Ovaio

(1)

Gynecologic Oncology Unit IRCCS Istituto Tumori Milano G. Maltese

Milan -

Italy

(2)

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

(3)

Alterazioni molecolari e opzioni terapeutiche

Sierosi HG

p53 p16

pRb pathway BRCA-HRD

PARP-I

Antiangiogenetici

Sierosi LG

BRAF K-ras ER-PgR

Selumetinib Trametinib MEK162 OT

Clear Cell

HNF-1β IL6/JAK2/STAT

PI3K/MSI ARID1A

Dasatinib

Temsirolimus Nintedanib

Endometrioide Mucinoso

PTEN;

β-Catenin, K-ras,

MSI ARID1A

OT

Temsirolimus

K-ras HER2

Trastuzumab

Pertuzumab

Lapatinib

Cetuximab

(4)

HIGH GRADE

SEROUS TUMORS

E PARP-INIBITORI

(5)

(6)

39 Set area descriptor | Sub level 1

(7)

Presented by:

(8)

Presented by:

(9)

(10)

(11)

Impact of Germline BRCA1/2 Mutations

(12)

(13)

Efficacy of platinum based therapy in BMOC

Response rate Comment Author

First line 87%-96%

(n= 105)

•

71% (p=0.002) in sporadic OC

•

No difference

between BRCA1 and BRCA2

Venken et al

¹

Tan et al

²

Recurrent

2nd- 3° line 65-100%

(n=67) Mostly platinum

sensitive

Only one cohort of 10 pts had primary platinum resistant disease with 8 reponders (80%)

Alsop et al

³

Tan et al

²

1. Venken et al Ann Onc2011 2. Tan et al Jco 2008 3. Alsop et al JCO2012

Platinum based therapy more active in BRCA mutated than in sporadic

patients

(14)

BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel:

a Gynecologic Oncology Group Study

Lesnock et al. British Journal of Cancer (2013) 108, 1231–1237

(15)

Efficacy of Pegylated liposomal doxorubicin (PLD)- based treatment in BMOC

Response rate (RECIST or Ca125)

Median PFS

(months) Comment Author

(n= 40) 68% 15.8 mo

•

PLD plus platinum in 22

•

Mostly platinum sensistive (31)

•

RR for PD/platinum in NH of 49%;

mPFS of 8 mo (p=0.009)

Safra et al

¹

56%

(n= 23) 6.3 mo

•

Single agent PLD

•

RR for PD/platinum in NH of 19%;

mPFS of 4 mo (p=0.004)

•

Non correlation with platinum sensitivity

Adams et al

²

39%

(n=33) 7.1 mo

• Single agent PLD

• Patients had 0-12 months of PFI

• Part of randomized trial vs olaparib wich had a RR of 59% and mPFS of 8.8 mo

Kaye et al

³

1. Safra et al Mol Canc Ther 2011 2. Adams et al Gyn Onc 2011 3. Kaye et al J Clin Oncol 2012

(16)

MITO-15 results

Lorusso D et al. ESMO 2014 Abstract 886PD.

According to BRCA mutational status

Overall population

(17)

Study 19: trial design, endpoints and BRCA testing

N=265

• Platinum-sensitive recurrent high-grade serous ovarian cancer

• ≥2 prior regimens of platinum-based chemotherapy

• Complete or partial response to most recent platinum-based regimen

Olaparib maintenance monotherapy (400 mg bid, capsules) n=136

n=129

Placebo (bid, capsules) Double-blind

randomization 1:1

Treatment until progression

BRCA testing:

• Previous local germline BRCA testing (case report forms)

• Retrospective germline BRCA testing or tumour BRCA testing

BRCAm: n=136 BRCAwt:* n=118

Primary endpoint:

Progression-free survival (PFS) by RECIST 1.0

Secondary endpoints included:

Overall survival (OS), safety and tolerability Exploratory endpoints:

Time to first subsequent therapy or death (TFST), time to second subsequent

therapy or death (TSST)

*BRCAwt patients did not have a detected BRCAm or had a BRCAm of unknown significance.

bid, twice daily; BRCAwt, BRCA1/2 wild type; RECIST, Response Evaluation Criteria in Solid Tumours

(18)

Primary endpoint

At DCO 30 June 2010, the study met its primary endpoint of a statistically significant PFS benefit in the overall study population

0 0.6 0.8 0.9

0 0.1 0.2 0.3 0.4 0.5 0.7 1.0

3 6 9 12 15 18

Probability of PFS

Time from randomisation (months) PFS HR=0.35

(95% CI: 0.25-0.49) p<0.001

Randomised treatment Placebo

Olaparib 400 mg bid monotherapy

Olaparib Placebo

Events: patients (%) 60:136 (44.1)

93:129 (72.1) Median (months) 8.4 4.8

Overall survival (OS) analysis in December 2011 (38% maturity) did not indicate

progression-free survival (PFS) benefit translating into OS benefit in the overall population (HR=0.94; 95% CI: 0.63-1.39, p=0.75

Ledermann J et al. N Engl J Med 2012;366:1382-92

+ 3,6 m

(19)

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

PFS by BRCA mutation status

Ledermann JA et al . J Clin Oncol 2013;31(15S); abstr 5505

BRCAm (n=136)

Olaparib Placebo Events: total

patients (%)

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

0

Time from randomization (months) 0

1.0

Proportion of patients progression-free

3 6 9 12 15

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Olaparib BRCAm Placebo BRCAm

Number at risk:

Olaparib BRCAm Placebo BRCAm

74 59 33 14 4 0

62 35 13 2 0 0

+ 6,9 m

(20)

Study 19 OS analyses

CI, confidence interval; DCO, data cut-off; FSI, first subject; OS, overall survival

OS data maturity: 77%

Alpha (two-sided) = 0.95%

Additional follow-up since previous analysis = 3 years

28 Aug 2008 31 Oct 2011 26 Nov 2012

FSI

OS data maturity: 38%

Alpha (two-sided) = 0.1%

HR=0.94

95% CI: 0.63-1.39, p=0.75

¹

OS data maturity: 58%

Alpha (two-sided) = 3%

HR=0.88

95% CI: 0.64-1.21, p=0.44

²

30 Sep 2015

DCO DCO DCO

1. Ledermann J et al. New Engl J Med 2012;366:1382-92; 2. Ledermann J et al. Lancet Oncol 2014;15:852-61

(21)

Olaparib vs Placebo in Relapsed Serous Ovarian Cancer: OS

 Restricted means analysis performed because of insufficient evidence to dismiss the proportional hazards assumption for OS

^[1,2]

– Difference in mean survival strengthens olaparib OS advantage – BRCAm patients demonstrated greatest OS advantage

 No inconsistency between OS data for somatic BRCAm subgroup and OS data for BRCAm, germline BRCAm, or overall population, however, conclusions limited by sample size (n = 20)

Slide credit: clinicaloptions.com 1. Grambsch P, et al. Biometrika. 1994;81:515-520.

2. Anderson PK, et al. Lifetime Data Anal. 2004;10:335-350.

3. Ledermann JA, et al. ASCO 2016. Abstract 5501.

OS

Overall study population (N = 265)

BRCAm subgroup (n = 136)

Olaparib (n = 136)

Placebo (n = 129)

Olaparib (n = 74)

Placebo (n = 62)

Restricted mean OS, mos 40.1 34.9 44.3 36.9

Difference in restricted

mean OS, mos (95% CI) 5.2 (-0.8 to 11.2) 7.4 (-1.1 to 16.0)

(22)

(23)

Secondary efficacy endpoints

27.9 7.1

18.4

Not reached

18.2 PFS2

0 10 20 30

Median (months)

Olaparib Placebo Data immature

Overall survival Time to first subsequent

therapy, or death (TFST)

Time to second subsequent therapy,

or death (TSST)

HR=0.28

95% CI: 0.21-0.38

p<0.0001

HR=0.50

95% CI: 0.34-0.72

p=0.0002

HR=0.37

95% CI: 0.26-0.53

p<0.0001 Median not reached

Median not reached

(24)

TOI over first 12 months Olaparib (n=185) Placebo (n=94)

Change from baseline, adjusted mean −2.90 −2.87

TOI, trial outcome index;

FACT-O, functional assessment of cancer therapy for ovarian cancer

Estimated difference in adjusted means = −0.03 (95% CI: −2.19-2.13, p=0.98)

Health-related quality of life: TOI of the FACT-O

(25)

*Primary endpoint for HRQoL was trial outcome index (TOI) of the FACT-O (Functional Assessment of Cancer Therapy – Ovarian)

Sensitivity analysis: PFS by blinded independent central review (BICR)

• Key secondary endpoints:

– Time to first subsequent therapy or death (TFST), time to second progression (PFS2),

time to second subsequent therapy or death (TSST), overall survival (OS)

– Safety, health-related quality of life (HRQoL*)

SOLO2/ENGOT-Ov21: study design

Placebo n=99 Olaparib 300 mg bid

n=196

Primary endpoint

Investigator-assessed PFS

Patients

• BRCA1/2 mutation

• Platinum-sensitive relapsed ovarian cancer

• At least 2 prior lines of platinum therapy

• CR or PR to most recent platinum therapy

Randomized 2:1

(26)

Months since randomization

Progression-free survival (%)

100 90 80 70 60 50 40 30 20 10 0

0 3 6 9 12 15 18 21 24 27 33

30.2 5.5

30

No. at risk Olaparib Placebo

196 99

176 62

148 26

128 18

112 16

103 14

88 14

82 11

30 6

28 5

3 0

1 0

Olaparib (n=196)

Placebo (n=99) Events (%) 81 (41.3) 70 (70.7) Median PFS, months 30.2 5.5

HR 0.25

PFS sensitivity analysis using BICR

Olaparib

Placebo

+ 24,7 m

(27)

gBRCAmut N=203

Niraparib N=138

Placebo N=65

Non-gBRCAmut N=350

Niraparib N=234

Placebo N=116

2:1 Randomization 2:1 Randomization

Platinum-Sensitive Recurrent High Grade Serous Ovarian Cancer

N=553

47 Ongoing Treatment*

46 Ongoing Treatment*

4 Ongoing Treatment*

12 Ongoing Treatment*

*Median duration of follow-up at time of data cutoff was 16.9 months

ENGOT-OV16/

NOVA Trial

(28)

Progression-free Survival: gBRCAmut

Treatmen

t PFS

Median

Hazard Ratio

% of Patients without PD

or Death 12

mo

18 mo Niraparib

(N=138)

21.0 (12.9,

NR)

0.27 (0.173,

0.410) p<0.0001

62% 50%

Placebo (N=65)

5.5 (3.8, 7.2) 16% 16%

PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox proportional hazards model, with the stratification factors used in randomization.

NR=not reached

+ 15,5 m

(29)

BRCAwt

Treatme

nt PFS

Median

Hazard Ratio

% of Patients without PD

or Death 12 mo

18 mo

Niraparib (N=71)

9.3 (5.8, 15.4)

0.38 (0.231,

0.628) p=0.0001

45% 27%

Placebo (N=44)

3.7

(3.3, 5.6) 11% 6%

Treatme

nt PFS

Median

% of Patients without PD

or Death 12 mo

18 mo Niraparib

(N=35)

20.9

(9.7, NR) 0.27 (0.081,

0.903) p=0.0248

62% 52%

Placebo (N=12)

11.0

(2.0, NR) 19% 19%

sBRCAmut

NR=Not reached

Treatme nt

Median PFS (

% of Patients rwithout PD

or Death 12 mo

18 mo Niraparib

(N=92)

6.9

(5.6, 9.6) 0.58 (0.361,

0.922) p=0.0226

27% 19%

Placebo (N=42)

3.8

(3.7, 5.6) 7% 7%

HRD-positive

Exploratory Analysis: PFS in Subgroups of Non-gBRCAmut Cohort

HRD-negative

+ 9,9 m + 5,6 m + 3,1 m

(30)

(31)

BRCA + + 11.2 m

HRD +

+ 8.2 m

(32)

(33)

Ruolo essenziale del VEGF nell’ovaio: fisiologia e patologia

Moghaddam, et al. Cancer Metastasis Rev 2012

(34)

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%

(35)

Four positive trials with antiangiogenic agents in

front line

(36)

Two positive trials with bevacizumab in front line

1,873 pz

Median PFS 18 vs 12 (+ 6) No OS

1,528 pz

Median PFS 20 vs 17 (+3)

Median PFS correct 19 vs 13 (+6)

OS + 5 m

(37)

(38)

STUDIO AURELIA

Overall survival (%) 75

50

25

0

0 6 12 18 24 30 36

Sopravvivenza globale: w paclitaxel

ASCO 2012

ESMO 2013

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)

0 12 18 24 Time (months)

100

75

50

25

0

Overall survival (%)

Sopravvivenza globale: popolazione generale

(39)

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

x 6 – 8 cycles

until PD

(40)

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?

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

(41)

Molecular Classification of HGS Ovarian Cancer

The Cancer Genome Atlas Research Network. Nature 474, 2011

Presented by: Boris Winterhoff

TCGA Tothill, et al

The Cancer Genome Atlas Research Network, Nature. 2011 Jun 29;474(7353):609-15

(42)

Presented by: Boris Winterhoff

Konecny GE, J Clin Oncol 31, 2013 (suppl; abstr 5510)

Proangiogenic Signatures {

OS for TCGA subtypes in

Separate Mayo Cohort (n=173)

Hypothesis: Subtypes with

proangiogenic signatures might derive more benefit from treatment with bevacizumab.

(43)

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

(44)

Cediranib and olaparib have synergistic activity in vitro

(45)

Study Design

(46)

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

Vantaggio in PFS

di 8 mesi

(47)

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

(48)

Secondary Outcome: Cediranib/olaparib significantly increased overall response rate (ORR) compared to olaparib alone

(49)

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

Presented By Jonathan Ledermann at 2014 ASCO Annual Meeting

(50)

Paola 1: Study Design

Bevacizumab is not provided

(51)

MITO 25

MITO 25 Study design

FIGO stage IIIB-IV high grade serous or endometrioid ovarian cancer, primary peritoneal and / or fallopian- tube cancer, HRD

positive

R A N D O M I Z A T I O N

1:1:

1 N= 216

ARM A: Carboplatin AUC 5+Paclitaxel 175

mg/mq q 21 for 6 cycles + Bevacizumab 15 mg/kg q 21 for 22 cycles

ARM B: Carboplatin AUC 5+ Paclitaxel 175

mg/mq q 21 + Bevacizumab 15 mg/kg for 22 cycles + Rucaparib 600 mg bid q 28 until progression or unacceptable toxicity

ARM C: Carboplatin AUC 5+ Paclitaxel 175

mg/mq q 21 + Rucaparib 600 bid q 28 mg until progression or unacceptable toxicity

Stratification Factor:

•Residual tumor at primary surgery;

•Stage of disease;

•HRD status (BRCA mutated vs BRCA like)

(52)

BRCA1/2-mutated tumors exhibited:

 significantly

increased CD3+ and CD8+ TILs



elevated expression of PD-1 and PD-L1 in tumor- associated immune cells compared to HR-proficient

tumors.

StricklandK et al. JCO ASCO Annual Meeting 2015

Strickland KC, et al. Oncotarget. 2016

 BRCA1/2-mutation status and number of TILs were independently associated with outcome

 very poor prognosis group (HR proficient with low number of TILs) and one with very good prognosis (BRCA1/2-mutated tumors with high number of TILs)

BRCA1/2-mutated HGSOCs may be more sensitive to PD-1/PD-L1 inhibitors compared to HR-proficient HGSOCs

• These findings support trials of immune-checkpoint inhibitors targeting the PD1/PDL1 pathway in BRCA1/2-mutated OC

• An elevated number of CD3+ and CD8+ in BRCA1/2-mutated OC may provide an additional explanation for the improved clinical outcomes associated with these mutations

• Evaluation in the future of additional immune checkpoint (e.g.CTLA4, IDO, LAG3) vs HR-intact tumors

(53)

Pembrolizumab (Keytruda):

Trials in OC

Relapsed Platinum resistant OC

Phase II MITO 29

Standard chemotherapy + Pembrolizumab

Standard chemotherapy

www.clinicaltrials.gov

First line treatment of

Advanced OC FIGO stage III-IV Phase II

Trial MITO 28

Carboplatin + Paclitaxel +Pembrolizumab

Carboplatin + w Paclitaxel + Pembrolizumab 6 cycles (or 3 IDS other 3 cy) followed by Pembrolizumab maintenance for 20 cycles

First line treatment of

Advanced OC FIGO stage III-IV Phase II

Trial

Relapsed OC -0-2 prior lines -3-5 prior lines Phase II

Trial KEYNOTE

100 Pembrolizumab for up to 24 months

(54)

Targeting PD1 Nivolumab

in Ovarian cancer a phase II trial

• Nivolumab ASCO 2014 preliminary results of efficacy in Platinum-resistant OC, but the potential of durable anti-tumor response was unknown.

Single center, open-label phase II trial, in two cohorts of advanced or relapsed platinum-resistant OC patients

Hamanishi J. 2015 ASCO Annual Meeting

(55)

[TITLE]

Pujade Lauraine E. et al, 2016 ASCO meeting

(56)

Atezolizumab (Tecentriq):

Trials in OC

First line

treatment of Advanced OC FIGO stage III-IV Phase II

Trial from MITO GROUP

Carboplatin + Paclitaxel + Bevacizumab + Atezolizumab

Carboplatin+ Paclitaxel+ Bevacizumab A

B

Recurrent Platinum Resistant OC Phase II

Trial

Bevacizumab

Atezolizumab + Placebo Atezolizumab + ASA

Atezolizumab + Bevacizumab + Placebo Atezolizumab + Bevacizumab + ASA

A B

C D E

Recurrent Platinum Sensitive OC Phase III

Trial ATLANTE

Platinum based chemotherapy + Bevacizumab + Placebo Platinum based chemotherapy+ Bevacizumab+

Atezolizumab A

B

www.clinicaltrials.gov

(57)

Carboplatin-Paclitaxel (IIIA) PFS = 16-23 months OS = 31-65 months Carboplatin-Paclitaxel + Bevacizumab

(IIIB-IIIC-IV) PFS = + 6 months

Intraperitoneal Chemotherapy (?) PFS = + 5.5 months OS = + 15 months Weekly Carboplatin-Paclitaxel (??) PFS = + 10.8 months

Karam A et al. Ann Oncol 2017

1 ^st line treatment options

in advanced ovarian cancer at present

PFS, progression-free survival; OS, overall survival

(58)

Platinum-free-interval

Platinum resistant/refractory Platinum interm-sensitive Platinum fully sensitive

Previous Treatment Beva vs No beva

BRCA Status BRCA WT vs BRCA mut

2 ^st line treatment options

in advanced ovarian cancer at present

(59)

(60)

Platinum sensitive recurrent ovarian cancer:

BRCA WT

PREVIOUS BEV

Platinum- based combinations

NON PREVIOUS BEV

Carboplatin- Gemcitabine-

Bevacizumab

Platinum-based combinations 1L

2L

Trabectedin-PLD is a valid option for patients not willing to

receive or unable to receive platinum based chemotherapy

(61)

Platinum based combinations

Olaparib maintenance (if partial or complete

response)

Carboplatin-Gemcitabine- Bevacizumab

(particoularly in patients with high tumor load and

ascites)

Platinum based combinations followed by Olaprib at subsequent platinum sensitive

recurrence

Platinum based combinations followed by

Olaparib (if patient in partial or complete

response)

Trabectedin-PLD combination at subsequent platinum sensitive recurrence or in patients unable to receive

platinum

Trabectedin-PLD combination at subsequent

platinum sensitive recurrence or in patients unable to receive platinum

PREVIOUS BEV NON PREVIOUS BEV

Platinum sensitive recurrent ovarian cancer: BRCA MUT

1L

2L

3L

(62)