Targeted Therapy In Ovarian Cancer

Atlal Abusanad, MD, MSc, CIP, FRCPC

No Disclosure

Outline

• Anti-angiogenic agents

– VEGF MoAb

• First line setting

• Recurrent setting

– TKIs of VEGF Receptors

– Other AAA (e.g. vascular disrupting agents)

• PARP inhibitors

• EGFR/HER2 inhibitors

Mechanisms of tumor neovascularization

Spannuth WA et al. (2008) Angiogenesis as a strategic target for ovarian cancer therapy Nat Clin Pract Oncol doi:10.1038/ncponc1051

Anti-VEGF/VEGFR in ovarian cancer: The rational

• VEGF receptor(s) and VEGF ligand(s) are both over-expressed in ovarian cancer

• VEGF pathways are strongly associated with the development of malignant ascites, malignant pleural effusions, and carcinomatosis

• VEGF pathway over-expression is a negative prognostic factor in ovarian cancer

Beva-ci-zu-mab

Bevacizumab Early Phase Trials

*Burger RA, et al. J Clin Oncol 2007; 25: 5165–5171; **Garcia AA, et al. J Clin Oncol 2008; 26: 76–82, ***Cannistra SA, et al. J Clin Oncol 2007; 25: 5180–5186

First line setting : GOG218

• Stratification variables

– GOG performance status

– stage/debulking status Bevacizumab 15mg/kg q3w

15 months

Paclitaxel (P) 175mg/m2

Carboplatin (C) AUC6

Carboplatin (C) AUC6

Paclitaxel (P) 175mg/m2

Carboplatin (C) AUC6

Paclitaxel (P) 175mg/m2

Placebo q3w

Placebo q3w

Front-line: epithelial OV, PP or FT cancer ● Stage III optimal (macroscopic) ● Stage III suboptimal ● Stage IV

N=1,873

I

II

III

Arm

1:1:1

Burger, et al. NEJM 2011 (Supplementary information) OV = ovarian; PP = primary peritoneal FT = fallopian tube; Bev = bevacizumab

Bev 15mg/kg

R

A

N

D

O

M

I

S

E

GOG-0218: significantly increased PFS with continued bevacizumab compared with

standard chemotherapy

I

CP + Pl

→ Pl

(n=625)

Median PFS (months) 10.6

Stratified analysis HR

(95% CI)

p value one-sided (log rank)

II

CP + B15

→ Pl

(n=625)

11.6

0.89

(0.78–1.02)

0.0437a

III

CP + B15

→ B15

(n=623)

14.7

0.70

(0.61–0.81)

<0.0001a

*p value boundary = 0.0116 Data cut-off date: 25 February 2010

0 6 12 18 24 30 36 42 48 Time (months)

1.0

0.8

0.6

0.4

0.2

0

PFS

est

imat

e

CP + B15 → Pl CP + Pl → Pl

CP + B15 B15

Data cut-off date: 26 August 2011 SmPC.

CP + Pl → Pl 625 595 558 506 447 322 202 117 55 27 13 1 -

CP + B15 → Pl 625 598 561 487 442 303 191 109 54 28 11 1 -

CP + B15 → B15 623 588 561 519 462 321 202 115 62 26 9 0 -

GOG-0218: final OS Kaplan-Meier curves (ITT)

CP + Pl

→ Pl

(n=625)

CP + B15

→ Pl

(n=625)

CP + B15

→ B15 (n=623)

Deaths, n (%) 299

(47.8%) 309

(49.4%) 270

(43.3%)

Median, months 40.6 38.8 43.8

Stratified OS HR* (95% CI) 1.07

(0.91–1.25) 0.88

(0.75-1.04)

Stratified 1-sided log-rank p value 0.2197 0.0641

Overall survival (months)

0 6 66 72

1.0

0.8

0.6

0.4

Pro

po

rtio

n s

urv

ivin

g

12 18 24 30 36 42 48 54 60

0.2

0.0

*Relative to CPP

QoL conclusions

• Bevacizumab-containing therapy produced statistically significant QOL disruption during chemotherapy

– this difference was small and below the MID

• QOL was not adversely or favourably affected by prolonged bevacizumab delivery

• Relative to placebo, adding bevacizumab does not appear to improve or impair QOL

Adverse event (grade when limited), n (%)

Arm I CP + Pl → Pl

(n=601)

Arm II

CP + B15 → Pl

(n=607)

Arm III

CP + B15 → B15

(n=608)

Gastrointestinal events* (grade ≥2) 7 (1.2) 17 (2.8) 16 (2.6)

Hypertension (grade ≥2) 43 (7.2)‡

100 (16.5)‡

139 (22.9)‡

Proteinuria (grade ≥3) 4 (0.7) 4 (0.7) 10 (1.6)

Pain (grade ≥2) 250 (41.7)‡

252 (41.5)‡

286 (47.1)‡

Neutropenia (grade ≥4) 347 (57.7) 384 (63.3) 385 (63.3)

Febrile neutropenia 21 (3.5) 30 (4.9) 26 (4.3)

Venous thromboembolism 35 (5.8) 32 (5.3) 41 (6.7)

Arterial thromboembolism 5 (0.8) 4 (0.7) 4 (0.7)

Wound disruption 17 (2.8) 22 (3.6) 18 (3.0)

CNS bleeding 0 0 2 (0.3)

Non-CNS bleeding (grade ≥3) 5 (0.8) 8 (1.3) 13 (2.1)

RPLS 0 1 (0.2) 1 (0.2)

*Perforation/fistula/necrosis/leak ‡p<0.05; RPLS = reversible posterior leucoencephalopathy syndrome

GOG-0218: adverse events consistent with those previously reported with bevacizumab

NEJM data

Burger, et al. NEJM 2011

First line setting : ICON7 Schema

Stratification variables:

• Stage and extent of debulking (I–III  debulked  ≤1 cm vs I–III debulked >1 cm vs IV and

inoperable stage III)

• Timing of intended treatment start (≤4  vs >4 weeks after surgery)

• GCIG group

Paclitaxel 175 mg/m2

Carboplatin AUC 5 or 6

Carboplatin AUC 5 or 6

Paclitaxel 175 mg/m2

18 cycles (12 months)

R

Bevacizumab 7.5 mg/kg q3w

1:1

AUC = area under the curve; OC = epithelial ovarian, primary peritoneal or fallopian tube cancer

n=1528 Dec 2006 to Feb 2009

• FIGO stage I–IIA

(clear cell or grade 3)

or FIGO stage IIB–IV

• Surgically debulked

histologically

confirmed OC

4

Perren, et al. NEJM 2011

ICON7: Primary PFS analysis (2010)

Primary PFS

analysis (2010)

7

100

75

50

25

0

Alive

with

ou

t pro

gre

ssio

n (

%)

Time (months)

0 3 6 9 12 15 18 21 24 27 30

17.3 19.0

HR = 0.81 (95% CI 0.70–0.94)

p=0.0041 10.5 15.9

Time (months)

100

75

50

25

0

Alive w

ith

ou

t p

rogre

ssio

n (

%)

0 3 6 9 12 15 18 21 24 27 30

Perren TJ, et al. N Engl J Med 2011

Control Research

All patients High risk

Number at risk

Control 764 484 294 239 198 66

Research 764 604 314 226 182 54

1.00

0.75

0.50

0.25

0

Pro

po

rtio

n a

live

w

itho

ut p

ro

gressio

n

Time (months)

0 6 12 18 24 30 36 42 48 54 60

PFS (2013 update)

Control Research ∆

Events, n (%) 526 (69) 554 (73) Restricted mean, months

27.7 29.2 +1.6

Median, months 17.5 19.9 +2.4

Log-rank test p=0.25

HR (95% CI) 0.93 (0.83–1.05)

Non-proportionality test: p<0.0001

BEV exposure 19.9 17.5

8

CT scans as clinically indicated

Number at risk

Control 254 109 43 24 18 6

Research 248 175 53 32 23 5

1.00

0.75

0.50

0.25

0

Pro

po

rtio

n alive w

ith

out p

ro

gre

ssio

n

Time (months)

0 6 12 18 24 30 36 42 48 54 60

PFS (2013 update):

High risk (n=502)

Control Research ∆

Events 228 223

Restricted mean, months

15.9 20.0 +4.1

Median, months 10.5 16.0 +5.5

Log-rank test p=0.001

HR (95% CI) 0.73 (0.61–0.88)

Non-proportionality test: p<0.0001

16.0 10.5

13

Stage III suboptimally debulked, any stage IV or no debulking surgery

BEV exposure

PFS (2013 update) PFS (2013 update): High risk (n=502)

Final OS by risk groups

6.2

2.5 2.1 1.3 0.4

11.6

4.1 1.5

0.40

29.1

2.0

9.2

25.9

4.4 5.0

1.71.3

39.6

6.7

3.6

0.4 0

28.3

2.8

12.5

ICON7: adverse events (all grades) consistent with those previously reported with bevacizumab

ATE = arterial thromboembolism; CHF = congestive heart failure RPLS = reversible posterior leucoencephalopathy syndrome VTE = venous thromboembolism

CP (n=753)

CP + B7.5 B7.5 (n=745)

Pati

ents

(%

)

40

30

20

10

0

Perren, et al. ESMO 2010

RECURRENT PLATINUM SENSITIVE OVARIAN CANCER

OCEANS: study schema

Stratification variables:

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

•Cytoreductive surgery for recurrent disease (yes vs no)

Placebo q3w until progression

Bevacizumab 15mg/kg q3w until progression

Platinum-sensitive recurrent epithelial

ovarian, primary peritoneal or fallopian

tube cancer

• Measurable disease • ECOG 0/1 • No prior chemotherapy

for recurrent ovarian cancer

• No prior Bev (n=484)

CG + Pl

CG for 6 (up to 10) cycles

G 1000 mg/m2, d1 & 8

C AUC 4

C AUC 4

G 1000 mg/m2, d1 & 8

CG + Bev

AUC=area under the curve; Bev=bevacizumab; C=carboplatin; ECOG=Eastern Cooperative Group; G=gemcitabine; P=placebo

Aghajanian et al. ASCO 2011

OCEANS: primary analysis of PFS CG + Pl

(n=242)

CG + Bev

(n=242)

Events, n (%) 187 (77.3) 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

Pro

po

rtio

n p

rog

res

sio

n f

ree

242 177 45 11 3 0

242 203 92 33 11 0

CG + Pl

CG + Bev

No. at risk:

1.0

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30

Time (months)

Aghajanian et al. ASCO 2011

100

80

60

40

20

0

OCEANS: objective response

Aghajanian et al. ASCO 2011

Duration of

response

CG + Pl

(n=139)

CG +

Bev

(n=190)

Median,

months

7.4 10.4

HR (95% CI) 0.534

(0.408–0.698)

p<0.0001a

%

78.5

57.4 PR = 61

PR = 48

CR = 17 CR = 9

Difference: 21.1%

p<0.0001

aCompared for descriptive purposes only

CG + Pl

(n=242)

CG + Bev

(n=242)

0 6 12 18 24 30 36 42 48 54 60

Pro

po

rtio

n s

urv

ivin

g

Months

OCEANS: third interim OS

analysisa GC + Pl

(n=242)

GC + Bev

(n=242)

Events, n (%) 142 (58.7) 144 (59.5)

Median OS, months

(95% CI)

33.7

(29.3‒38.7)

33.4

(30.3‒35.8)

HR (95% CI)

Log-rank P value

0.960 (0.760–1.214)

p=0.7360

aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients)

1.0

0.8

0.6

0.4

0.2

0

242 221 159 77 23 0

242 226 171 78 27 0

CG + Pl

CG + Bev

No. at risk:

235

239

190

201

117

127

44

48

7

7

Aghajanian et al. ESMO 2012

OCEANS: AEs of special interest

ATE=arterial thromboembolic event; CHF=congestive heart failure; GI=gastrointestinal;

RPLS=reversible posterior leukoencephalopathy syndrome; VTE=venous thromboembolic event aTwo GI perforations occurred 69 days after last BV dose

Patients, %

CG + Pl (n=233)

CG + Bev (n=247)

ATE, all grades 1 3

VTE, grade ≥3 3 4

CNS bleeding, all grades <1 1

Non-CNS bleeding, grades ≥3 1 6

CHF, grades ≥3 1 1

Neutropenia, grade ≥3 56 58

Febrile neutropenia, grade ≥3 2 2

Hypertension, grade ≥3 <1 17

Fistula/abscess, all grades <1 2

GI perforation, all grades 0 0a

Proteinuria, grade ≥3 1 9

RPLS, all grade 0 1

Wound-healing complication, grades ≥3 0 1

Aghajanian et al. ASCO 2011

PD = progressive disease

aEpithelial ovarian, primary peritoneal, or fallopian tube cancer; bOr 10 mg/kg q2w; c15 mg/kg q3w, permitted on clear evidence of progression

AURELIA Platinum Resistant Ovarian Cancer: trial design

Stratification factors:

• Chemotherapy selected

• Prior anti-angiogenic therapy

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

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

Investigator’s choice

(without BEV)

Optional BEV monotherapyc

BEV 15 mg/kg q3wb + chemotherapy

Chemotherapy

R

1:1

Chemotherapy options (investigator’s choice):

• Paclitaxel 80 mg/m2 days 1, 8, 15, & 22 q4w

• Topotecan 4 mg/m2 days 1, 8, & 15 q4w (or 1.25 mg/m2, days 1–5 q3w)

• PLD 40 mg/m2 day 1 q4w

ASCO 2012

AURELIA: PFS

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

Time (months)

182 37 8 1 0

179 88 18 1 0

CT

BEV + CT

No. at risk:

93

140

20

49

1

4

0

1

3.4 6.7

Pujade-Lauraine, et al. ASCO 2012

Esti

mat

ed

pro

bab

ility

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30

Subgroup No. of

patients

Median PFS, months

HR* BEV + CT

better CT

better CT BEV + CT

All patients 361 3.4 6.7 0.48

Age, years <65

≥65

228

133

3.4

3.5

6.0

7.8

0.49

0.47

PFI, months† <3

3‒6

96

257

2.1

3.6

5.4

7.8

0.53

0.46

Measurable disease, cm No (<1)

Yes (1‒<5)

Yes (≥5)

74

126

161

3.7

3.3

3.3

7.5

7.5

6.0

0.46

0.50

0.47

Ascites Yes

No

113

248

2.5

3.5

5.6

7.6

0.40

0.48

Chemotherapy Paclitaxel

PLD

Topotecan

115

126

120

3.9

3.5

2.1

10.4

5.4

5.8

0.46

0.57

0.32

Subgroup analysis of PFS

*Unadjusted. †Missing n=8

0.2 0.3 0.5 1 2 3 4 5

Pujade-Lauraine, et al. ASCO 2012

OS: ITT population

Data cut-off: 25 January 2013. Median duration of follow-up: 27.4 months in both arms *2-sided log-rank, unadjusted; OS = overall survival

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*

182 130 98 63 29 12 1 0

179 148 106 75 39 13 1 0

0 6 12 18 24 30 36 42

Time (months)

100

75

50

25

0

Ove

rall

surv

ival

(%

)

Witteveen, et al. ECC 2013

Median OS by chemotherapy cohort

Chemotherapy cohort

BEV + CT CT alone HR (95% CI)

BEV + paclitaxel 22.4 months (n=60)

13.2 months (n=55)

0.64 (0.41–1.01)

BEV + topotecan

13.8 months (n=57)

13.3 months (n=63)

1.12 (0.73–1.73)

BEV + PLD 13.7 months (n=62)

14.1 months (n=64)

0.94 (0.63–1.42)

Incidence of paracentesis during study therapy: subgroup of patients with ascites at baseline (31% of study cohort)

Data not shown for cycles with <10 patients in one or both arms

0

2

4

6

8

10

12

14

16

18

20

All cycles Screening 1 2 3 4 5 6

CT (n=54)

BEV + CT (n=59)

Pat

ien

ts (

%)

Cycle number

CT

BEV + CT

No. at risk:

54 54 36 17

59 59 52 37

54

59

48

57

26

44

13

32

Kristensen, et al. IGCS 2012

Grade ≥3 adverse events of special interest, n (%) CT

(n=181) BEV + CT (n=179)

Hypertension 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 0

RPLS 0 1 (0.6)

CHF 1 (0.6) 1 (0.6)

Cardiac disorders (excluding CHF) 0 0

AURELIA: adverse events of special interest

Pujade Laurraine et al. ASCO 2012 RPLS = reversible posterior leukoencephalopathy syndrome CHF = congestive heart failure

Summary : Bevacizumab & Ovarian Ca Cancer Clinical Setting Trial Name Result Impact on practice?

First Line therapy

ICON 7

GOG-0218

PFS improved 3 mo

No OS advantage

No

? High risk patients

Recurrent – platinum sensitive

OCEANS

PFS improved

3 mo

No OS

advantage

No

Recurrent - Platinum resistant

AURELIA

PFS improved

3 mo

OS is not statistically significant

palliative benefit and PFS in a challenging group

? Trend toward improved OS in a subgroup

VEGFR TKI

• AGO-OVAR16

Incorporation of Pazopanib in

Maintenance Therapy of Ovarian Cancer

PARP Inhibitors

Randomized, open-label, Phase II study in patients with

platinum-sensitive, advanced serous ovarian cancer

Patients with:

• Platinum-sensitive

advanced ovarian

cancer

• A serous histology

or serous

component

• Measurable disease

• 3 previous

platinum-containing

regimens

• Progression free for

6 months following

completion of last

platinum-containing

regimen

Olaparib 200 mg bid*

(d1–10 every 21 days)

+ paclitaxel 175 mg/m2

(iv, d1)

+ carboplatin AUC4

(iv, d1)

Paclitaxel 175 mg/m2

(iv, d1)

+ carboplatin AUC6

(iv d1)

Randomization

(1:1)

All patients

followed for

objective

radiologic

progression

and survival

Maintenance

phase

Olaparib 400 mg bid

continuously

Maintenance

phase

No further study

treatment

Completion of

4–6 x 21-day cycles

of chemotherapy

Arm B Arm A

n=81

n=81

n=66

n=55

Multinational study; 43 sites in 12 countries * Capsule formulation

• Statistically significant PFS improvement (HR 0.35, P<0.00001)

• Interim OS analysis: HR=0.94; 95% CI, 0.63–1.39; P=0.75

Ledermann J et al. N Engl J Med 2012;366:1382–1392

0

0.6

0.8

0.9

0

0.1

0.2

0.3

0.4

0.5

0.7

1.0

3 6 9 12 15 18

Pro

ba

bil

ity o

f

pro

gre

ss

ion

-fre

e s

urv

iva

l

Time from randomization (months)

Hazard ratio 0.35

(95% CI, 0.25–0.49)

P<0.00001

Randomized treatment

Placebo

Olaparib 400 mg bid monotherapy

• Statistically significant PFS improvement (HR 0.35, P<0.00001)

• Interim OS analysis: HR=0.94; 95% CI, 0.63–1.39; P=0.75

Ledermann J et al. N Engl J Med 2012;366:1382–1392

0

0.6

0.8

0.9

0

0.1

0.2

0.3

0.4

0.5

0.7

1.0

3 6 9 12 15 18

Pro

ba

bil

ity o

f

pro

gre

ss

ion

-fre

e s

urv

ival

Time from randomization (months)

Hazard ratio 0.35

(95% CI, 0.25–0.49)

P<0.00001

Randomized treatment

Placebo

Olaparib 400 mg bid monotherapy

Ledermann J et al. N Engl J Med 2012;366:1382–1392

PFS & OS in BRCAm

52

53

Conclusion

• Olaparib 200 mg bid (10 days) + P + C (AUC4) followed by olaparib 400 mg bid maintenance monotherapy resulted in:

• – Significant PFS improvement vs P + C (AUC6) alone in platinum-sensitive relapsed ovarian cancer (HR=0.51) – Median PFS improvement of 2.6 months vs P + C

(AUC6) alone

• Combination phase: both arms had generally similar toxicity profiles

EGFR/HER2 Inhibitors

Rationale: ErbB targeted therapy in

refractory/resistant ovarian cancer

n ErbB+ DRUG ORR SD

Bookman 2003 837 95 Herceptin 7%* 39%

Schilder 2005 27 27 Gefitininb 3% 15%

Gordon 2005 34 34 Erlotinib 6% 44%

Campos 2005 105 82+ CI-1003 0% 34%/26%

Friberg 2006 13 NK Erlot + Bev 15% ° 54%

Seiden 2007 75 37 Matuzumab 0% 8%

Schilder 2007 25 26 Catuximab 0% 8%

Gordon 2007 117 28 Pertuzumab 4% 7%

PRESENTED BY: Ignace Vergote

Targeted Therapy In Ovarian Cancer: Conclusion

• Bevacizumab is the first anti-VEGF agent to show improved PFS and manageable S/E profile in Ovarian Ca.

• VEGFR TKI(s) showed improved outcomes but simultaneous increased toxicity

• Several AAA(s) are in development

• Up to date, No anti-EGFR/HER2 agents showed improved outcomes

Targeted Therapy In Ovarian Cancer: Conclusion

• OS is the gold standard outcome in assessing new agent efficacy, However – Longer F/U periods are required – Large number of patients is required – Post-progression treatments – Crossover

• Alternative endpoints (PFS, QoL, RR or combined) need to be better defined and utilized

• Surrogacy between PFS and OS in Ovarian cancer is to be established

• Better-selection of patients is essential • Better molecular characterization of ovarian cancer is

crucial to direct therapy

“And mankind have not been given of knowledge except a little.”

قليل أوتيتم من العلم إلا وما { {