l’innovazione dei trattamenti nel carcinoma dell’ovaio · l’innovazione dei trattamenti nel...

XVIII Congresso Nazionale Cipomo La Gestione della Complessita’ in

Oncologia Lazise 15-17 Maggio 2014

Complessita’ Clinico Professionali e

l’Innovazione dei Trattamenti nel

Carcinoma dell’Ovaio

Domenica Lorusso Gynecologic Oncologic Unit

National Cancer Institute-Milan

FIGO Annual Report Carcinoma of the Ovary: 5-yr Survival Rates

34

36

38

40

42

44

46

% o

f P

atie

nts

Su

rviv

ing F

ive

Ye

ars

Year of Diagnosis

5-year survival rates

1990-1992 42.5%

1993-1995 43.5%

1996-2003 45%

Carbo = carboplatin; cis = cisplatin; CR = complete response; cyclo = cyclophosphamide; gem = gemcitabine; IP = intraperitoneal; IV = intravenous; pac = paclitaxel; PLD = pegylated liposomal doxorubicin; topo = topotecan

The challenge of going beyond carboplatin/paclitaxel: key trials worldwide

Trial n Regimens compared Outcome

GOG-0162 324 Cis + either 24 h or 96 h pac Efficacy similar

AGO-GINECO 1,282 Carbo/pac vs carbo/pac/epirubicin No benefit of a third agent

MITO-1 273 Carbo/pac x6 topo x4 or surveillance No PFS benefit with topo maintenance

GOG-0172 429 IV cis/IV pac vs IP cis/IP pac IP has better efficacy/worse toxicity and QoL

GCIG 887 Carbo/pac vs carbo/pac/epirubicin No benefit of a third agent

AGO-GINECO 1,308 Carbo/pac topo x4 or surveillance No benefit of topo maintenance

GOG-0178 277 Cis/pac pac x3 vs x12 cycles in patients in CR

PFS improved with pac x12 cycles/no OS difference in a selected patient population

GOG-0182 4,312

Carbo/pac vs carbo/pac/gem (2 regimens) vs carbo/pac/topo vs carbo/pac/PLD

No benefit of a third agent

OV16

819 Carbo/pac x8 vs cis/topo x4 carbo/pac x4

Efficacy similar; tolerability better with carbo/pac

AGO-OVAR9 1,742 Carbo/pac vs carbo/pac/gem No benefit of a third agent

1995

2010

Katsumata et al.(JGOG) Lancet 2009 Dose dense weekly paclitaxel

• Epithelial ovarian cancer FIGO stage II-IV (80% Stage III-IV)

• RT< 1 cm: 45%; Clear Cell 10%

RANDOM

Carboplatino AUC 6

Paclitaxel 180 mg/mq

• 637 patients

Carbo AUC 6 ogni 21

Paclitaxel 80 mg/mq 1, 8, 15

EVERY 21 DAYS

OVARIAN CANCER TREATMENT: PERSPECTIVES

• INDIVIDUALIZE THERAPY

- TOXICITY CRITERIA

- HYSTOTIPE

- GENETIC OR EPIGENETIC MUTATIONS

• CHRONIC DISEASE

- MAINTENANCE THERAPIES

- ARTIFICIAL PROLONGATION OF PLATINUM FREE INTERVAL

A randomized multicentre phase III study comparing weekly vs every 3 weeks carboplatin plus paclitaxel

in patients with advanced ovarian cancer: MITO-7 (Multicentre Italian Trials in Ovarian cancer) – ENGOT-ov-10

(European Network of Gynaecological Oncological Trial Groups) - GCIG (Gynecologic Cancer Intergroup) trial.

Sandro Pignata1,Giovanni Scambia2, Rossella Lauria3, Francesco Raspagliesi4, Pierluigi Benedetti Panici5,

Gennaro Cormio6, Dionyssios Katsaros7, Roberto Sorio8, Giovanna Cavazzini9, Gabriella Ferrandina10,

Enrico Breda11, Viviana Murgia12, Cosimo Sacco13, Nuria Maria Asensio Sierra 14, Carmela Pisano1,

Vanda Salutari2, Beatrice Weber15, Eric Pujade-Lauraine16, Ciro Gallo17, Francesco Perrone1

on behalf of the MITO-7 Investigators

1 National Cancer Institute – “G.Pascale” Foundation, Napoli, Italy; 2 Catholic University of the Sacred Heart, Rome, Italy;

3 Federico II University, Napoli, Italy; 4 Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy; 5 "Sapienza" University of Rome, Rome, Italy; 6 University of Bari, Bari, Italy; 7 S. Anna Hospital, University of Torino, Italy;

8 National Cancer Institute CRO, Aviano (PN), Italy; 9 “C.Poma” Hospital, Mantova, Italy; 10 Catholic University of the Sacred Heart, Campobasso, Italy; 11 Fatebenefratelli Hospital, Rome, Italy; 12 Santa Chiara Hospital, Trento, Italy; 13 University Hospital "S. Maria della Misericordia", Udine, Italy;

14 Arcispedale “S. Maria Nuova” IRCCS, Reggio Emilia, Italy; 15 Centre Alexis Vautrin, Vandoeuvre-les-Nancy, France;

16 Hôpitaux Universitaires Paris-Centre, site Hôtel-Dieu, AP-HP, Université Paris Descartes, Paris, France; 17 Second University of Napoli, Napoli, Italy.

0 6 12 18 24 30 36 42 48

Months

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0.6

0.8

1.0

Pro

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of p

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n-f

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su

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Patients Events

Median PFS

Months (95% CI)

Every 3-week 403 214 16.5 (14.6 – 20.0)

Weekly 405 196 18.8 (17.1 – 22.0)

Log-rank test p = 0.18

Unadjusted HR: 0.88 (0.72 – 1.06)

Analysis: March 2013, median follow-up 19.9 months

Progression-free survival

Patients at risk

Every 3-week 403 354 217 118 72 38 14 1 -

Weekly 405 346 231 124 71 36 20 9 -

Presented by: S.Pignata

0 6 12 18 24 30 36 42 48

Months

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

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of su

rviv

al

Patients Events

Median OS

Months (95% CI)

Every 3-week 403 76 47.9 (47.9 – n.a.)

Weekly 405 89 n.a. (36.3 – n.a.)

Log-rank test p = 0.24

Unadjusted HR: 1.20 (0.88 – 1.63)

Overall survival

Patients at risk

Every 3-week 403 380 303 193 120 75 31 5 2

Weekly 405 372 294 190 123 68 32 10 -


Analysis: March 2013, median follow-up 19.9 months

FA

CT

-O T

OI

mea

n s

core

40

50

60

70

80

90

QoL: FACT-O TOI, first 9 weeks

Week 0 1 2 3 4 5 6 7 8 9

Pts (weekly) 308 266 254 237 239 238 218 212 223 177

Pts (q3w) 301 229 208 250 209 195 221 193 177 169

Weekly

Every 3-week

** ** **

*

*

* p<0.05 vs. baseline

** p<0.001 vs. baseline

In all scales, higher values represent better outcome.

All tests are adjusted by performance status, stage, residual disease after surgery, age category, and size of the institution

Treatment:time interaction p<0.0001


Ovarian cancer not one disease

8704 patients from 7 randomised trials

Mackay et al. Int J Gynecol Cancer 2010 Adenoca: adenocarcinoma

Mutations typically associated with ovarian carcinoma subtypes

High-grade serous ovarian cancer

• TP53: encodes a protein that regulates the cell cycle

• BRCA1 and BRCA2: encode proteins that are involved in genome protection

Low-grade

serous

BRAF; KRAS

Mucinous

carcinoma

KRAS

Endometrioid

carcinoma

PTEN (low grade);

TP53; BRCA1/2

Clear cell

carcinoma

PTEN; PIK3CA;

ARID1A

Other

subtypes

Romero I et al. Endocrinology 2012;153:1593–1602

TP53, tumour protein 53

mEOC

A multicentre randomised factorial trial

comparing oxaliplatin + capecitabine,

bevacizumab and carboplatin + paclitaxel in

patients with previously untreated mucinous

Epithelial Ovarian Cancer (mEOC)

Cancer Research UK & UCL Cancer Trials Centre

mEOC is an intergroup study with two identical protocols from GOG and NCRI with a single analysis

GCIG Study

RA

ND

OM

IZA

TIO

N

TC

Paclitaxel 175 mg/m2 (d1)

Carboplatin AUC 6 (d1)

Every 3 wk x 6

CPT-11/CDDP

CPT-11 60 mg/m2 (d1, 8, 15)

Cisplatin 60 mg/m2 (d1)

Every 4 wk x 6

International Cooperative Phase III Study

for Clear Cell Carcinoma

-Clear Cell Ca

-Stage I~IV

326 patients in each arm, 652 total for 4.25 years

Randomization

2:1

Stratification

Platinum-Free Interval:

≤6 months vs. > 6 months

Prior Systemic Tx:

1-2 vs. >2

MEK162

45mg BID

Patients with Recurrent or Persistent Low-grade Serous

Carcinomas of the Ovary, Fallopian Tube or Primary

Peritoneum

Must have received prior platinum-containing therapy,

but no more than 3 prior chemotherapies; unlimited

prior hormonal therapy

N=300

Primary endpoint: PFS (Assumed true HR = 0.60, 7 vs 11.67 months)

Key secondary endpoint: OS

Other secondary: ORR, DOR, DCR, Safety, QOL, TR (predictive markers)

FPI planned: May 2013

Sponsor: Array

ENGOT Model: C

Paclitaxel 80 mg/m² d1,8,

15 q 4 wks, or

PLD 40 mg/m² q 4 wks, or

Topotecan 1,25 mg/m²

d1-5 q 3 wks

18

N = 300

High grade serous Muellerian cancer is a disease of homologous recombination dysfunction

TCGA, Nature 2011; Swisher et al, PNAS 2011 in press; Turner, et al NatRevCancer 2004; Weberpals, et al JCO 2008;

Tan et al, JCO 2008; Mendes-Pereira et al, EMBO Mol. Med. 2009

BRCA1 germline

8%

BRCA2 germline

6% BRCA1 somatic

3% BRCA2 somatic

3%

BRCA1 methyl’n

11%

EMSY ampl 6%

PTEN loss 5% other HRD

7%

CCNE1 amp 15%

MMR germline

2%

other 34%

Other HRD 7%: TP53, RAD51C,

PALB2, RAD50,

MRE11A, BARD1,

CHEK2, BRIP1,

FANCD2, ATR, ATM

Study 19: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer

• Interim OS analysis (38% maturity): HR=0.94; 95% CI, 0.63–1.39; P=0.75

Presented by: Jonathan Ledermann

0

0.6

0.8

0.9

0

0.1

0.2

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0.7

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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)

Primary analysis

(58% maturity; n=154/265)

PFS hazard ratio=0.35

(95% CI, 0.25–0.49)

P<0.00001

Randomized treatment*

Placebo (n=129)

Olaparib 400 mg bd monotherapy (n=136)

Ledermann J et al. N Engl J Med 2012;366:1382–1392 *Patients were treated until disease progression

• Patients were randomized after response to platinum-based chemotherapy

PFS by BRCAm status

Presented by: Jonathan Ledermann

0


0

1.0

Pro

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3 6 9 12 15

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

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

Olaparib BRCAm

Placebo BRCAm

Number at risk

Olaparib BRCAm

Placebo BRCAm

74 59 33 14 4 0

62 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=0.18

95% CI (0.11, 0.31);

P<0.00001

Parp inibitori in mantenimento dopo

chemioterapia in pazienti BRCA mutate e

fenotipi BRCAness

• Trial Solo1 Olaparib Prima linea

• Trial Solo2 Olaparib Recidiva platino sensibile

• Trail Tesaro Nova Niraparib Recidiva platino sensibile

• Trail ARIEL 3 Rucaparib Recidiva platino sensibile

The Angiogenic Switch and Antiangiogenic Therapy

Somatic mutation

Small avascular

tumor

Tumor secretion of proangiogenic

factors stimulates angiogenesis

Rapid tumor growth and metastasis

Angiogenic inhibitors may reverse this process

The essential role of VEGF in

ovarian cancer

Moghaddam, et al. Cancer Metastasis Rev 2012

GOG Phase II studies: Response Rates

Tumor Type Dose ORR (PR+CR)

Ovarian Cancer 15mg/kg q3wk 16-21%

Renal Cell 10mg/kg q2wk 10%

Met Breast Cancer 3-20mg/kg q2wk 7%

NHL 10mg/kg q2wk 5%

CRC 10mg/kg q2wk 3%

HRPC 10mg/kg q2wk 0%

Placebo

GOG-0218: Schema

• Stratification variables

– GOG performance status

– Stage/debulking status Bevacizumab 15 mg/kg

15 months

Paclitaxel (P) 175 mg/m2

Carboplatin (C) AUC 6





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

N=1873

I

II

III

Arm

1:1:1

OV = ovarian; PP = primary peritoneal FT = fallopian tube; Bev = bevacizumab

R

A

N

D

O

M

I

S

E

(CP)

(CP + Bev)

(CP + Bev Bev)

Bev 15 mg/kg

Burger et al. ASCO 2010

*p value boundary = 0.0116

Data cut-off date: September 29, 2009

GOG 218- Significant PFS improvement, censored for CA-125 events and non-protocol therapy

1.0

0.8

0.6

0.4

0.2

0

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

PF

S e

sti

ma

te

CP + Pl Pl

CP + Bev15 Bev15

CP + Pl Pl

(n=625)

CP + Bev15

Bev15

(n=623)

Median PFS (months) 12.0 18.2

Stratified analysis HR

(95% CI)

0.62

(0.52–0.75)

p value one-sided (log rank) <0.0001*

N Engl J Med 365;26,2011

OS benefit is suggested with chemotherapy + Avastin and continued single-agent Avastin in stage IV disease

129 113 95 28 72 42 15 5

142 117 104 30 73 44 15 10

144

149

154 144 130 117 37 83 57 21 10

3

3

3

0

1

0

Time (months)

0 72

1.0

0.8

0.6

0.4

OS

es

tim

ate

12 24 36 48 60

0.2

0.0

CPP

CPB

CPB15

165

165

153

0

0

0

CPP (n=153)

CPB15 (n=165)

CPB15+ (n=165)

CPP CPB CPB15

Deaths, n

(%)

93 (61) 99 (60) 81 (49)

Median

survival

(months)

32.8 32.9 40.6

HR

(95% CI)

0.98

(0.74–1.31)

0.72

(0.53–0.97)

Randall, et al. SGO 2013: Abstract 80 Randall, et al. SGO 2013: Abstract 80

ICON 7 Schema

Stratification variables:

• Stage & extent of debulking (I–III debulked ≤1cm 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

OC = epithelial ovarian, primary peritoneal or fallopian tube cancer

• FIGO stage I–IIA

(clear cell or grade 3)

or FIGO stage IIB–IV

• Surgically debulked

histologically

confirmed OC

n=1528

Dec 2006 to Feb 2009

30

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 a

live

with

ou

t p

rog

ressio

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

31

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

Total

451 (90)

BEV exposure

Final OS: High-risk

(n=502)

Number at risk

Control 254 208 156 101 82 21

Research 248 224 180 135 95 27

1.00

0.75

0.50

0.25

0

Pro

po

rtio

n a

live

Time (months)

0 6 12 18 24 30 36 42 48 54 60

Control Research ∆

Deaths (%) 174 158 Restricted mean, months

34.5 39.3 +4.8

Median, months 30.3 39.7 +9.4 Log-rank test p=0.03

HR (95% CI) 0.78 (0.63–0.97)

Non-proportionality test:

p=0.0072

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

39.7 30.3

9.4

32

BEV exposure

Total

332 (66)

Avastin RCP Dicembre 2011:

Avastin, in combinazione con carboplatino e paclitaxel è indicato per il

trattamento in prima linea del carcinoma ovarico epiteliale, del carcinoma

alle tube di Falloppio o del carcinoma peritoneale primario in stadio

avanzato (stadio III B, III C e IV, secondo la classificazione FIGO).

Avastin è somministrato in aggiunta a carboplatino e a paclitaxel fino a 6 cicli di

trattamento, seguiti dalla somministrazione di Avastin in monoterapia da proseguire

fino alla progressione della malattia o per un massimo di 15 mesi o fino a che non compare

tossicità inaccettabile, qualsiasi si manifesti prima.

La dose raccomandata di Avastin è di 15 mg/kg di peso corporeo, da somministrarsi

una volta ogni 3 settimane mediante infusione endovenosa

‘Boost Trial’

Trial Chemotherapy Bevacizumab PFS HR

First line

GOG-02181 (n=1873)

Paclitaxel Carboplatin

Concurrent and maintenance

15 mg/kg q3w (3-arm placebo)

0.72

ICON72

(n=1528) Paclitaxel

Carboplatin

Concurrently only 7.5 mg/kg q3w

(2 arm) 0.81

Second line

Platinum resistant Aurelia3

(n=361)

Caelyx Topotecan Paclitaxel

Concurrent 10 mg/kg q2w

(2 arm) 0.48

Platinum sensitive OCEANS4

(n=484) Gemcitabine Carboplatin

Concurrent 15 mg/kg q3w

(2 arm) 0.48

Bevacizumab in ovarian cancer: four pivotal trials

1. Burger et al. N Engl J Med 2011

2. Perren et al. N Engl J Med 2011

3. Pujade-Laurain et al. J Clin Oncol 2012

4. Aghajanian et al. J Clin Oncol 2012

Subgroup

Restricted mean Median, months

HR (95% CI) Events/n

Research

better

Control

better Control Research Control Research

All patients 27.7 29.2 17.5 19.9 0.93

(0.83–1.05) 1080/1528

Non-high riska 33.8 33.7 26.0 25.0 1.03

(0.88–1.21) 629/1026

High riskb 15.9 20.0 10.5 16.0 0.73

(0.61–0.88) 451/502

Stage I, II, III (0 cm) 37.9 39.3 45.5 38.8 0.97

(0.79–1.18) 378/725

Stage III >0, ≤1 cm 22.7 21.3 13.7 17.7 1.07

(0.83–1.38) 251/301

Stage III >1 cm 17.0 20.8 11.1 17.0 0.75

(0.59–0.96) 260/290

Stage IV 15.5 19.4 10.2 14.9 0.75

(0.55–1.02) 163/182

Inoperable 10.4 15.8 8.4 12.4 0.58

(0.26–1.29) 28/30

Trend

interaction

p=0.014

Interaction

p=0.005

PFS (2013 update)

36

0.2 0.5 1 2 5

HR (95% CI)

aAll stage I and II, stage III ≤1 cm bNo debulking surgery, stage III >1 cm, any stage IV

DISCREPANCY BETWEEN SURGEON AND POST OPERATIVE CT SCAN EVALUATION IN RESIDUAL

TUMOR DETECTION

Author

No patients % discrepancy Site of failure

Chi D 2007 78 48% Perihepatic region, small bowel peritoneum

Lakhman Y 2011 63 49% Perihepatic Region, Upper abdominal lymphnodes

Lorusso D 2013 (submitted)

64 20.3% Perihepatic region, small bowel peritoneum

AURELIA (GINECO)

Stratification variables:

• Chemotherapy regimen

• Previous anti-angiogenic

therapy

• PFI <3 vs 3–6 months

Chemotherapy

to progression

Chemotherapy

to progression

Bevacizumab 10 mg/kg

q2w* to progression

Platinum-

resistant

OC, PP, FTC,

(PFI <6 months)

Prior

bevacizumab

allowed

n=360

(4/2011)

Primary endpoint:

PFS

Secondary

endpoints:

ORR, PFIbio, OS, QoL,

safety

Chemotherapy options (physician’s choice):

• Weekly paclitaxel 80 mg/m2

• Topotecan (4 mg/m2 d1, 8, 15 OR 1.25

mg/m2 d1–5 q3w)

• Pegylated liposomal doxorubicin 40 mg/m2

d1 q4w *15 mg/kg q3w if combined with topotecan q3w

P R O G R E S S I O N

Physician’s

choice: SOC or

bevacizumab 15

mg/kg q3w

SOC (Optional

bevacizumab)

Paclitaxel cohort: OS O

vera

ll surv

ival (%

)

75

50

25

0 0 6 12 18 24 30 36 42

100

CT

BEV + CT

No. at risk:

55 40 32 22 13 3 0

60 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)

OCEANS, a phase III, multicenter, randomized, blinded, placebo-controlled trial of carboplatin and gemcitabine plus bevacizumab in

patients with platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer

CG + PL

CG for 6 (up to 10) cycles Stratification variables:

• Platinum-free interval

(6–12 vs >12 months)

• Cytoreductive surgery for

recurrent disease (yes vs no)

Platinum-sensitive

recurrent OCa

•Measurable disease

•ECOG 0/1

•No prior chemo for

recurrent OC

•No prior BV

(n=484)

G 1000 mg/m2, d1 & 8

C AUC 4

PL q3w until progression

C AUC 4

BV 15 mg/kg q3w until progression

G 1000 mg/m2, d1 & 8

CG + BV

242 177 45 11 3 0 CG + PL

OCEANS: Primary analysis of PFS

CG + 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

Months No. at risk

242 203 92 33 11 0 CG + BV

1.0

0.8

0.6

0.4

0.2

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Pro

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MITO-16/MaNGO OV-2: Avastin plus chemotherapy at progression after front-line Avastin plus chemotherapy in platinum sensitive

Principal investigators: Sandro Pignata, Nicoletta Colombo

Stage IIIB–IV EOC, FT or PPC

progressing or recurring at least

6 months after

front-line chemotherapy

plus Avastin

(n≈400)

• Primary endpoint: PFS

• Secondary endpoint: OS

• 60 Italian centres involved and involvement of others European groups (ENGOT –

Italy, Germany, France, Greece, Switzerland) (sponsor: INT Napoli)

1:1

Avastin15mg/kg q3w

PLD or gemcitabine or paclitaxel

Carboplatin

PLD or gemcitabine or paclitaxel

Carboplatin

x 6

– 8

cycle

s

until PD

Target therapies in Ovarian Cancer

Bevacizumab

Pazopanib

Nintedanib

Trebananib

Cediranib

• Phase III randomized, placebo-controlled, double-blind, multicenter

• N=940 patients randomized (1:1) from June 2009 to August 2010

• Pazopanib administered at 800 mg daily for up to 24 months*

ICF

Survival

follow-up

(post-PD)

First-line

surgery and

chemotherapy

(allowed: dose-

dense, IP,

neoadjuvant)

Placebo

24 months

Pazopanib

24 months

R

A

N

D

O

M

I

Z

E

Observation

(to PD)

Study Design

If not PD

+ tumor

< 2 cm

Median 7 months from diagnosis to randomization

*Original design was for 12 months and later amended to 24 months

Pazopanib trial: 1st Endpoint: Progression-free Survival (RECIST)

(months)

Δ= 5.6 months

Median time from

Diagnosis: 7 months

472 332 234 171 91 19

468 318 208 164 88 20 1

Patients

at risk

0

0,5

1

0 6 12 18 24 30 36

HR = 0.766 (95% CI: 0.643-0.911)

Stratified log-rank test: P = 0.0021

Pazopanib: 472 pts. / 237 events

median 17.9 (15.9 - 21.8) mos

Placebo: 468 pts. / 273 events

median 12.3 (11.8 - 17.7) mos

Adverse Events Grade 3-4 per Patient occurring in at least 1% in the Pazopanib Arm

Grade 3/4 adverse events Placebo (N=461)

Pazopanib (N=477)

Δ

Hypertension 26 (6%) 147 (31%) 121 (25%)

• Hypertension (including Grade 2) 80 (17%) 248 (52%) 168 (35%)

Liver-related toxicity 3 (<1%) 45 (9%) 42 (9%)

Neutropenia 7 (2%) 47 (10%) 40 (8%)

Diarrhea 5 (1%) 39 (8%) 34 (7%)

Asthenia / Fatigue 1 (<1%) 13 (3%) 12 (3%)

Thrombocytopenia 3 (<1%) 12 (3%) 9 (2%)

Palmar-plantar erythrodysesthesia 1 (<1%) 9 (2%) 8 (2%)

Headache 3 (<1%) 8 (2%) 5 (1%)

Abdominal pain 5 (1%) 8 (2%) 3 (<1%)

Proteinuria 2 (<1%) 6 (1%) 4 (<1%)

Arthralgia 3 (<1%) 5 (1%) 2 (<1%)

Drug Exposure: Mean Daily Dose

Patient Daily Dose (mg)

Placebo

(N=461)

Pazopanib

(N=477)

Mean 761.0 585.6

Median 800.0 607.4

Patients with any dose reduction 63 (14%) 277 (58%)

weeks

Multicenter, randomised, double-blind, Phase III trial to investigate the

efficacy and safety of Vargatef (BIBF 1120) in combination with standard

treatment of carboplatin and paclitaxel compared to placebo plus carboplatin

and paclitaxelin patients with advanced ovarian cancer

AGO-OVAR12

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

= Vargatef 2 x 200 mg po qd

= Placebo

120 weeks

C = Carboplatin AUC 5-6 d1

T = Paclitaxel 175 mg/m2 (3h) d1

q21d / 6 courses

Vargatef / 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 weeks in non-progressing pts

2

1

S

U

R

G

E

R

Y

n=1300

Nintedanib: Primary Endpoint:

Progression-Free Survival

RECIST 1.1 and CA-125 in conjunction with Clinical MBO Criteria

0

0,5

1

0 6 12 18 24 30 36 42


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

Exploratory Subgroup Analysis

“ICON 7 defined low-risk patients subgroup”

(FIGO II or FIGO III and ≤ 1cm residual postoperative tumor)

Patients at risk

Esti

mat

ed p

erce

nta

ge a

live

a

nd

pro

gres

sio

n-f

ree


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)


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

0

0,5

1

0 6 12 18 24 30 36 42

median PFS difference: + 6.3 months (similar to OVAR 16)

Nintedanib trial: non-haematological AEs

(>15%), all CTCAE Grades

Placebo + chemo

Nintedanib + chemo

Dose intensity – Drug exposure Placebo + chemo

n (%)

Nintedanib + chemo

n (%)

Chemo dose reductions, number of pts 450 902

any dose reduction of chemotherapy 50 (11.1) 190 (21.1)

Carboplatin and Paclitaxel 6 ( 1.3) 40 ( 4.4)

Carboplatin (regardless of Paclitaxel) 24 ( 5.3) 90 ( 9.9)

Paclitaxel (regardless of Carboplatin) 32 ( 7.1) 140 (15.5)

Chemo courses, number of patients 450 902

mean n courses 5.8 5.5

reaching 6 courses 414 (92.0%) 778 (86.3%)

Nintedanib or placebo, number of pts 445 890

Patients without any dose reductions 407 (91.5) 430 (48.3)

One dose reduction 32 ( 7.2) 297 (33.4)

Two dose reductions 6 ( 1.3) 163 (18.3)

TRINOVA-1

Weekly paclitaxel

AMG-386 IV 15 mg/kg qw to

progression

Recurrent partially platinum sensitive or resistant OC, PP, FTC, (PFI <12 months, >6months after the beginning of the first-line platinum-based chemotherapy) Radiographically evaluable disease, documented PD Prev Chemo <3 Toxicity <G3

n=900 Primary endpoint: PFS

Secondary endpoints: OS, ORR, DOR, CA125 response

rate, safety and tolerbality of AMG386, PK of AMG386

Weekly paclitaxel

Placebo IV qw

to progression

ClinicalTrials.gov. Identifier NCT01204749

12 June 2013

Press release

AMGEN announces PFS benefit of

2 months in favour of trebananib

arm

(HR 0.66)

Progression-free Survival

(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

Presented by Monk BJ at European Cancer Congress

European Journal of Cancer 49; suppl 3, Sept 2013 LBA 41

Treatment-emergent AEs in

≥ 25% of Patients

Patient Incidence, n (%)

Paclitaxel +

Placebo

N = 458

Paclitaxel +

Trebananib

N = 461

All Grades Grade ≥ 3 All Grades Grade ≥ 3

Any 434 (96) 244 (54) 446 (97) 258 (56)

Localized edema 116 (26) 4 (1) 264 (57) 24 (5)

Nausea 171 (38) 6 (1) 187 (41) 8 (2)

Alopecia 163 (36) 2 (<1) 154 (33) 0

Diarrhea 122 (27) 13 (3) 136 (30) 11 (2)

Abdominal pain 131 (29) 21 (5) 132 (29) 22 (5)

Asthenia 119 (26) 15 (3) 129 (28) 13 (3)

Fatigue 137 (30) 17 (4) 127 (28) 15 (3)

Vomiting 101 (22) 12 (3) 122 (26) 14 (3)

Constipation 128 (28) 4 (1) 105 (23) 3 (1)

Neutropenia 125 (28) 40 (9) 99 (21) 26 (6) Presented by Monk BJ at European Cancer Congress

European Journal of Cancer 49; suppl 3, Sept 2013 LBA 41

OV6 TRINOVA-2

Pegylated Liposomal Doxorubicin

50 mg/m² IV Q4W

AMG-386 IV 15 mg/kg qw to

progression

Recurrent partially platinum sensitive or resistant OC, PP, FTC, (PFI <12 months, >6months after the beginning of the first-line platinum-based chemotherapy) Radiographically evaluable disease, documented PD Prev Chemo <3 Toxicity <G3

n=380 Primary endpoint: PFS

Secondary endpoints: OS, ORR, DOR, CA125 response

rate, safety and tolerbality of AMG386, PK of AMG386

Pegylated Liposomal Doxorubicin

50 mg/m² IV Q4W

Placebo IV qw

to progression

ClinicalTrials.gov Identifier: NCT01281254

TRINOVA-3/ENGOT-ov2/ BGOG-ov7

TC ± AMG 386 as first-line therapy of stage III–IV

ovarian cancer

Concurrent treatment Maintenance phase

RA

ND

OM

IZA

TIO

N

ARM A:

AMG 386*

Paclitaxel**

Carboplatin**

ARM B:

AMG 386/Placebo*

Paclitaxel**

Carboplatin**

Paclitaxel 175 mg/m2 IV Q3W

Carboplatin AUC 5 or 6 IV Q3W

for

maximum of 6 cycles

Plus

AMG 386 15 mg/kg IV QW or

AMG 386 placebo IV QW

AMG 386

monotherapy

until progression or

18 months

AMG 386 Placebo

monotherapy

Until progression or

18 months

EN

D O

F T

RE

AT

ME

NT

(P

rog

ress

ive

dis

ea

se

or

un

acc

ep

tab

le t

oxic

ity o

r

wit

hd

raw

al o

f co

nsen

t o

r d

eath

Up to 7 days from

randomization to 1st dose Treatment phase

Neoadjuvant chemo +

Interval Debulking

allowed in both arms

After 3 courses

N = 1000

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)

http://www.gcig.igcs.org/index.html

Dec 2007: Trial opened in seven centres in UK and Canada. Cediranib 30 mg

reduced to 20 mg after 30 patients enrolled

Nov 2009: Completed new Stage I (toxicity phase) recruitment at 20 mg dose.

Stage II (efficacy phase) trial expanded

Sept 2011: AZ ceased development of cediranib.

• Trial size reduced

• PFS instead of OS as primary endpoint

• Trial re-designed without Interim Analysis

• Primary comparison: Arm A (Chemo only) vs. Arm C (Maintenance)

• Secondary: OS and Chemo only vs. Concurrent vs. Maintenance, Toxicity, QoL

• 80% power, at 5% alpha, to detect a HR=0.65 would require 176 PFS events (470

patients)

Dec 2011: Trial closed 486 patients (456 at 20 mg dose)

• 176 PFS events occurred around Q4 2012. Analysis delay until ~5% remained on trial

drug

Chronology and Statistical Design – Summary

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 by

3.1 months with maintenance treatment

Chemo. Maint.

PFS events, n (%) 112 (94.9) 139 (84.8)



HR (95% CI) 0.57 (0.45 – 0.74)

Test for non-proportionality p=0.024

Restricted means, months 9.4 12.5

CEDIRANIB IN RECURRENT PLATINUM SENSITIVE

OC: Progression-free survival – arms A vs. C

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)



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)

CEDIRANIB IN RECURRENT PLATINUM SENSITIVE

OC : Overall survival

Chemo. Maint.

Chemotherapy

Maintenance

CONCLUSIONS

• Treatment according to histotype is the future

• Angiogenesis is the driving pathway in ovarian cancer carcinogenesis

- 4 positive phase III trials in first line treatment

- 2 positive second line trials in platinum resitant disease

- 3 positive second line trials in platinum sensitive disease

…..The pitfalls:

• NO predictive factors of response

• NO idea which phase of disease

• NO idea what schedule and for how long

• NO idea which type of therapy

• NO clear mechanism of resistance that may conditionate the most appropriate sequence of treatment, if any.

• NO comparison data between drugs

……many trials to do, MANY LESSONS TO LEARN……

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