management of recurrent ovarian cancer: insights, limitations, and future directions

Management of Recurrent Ovarian Cancer: Insights, Limitations, and Future Directions

Bradley J. Monk, MD, FACS, FACOGProfessor and Director

Division of Gynecologic OncologyDepartment of Obstetrics and GynecologyCreighton University School of Medicine atSt. Joseph’s Hospital and Medical Center

[email protected]

Disclosures

Dr. Monk discloses the following commercial relationships: Consultant/advisor: Amgen, AstraZeneca, Bayer,

Cerulean, Clovis, Gradalis, Insys Therapeutics, Merck, Oxigen, Pfizer, PPD Development, Roche/Genentech, TESARO,

Speakers’ bureau: AstraZeneca, Janssen/Johnson & Johnson, Myriad, Roche/Genentech

Grants/research support: Amgen, Array, Genentech, Janssen/Johnson & Johnson, Lilly, Morphotek, TESARO

Learning Objectives

Assess criteria for initiating treatment of recurrent ovarian cancer

Evaluate patient- and tumor-related factors that can affect treatment selection for recurrent ovarian cancer

Describe emerging and evolving data on novel therapies for recurrent ovarian cancer

Controversies in the Treatment of Newly Diagnosed Advanced Ovarian

Cancer Neoadjuvant chemotherapy

EORTC and CHORUS Weekly chemotherapy

JGOG and GOG 262 Intraperitoneal chemotherapy (IP)

GOG 172 and GOG 252 Adding bevacizumab

GOG 218 and ICON 7

Traditional Clinical Trial End Points

McKee et al, 2010.

End Point Regulatory Advantages DisadvantagesOverall survival (OS)

Clinical benefit Regular approval

• Accepted as direct measure of benefit

• Precise; easily measured

• Requires large studies• Affected by sequential Tx• Includes noncancer

deaths

Symptom end points (eg, patient-reported outcomes)

Clinical benefit Regular approval

• Patient subjective report of benefit

• Blinding difficult• Missing data• Lack of validated

instruments• Multiple analyses

Progression-free survival (PFS) or time to progression (TTP)

Surrogate Accelerated or regular approval

• Smaller, shorter studies• Generally insulated

from effect dilution by crossover or subsequent therapy

• Can be difficult to measure

• Decreasing statistical association with OS as survival increases

All are surrogates derived from the 1962 amendment to the FD&C Act mandating effectiveness as the newest standard for marketing approval, defined broadly as clinical benefit to the patient.

FDA Requirements for New Drug Approvals

FD&C Act 1962: Substantial evidence of effectiveness required by Congress Generally understood to mean evidence from at least

two adequate and well-controlled studies FDAMA 1997: One trial may suffice with other

confirmatory evidence Effectiveness Guidance Document 1998: A single

trial should be of excellent design, internally consistent, and demonstrate a compelling result Statistically strong evidence of an important clinical

benefit such as survival

FDA, 2009.

FDA Requirements for Approval Regular approval – requires substantial evidence of

clinical benefit based on: Prolongation of life – OS is the cleanest recognized end

point– Issues of appropriateness in a disease where subsequent therapy

cannot be controlled and may be unbalanced – Time-sensitive in a disease with a median survival approaching 5

years A better life

– No clearly validated tool in ovarian cancer of what this entails– Has never been tested at the FDA

Or an established surrogate for either of the above– Is PFS a reasonable surrogate for OS? Response rate (RR)?

FDA, 2011.

FDA Requirements for Approval (cont.)

Regular approval Clinical benefit or established surrogate (PFS)

Accelerated approval Use of a surrogate end point reasonably likely

to predict clinical benefit (ORR) Subsequent confirmation of clinical benefit

FDA, 2011.

FDA Guidance

FDA enrichment draft guidance:http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM332181.pdf

FDA in vitro companion diagnostic device draft guidance:

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf

Approved Drugs in Ovarian Cancer

1978

Cisp

latin

Carb

oplat

inAlt

reta

mine

Pacli

taxe

lTo

pote

can

Lipos

omal

doxo

rubic

in (P

LD)

(acc

elera

ted)

Lipos

omal

doxo

rubic

in (fu

ll)

Gem

citab

ine

(with

carb

oplat

in)

2006

1989

1990

1992

1996

1999

2005 20

14

Beva

cizum

ab(w

ith ch

emot

hera

py)

1964

Melph

alan

Doxo

rubic

in

1974 20

14

Olap

arib

(acc

elera

ted)

When Does Advanced Ovarian Cancer Recur?

Carb = carboplatin; cis = cisplatin; doc = docetaxel; GOG = Gynecologic Oncology Group; pac = paclitaxel.Markman et al, 2001; Armstrong et al, 2006; Ozols et al, 2003; McGuire et al, 1996; Spriggs et al, 2007; Rose et al, 2004; Vasey et al, 2004; Bookman MA, 2006.

Population Study Treatment PFSOptimal stage III

GOG 114 IV carb & pac, IP cis 28 mo

GOG 172 IV pac, IP cis & pac 24 moGOG 158 IV pac & carb 21 moGOG 114 IV pac & cis 22 moGOG 158 IV pac & cis 19 moGOG 172 IV pac & cis 18 mo

Suboptimal III/IV

GOG 111 IV pac & cis 18 mo

GOG 162 IV pac cis 12 moGOG 152 IV pac cis 11 mo

All stage III/IV GOG 182 IV pac/carbo x 8 16 mo

Recurrent Ovarian Cancer:Population Characteristics

NCCN, 2016b; Pisano et al, 2009.

PRIMARY

THERAPY

0 3 6 12 18 24

Refractory

Resistant

Partially Sensitive

Sensitive

months

Treatment Considerations and Goals

Primary goals of therapy for the treatment of recurrent ovarian cancer: Progression-free survival Increased survival Prevention of treatment-related symptoms Palliation of cancer-related symptoms Quality of life (QOL) and survivorship

Critical Issues in Recurrent Ovarian Cancer

How to treat? Single agent vs combination Platinum vs nonplatinum Conventional vs experimental therapy

(eg, targeted agents) Sequencing????

The ideal goal: Maximum time without symptoms and

without treatment toxicity

Recurrence After First-Line Chemotherapy

Platinum-Sensitive

>6 Months

ChemotherapyDoublet ±

Bevacizumab

Platinum- Refractory/Resistant

<6 Months

NonplatinumSingle Agent ± Bevacizumab

The Traditional Treatment Paradigm

NCCN, 2016.

Markman et al, 1991; Alvarez et al, 2016.

The designation of a patient as either “platinum-sensitive” or “platinum-resistant” solely on the basis of a timeline is severely limited.

Limitations of the “Platinum-Sensitive” and “Platinum-Resistant” Designations

Markman et al, 1991; Alvarez et al, 2016.


(cont.)

WNL = within normal limits.Markman et al, 1991; Alvarez et al, 2016.


(cont.)

Proposed Multiplex Classification System for Patients With Recurrent Ovarian Cancer

(cont.)

HGSC = high-grade serous carcinoma.Alvarez et al, 2016.

Alvarez et al, 2016.


(cont.)

Treated same as primary peritoneal and fallopian tube cancers.Karst & Drapkin, 2010.

Subtypes of Epithelial Ovarian Cancer

Histologic Classification of Ovarian Cancer

Specific molecular features define these categories and shape clinical trial design, ie:

Mucinous tumors: KRAS mutations

High-grade serous cancers: Homologous recombination deficiency (BRCA 1 and 2) is common and thus displays high rate of platinum sensitivity

Low-grade serous cancers: KRAS mutations; usefulness of MEK inhibitors

Clear cell cancers: Chemotherapy insensitivity, PIK3CA mutations, and sensitivity to VEGFR2 inhibitors

Serous

Endometrioid

Mucinous

Clear cell

Low grade High grade

Karst & Drapkin, 2010.

Ovarian Cancer Is a Heterogeneous Disease

Genetic characteristics can be used to classify ovarian cancers as distinct clinical subtypes

SEX CORD-STROMAL

OTHERS, INCLUDING GERM CELLS

NONEPITHELIAL

HIGH-GRADE SEROUS

LOW-GRADE SEROUS CLEAR CELL ENDOMETRIOID MUCINOUS

EPITHELIAL

BRCA1 and 2TP53NF1RB1

CDK12

Homologous recombination repair genes

KRASBRAFNRASERBB2

ARID1APIK3CAPTEN

CTNNB1PPP2R1α

ARID1APIK3CAPTEN

PPP2R1αMMR deficiency

BRCA1 and 2

KRAS

HER2 amplification

Granulosa cell FOXL2

Sertoli-Leydig cell DICER1

BRCA1 and 2

Regardless of histology and genetic heterogeneity, the majority of patients are treated similarly

Coleman et al, 2013; Banerjee et al, 2013; Lakhani et al, 2004; Goodheart et al, 2009.



(cont.)

The Designation of a Patient as Either “Platinum-Sensitive” or “Platinum-Resistant” Solely on the Basis of a Timeline Is Severely

LimitedConceptual depiction of differential weighing of classification variables over continuum of treatments:


PARP Inhibition andHomologous Recombination Repair

PARP

Survival

Normal cellRepair by Homologous Recombination

DNA SSBs occur all the time in cells and PARP detects and repairs themDuring the replication process unrepaired SSBs are converted into DSBs

Replicating cells

No effective repair(No HR pathway)Cell

death

Cancer cell with HRD

Tumour specific

killing by PARP

InhibitorsSSB = single strand binding protein; DSB = double strand binding protein; PARP = poly (ADP-ribose) polymerase;HRD = homologous recombination deficiency.

Surv

ivin

g Fr

actio

n (L

og10

)

PARP Inhibitor Concentration (M)

1000xMore Sensitive

0

-1

-2

-3

0 10-9 10-8 10-7 10-6 10-5 10-4-4

Mouse Embryonic Stem Cells

BRCA2 +/-BRCA2 -/-

BRCA2 +/+

Ashworth, 2008.

BRCA2-deficient cells are more than 1,000-fold more sensitive than wild-type or heterozygous cells to PARP inhibition.

In vitro Data Support the Hypothesis of PARP Inhibition in BRCA-Mutated Tumor

Cells

BRCA1/2 Mutations Are the Most Common Homologous Recombination Deficiency in Ovarian Cancers

Staples & Goodman, 2013; Pal et al, 2005.

8%

6%

4%3%

11%

6%

6%5%

14%

4%2%

31%

BRCA1 germline

BRCA2 germline

BRCA1 somaticBRCA2 somatic

BRCA1 methylation

EMSY amplification

PTEN loss

Other HRDCCNE1

amplification

Other

Rb1 loss

MMR germline

Non-HRD HRDApproximately

14% of women with ovarian cancer have a

deleterious germline mutation in the BRCA1

or BRCA2 gene

BRCA1/2 Mutations Can Be Present Both in Tumor and Germline

BRCA intact cells

BRCA mutated cells

Somatic mutation

Positive blood testNegative blood test

Germline mutation

~25% of patients will have a positive tumor BRCA result

tBRCA+result

Clinical Utility: Identify More Patients Whose Tumors Have HRD

HRD testing identifies 2x as many patients as tumor BRCA testing and 3.5x as many as germline BRCA testing

Yates et al, 2014; Cancer Genome Atlas Research Network, 2011.

HRD testing identifies 2x as many patients as tumor BRCA

sequencing

HRD Assays Will Identify More Patients Who May Respond Better to DNA-Damaging

Therapy

Yates et al, 2014; Cancer Genome Atlas Research Network, 2011; Timms et al, 2014.

Current PARP Inhibitors

PARP inhibitors in clinical trials: Olaparib Niraparib Rucaparib Veliparib Others

Current PARP Inhibitors: Olaparib

Olaparib clinical trials to date Study 1 (NCT01078662) Randomized phase II maintenance trial

(NCT00753545) Randomized phase II trial with paclitaxel/carboplatin

(NCT01081951) SOLO-1 (NCT01844986) SOLO-2 (NCT01844986) SOLO-3 (NCT02282020) Olaparib/cediranib (NCT01116648, NCT02446600,

NCT02502266) PAOLA1 (NCT02477644)

Maintenance Olaparib:Study 19 Design

PR = partial response; CR = complete response.Ledermann et al, 2011.

Patients • Platinum-sensitive high-grade serous ovarian cancer• ≥2 previous platinum regimens• Maintained PR or CR following last platinum regimen

Placebo(n=129)

Olaparib400 mg bid,

orally(n=136)

Primary end pointPFS by RECISTSecondary end pointsTTP by CA-125 (GCIG criteria) or RECIST, OS, safety

Randomized 1:1

82 sites in 16 countries

0Time From Randomization (months)

136 104 51 23 6 0 0129 72 23 7 1 0 0

At Risk (n)OlaparibPlacebo

0.6

0.80.9

00.10.20.30.40.5

0.7

1.0

3 6 9 12 15 18

No. of events : Total patients (%)Median PFS (months)

Olaparib60:136 (44.1)8.4

Placebo93:129 (72.1)4.8

HR=0.35 (95% CI, 0.25-0.49)P<0.00001

Olaparib 400 mg bidPlacebo

Randomized treatment:Pr

opor

tion

of P

atie

nts

Prog

ress

ion

Free

Study 19: Progression-Free Survival

Ledermann et al, 2011.

Study 19: Common Adverse Eventsa

Placebo(n=128)

aAdverse events graded according to maximum CTCAE version 3.0 grade, experienced by >15% of patients in either treatment group.Ledermann et al, 2011.

Adverse eventAny eventNauseaFatigueVomitingDiarrheaHeadacheDecreased appetiteAbdominal painAnemiaDyspepsia

Grade 1/261664229211818161216

Olaparib 400 mg bid(n=136)

Grade 3/435272200250

Grade 1/2703534132011132349

Grade 3/420031210310

Percentage of Patients

Study 19: PFS by BRCAm Status

82% reduction in risk of disease progression or death with olaparib



0

1.0

Prop

ortio

n of

Pat

ient

s Pr

ogre

ssio

n Fr

ee

3 6 9 12 15

0.90.80.70.60.50.40.30.20.1

Olaparib BRCAmPlacebo BRCAm

Number at RiskOlaparib BRCAmPlacebo BRCAm

74 59 33 14 4 062 35 13 2 0 0

BRCAm (n=136)Olaparib Placebo

Events : total pts (%)

26:74 (35.1)

46:62 (74.2)

Median PFS, months

11.2 4.3

HR=0.1895% CI (0.11-0.31);

P<0.00001

Study 19: PFS by BRCAm Status


0

1.0

Prop

ortio

n of

Pat

ient

s Pr

ogre

ssio

n Fr

ee

3 6 9 12 15

Olaparib BRCAm

Olaparib BRCAwt

0.90.80.70.60.50.40.30.20.1

BRCAm (n=136) BRCAwt (n=118)Olaparib Placebo Olaparib Placebo

Events : total pts (%)

26:74 (35.1)

46:62 (74.2)

32:57 (56.1)

44:61 (72.1)

Median PFS, months

11.2 4.3 5.6 5.5

HR=0.1895% CI (0.11-0.31);

P<0.00001

HR=0.5395% CI (0.33-0.84);

P=0.007

Placebo BRCAm

Placebo BRCAwt

Number at RiskOlaparib BRCAm

Olaparib BRCAwtPlacebo BRCAm

Placebo BRCAwt

74 59 33 14 4 0

57 44 17 9 2 062 35 13 2 0 0

61 35 10 4 1 0

BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance)


Study 19: OS in BRCAm Patients

OS in BRCAwt patients: HR=0.98; 95% CI, 0.62-1.55; P=0.946- Median OS: olaparib, 24.5 months; placebo, 26.2 months

14/62 (22.6%) placebo patients switched to a PARP inhibitor


048

1.0

Prop

ortio

n of

Pat

ient

s Aliv

e

3 6 9 12 15 18 21 24 27 30 33 36 39 42 45Number at Risk

62 62 58 52 50 46 39 36 33 29 29 27 21 12 4Placebo BRCAm74 71 69 67 65 62 57 54 50 48 39 36 26 12 7Olaparib BRCAm

Randomized treatment

Placebo BRCAmOlaparib BCRAm

0.90.80.70.60.50.40.30.20.1

BRCAm (n=136)Olaparib Placebo

Deaths : total pts (%) 37:74 (50.0) 34:62 (54.8)Median OS, months 34.9 31.9

HR=0.7495% CI (0.46-1.19)

P=0.208


Olaparib: Study 1 Design

Phase II, Single-Arm, Multicenter Trial

Kaufman et al, 2015; Lynparza™ prescribing information, 2014.

400 mg olaparib twice daily

Treatment until progression

137 patientswith measurable, gBRCA mutation–

associated ovarian cancer

treated with ≥3 prior lines of chemotherapy

Objective response rate and duration of

response

assessed according to RECIST v1.1

Study 1: Patient Demographics

Baseline Patient Characteristics (N=137)

ECOG = Eastern Cooperative Oncology Group.Kaufman et al, 2015; Lynparza™ prescribing information, 2014.

CharacteristicMedian age, years (range) 58 (35-79)

<50 19%≥50 to <65 61%≥65 20%

RaceWhite/Caucasian 94%Black/African American 1%Asian 4%Other 1%

ECOG performance status0 56%1 38%2 6%Missing 1%

CharacteristicBRCA status

BRCA1 77%BRCA2 22%Both 1%

Platinum sensitivityPlatinum-sensitive 28%Platinum-resistant 56%Platinum-refractory 10%Unknown 6%

Prior chemotherapy regimens3 prior regimens 30%4 prior regimens 19%5 prior regimens 18%6-14 prior regimens 34%

Study 1: Treatment Outcomes

Efficacy results Response rate

– Overall response 34%– Partial response 32%– Complete response 2%

Response duration– Median 7.9 months– 95% CI: 5.6-9.6 months

Kaufman et al, 2015; Lynparza™ prescribing information, 2014.

Study 1: Response by Platinum Sensitivity

(N=137)

Domchek et al, 2016.

Platinum Sensitivity Status Patients Responders Response Rate (95% CI)

Platinum-sensitive 38 17 45% (29%, 62%)

Platinum-resistant 77 22 29% (19%, 40%)

Platinum-refractory 14 2 14% (2%, 43%)

Unknown 8 5 63% (24%, 91%)

TOTAL 137 46 34% (26%, 42%)

Study 1: Adverse Eventsa

Grades 1-4, % Grades 3-4, %Fatigue/asthenia 66 8Anemia 34 18

Abdominal pain/discomfort 43 8Decreased appetite 22 1Nausea 64 3Vomiting 43 4Diarrhea 31 1Dyspepsia 25 0

Nasopharyngitis/URI 26 0Arthralgia/musculoskeletal pain 21 0Myalgia 22 0

aData on adverse effects derived from pooled analysis of Study 1 plus 5 other trials (2 phase I and 3 phase II) for a total of 223 patients.Lynparza ™ prescribing information, 2014.

Grades 1-4, % Grades 3-4, %Decrease in hemoglobin 90 15Decrease in absolute neutrophils 25 7Decrease in platelets 30 3Decrease in lymphocytes 56 17Increase in creatinine 30 2

Study 1: Laboratory Abnormalitiesa

aData on laboratory abnormalities derived from pooled analysis of Study 1 plus 5 other trials (2 phase I and 3 phase II) for a total of 223 patients.Lynparza ™ prescribing information, 2014.

FDA Approval

Olaparib FDA Indication

Deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer

– BRACAnalysis CDx (Myriad Genetics) Three or more prior lines of chemotherapy Recommended dose is 400 mg orally

twice daily

Lynparza™ prescribing information, 2014.

Disconnect Between the EMA and FDARegarding Indications for Olaparib EMA: Platinum-sensitive maintenance

BRCA germline and somatic mutation FDA: 4th line and beyond with measurable

disease BRCA germline mutation Myriad companion diagnostic (BRACAnalysis

CDx)

Niraparib: Topline NOVA Results

Tesaro, Inc, 2016; Ledermann et al, 2012.

Study 19Population (N=136) gBRCAm

PFS with olaparib 11.2 moPFS with PBO 4.1 moHR 0.17P value <0.00001

Population (N=541) gBRCAm (n=194) Overall non-gBRCAm (n=347)

HRD+ (including sBRCA)

PFS with niraparib 21.0 mo 9.3 mo 12.9 moPFS with PBO 5.5 mo 3.9 mo 3.8 moHR 0.27 0.45 0.38P value <0.0001 <0.0001 <0.0001

NOVA: Safety and Tolerability

Mirza at al, 2016.

Grade 3/4 AEs (%) Niraparib (NOVA) Olaparib (Study 19)Thrombocytopenia 28.3% 1.4%Anemia 24.8% 6.8%Neutropenia 11.2% 4.1%

Discontinuation rates: 14.7% 8.1%

Genetic Testing Guidelines and Recommendations

NCCN, 2016a; Lu et al, 2014; SGO 2014.

Hereditary ovarian cancer testing criteria• Personal history of epithelial ovarian cancer

NCCN Guidelines (2016)

Cancers for which genetic counseling and testing should be considered, even in absence of family history: • Epithelial ovarian, fallopian tube, or primary peritoneal cancer

(most commonly, high-grade serous histology)

ASCO Expert Statement

The Society of Gynecologic Oncology encourages the medical community to offer genetic counseling and testing to all women with ovarian, fallopian tube and peritoneal carcinoma.

SGO Clinical Practice Statement October 2014

Screening on the Basis of Family History or Age May Miss a Significant Percentage of Patients

With a BRCA1/2 Mutation

Norquist et al, 2013; Song et al, 2014; Alsop et al, 2012; NCCN, 2016a; Lu et al, 2014.

Test all patients diagnosed with epithelial ovarian cancer for a BRCA1/2 mutation

Of women with BRCA-mutated ovarian cancer:

32%

39%29%

50-59 >60 <50

71%50 OR OLDER AT

DIAGNOSIS

47%53%

No relevant family historyRelevant family history

UP TO

47%HAVE NO RELEVANT

FAMILY HISTORY

Proposed New Multiplex Classification System for Patients With Recurrent Ovarian

Cancer


Pujade-Lauraine, 2002.

0 0

Recurrent Ovarian Cancer: Effect of Platinum-Free Interval on Survival

Refractory Partial Response 3-12 months 12-18 months 18+ monthsPFS (d) 90 176 174 275 339OS (d) 217 375 375 657 957Response (%) 9 24 35 52 62

Days

1000900800700600500400300200100

Percentage

100908070605040302010

Recurrence After First-Line Chemotherapy

Platinum-Sensitive

>6 Months

ChemotherapyDoublet ±

Bevacizumab

Platinum- Refractory/Resistant

<6 Months

NonplatinumSingle Agent ± Bevacizumab

The Traditional Treatment Paradigm

NCCN, 2016.

Proposed New Multiplex Classification System For Patients With Recurrent Ovarian

Cancer


Foley et al, 2013; Armstrong, 2002; Markman & Bookman, 2000; Salzberg et al, 2005.

Duration of response to

initial platinum therapy

Previous agents used

Toxicities experienced in first-line

setting

Patient’s performance

status

Patient and physician preference Choice of

second-line

therapy

Olaparib FDA Indication

Deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer BRACAnalysis CDx (Myriad Genetics)

Three or more prior lines of chemotherapy Recommended dose is 400 mg orally

twice daily

FDA, 2014; Lynparza™ prescribing information, 2014.

Single-Agent Bevacizumab in Ovarian Cancer

Burger et al, 2007; Cannistra et al, 2007; Smerdel et al, 2010.

nPrior

Regimens

Platinum- Sensitive

Platinum-

Resistant Study TherapyORR (%)

Median PFS (mo)

Median OS (mo)

Burger 2007 62 ≤2 Bevacizumab 21 4.7 17

Cannistra 2007 44 2-3 Bevacizumab 16 4.4 10.7

Smerdel 2009 38 Median 5 Bevacizumab 30 5.9 8.6Increased risk of GI perforation with more lines of therapy = 11%.

Angiogenesis as a Target: OvarianStudy Agent Target HR-PFS

(95% CI)HR-OS

(95% CI)GOG 218 Bevacizuma

b

VEGF Ligand - Antibody

0.72 (0.63-0.82) 0.89 (0.75-1.04)

ICON7 Bevacizumab

0.81 (0.70-0.94) 0.99 (0.85-1.14)

AURELIA Bevacizumab

0.48 (0.38-0.60) 0.85 (0.66-1.08)

OCEANS Bevacizumab

0.53 (0.41-0.70) 0.96 (0.76-1.21)

GOG0213 Bevacizumab

0.61 (0.52-0.72) 0.83 (0.68-1.005)

AGO-OVAR12 Nintedanib VEGFR, FGFR,

PDGFR

0.84 (0.72-0.98) NR

AGO-OVAR16 Pazopanib 0.77 (0.64-

0.91) 0.99 (0.75-1.32)

ICON6 Cediranib VEGFR 0.57 (0.44-0.74) 0.70 (0.51-0.99)

TRINOVA-1 Trebananib Ang ligand 0.66 (0.57-0.77) 0.86 (0.69-1.08)

Burger et al, 2011; Perren et al, 2011; du Bois et al, 2013; du Bois et al, 2013; Pujade-Lauraine et al, 2012; Aghajanian et al, 2012; Ledermann et al, 2013; Coleman et al, 2015.

AURELIA Study Design

Stratification variables: - Chemotherapy regimen- Previous antiangiogenic

therapy- PFI <3 vs 3-6 months

Chemotherapy to progression

Chemotherapy to progression

Arm

A

Arm B

Bevacizumab 10 mg/kg q2wa to progression

Platinum-resistant

OC, PP, FTC, (PFI <6 months)

Prior bevacizumab

allowed n=331

Primary end point: PFS

Secondary end points:ORR, PFIbio, OS, QOL, safety

Chemotherapy options (physician’s choice):- Weekly paclitaxel 80 mg/m2

- Topotecan (4 mg/m2 D 1, 8, 15 OR 1.25 mg/m2 D 1–5 q3w)

- Pegylated liposomal doxorubicin 40 mg/m2

D 1 q4wa15 mg/kg q3w if combined with topotecan q3w.PP = primary peritoneal; FTC = fallopian tube cancer; SOC = standard of care; PFI = platinum-free interval.Pujade-Lauraine et al, 2012.

PROGRESSION

Physician’s choice: SOC or bevacizumab 15 mg/kg q3w

SOC

2nd and 3rd line

AURELIA: Demographics and Baseline Characteristics

Patient Characteristics ITT Population(N=361)

AgeMedian age, yearsRange, years≥65 years<65 years

6125-8437%63%

ECOG Performance Status

012

59%34%7%

Baseline characteristics

Measurable disease at baselineBaseline CA-125 levels ≥2 x ULNAscites at baseline

79%87%31%

Platinum-free interval PFI of 3-6 monthsPFI of <3 months

73%27%

ULN = upper limit of normal; ITT = intent to treat.Avastin® prescribing information, 2015.

AURELIA: Progression-Free Survival

Median duration of follow-up: 13.9 months (CT arm) vs 13.0 months (BEV + CT arm)

CT (n=182)

BEV + CT (n=179)

Events, n (%) 166 (91%) 135 (75%)Median PFS, months (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)

<0.001

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

Pro

babi

lity

0 6 12 18 24 30Time (months)

182 37 8 1 0179 88 18 1 0

CTBEV + CT

No. at Risk: 93140

2049

14

01

3.4 6.7

Bev = bevacizumab.Pujade-Lauraine et al, 2012.

AURELIA Intent-to-Treat Population:Summary of Efficacy Outcomes

Primary End Point:Median

PFS

Secondary End Point:Median

Overall Survival

6.8(n=179)

16.6(n=179)

3.4(n=182)

13.3(n=182)

Mon

ths

Mon

ths

HR=0.38(95% CI, 0.30-0.49)

P<0.0001

HR=0.89(95% CI, 0.69-1.14)

Bevacizumab + Chemotherapya vs Chemotherapy AloneSecondary End Point:

Objective Response Rate

28%(n=142)

13%(n=144)

Perc

enta

ge

(95% CI, 21-36)

(95% CI, 7-18)

aChemotherapy consisted of paclitaxel, topotecan, or pegylated liposomal doxorubicin.Avastin® prescribing information, 2015.

9.6(n=60)

6.2(n=57) 5.1

(n=62)3.9(n=55)

2.1(n=63)

3.5(n=64)

Bev + Chemo-therapy

Chemotherapy Alone

Bev + Paclitaxel Cohort

Bev + Topotecan Cohort

Bev + PLD Cohort

HR=0.47(95% CI, 0.31-0.72)

HR=0.24(95% CI, 0.15-0.38)

HR=0.47(95% CI, 0.32-0.71)

• Cohort analysis was based on a prespecified end point (PFS). This analysis was not designed to evaluate statistical significance between treatment arms or compare among the three chemotherapy cohorts

Avastin® prescribing information, 2015.

AURELIA: Summary of Median PFS Outcomes

in Chemotherapy CohortsM

onth

s Mon

ths M

onth

s

Median Progression-Free Survival

53%(n=60)

17%(n=57)

16%(n=62)

30%(n=55)

2%(n=63)

8%(n=64)

Bev + Chemo-therapyChemotherapy Alone

Bev + Paclitaxel Cohort

Bev + Topotecan Cohort

Bev + PLD Cohort

95% Confidence Intervals:

• Cohort analysis was based on a non-prespecified end point (ORR). This analysis was not designed to evaluate statistical significance between treatment arms or compare among the three chemotherapy cohorts

Avastin® prescribing information, 2015.

AURELIA: Summary of ORR Outcomes in Chemotherapy Cohorts

Perc

enta

ge

Perc

enta

ge

Perc

enta

ge

Objective Response Rate

39-68% 17-44% 6-28% 0-6% 6-26% 0-15%

AURELIA: Grade 3/4 Adverse Events

There were no grade 5 events occurring at a higher incidence ( ≥2%) in patients receiving bevacizumab plus chemotherapy compared to patients receiving chemotherapy alone

Patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded in this study

Occurring at a Higher Incidence (≥2%) in the Bevacizumab + Chemotherapya Arm vs the Chemotherapy Alone Arm


Grade 3/4 Adverse Events

Bevacizumab + Chemotherapy

(n=179)Chemotherapy Alone

(n=181)

Hypertension 6.7% 1.1%Palmar-plantar erythrodysaesthesia 4.5% 1.7%

AURELIA: Grade 2 to 4 Adverse EventsOccurring at a Higher Incidence (≥5%) in the

Bevacizumab + Chemotherapya Arm vs the Chemotherapy Alone Arm

Grade 2-4 Adverse EventsBevacizumab + Chemotherapy

(n=179)Chemotherapy Alone (n=181)

Blood and lymphatic system disordersNeutropenia 30.7% 25.4%

General disorders and administration site conditionsMucosal inflammation 12.8% 5.5%

Infections and infestationsInfection 10.6% 4.4%

Nervous system disordersPeripheral sensory neuropathy 17.9% 7.2%

Renal and urinary disordersProteinuria 12.3% 0.6%

Respiratory, thoracic and mediastinal disordersEpistaxis 5.0% 0.0%

Skin and subcutaneous tissue disordersPalmar-plantar erythrodysaesthesia syndrome 10.6% 5.0%

Vascular disordersHypertension 19.0% 5.5%


FDA Approval

FDA, 2014.

OCEANS Study Design

Stratification variables: • Time to recurrence• Cytoreductive surgery

Gemcitabine 1,000 mg/m2 D 1/8

Carboplatin AUC 4

Carboplatin AUC 4

Gemcitabine 1,000 mg/m2 D 1/8

Arm

A

Arm B

Placebo to progression

Bevacizumab 15 mg/kg to progression

Platinum-sensitive, recurrent

OC, PP, FTC

No prior bevacizumab

N=480

Primary end point: PFS

Secondary end points:ORR, OS, DR, safety

Exploratory end points:IRC, CA 125 response, ascites

IRC present

Aghajanian et al, 2011.

242 177 45 11 3 0CG + PL

OCEANS: Primary Analysis of PFSCG + PL(n=242)

CG + BV(n=242)

Events, n (%) 187 (77) 151 (62)Median PFS, months (95% CI)

8.4(8.3–9.7)

12.4(11.4–12.7)

Stratified analysis HR (95% CI)Log-rank p-value

0.484 (0.388–0.605)

<0.0001

MonthsNo. at risk

242 203 92 33 11 0CG + BV

1.0

0.8

0.6

0.4

0.2

0Prop

ortio

n Pr

ogre

ssio

n Fr

ee

0 6 12 18 24 30

Carbo

Carbo/Gem

CG = carboplatin/gemcitabine.Aghajanian et al, 2011; Pfisterer et al, 2006.

Pts at Risk

The “OS” Creep….

Pfisterer et al, 2006; Aghajanian et al, 2012.

17.3 mo18.0 mo

OS (median)

GC+P33.7 mo33.4 mo GC+Bev

A Phase III Randomized Controlled Clinical Trial of Carboplatin and Paclitaxel Alone or in Combination With Bevacizumab Followed by Bevacizumab and Secondary Cytoreductive Surgery in Platinum-Sensitive, Recurrent Ovarian, Peritoneal Primary and Fallopian Tube Cancer

(Gynecologic Oncology Group 213)

RL Coleman, MF Brady, TJ Herzog, P Sabbatini, DK Armstrong, JL Walker, BG Kim, K Fujiwara, KS Tewari, DM O'Malley, S Davidson

2015 Annual Meeting on Women’s Cancer: Chicago 2015(Society of Gynecologic Oncology)

GOG 213 Schema

Coleman et al, 2015.

GOG 213: Demographics (N=674)

Asian Black/AA

Amer Indian

Pacific Island

White Other0

50

100

150

200

250

300Race (PC)Race (PC + B)

<40 40-49 50-59 60-69 70-79 ≥800

20

40

60

80

100

120

140Age (PC)Age (PC + B)

Years

N

PC = paclitaxel/carboplatin.Coleman et al, 2015.

GOG 213: Histologies (N=674)

Adeno NS2%

Clear Cel

l4%

Endometrioid7%

Mucinous1%

Serous81%

Other6%

Histology (PC)Adeno NS1%Clear Cel

l3%Endometrioid6%

Mucinous1%

Serous81%

Other8%

Histology (PC + B)


GOG 213: Demographics (N=674)

aDeclared on enrollment onto the study.Coleman et al, 2015.

Characteristic

PC(n=337)

PC + B(n=337)

Total(n=674)

Prior BevacizumabYes 33 (10%) 34 (10%) 67 (10%)No 303 (90%) 303 (90%) 606 (90%)Unspecified 1 (0.3%) 0 1 (0.1%)

Cytoreductive SurgeryRandomized, no surgeryRandomized, surgery

27 (8%)27 (8%)

27 (8%)26 (8%)

54 (8%)53 (8%)

Not randomly assigned 283 (84%) 284 (84%) 567 (84%)Prior Platinum-Free Intervala

6-12 months 105 (31%) 105 (31%) 210 (31%)>12 months 232 (69%) 232 (69%) 464 (69%)

Measurable diseaseNo 50 (15%) 63(19%) 113 (17%)Yes 287 (85%) 274 (81%) 561 (83%)

GOG 213: Progression-Free Survival


HRadj=0.61 (0.52-0.72), P<0.0001

GOG 213: Overall Survival


HRadj=0.829 (0.683-1.005), P=0.056

Stratification Variables: Overall Survival


Objective 2

PFI

N=107 (16%)N=567 (84%)

N=181 (27%)N=493 (73%)

Stratification Variables:Overall Survival (cont.)


Prior BevN=67 (10%)N=606 (90%)

GOG 213 Treatment Outcomes: Response


CR PR SD Inc Disease NE ORR0

20

40

60

80

100

17.7

40.8

28.8

3.59.2

58.5

31.7

47

15.7

0.45.2

78.7PC PC+B N=509 (RECIST)

Perc

ent (

%)

P<0.0001

FDA Approval

NCCN Guideline Recommendations for Bevacizumab

Bevacizumab in combination with weekly paclitaxel, liposomal doxorubicin, or topotecan are NCCN category 2A recommendations for platinum-resistant ovarian cancer In patients who have not previously received bevacizumab Contraindicated for patients at increased risk of gastrointestinal perforation

NCCN, 2016b.

Category 2A

Category 2A

Bevacizumab + paclitaxel (weekly)

Bevacizumab + liposomal doxorubicin

Category 2A Bevacizumab + topotecan

NCCN Ovarian Cancer Guidelines Preferred Combinations for Platinum-Resistant Ovarian Cancer

Disconnect Between the EMA and FDA:Indications for Bevacizumab

EMA

Frontline + maintenance

Platinum-resistant recurrent

Platinum-sensitive recurrent

FDA

Frontline + maintenance

Platinum-resistant recurrent

Platinum-sensitive recurrent

Avastin® prescribing information, 2015; EMA, 2015.

ConclusionsRecurrent ovarian cancer treatment must be

personalized!


Clinical trials with relevant endpoints have led to recent drug approvals in ovarian cancer Drug approval by EMA and FDA differs, although PFS is an

established metric After approval uptake driven by guidelines (country,

ESMO, NCCN, value) Accelerated approval is the fastest and most efficient

path to FDA approval Biomarker enrichment enhances success

Individualization and moving beyond the classical “sensitive” and “resistant” paradigm key to improving patient care

Key Takeaways

Case Study 1

57-year-old G2 P2 underwent debulking surgery for stage IIIC high-grade serous ovarian cancer, BRCA1 deleterious germline mutation carrier in 2014 Hypertension controlled with amlodipine

Six cycles of IV carboplatin/paclitaxel every 3 weeks June to December 2015 Complete response, grade 1 neuropathy

Complete response to 6 cycles carboplatin/pegylated liposomal doxorubicin January to May 2016 Platinum-free interval 18 months, grade 1 hand foot syndrome

August 2016: Ascites, bloating, elevated CA125 Platinum-free interval 3 months

Third-Line Ovarian Cancer

Case Study 1 (cont.)

Which treatment options do you recommend?

Chemotherapy:a. Weekly paclitaxelb. Topotecanc. Gemcitabined. Other

Bevacizumab?e. Yesf. No

Third-Line Ovarian Cancer

Case Study 2

Patient has a partial response to weekly paclitaxel and bevacizumab lasting 7 months with resolution of symptoms and then begins to slowly progress. Experiences grade 2 anemia and grade 1 neuropathyYou recommend:

a. Olaparibb. Topotecanc. Gemcitabined. Other

Fourth-Line Ovarian Cancer

Case Study 2 (cont.)

Which type of supportive care would be appropriate for a patient receiving olaparib?a. Proton pump inhibitor or other antacidb. Lomotil or other antidiarrhealc. Ondansatron or other 5-HT3 antagonistd. All of the above

Fourth-Line Ovarian Cancer

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management of recurrent ovarian cancer: insights, limitations, and future directions

Education