEV + CT

No. at risk:No. at risk: 93 93140140

20204949

1144

0011

3.4 6.7

Median duration FU: 13.9 mos (CT arm) vs. 13.0 mos (BEV + CT arm)

Progression-Free Survival Progression-Free Survival

Summary of Best ORRSummary of Best ORR

a2-sided chi-square test with Schouten correction.

p = .001a

p < .001ap < .001a

Pujade-Lauraine et al, 2012.

Pa

tient

s (%

)

Adverse Events of Special InterestAdverse Events of Special Interest

Grade ≥ 3 Adverse Events of Special Interest, n (%)

CT (n = 181)

BEV + CT(n = 179)

HTN 2 (1.1) 13 (7.3)

Grade ≥ 2 12 (6.6) 36 (20.1)Proteinuria 0 3 (1.7)

Grade ≥ 2 1 (0.6) 19 (10.6)GI perforation 0 3 (1.7) Grade ≥ 2 0 4 (2.2)Fistula/Abscess 0 2 (1.1) Grade ≥ 2 0 4 (2.2)Bleeding 2 (1.1) 2 (1.1)Thromboembolic Event Arterial Venous

8 (4.4)0

8 (4.4)

9 (5.0)4 (2.2)5 (2.8)

Wound-Healing Complication 0 0RPLS 0 1 (0.6)CHF 1 (0.6) 1 (0.6)Cardiac Disorders (excluding CHF) 0 0

RPLS = reversible posterior leukoencephalopathy syndrome; CHF = congestive heart failure.Pujade-Lauraine et al, 2012.

CG + PL

OCEANS: Study SchemaOCEANS: Study Schema

CG for 6 (up to 10) cyclesStratification Variables

• Platinum-free interval (6–12 vs. > 12 mos)

• Cytoreductive surgery for recurrent disease (yes vs. no)

Platinum-Sensitive Recurrent OCa

• Measurable disease• ECOG 0/1• No prior chemo for recurrent ovarian cancer• No prior BEV

N = 484

ECOG = Eastern Cooperative Oncology Group.aEOC, FT, or PP.

G 1,000 mg/m2, Day 1 & 8

C AUC 4

PL q3wks until progression

C AUC 4

BEV 15 mg/kg q3wks until progression

G 1,000 mg/m2, Day 1 & 8CG + BEV

OCEANS: PFS, ORR, and DOROCEANS: PFS, ORR, and DOR

Data cutoff date: September 17, 2010

GC + PL(n = 242)

GC + BV(n = 242)

PFS by INV

Median PFS (mos) 8.4 12.4

Stratified Analysis, HR (95% CI)

0.484 (0.388–0.605)

Log-Rank p Value < .0001

PFS by IRC

Median PFS (mos)8.6 12.3

Stratified analysis, HR (95% CI)

0.451 (0.351–0.580)

Log-Rank p Value < .0001

ORR and DOR by INV

ORR (%) 57 79

Median DOR (mos) 7.4 10.4

HR (95% CI) 0.53 (0.41–0.70)

INV-Assessed

GC + PL(n = 242)

GC + BEV(n = 242)

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30

Time (mos)

Pro

po

rtio

n P

FS

(%

)

DOR = duration of response; INV = investigator-assessed; IRC = independent review committee; ORR = objective response rate.Aghajanian et al, 2012.

Pro

po

rtio

n S

urv

ivin

g (

%)

OCEANS: OS AnalysesOCEANS: OS Analyses

aData cutoff date: September 17, 2010. Median FU 24 mos in both arms, with 141 deaths (29% of patients). bData cutoff date: August 29, 2011. Median FU 33.7 mos in PL arm and 35.4 mos in BV arm, with 235 deaths (49% of patients)..

GC + PL(n = 242)

GC + BV(n = 242)

No. Events (%) 78 (32.2) 63 (26.0)

Median OS (mos) 29.9 35.5

HR (95% CI) 0.751 (0.537–1.052)

Log-Rank p Value .0944

GC + PL (n = 242)

GC + BV(n = 242)

No. Events (%) 112 (46.3) 123 (50.8)

Median OS (mos) 35.2 33.3

HR (95% CI) 1.027 (0.792–1.331)

Log-Rank p Value .8422

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

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n S

urv

ivin

g (

%)

GC + PL(n = 242)

GC + BEV(n = 242)

First Interim Analysisa

1.0Second Interim Analysisb

0 6 12 18 24 30 36 42 48 54

Time (mos)

0.8

0.6

0.4

0.2

0.0

Aghajanian et al, 2012.

DOR CG + PL (n = 139)

CG + BV (n = 190)

Median (mos) 7.4 10.4

HR (95% CI) 0.534(0.408–0.698)

p < .0001a

OCEANS: Objective ResponseOCEANS: Objective Response

100

80

60

40

20

0

100

80

60

40

20

0

%%

78.5

57.4 PR = 61

PR = 48

CR = 17CR = 9

Difference: 21.1% p < .0001

aCompared for descriptive purposes only.

CG + PL (n = 242)

CG + BV (n = 242)

Aghajanian et al, 2012.

Pre-Treatment Post-4 cycles

Single-Agent Bevacizumab in Single-Agent Bevacizumab in Refractory Ovarian Cancer: GOG 170DRefractory Ovarian Cancer: GOG 170D

Key TakeawaysKey Takeaways

There are multiple cytotoxic agents with modest activity in platinum-refractory and platinum-resistant ovarian cancer

Antiangiogenic agents have significant single-agent activity in recurrent ovarian cancer

Bevacizumab added to chemotherapy improves response and PFS in recurrent ovarian cancer (platinum-resistant and platinum-sensitive)

A recent history of bowel obstruction symptoms may be associated with an increased risk of perforation in patients treated with bevacizumab