Novità nel trattamento delle neoplasie ginecologiche: Ovaio

(1)

SUPERNOVAE IN ONCOLOGIA

Pisa 13-14 Novembre 2015

NOVITA’ NEL TRATTAMENTO DELLE NEOPLASIE GINECOLOGICHE: OVAIO

Domenica Lorusso

Gynecologic Oncologic Unit

National Cancer Institute-Milan

(2)

34 36 38 40 42 44 46

% o f P a tie n ts S u rv iv ing Fiv e Y e a rs

Year of Diagnosis

5-year survival rates

 1990-1992 42.5%

 1993-1995 43.5%

 1996-2003 45%

(3)

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

(4)

(5)

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

(6)

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%

(7)

Trial Chemotherapy Schedule PFS HR First line

Bevacizumab

GOG-0218 ¹ (n=1873)

Paclitaxel Carboplatin

Concurrent and maintenance 15 mg/kg q3w (3-arm placebo)

0.72 Bevacizumab

ICON7 ² (n=1528)

Paclitaxel Carboplatin

Concurrently only

7.5 mg/kg q3w (2 arm)

0.81 Pazopanib

AGO-OVAR 16 Paclitaxel carboplatin

Only maintenance

800 mg (2 arm, placebo)

0.76 Nintedanib

AGO-OVAR 12 Paclitaxel carboplatin

Concurrent and maintenance (2 arm-placebo)

400 mg/die

0.84 Antiangiogenic agents in ovarian cancer:

10 positive randomized phase III trials in 4 years:

(8)

Placebo

GOG-0218: Schema

• Stratification variables

– GOG performance status

– Stage/debulking status Bevacizumab 15 mg/kg

15 months

Paclitaxel (P) 175 mg/m ² Carboplatin (C) AUC 6

Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m ²

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

(9)

Primary Endpoint: PFS

With permission from Burger RA et al. Proc ASCO 2010;Abstract LBA1.

1.0 0 Proportion

surviving progression free

Months since randomization CP (Arm I)

12 24 36

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

+ Bev (Arm II)

+ Bev  Bev maintenance (Arm III)

Arm I CP (n = 625)

Arm II CP + Bev (n = 625)

Arm III CP + Bev 

Bev (n = 623) Patients with event

(%) 67.7 66.9 57.8

Median PFS,

months 10.3 11.2 14.1

Hazard ratio 0.908 0.717

One-sided p-value 0.080 <0.0001

(10)

GOG-0218: Overall Survival Analysis At time of final PFS analysis

P ro p o rti o n a li v e

Months since randomization 1.0

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

0 12 24 36 48

10 ASCO 2010

(11)

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

129 113 95 72 42 28 15 5

142 117 104 73 44 30 15 10

144 149

154 144 130 117 83 57 37 21 10

3 3 3

0 1 0

Time (months)

0 72

1.0

0.8

0.6

0.4 OS estimate

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

(12)

Second line

Platinum resistant Bevacizumab

Aurelia ³ (n=361)

Caelyx Topotecan

Paclitaxel

Concurrent 10 mg/kg q2w

(2 arm)

0.48 Platinum resistant

Pazopanib MITO 11 Weekly Paclitaxel Concurrent 800 mg/die

0.42 OS 0.6 Platinum resistant

and partially sensitive Trebananinb

Trinova 1 Weekly Paclitaxel Concurrent

AMG 386 15 mg/kg 0.66

Platinum sensitive Bevacizumab

OCEANS ⁴ (n=484)

Gemcitabine Carboplatin

Concurrent 15 mg/kg q3w

(2 arm)

0.48 Platinum sensitive

Bevacizumab GOG 213 Carboplatin

Paclitaxel

Concurrent 15 mg/kg q3w

(2 arm)

0.6 OS 0.8

Platinum sensitive

Cediranib Icon 6 Carboplatin

Paclitaxel Manteinance 0.57

OS 0.7

Antiangiogenic agents in ovarian cancer:

10 positive randomized phase III trials in 4 years:

(13)

AURELIA (GINECO)

Stratification variables:

• Chemotherapy regimen

• Previous anti-angiogenic therapy

• PFI <3 vs 3–6 months

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, PFI _bio , OS, QoL, safety

Chemotherapy options (physician’s choice):

• Weekly paclitaxel 80 mg/m

²

• Topotecan (4 mg/m

²

d1, 8, 15 OR 1.25 mg/m

²

d1–5 q3w)

• Pegylated liposomal doxorubicin 40 mg/m

²

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)

(14)

(15)

Paclitaxel cohort: OS

Ov er al l su rv iv al (% ) 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)

(16)

Stratification variables:

• Time to recurrence

• Cytoreductive surgery

Gemcitabine 1000 mg/m ² d1/8

Carboplatin AUC 4

Carboplatin AUC 4 Gemcitabine 1000 mg/m ² d1/8

Placebo to progression

Bevacizumab 15 mg/kg to progression Platinum-

sensitive, recurrent OC, PP, FTC

No prior

bevacizumab n=480

Primary

endpoint: PFS

Secondary endpoints:

ORR, OS, DR, safety

Exploratory endpoints:

IRC, CA 125

response, ascites IRC present

OCEANS

(17)

(18)

GOG-0213: primary analysis of PFS

• Coleman, et al. SGO 2015 (Abstract 3)

12 24 36 48 60

0 P ropo rtio n s urv iv ing prog res s ion -free

Carboplatin + Paclitaxel

(n=337)

Carboplatin + Paclitaxel +

Avastin (n=337) Events, n (Total) 304 296

Median (months) 10.4 13.8

HR, adj. (95% CI) 0.614 (0.522–0.722)

p-value p<0.0001*

39% reduction in risk of PD or death

0.0 0.8

0.6

0.4

0.2

(19)

GOG-0213: primary analysis of OS

• Coleman, et al. SGO 2015 (Abstract 3)

17% reduction in risk of death 5-month difference in median overall

survival, favouring Avastin arm

12 24 36 48 60

0 Time (months on study)

P ropo rtio n s urv iv ing

Carboplatin + Paclitaxel

(n=337)

Carboplatin + Paclitaxel +

Avastin (n=337)

Events, n 214 201

Median (months) 37.3 42.2 HR, adj. (95% CI) 0.829 (0.683–1.005) 2 tailed p-value p=0.056

1.0 0.0 0.8

0.6

0.4

0.2

(20)

• GOG 218 and AURELIA trials : 40% of patients initially

randomised to CT alone crossed over to BEV monotherapy after progression

• AURELIA Study not powered to detect a statistically significant difference in the secondary endpoint, OS

• No systematic capture of post-progression therapy in no trial (except for BEV in the control arm)

Limitations of OS analysis

(21)

Significant OS Improvements are More Difficult to Measure as Patients Survive Longer after Progression

– The chance of obtaining a significant OS improvement depends on the length of time that patients live after progression

(post-progression survival [PPS])

¹

– If PPS is longer than 12 months, there is a less than 30% chance that a trial will report a significant OS, even after reporting a PFS improvement at a high level of significance (p<0.001)

¹

– PPS is longer than 12 months in all three phase III trials of first-line Bevacizumab in mBC

^2–4

– The influence of PPS means that a lack of statistical significance in OS does not imply lack of improvement in OS

¹

1. Broglio, Berry. J Natl Cancer Inst 2009

2. 2. Gray, et al. J Clin Oncol 2009

3. 3. Robert, et al. ASCO 2009

4. 4. Miles, et al. SABCS 2009

(22)

Chemotherapy + Avastin with continued single-agent Avastin improves progression-free interval (cont’d)

– The proportion of patients progression-free 6 and 12 months after last dose of carboplatin is increased with Avastin-based therapy (70.6 vs 52.7) at 6 months and (41.7 vs 25.9) at 12 months

Randall, et al. SGO 2013: Abstract 287

GOG analysis

52.7 70.6 65.6

25.9 41.7 32.1

14.0 8.4 9.2

Randall, et al. SGO 2013: Abstract 287

(23)

23 23 Study design

a

Cisplatin permitted in patients with hypersensitivity to carboplatin

b

A change from one paclitaxel regimen to the alternative during the study was not permitted ECOG PS = Eastern Cooperative Oncology Group performance status; ORR = overall response rate

IV paclitaxel 175 mg/m ² d1 or

80 mg/m ² d1, 8, 15 q3w (4–8 cycles) ^b IV carboplatin AUC 5–6 q3w

(4–8 cycles) ^a

BEV 15 or 7.5 mg/kg IV q3w for up to 36 cycles (2 years) or until disease progression or unacceptable toxicity

Patients without progression at cycle 36 could

continue therapy after discussion with the Steering Committee

• Epithelial ovarian,

fallopian tube or primary peritoneal cancer:

– Stage IIB–IV

– Grade 3 stage I/IIA – Clear-cell carcinoma

(any stage) – Carcinosarcoma

• Maximally debulked (prior neoadjuvant chemotherapy allowed)

• ECOG PS 0–2

– Primary endpoint: Safety (AEs by NCI-CTCAE version 4.03)

– Secondary endpoints: PFS, ORR, duration of response, overall survival – Exploratory objectives: Optional translational research

Dec 2010‒May 2012:

1021 patients enrolled

(24)

24 24

1.00

0.75

0.50

0.25

0 Estimated prob abilit y of PFS

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time (months)

PFS in ROSiA and ICON7 (ITT populations)

19.3 25.5

1

Avastin SmPC;

2

Roche data on file 2012 (ICON7 CSR addendum).

ICON7 BEV 7.5 mg/kg

+ CP ^1,2

ROSiA

BEV 15 (or 7.5) mg/kg + CP

Caveats

• Differing tumour assessment schedules

• Prior neoadjuvant chemotherapy permitted in ROSiA

CP = carboplatin + paclitaxel

(25)

Paclitaxel 175 mg/m²

Carboplatin AUC5 q21 days

Bevacizumab 15mg/kg q21 days 15 months

= 22 cycles

Paclitaxel 175 mg/m²

Carboplatin AUC5 q21 days Bevacizumab 15mg/kg q21 days

30 months

= 44 cycles

ENGOT Ov-15 Trial AGO-OVAR 17

Study Design

R

N= 900 1:1

Strata

 macroscopic residual tumor (yes vs no)

 FIGO Stage (IIB-IIIC vs IV)

 Study Group Primary endpoint:

 PFS (non inferiority -> superiority)

Main question: treatment duration Bev

(26)

Trial Chemotherapy Bevacizumab PFS HR First line

GOG-0218 ¹ (n=1873)

Paclitaxel Carboplatin

Concurrent and maintenance 15 mg/kg q3w (3-arm placebo)

0.72 ICON7 ² (n=1528)

Paclitaxel Carboplatin

Concurrently only 7.5 mg/kg q3w

(2 arm)

0.81 Second line

Platinum resistant Aurelia ³ (n=361)

Caelyx Topotecan

Paclitaxel

Concurrent 10 mg/kg q2w

(2 arm)

0.48 Platinum sensitive OCEANS ⁴ (n=484)

Gemcitabine Carboplatin

Concurrent 15 mg/kg q3w

(2 arm)

0.48 Bevacizumab in ovarian cancer:

four pivotal trials : Dose? Duration? Setting?

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

(27)

(28)

Mucinous

Clear cell

High-grade serous

Histopathological subtypes of ovarian cancer

Soslow. Int J Gynecol Pathol 2008

McCluggage. Pathology 2011

(29)

Ovarian cancer not one disease

8704 patients from 7 randomised trials

Mackay et al. Int J Gynecol Cancer 2010

Adenoca: adenocarcinoma

(30)

SIEROSO ALTO GRADO

SIEROSO

BASSO GRADO CELLULE CHIARE ENDOMETRIOIDE MUCINOSO

SEDE ORIGINE presunta

Tuba fimbria o metaplasia tubarica in cisti inclusione OSE

Tumore Sieroso Borderline

Endometriosi Adenofibroma

Borderline

Endometriosis Adenofibroma

Borderline

Adenoma Borderline

Teratoma

Richio Genetico BRCA1/2 ? ? HNPCC ?

Stadio alla diagnosi Avanzato Precoce

Avanzato

Precoce Precoce Precoce

ALTERAZIONI MOLECOLARI

p53 p16 pRb pathway

BRAC-HRD

BRAF or K-ras

HNF-1β IL6/JAK2/STAT3

PI3K MSI ARID1A

PTEN;

β-Catenin, K-ras,

MSI ARID1A

K-ras HER2

Risposta chemioterapia

80% 26-28% 15% ? 15%

POTENZIALI

TARGTES PARPi

Angiogenesi BRAF

MEK Angiogenesi

Come rene? Terap Ormo

mTOR Come

colon?

 5 TIPI ISTOLOGICI

CARCINOMA OVAIO il punto di vista del patologo

(31)

≈50% of HGOC patients may have alterations in the HR pathway per TCGA

Presented By Iain McNeish at 2015 ASCO Annual Meeting

(32)

(33)

References/year BRCA-Ovarian cancers median survival

Sporadic cancer Median survival

Pharoah et al.1999 20.6 (BRCA1), 16 (BRCA2) months 19.5 months

Aida et al.1998 91.43 months of DF Interval 40.92 months of DF Interval

Boyd et al. 2000 40 months 25 months

Cass et al. 2003 91 months 54 months

Johannsson et al.1998 30% of BRCA1 pts at 5-years 45% control pts at 5-years

Ben David et al. 2002 53.4 months 37.8 months

Zweemwer et al. 2001 40 % 5-years 46% 5-years

Ramus et al. 2001 52 months BRCA1

49 months BRCA2

35 months

Buller et al. 2002 4.5 years 4.6 years

Kringenm et al. 2005 33% BRCA1 5-years 23% 5-years

Pal et al. 2007 27% BRCA1 4 –years

87% BRCA2 4-years

12% 4 years

Chetrit et al. 2008 53.7 months 37.9 months

(34)

Phase II, Open-Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of Olaparib, a Poly (ADP-Ribose) Polymerase Inhibitor, and Pegylated

Liposomal Doxorubicin in Patients With BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer

Stan B. Kaye et al. JCO 2012;30:372-379

(35)

Phase II prospective study on trabectedin in BRCA mutated and

BRCAness phenotype

advanced ovarian cancer patients:

the MITO 15 trial

Lorusso D, Ferrandina G, Pignata S, Sorio R, Pietragalla A, Mosconi A, Pisano C, Mangili G,

Martinelli F, Masini C, Artioli G, Narducci F, Di Napoli M, Raspagliesi F, Scambia G

Abstract #5530

(36)

Results

Presented by: Domenica Lorusso

PR

n=46

PS n=42

CR (%) 0 4 (9.5)

PR (%) 15 (32.6) 17 (40.5) ORR (%) 15 (32.6) 21 (50) SD (%) 12 (26.1) 10 (23.8) PD (%) 19 (41.3) 11 (26.2) PFS (weeks) 11 24

OS (weeks) 40 NR

CR, complete response; PR, partial response; ORR, overall response rate SD, stable disease; PD, progressive disease; PFS, progression-free survival;

OS, overall survival

Toxicities (% per cycle)

Grade 3-4 Neutropenia 17.3 Leukopenia 7.7 Anemia 2.7

Thrombocytopenia 2.3

Grade 3 Transaminitis 5.2

(37)

(38)

(39)

PFS by BRCAm status

0 Time from randomization (months)

0 1.0

Pr o p o rti o n o f p ati en ts p ro g ression -fr e e

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

(40)

Study 19 updated overall survival:

all patients

0 Time from randomization (months)

0 48 1.0

Pr o p o rti o n o f p ati en ts al iv e

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

Number at risk

129 127 120 111 108 96 87 81 71 59 55 51 37 23 6 1 1 Placebo

136 132 129 124 117 109 97 87 78 73 61 57 39 18 9 Olaparib 400 mg bd

Randomized treatment Placebo

Olaparib 400 mg bd

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Overall population (n=265) Olaparib 400 mg bd Placebo

Deaths: total pts (%) 77:136 (56.6) 77:129 (59.7)

Median OS, months 29.8 27.8

HR=0.88

95% CI (0.64, 1.21); 80% CI (0.72, 1.09) P=0.438

• At the interim OS data cut-off (26 Nov 2012), 154/265 (58.1%) patients had died

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

(41)

QoL in patients with a BRCAm

FACT-O domain ^Olaparib ^Placebo

TOI improved, n (%) 16/64 (25.0) 10/53 (18.9) OR, 1.37

95% CI 0.56–3.46, P=0.49

Presented by: Jonathan Ledermann

TOI, Trial Outcome Index; FACT-O, functional assessment of cancer therapy for ovarian cancer; FOSI, FACT-O Symptom Index

Odds ratio (OR) >1 favours olaparib

• In patients with a BRCAm:

– No statistically significant differences were observed in improvement rates or time to worsening of TOI, FOSI and Total FACT-O

– A numerically higher proportion of patients reported

improvements in TOI, FOSI and Total FACT-O following

treatment with olaparib vs placebo

(42)

Phase III trials with PARP inhibitors

Recruiting:

• SOLO 1 and 2 (olaparib)

– Randomised maintenance trials in

first line and platinum-sensitive recurrent BRCAm ovarian cancer

• NOVA (niraparib)

– Randomised maintenance trial following platinum-based

chemotherapy in BRCAm and BRCAwt high-grade serous cancer

• ARIEL 3 (rucaparib)

– Randomised maintenance trial following platinum-based

chemotherapy in BRCAm and BRCAwt high-grade serous cancer

with companion diagnostic

(43)

Results of ARIEL2:<br />A phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis

Presented By Iain McNeish at 2015 ASCO Annual Meeting

(44)

HRD causes genome-wide loss of heterozygosity (LOH) that can be measured by comprehensive genomic profiling based on NGS

Presented By Iain McNeish at 2015 ASCO Annual Meeting

(45)

Initial genomic LOH cutoff derived from public data and prospectively tested in ARIEL2

Presented By Iain McNeish at 2015 ASCO Annual Meeting

(46)

ARIEL2 designed to assess rucaparib efficacy in three prospectively defined molecular subgroups

Presented By Iain McNeish at 2015 ASCO Annual Meeting

(47)

In BRCAwt tumors, the BRCA-like subgroup derives enhanced benefit from rucaparib

Presented By Iain McNeish at 2015 ASCO Annual Meeting

(48)

Primary efficacy analysis: PFS in BRCAmut and BRCA-like versus Biomarker Negative patients

Presented By Iain McNeish at 2015 ASCO Annual Meeting

(49)

A Randomized Phase 2 Trial Comparing Efficacy of the Combination of the PARP-inhibitor Olaparib and the Anti-angiogenic Cediranib Against Olaparib Alone in Recurrent Platinum- sensitive Ovarian Cancer

Presented By Joyce Liu at 2014 ASCO Annual Meeting

(50)

Cediranib and olaparib have synergistic activity in vitro

Presented By Joyce Liu at 2014 ASCO Annual Meeting

(51)

Study Design

Presented By Joyce Liu at 2014 ASCO Annual Meeting

(52)

Primary Outcome: Cediranib/olaparib significantly increased PFS compared to olaparib alone

Presented By Joyce Liu at 2014 ASCO Annual Meeting

(53)

Cediranib/olaparib significantly increased PFS in patients without a BRCA mutation

Presented By Joyce Liu at 2014 ASCO Annual Meeting

(54)

Response to platinum-based chemotherapy in Platinum-sensitive relapsed ovarian cancer

Presented By Jonathan Ledermann at 2014 ASCO Annual Meeting

(55)

Platine, Avastin and OLAparib in 1 ^st line of advanced high grade epithelial ovarian, fallopian tube, or

primary peritoneal cancer

Randomized, double-blind, Phase III Trial of olaparib vs. placebo in patients

with advanced high grade epithelial ovarian, fallopian tube, or primary

peritoneal cancer treated with standard first-line treatment, combining

platinum-taxane chemotherapy and bevacizumab concurrent with

chemotherapy and in maintenance.

(56)

Randomised Trial of Cediranib and Olaparib Maintenance in Patients

with Relapsed Platinum Sensitive Ovarian Cancer

Shibani Nicum and Jonathan Ledermann For the NCRI Clinical Studies Group

Recurrent platinum sensistive trial: ICON 9

(57)

PD-1/ PD-L1 pathway in suppressing anti-tumor immunity

Presented By Junzo Hamanishi at 2014 ASCO Annual Meeting

(58)

Efficacy and safety of anti-PD-1 antibody (Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer

Presented By Junzo Hamanishi at 2014 ASCO Annual Meeting

(59)

Clinical Effect : Best Overall Response

Presented By Junzo Hamanishi at 2014 ASCO Annual Meeting

(60)

A Responder with Clear cell carcinoma :<br />Nivolumab 3mg/kg

Presented By Junzo Hamanishi at 2014 ASCO Annual Meeting

(61)

BRCA and Ovarian cancer: conclusions

 Treatment according to histotype is the future!

 Antiangiogenic therapies and PARP inhibitors are changing the treatment algorytm of ovarian cancer

 Up to 50% of high grade serous and endometrioid tumors present a malfunctioning of HR

 In up to 30% of patients without a family history of breast and ovarian cancer BRCA genes are mutated

Olaparib and Cediranib combination the first non

chemotherapy treatment in recurrent platinum sensitive disease and a promising combination

 The future is very dynamic!!!!

Novità nel trattamento delle neoplasie ginecologiche: Ovaio

SUPERNOVAE IN ONCOLOGIA

Pisa 13-14 Novembre 2015

NOVITA’ NEL TRATTAMENTO DELLE NEOPLASIE GINECOLOGICHE: OVAIO

Domenica Lorusso

Gynecologic Oncologic Unit

National Cancer Institute-Milan

34 36 38 40 42 44 46

% o f P a tie n ts S u rv iv ing Fiv e Y e a rs

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

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

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%

Trial Chemotherapy Schedule PFS HR First line

Bevacizumab

GOG-0218 1 (n=1873)

Paclitaxel Carboplatin

Concurrent and maintenance 15 mg/kg q3w (3-arm placebo)

0.72

Bevacizumab

ICON7 2 (n=1528)

Paclitaxel Carboplatin

Concurrently only

7.5 mg/kg q3w (2 arm)

0.81

Pazopanib

AGO-OVAR 16 Paclitaxel carboplatin

Only maintenance

800 mg (2 arm, placebo)

0.76

Nintedanib

AGO-OVAR 12 Paclitaxel carboplatin

Concurrent and maintenance (2 arm-placebo)

400 mg/die

0.84

Antiangiogenic agents in ovarian cancer:

10 positive randomized phase III trials in 4 years:

Placebo

GOG-0218: Schema

• Stratification variables

– GOG performance status

– Stage/debulking status Bevacizumab 15 mg/kg

15 months

GOG-0218 ¹ (n=1873)

ICON7 ² (n=1528)

Paclitaxel (P) 175 mg/m ² Carboplatin (C) AUC 6

Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m ²

Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m ²