Impact of targeted therapy in ovarian cancerfile.lookus.net/memago/middle-east-and-turkish...Impact...

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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

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

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

0–3/PR 0–3 3–6 6–9 9–12 12–18 ≥18Platinum-free interval (months)

Resistant/ refractory

Partially sensitive

Fully sensitive

Response rate

PFS217

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

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)

00 1 2 3 4 5 6 7 8 9 10 11

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

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

Placebo q3w

Front-line: epithelial OV, PP or FT cancer

● Stage III optimal (macroscopic)

● Stage III suboptimal

● Stage IV

N=1,873

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)

0.89(0.78–1.02)

0.0437a

III CP + B15

→ B15(n=623)

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)

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

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

12 18 24 30 36 42 48 54 60

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

12 18 24 30 36 42 48 54 60

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*

Paclitaxel 175mg/m2

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 + B7.5 B7.5

Perren, et al. NEJM 2011

ICON7: PFS analysis (2011)

CPCP + B7.5 B7.5

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)

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

00 6 12 18 24 30 36 42 48

Number at riskControl 254 109 43 24 18 6Research 248 175 53 32 23 5

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

Non-proportionality test: p=0.0072

39.730.3

Total332 (66)

Time (months)0 6 12 18 24 30 36 42 48 54 60

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

0.1 0.4 0.9 0.4 0.4 1.71.3

2.0 2.0

0.5 1.3 0.81.3

1.24.3 2.7

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

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

242 177 45 11 3 0242 203 92 33 11 0

CG + PlCG + Bev

No. at risk:

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

Investigator’s choice

(without BEV)

Optional BEV monotherapy‡

BEV15mg/kg q3w†

+ chemotherapy

Chemotherapy

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

3.4 6.7

Pujade-Lauraine, et al. ASCO 2012

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)

Time (months)CTBEV + CT

No. at risk:

0 6 12 18 21 243 9 15

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

Time (months)

0 6 12 18 21 243 9 15

CTBEV + CT

No. at risk:

CT (n=64)

BEV + CT (n=62)

3.5(1.9‒3.9)

5.4(3.9‒6.6)

HR (not stratified) (95% CI)

0.57 (0.39‒0.83)

PFS: cohort treated with topotecan

63 22 7 1 0 0 0 0 057 43 26 8 1 0 0 0 0

Time (months)

0 6 12 18 21 243 9 15

CTBEV + CT

No. at risk:

CT (n=63)

BEV + CT (n=57)

2.1(1.9‒3.3)

5.8(5.3‒7.5)

HR (not stratified)(95% CI)

0.32 (0.21‒0.49)

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

≈≈

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)

Witteveen, et al. ECC 2013

Paclitaxel cohort: OSO

00 6 12 18 24 30 36 42

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)

13.2(8.2‒19.7)

22.4(16.7‒26.7)

0.65 (0.42‒1.02)

PLD cohort: OSO

CTBEV + CT

No. at risk:64 48 32 20 13 8 162 50 32 22 15 9 0

Time (months)

0 6 12 18 24 30 36 42

CT (n=64)

BEV + CT (n=62)

14.1(9.9‒17.8)

13.7(11.0‒18.3)

0.91 (0.62‒1.36)

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)

1.09 (0.72‒1.67)

0 6 12 18 24 30 36 42

CTBEV + CT

No. at risk:63 42 34 21 3 1 057 46 31 19 5 1 1

Time (months)

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

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