Impact of targeted therapyin ovarian cancer
Georges Chahine, M.D.Professor of Hematology – OncologySaint-Joseph University, Beirut
IntroductionOvarian cancer is the leading cause of death from GU cancer is the US
In 2015, 21290 newly diagnosed cases and 14180 deathfrom ovarian carcinoma were reported in USA
70% of patients present with advanced disease and lessthan 40% of them are cured
Nearly 70% of advanced stage cancer relapse
For many years, ovarian cancer has been managed using …
ChemotherapySurgery
Goal = Ro Resection No residual tumor Specialized surgeon
ChemotherapySurgery
Evolution of therapy in ovarian cancer
Goal = Ro Resection No residual tumor Specialized surgeon
Platinum increase OS vs no Platinum chemotherapy
Carboplatinum + Paclitaxel is the gold standard
ChemotherapySurgery
Evolution of therapy in ovarian cancer
Strategies examined to increase efficacy of carboplatin/paclitaxelReplacing paclitaxel
Triplet versus doublet regimens
Maintenance therapy
Neoadjuvant therapy
Intraperitoneal therapy
Dose-dense regimens
No benefit
No benefit
No benefit
Better tolerability but no OS benefit
Improves OS but increases toxicityImproves OS but increases toxicity
Ovarian Carcinoma : Clinical Course
Chemo 2Chemo 1 Chemo 3
Diagnosis DebulkingSurgery
Cure
Progression
Secondary cytoreductionDeath
Platinumsensitive
>6 months
Carboplatin combination
Platinum resistant
<6 months
Non-platinumsingle agent
Generally accepted guideline for chemotherapy at recurrence
Effect of platinum-free interval on patient outcomes
Pujade-Lauraine, et al. JCO 2002
Surv
ival
(day
s)
Res
pons
e ra
te (%
)
0–3/PR 0–3 3–6 6–9 9–12 12–18 ≥18Platinum-free interval (months)
Resistant/ refractory
Partially sensitive
Fully sensitive
OS
Response rate
PFS217
9
90
366
32
166
1,000
800
600
400
200
0
100
80
60
40
20
Management of previously treatedovarian cancer
Tumour resection and subsequent chemotherapy should be considered for all women with previously treated, platinum-sensitive ovarian cancer
– complete reresection significantly improves overall survival
The improvement in survival in patients with advanced stage ovarian cancer has been obtained by better management of recurrent disease and increased drug options, but we seem to have reached a plateau with chemotherapy
Harter, et al. Ann Surg Oncol 2006
Other strategies are needed…..Antiangiogenesis in ovarian cancer
Angiogenesis (VEGF) in ovarian cancer
Preclinical data• VEGF inhibitors inhibit tumour growth, abrogate ascites formation and normalise
vessels
Human data• VEGF overexpressed and associated with worse outcome• Associated with ascites and carcinomatosis• VEGF inhibition is synergistic with chemotherapy
5
4
3
Tum
our b
urde
n (g
)
2
1
0Control VEGF inhibitor
*p<0.001
Zhang, et al. Cancer Res 2003; Bozas, et al. Int J Gynecol Cancer 2010Li, et al. Anticancer Res 2004; Byrne, et al. Clin Cancer Res 2003
Yamamoto, et al. Br J Cancer 1997
High VEGF expression is associated with poorer survival in patients with ovarian cancer
Low VEGF levels (n=31)
p<0.01
High VEGF levels (n=39)
100
50
00 1 2 3 4 5 6 7 8 9 10 11
Years
Surv
ival
(%)
VEGF (++)
VEGF (–)/(+)
(n=39)
(n=31)
p<0.01
Angiogenesis as a Target in Ovarian Cancer
• Improvement in progression-free survival 1. GOG 218 Front-line: Bevacizumab
HR = 0.72; 95% CI, 0.63–0.821
2. ICON 7 Front-line: BevacizumabHR = 0.81; 95% CI, 0.70–0.942
3. AGO-OVAR12 Front-line: NintedanibHR = 0.84; 95% CI, 0.72, 0.983
4. AGO-OVAR16 Maintenance: PazopanibHR = 0.77; 95% CI, 0.64–0.914
5. AURELIA Platinum-resistant, recurrent / 1 or 2 prior regimens: BevacizumabHR = 0.48; 95% CI, 0.38–0.605
6. TRINOVA-1 Platinum-resistant and partially-sensitive, recurrent / 1 -3 prior regimens: TrebananibHR = 0.66; 95% CI, 0.57–0.776
7. OCEANS Platinum-sensitive, recurrent / 1 prior regimen: BevacizumabHR = 0.53; 95% CI, 0.41–0.707
8. ICON6 Platinum-sensitive, recurrent / 1 prior regimen: CediranibHR = 0.57; 95% CI, 0.44–0.748
1. Burger RA et al. N Engl J Med. 2011;365:2473‒2483. 2. Perren TJ et al . N Engl J Med. 2011;365:2484‒2496. 3. du Bois A et al. LBA ESGO 2013 Liverpool, UK4. du Bois A et al. J Clin Oncol. 2013;31(18suppl):LBA5503. 5. Pujade-Lauraine E et al. J Clin Oncol. 2012;30(18suppl):LBA5002. 6. Monk BJ et al. European Cancer Congress Eur J
Cancer. 2013;41(suppl):LBA 7. Aghajanian C et al. J Clin Oncol. 2012;30:2039‒2045. 8. Ledermann JA et al . European Cancer Congress Eur J Cancer. 2013;49(suppl):LBA
Bevacizumab, a humanised monoclonal antibody, precisely targets VEGF
Bevacizumab
VEGF receptor
VEGF
1. Avastin Summary of Product Characteristics; 2. Presta, et al. Cancer Res 1997; 3. Avastin prescribing information, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000582/WC500029271.pdf
Bevacizumab prevents binding of VEGF to receptors1,2
Bevacizumab has a long elimination half life (approximately 20 days) which may contribute to continuous tumour control3
Single-agent bevacizumab in ovarian cancer
nPrior
regimensPlatinum sensitive
Platinum resistant
Studytherapy
OR (%)
Median PFS (months)
Median OS (months)
Burger 20071 62 ≤2 Bevacizumab 21 4.7 17
Cannistra 20072 44 2–3 Bevacizumab 16 4.4 10.7
1. Burger, et al. JCO 2007; 2. Cannistra, et al. JCO 2007
Bevacizumab provides proof of concept for anti-VEGF therapy
1. Burger, et al. NEJM 2011; 2. Perren, et al. NEJM 20113. Aghajanian, et al. JCO 2012; 4. Pujade-Lauraine, et al. ASCO 2012
Front-line Recurrent
Advanced, stage III/IV patients HR1
Early and advanced stage patients PFS2
Recurrent,platinum resistant4
Recurrent,platinum sensitive3
Four positive phase III trials of bevacizumab in ovarian cancer patients
Bevacizumab in the treatment of front-line ovarian cancer:GOG-0218 and ICON7
GOG-0218: a randomised, double-blindphase III trial
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 peritonealFT = fallopian tube; Bev = bevacizumab
Bev 15mg/kg
RANDOMISE
GOG-0218: significantly increased PFS with continued bevacizumab compared with standard chemotherapy
Avastin Summary of Product CharacteristicsRoche, data on file
ICP + Pl
→ Pl(n=625)
Median PFS (months) 10.6
Stratified analysis HR (95% CI)
p value one-sided (log rank)
IICP + 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 = 0.0116Data cut-off date: 25 February 2010
0 6 12 18 24 30 36 42 48Time (months)
1.0
0.8
0.6
0.4
0.2
0
PFS
estim
ate
CP + B15 → Pl CP + Pl → Pl
CP + B15 B15
GOG-0218: significant improvement in PFS in CA-125 censored and NPT censored analysis with continued bevacizumab vs chemotherapy
*p value boundary = 0.0116Data cut-off date: 29 September 2009
CP + B15 B15
CP + Pl → Pl
1.0
0.8
0.6
0.4
0.2
0
PFS
estim
ate
0 6 12 18 24 30 36 42 48Time (months)
ICP + Pl
→ Pl(n=625)
IIICP + B15
→ B15(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*
Avastin Summary of Product CharacteristicsRoche, data on file
GOG-0218: independent review confirms the PFS benefit
IRC-assessed PFS* Investigator-assessed PFS‡
Arm ICP + Pl → Pl
(n=625)
Arm IIICP + B15
→ B15(n=623)
Arm ICP + Pl → Pl
(n=625)
Arm IIICP + B15
→ B15(n=623)
Median (months) 13.1 19.1 12 18.2Hazard ratio, stratified (95% CI) 0.62 (0.50–0.77) 0.62 (0.52–0.75)
Data cut-off date: 29 September 2009
*NPT censored‡CA-125 and NPT censored
Avastin Summary of Product Characteristics
GOG-0218: No OS benefit (ITT population)
Overall survival (months)0 6 66 72
1.0
0.8
0.6
0.4
Prop
ortio
n su
rviv
ing
12 18 24 30 36 42 48 54 60
0.2
0.0
Data cut-off date: 26 August 2011; ITT, intent-to-treat. Avastin SmPC; Roche data on file
CP + Pl → Pl
(n=625)
CP + B15 →B15
(n=623)
Deaths, n (%) 298(47.7%)
269(43.2%)
Median, months 40.6 43.8
Stratified OS HR* (95% CI) 0.88(0.75–1.04)
Stratified 1-sided log-rank P 0.0641
CP + Pl → PlCP + B15 → PlCP + B15 → B15
GOG-0218: OS for stage IV patients
Randall, et al. SGO 2013 (abstract 80 and associated presentation)
Time (months)0 6 66 72
1.0
0.8
0.6
0.4
Prop
ortio
n su
rviv
ing
12 18 24 30 36 42 48 54 60
0.2
0.0
CP + Pl → PlCP + B15 → Pl CP + B15 → B15
CP + Pl → Pl 153 144 129 113 95 72 42 28 15 5 3 0 0CP + B15 → Pl 165 149 142 117 104 73 44 30 15 10 3 1 0CP + B15 → B15 165 154 144 130 117 83 57 37 21 10 3 0 0
OSCP + B15 → Plvs CP + Pl → Pl
CP + B15 → B15vs CP + Pl → Pl
Deaths, n 93 93 81 93
Median time, months 32.9 32.8 40.6 32.8
Hazard ratio (95% CI)
0.98(0.74–1.31)
0.72(0.53–0.97)
Adverse event (grade when limited), n (%)
Arm ICP + Pl → Pl
(n=601)
Arm IICP + B15 → Pl
(n=607)
Arm IIICP + 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
Burger, et al. NEJM 2011
GOG-0218: conclusions
GOG-0218 met its primary objective of increasing PFS in front-line treatment of advanced ovarian cancer
PFS with CP + bevacizumab continued single-agent bevacizumab at 15mg/kg for 15 months (Arm III) was statistically superior to CP + placebo placebo (Arm I) in all analyses (13.1 vs 18.2 months)
Side effects were generally manageable, with a safety profile similar to that in bevacizumab studies in other tumour types
RANDOMISE
ICON7: a randomised, open-label phase III trial
Stratification variables: Stage and extent of debulking: I–III debulked ≤1cm vs stage I–III debulked >1cm vs stage IV
and inoperable stage III Timing of intended treatment start: ≤ vs > 4 weeks after surgery GCIG group (*also choice of AUC dose 5 [AGO, NSGO, GINECO] or 6)
Paclitaxel 175mg/m2
Carboplatin AUC5 or 6*
Carboplatin AUC5 or 6*
Paclitaxel 175mg/m2
1:1
Stage I–IIa (grade 3 or clear
cell) or Stage IIb–IV (all grades/
histologic types) debulked ≤1cm or >1cm OC, PP, FTC
(n=1,528)
Bevacizumab 7.5mg/kg q3w
12 months
CP
CP + B7.5 B7.5
Perren, et al. NEJM 2011
ICON7: PFS analysis (2011)
CPCP + B7.5 B7.5
PFS
estim
ate
764 474 221 39 0764 599 229 27 0
CPCP + B7.5 B7.5
Events, n (%) 464 (61) 470 (62)Median, months 17.4 19.8Log-rank test p=0.039HR (95% CI) 0.87 (0.77–0.99)
1.0
0.8
0.6
0.4
0.2
0
Time (months)0 6 12 18 24 30 36 42 48
Perren, et al. NEJM 2011Data cut-off date: November 30, 2010
Number at riskCPCP + B7.5 → B7.5
ICON7: OS analysis (2011)
764 724 672 623 421 212 71 6 0764 737 702 657 459 228 69 4 0
Time (months)
CPCP + B7.5 B7.5
Events, n (%) 200 (26) 178 (23)Median, months Not yet reachedLog-rank test p=0.11HR (95% CI) 0.85 (0.69–1.04)1-year OS rate (%) 92 95
Perren, et al. NEJM 2011Data cut-off date: November 30, 2010
Number at riskCPCP + B7.5 → B7.5
1.00
0.75
0.50
0.25
00 6 12 18 24 30 36 42 48
OS
estim
ate
Number at riskControl 254 109 43 24 18 6Research 248 175 53 32 23 5
1.00
0.75
0.50
0.25
0
Prop
ortio
n al
ive
with
out p
rogr
essi
on
Time (months)0 6 12 18 24 30 36 42 48 54 60
ICON7: PFS (2013 update) high-risk (n=502)
Control Research ∆
Events (%) 228 223Restricted mean, months 15.9 20.0 +4.1
Median, months 10.5 16.0 +5.5Log-rank test p=0.001HR (95% CI) 0.73 (0.61–0.88)
Non-proportionality test: p<0.0001
16.010.5
Stage III suboptimally debulked , any stage IV or no debulking surgery
Total451 (90)
BEV exposure
Oza, et al. ECC 2013 (LBA6)
Control Research ∆Deaths (%) 174 158Restricted mean, months 34.5 39.3 +4.8Median, months 30.3 39.7 +9.4Log-rank test p=0.03HR (95% CI) 0.78 (0.63–0.97)
ICON7: final OS high-risk (n=502)
Number at riskControl 254 208 156 101 82 21Research 248 224 180 135 95 27
Prop
ortio
n al
ive
Non-proportionality test: p=0.0072
39.730.3
9.4
Total332 (66)
Time (months)0 6 12 18 24 30 36 42 48 54 60
1.00
0.75
0.50
0.25
0
Stage III suboptimally debulked , any stage IV or no debulking surgery
BEV exposure
Oza, et al. ECC 2013 (LBA6)
ICON7: grade ≥3 adverse events consistent with those previously reported with bevacizumab
*Grade ≥2 Perren, et al. ESMO 2010
Patie
nts
(%)
40
30
20
10
02.1
0.1 0.4 0.9 0.4 0.4 1.71.3
0.4 0
15.1
2.0 2.0
18.3
0.5 1.3 0.81.3
1.24.3 2.7
0.3 0
16.5
2.6 3.5
CP (n=753)
CP + B7.5 B7.5 (n=745)
Bevacizumab in recurrent ovarian cancer:OCEANS (platinum sensitive OC)
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 & 8CG + 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 PFSCG + 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
Prop
ortio
n pr
ogre
ssio
n fr
ee
242 177 45 11 3 0242 203 92 33 11 0
CG + PlCG + Bev
No. at risk:
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30
Time (months)
Aghajanian et al. ASCO 2011
OCEANS: overview of AEs
Patients, %CG + Pl(n=233)
CG + Bev(n=247)
Any AE 100 100
Serious AE 25 35
Grade 3–5 AE 82 90
Grade 3–5 AE of special interest 62 74
Grade 5 AE <1a <1b
aAcute myocardial infarction in one patientbIntracranial hemorrhage in one patient Aghajanian et al. ASCO 2011
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 3VTE, grade ≥3 3 4CNS bleeding, all grades <1 1Non-CNS bleeding, grades ≥3 1 6CHF, grades ≥3 1 1Neutropenia, grade ≥3 56 58Febrile neutropenia, grade ≥3 2 2Hypertension, grade ≥3 <1 17Fistula/abscess, all grades <1 2GI perforation, all grades 0 0a
Proteinuria, grade ≥3 1 9RPLS, all grade 0 1Wound-healing complication, grades ≥3 0 1
Aghajanian et al. ASCO 2011
OCEANS: conclusions
Bevacizumab + carboplatin + gemcitabine followed by bevacizumab until progression provides a clinically meaningful benefit over chemotherapy alone in recurrent OC– improved PFS: HR 0.484 (p<0.0001);
median 8.4 → 12.4 months– improved ORR and duration of response– OS data not yet mature
Safety data consistent with bevacizumab profile– no GI perforations and no new safety signals
This regimen should be considered a new option for recurrent platinum-sensitive OC
Bevacizumab recurrent in ovarian cancer:AURELIA (platinum resistant OC)
AURELIA trial design
PD = progressive disease; BEV = bevacizumab; *Epithelial ovarian, primary peritoneal, or fallopian tube cancer; †Or 10mg/kg q2w; ‡15 mg/kg q3w, permitted on clear evidence of progression
Stratification factors: • Chemotherapy selected• Prior anti-angiogenic therapy• Treatment-free interval
(<3 vs 3‒6 months from previous platinum to subsequent PD)
Platinum-resistant OC*• ≤2 prior anticancer regimens
• No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoidinvolvement
Treat to PD/toxicity
Treat to PD/toxicity
Investigator’s choice
(without BEV)
Optional BEV monotherapy‡
BEV15mg/kg q3w†
+ chemotherapy
Chemotherapy
R
1:1
Chemotherapy options (investigator’s choice):• Paclitaxel 80mg/m2 days 1, 8, 15, & 22 q4w• Topotecan 4mg/m2 days 1, 8, & 15 q4w
(or 1.25mg/m2, days 1–5 q3w)• PLD 40mg/m2 day 1 q4w
Pujade-Lauraine, et al. 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 0179 88 18 1 0
CTBEV + CT
No. at risk:93
1402049
14
01
3.4 6.7
Pujade-Lauraine, et al. ASCO 2012
Estim
ated
pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30
PFS: cohort treated with paclitaxel
55 39 16 11 6 1 1 0 060 51 38 27 11 3 1 1 0
CT (n=55)
BEV + CT (n=60)
Events, n (%) 49 (89) 37 (62)Median PFS, months (95% CI)
3.9(3.5‒5.6)
10.4(7.9‒11.9)
HR (not stratified) (95% CI)
0.46 (0.30‒0.71)
Median duration of follow-up: 12.7 months (CT arm) vs 12.8 months (BEV + CT arm)
Time (months)CTBEV + CT
No. at risk:
29%
69%
16%
33%
5%16%
0.75
0.50
0.25
0 6 12 18 21 243 9 15
Estim
ated
pro
babi
lity
0.0
1.00
Poveda, et al. ESMO 2012
PFS: cohort treated with PLD
64 32 14 8 2 0 0 0 062 46 24 14 6 1 0 0 0
23%
41%
4%
14%
Time (months)
0.75
0.50
0.25
0 6 12 18 21 243 9 15
Estim
ated
pro
babi
lity
0.0
1.00
Median duration of follow-up: 15.8 months (CT arm) vs 16.7 months (BEV + CT arm)
CTBEV + CT
No. at risk:
CT (n=64)
BEV + CT (n=62)
Events, n (%) 61 (95) 54 (87)Median PFS, months (95% CI)
3.5(1.9‒3.9)
5.4(3.9‒6.6)
HR (not stratified) (95% CI)
0.57 (0.39‒0.83)
Poveda, et al. ESMO 2012
PFS: cohort treated with topotecan
63 22 7 1 0 0 0 0 057 43 26 8 1 0 0 0 0
13%
50%
8%
Time (months)
0.75
0.50
0.25
0 6 12 18 21 243 9 15
Estim
ated
pro
babi
lity
0.0
1.00
Median duration of follow-up: 9.0 months (CT arm) vs 10.5 months (BEV + CT arm)
CTBEV + CT
No. at risk:
CT (n=63)
BEV + CT (n=57)
Events, n (%) 56 (89) 44 (77)Median PFS, months (95% CI)
2.1(1.9‒3.3)
5.8(5.3‒7.5)
HR (not stratified)(95% CI)
0.32 (0.21‒0.49)
Poveda, et al. ESMO 2012
AURELIA: additional grade ≥3 adverse events* in ≥2% of patients in either arm
HFS = hand-foot syndrome *Preferred terms; † Includes abdominal pain upper Pujade Laurraine et al. ASCO 2012
Patie
nts
(%)
≈≈
≈
≈
0
2
4
6
8
10
12
14
16
18CT (n=181)
BEV + CT (n=179)
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
CTBEV + CT
No. at risk:
CT (n=182)
BEV + CT (n=179)
Events, n (%) 136 (75) 128 (72)Median OS,months (95% CI)
13.3(11.9‒16.4)
16.6(13.7‒19.0)
HR (unadjusted)(95% CI)
0.85 (0.66‒1.08)p=0.174*
182 130 98 63 29 12 1 0179 148 106 75 39 13 1 0
0 6 12 18 24 30 36 42Time (months)
100
75
50
25
0
Ove
rall
surv
ival
(%)
Witteveen, et al. ECC 2013
Paclitaxel cohort: OSO
vera
ll su
rviv
al (%
) 75
50
25
00 6 12 18 24 30 36 42
100
CTBEV + CT
No. at risk:55 40 32 22 13 3 060 52 43 34 19 4 1
Time (months)
CT (n=55)
BEV + CT (n=60)
Events, n (%) 41 (75) 36 (60)Median OS,months (95% CI)
13.2(8.2‒19.7)
22.4(16.7‒26.7)
HR (unadjusted)(95% CI)
0.65 (0.42‒1.02)
Witteveen, et al. ECC 2013
PLD cohort: OSO
vera
ll su
rviv
al (%
)
CTBEV + CT
No. at risk:64 48 32 20 13 8 162 50 32 22 15 9 0
Time (months)
100
0 6 12 18 24 30 36 42
75
50
25
0
CT (n=64)
BEV + CT (n=62)
Events, n (%) 52 (81) 48 (77)Median OS,months (95% CI)
14.1(9.9‒17.8)
13.7(11.0‒18.3)
HR (unadjusted)(95% CI)
0.91 (0.62‒1.36)
Witteveen, et al. ECC 2013
Topotecan cohort: OSCT
(n=63)BEV + CT
(n=57)Events, n (%) 43 (68) 44 (77)Median OS,months (95% CI)
13.3(10.4‒18.3)
13.8(11.0‒18.3)
HR (unadjusted)(95% CI)
1.09 (0.72‒1.67)
0 6 12 18 24 30 36 42
100
75
50
25
0
CTBEV + CT
No. at risk:63 42 34 21 3 1 057 46 31 19 5 1 1
Ove
rall
surv
ival
(%)
Time (months)
Witteveen, et al. ECC 2013
Future Directions
Significant clinical interest in angiogenesis inhibition in ovarian cancerAgent Trial Setting Regimen
Estimated enrolment
Estimated primary completion date
Pazopanib AGO-OVAR16 (NCT00866697) Front-line Pazopanib monotherapy versus
placebo 900 March 2013
BIBF 1120 AGO-OVAR12 (NCT01015118) Front-line BIBF 1120 in combination with CP
compared to placebo plus CP 1,300 July 2016
Cediranib ICON6 Recurrent (platinum sensitive)
Platinum-based therapy ±cediranib either combined with chemotherapy only or continued
470 Recruitment complete
AMG 386
TRINOVA-1 (NCT01204749)
Recurrent (partially platinum sensitive or platinum resistant)
AMG 386 or placebo, in combination with weekly paclitaxel
900 July 2013
TRINOVA-2 (NCT01281254)
Pegylated liposomal doxorubicin (PLD) plus AMG 386 or placebo 380 April 2014
TRINOVA-3 (NCT01493505) Front-line AMG 386 with CP followed by
single-agent AMG 386 2,000 May 2016
Bevacizumab
AGO-OVAR 17 (BOOST; NCT01462890)
Front-line
Carboplatin/paclitaxel + bevacizumab (15 vs 30 months) 800 November 2018
GOG-0262 (NCT01167712) CP (qw vs q3w) + bevacizumab 625 February 2012
GOG-0252 (NCT00951496)
IV vs IP chemotherapy + bevacizumab 1,500 January 2016
GOG-0213 (NCT00565851)
Recurrent (platinum sensitive) CP + bevacizumab 660 December 2009
Total >9,500
Further optimisation of bevacizumab use Ongoing trials have been designed to address the
following in relation to bevacizumab– duration (AGO-OVAR 17)– combination with weekly paclitaxel (GOG-0262, OCTAVIA,
GOG-0252)– combination with intraperitoneal therapy (GOG-0252)– neoadjuvant setting (GOG-0262, ANTHALYA and NOVA)– use following progression after front-line bevacizumab
(MITO-16/MaNGO OV-2)
Conclusions
Conventional approaches to treating ovarian cancer have provided significant improvements in outcomes
The ability of such approaches to continue to improve outcomes has reached a plateau
Further progress appears likely based on the optimisation of bevacizumab use, other anti-angiogenic agents and other targeted therapies