Noves dianes terapèutiques en Càncer Epitelial d´Ovari. · PDF fileCurvas...

Institut Català d'Oncologia

Noves dianes terapèutiques en

Càncer Epitelial d´Ovari.

10 de març 2015


-És la primera causa de mort per càncer ginecològic.

-La 5ª causa de mort per càncer en dones.

-Correspón al 5% de la incidència de tots els tumors en dones.

-A Europa ~66730 casos nous/any, 41940 morts/any (2008).

-El 75% dels diagnòstics són a estadis avançats (III/IV).

-Té una alta taxa de recurrència (80% en estadis avançats).

-Mitjana de supervivència de 4-5 anys.

CANCER EPITELIAL D´OVARI. EPIDEMIOLOGIA


5-year survival rate

du Bois A, Reuss A, Pujade-Lauraine E, et al. Cancer 2009;15:1234–44

The impact of residual tumour on outcome in advanced ovarian cancer Data from an individual patient meta-analysis of three randomised phase III trials with 3,126 patients

log-rank: p<0.0001

0%

25%

50%

75%

100%

0 12 24 36 48 60 72 84 96 108 120 132 144

Ove

rall

surv

ival

(%

)

0mm

1–10mm >10mm

HR (95% CI)

1–10mm vs 0mm: 2.70 (2.37, 3.07)

>10mm vs 1–10mm: 1.34 (1.21, 1.49)

Time (months)

Med OS: 99,1m.

Med. OS: 29,6 m.

Med OS: 36,2 m


estadis inicials alt risc (a partir de FIGO IA-B g2 i tots els alt graus, sobre tot si dubtes de cirurgia òptima)

tots estadis avançats:

Paclitaxel ev + Carboplatí ev x 6 cicles

Phase III Trial of Carboplatin and Paclitaxel compared with Cisplatin and Paclitaxel in Patients with

optimally resected stage III Ovarian Cancer (GOG 158) JCO 2003

QUIMIOTERÀPIA ADJUVANT


- Dedrick et al.(1978) and Howell et al (1982):

Els tumors de la cavitat peritonial poden exposar-se a concentracions de tractament QT majors amb administració directa, que amb la pauta endovenosa.

QUIMIOTERÀPIA INTRAPERITONIAL

Institut Català d'OncologiaArmstrong D. N Engl J Med 2006; 354 (1): 34-43

Mitjana SG:

- IV group: 49.7m

- IP group: 65.6m

INDICACIONS: - Estadis III

(FIGO IIIA-IIIC) - Cirurgies òptimes

Benefici en SG >12m

Metanàlisi 2006

Recomenació NCI: January 4, 2006

Institut Català d'OncologiaEORTC 55971 Vergote I. NEJM, 2010 Sep; 363:943-53

Pacients estadi FIGO IIIC-IV

Cirurgia vs

QT NA + cirurgia

No diferències a SG entre els grups


RECIDIVA A CÀNCER D’OVARI

0 3 6 12 18 24

Refractària

Resistent

Sensible

Molt sensible

1

ª lín

ia d

e Q

T

Sensibilitat intermitja

mesos


SUPERVIVÈNCIA A LA RECIDIVA A CÀNCER D’OVARI


In the end almost all relapsing patients Become platinum-resistant

Influence of bev and other drugs on % platin-resistant after first line therapy!!


Noves estratègies en Càncer Epitelial d´Ovari.

• L´objectiu de nous fàrmacs hauria de ser perllongar la SLP i la SG de les pacients.

• Els fàrmacs que fins ara han evidenciat en assajos randomitzats més eficàcia són

-Antiangiogènics

-Inhibidors del PARP


Gilks Human Pathol 2009

HG-SOC CCC

EC MC

LGSOC

“OVARIAN CANCER IS ERRONEOUSLY REGARDED AS A

SINGLE DISEASE”: DUALISTIC MODEL

Institut Català d'OncologiaBanerjee S , and Kaye S B Clin Cancer Res 2013;19:961-968


A2: Are there any subgroups defined by tumor biology who

need specific treatment options/trials?

• Histopathology remains the gold standard to classify epithelial

ovarian cancer subgroups; however, there is emerging evidence to

show different genetic and molecular profiles.

• Since there are different clinical behaviour patterns for some of the

histopathological subgroups, it is advised that separate trials are

developed for the subgroups listed below:

• Clear cell carcinoma

• Low grade serous cancer

• Mucinous carcinoma

• When trials for the above are not available, patients within these

subgroups should be entered into ongoing phase III studies.

4th Ovarian Cancer Consensus Conference

June 25 – 27, 2010

Vancouver, British Columbia , Canada


Abs # 5507 : Randomized phase III trial of paclitaxel/carboplatin (PC) versus

Cisplatin/Irinotecan (CPT-P) as first-line chemotherapy in patients with CCC

of the ovary. A JGOG/GCIG study.

End point: SLP Secundarios SG, TR, y efectos adversos


Abstract 5507

Curvas SLP: CT vs CPT/CDDP


Low grade serous ovarian

carcinoma


Lancet Oncol , Feb 2013


Vías de señalización alteradas

Institut Català d'OncologiaTCGA, Nature 2011

Subset-specific therapy prediction

Mesenchymal: angiogenesis and vascular inhibitors

(bevacizumab, VEGFRi, PDGFRBi)

Immunoreactive: immune induction or inhibition

(ipilimumab, anti-PD-1, birinapant)

Differentiated: chemotherapy

Proliferative: chemotherapy with stromal targeting

(angiogenesis)

TCGA, Nature 2011

Tothill, Clin Cancer Res 2008


Is Angiogenesis a target?

Tumor Blood Vessels


ANGIOGENESIS: DIANA PEL CONTROL DEL CREIXEMENT TUMORAL

La angiogènesis és necesaria per la difusió i creixement dels tumors.

Tumor petit

Les mutacions genètiques transformen la cèl ·lula en cancerosa.

Senyal química Capilars de creixement

Nutrients

Les cèl·lules canceroses migren

Tumor en creixement


VEGF FAMILY AND ITS RECEPTORS: CENTRAL MEDIATOR OF ANGIOGENESIS

VEGFR-3 (Flt-4)

VEGFR-2 (Flk-1/KDR)

VEGFR-1 (Flt-1)

PlGF = placenta growth factor; VEGFR = VEGF receptor.

Angiogenesis

Angiogenesis Lymphangiogenesis Lymphangiogenesis

PlGF VEGF-A VEGF-B VEGF-C VEGF-D VEGF: Expresió elevada en càncer d ovari. • Ascites • Malaltia avançada • Histologia indiferenciada • Metàstasis

Correlaciona amb

> estadiatge / < supervivencia


Ovarian Cancer:

Key Signalling Pathways Involved in Angiogenesis

Yap TA, et al. Nat Cancer Rev 2009; 9:2583


Estudis d´antiangiogènics en Càncer d´Ovari

• Anti-vascular endothelial growth factor (VEGF) therapy

improves progression-free survival (PFS)

– GOG 218 Front-line: Bevacizumab

HR = 0.72; 95% CI, 0.63–0.821

– ICON 7 Front-line: Bevacizumab

HR = 0.81; 95% CI, 0.70–0.942

– AURELIA Platinum-resistant, recurrent / 1 or 2 prior regimens: Bevacizumab

HR = 0.48; 95% CI, 0.38–0.604

– OCEANS Platinum-sensitive, recurrent / 1 prior regimen: Bevacizumab

HR = 0.53; 95% CI, 0.41–0.705

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. J Clin Oncol. 2013;31(18suppl):LBA5503. 4. Pujade-Lauraine E et al. J Clin Oncol. 2012;30(18suppl):LBA5002. 5. Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045.


GOG#218

ICON-7


CP (Arm I)

Arm I

CP

(n=625)

Patients with event, n (%) 423

(67.7)

Median PFS, months 10.3

Stratified analysis HR

(95% CI)

One-sided p-value (log rank)

GOG-0218: Investigator-Assessed PFS Population: Stage IV, Stage III all with macroscopic residual disease regardless of surgery

+ BEV (Arm II)

ap-value boundary = 0.0116

+ BEV → BEV maintenance (Arm III)

Pro

po

rtio

n s

urv

ivin

g p

rogr

ess

ion

fre

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

Arm III

CP + BEV BEV

(n=623)

360

(57.8)

14.1

0.717

(0.625–0.824)

<0.0001a

Arm II

CP + BEV

(n=625)

418

(66.9)

11.2

0.908

(0.759–1.040)

0.080a

N Engl J Med 2011;365:2473-83.


Summary of Updated Results

Perren T et al N Engl J Med. 2011 Dec 29;365(26):2484-96.

HR = 0.81 (95% CI 0.70–0.94)

HR 0.68 (95% CI 0.55-0.85) Median 10.5 vs 15.9mo

HR 0.64 (95% CI 0.48-0.85) Median 36.6 vs 28.8mo

HR = 0.81 (95% CI 0.63–1.04)

High risk: FIGO IV or III with >1cm RD


Bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of advanced (FIGO stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer

Bevacizumab is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Bevacizumab as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier

The recommended dose of Bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion


CG + PL

OCEANS: Study schema

CG for 6 (up to 10) cycles

Platinum-sensitive recurrent OCa

•Measurable disease •ECOG 0/1 •No prior chemo for recurrent OC

•No prior BV

(n=484)

Aghajanian et al. J Clin Oncol; Vol 30;17;2012

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

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

AURELIA trial design & PFS

Results

Platinum-resistant OCa

•≤2 prior anticancer regimens

•No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvement

Treat to PD/toxicity

Treat to PD/toxicity

Investigator’s choice

(without BEV)

Optional BEV monotherapyc

BEV 15 mg/kg q3wb + chemotherapy

Chemotherapy

R

1:1


Incorporating BEV in clinical practice

Benefit most marked with BEV in highest risk patients:

First line: Ptes with Stage IV or Stage III w any amount of residual disease.

Relapse: Ptes w measurable disease.

Proportional benefit with BEV greatest at end of maintenance in first line:

Does duration of therapy need to be extended

Treatment guided by clinical characteristics. Neither biomarker nor molecular profile so far.


Inhibidors de PARP en Càncer d´Ovari. DNA Damage Repair Pathways:

BRCAs;

FANCs CELL

DEATH


Vías de señalización alteradas


Mutació BRCA en càncer d´ovari

• Els tumors amb mutació de BRCA

-Responen més a quimioteràpia basada en platí

- Tenen millor SG i SLP que els tumors sense mutació

-La histologia més freqüent és la de tumors serosos d´alt grau.


Olaparib

Phase I and BRCA

mutation expansion

studies in ovarian

cancer patients1

Olaparib multicenter

Phase II BRCA

mutation ovarian

cancer study2

Olaparib multicenter

Phase II BRCA+/–

study (ovarian

cancer patients)3

Olaparib patients n=50 n=33 n=64

Olaparib dose 200 mg bid 400 mg bid 400 mg bid

RECIST response

(CR + PR) 28% 33%

BRCA+ 41%

BRCA– 24%

Disease control

rate* 34% 69%

BRCA+ 76%

BRCA– 62%

Median duration of

response 7.0 months 9.5 months Not reported

Complete response (CR) + partial response (PR) + stable disease (SD)

1.Fong PC et al. J Clin Oncol 2010;28:2512–2519;

2. Audeh MW et al. Lancet 2010;376:245–251;

3. Gelmon KA et al. Lancet Oncol 2011;12:852–861

Provides clinical evidence of activity in ovarian cancer patients with and

without BRCA1/2 mutations

Olaparib( AZD2281): an orally active PARP inhibitor in ovarian cancer


PARP Inhibitors in Clinical Trials

Agent Administration Phase*

Comments

Olaparib

(AZD-2281)

Oral I, II, III Single Agent and Combination, BRCA and non-BRCA, Platinum-sensitive and resistant, Primary and Recurrent

SOLO-1;SOLO-2

AZD-2461 Oral I, II FIH, Solid Tumors

Veliparib

ABT-888

Oral I, II, III Single Agent and Combination, BRCA and non-BRCA, Platinum-sensitive and resistant, Primary and Recurrent

(GOG-9923, PIS1004, GOG-280)

BMN 673 Oral I, II BRCA mutation carriers, Platinum Sensitive

CEP-9722 Oral I Combination, Solid Tumors

Niraparib

(MK4827)

Oral I, II, III Single Agent and Combination, BRCA and non-BRCA, Platinum-sensitive and resistant : NOVA Trial

Rucaparib

(CO-338)

Oral I, II, III BRCA mutation carriers and no carriers, Platinum Sensitive: ARIEL-2, ARIEL-3

AG014699 IV II Single Agent, BRCA, Platinum-sensitive and resistant

*Available at: http://www.clinicaltrials.gov.


• Primary- End Point: PFS

• Pre-specified exploratory analysis of all efficacy end-points according

to BRCA status


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

Pro

bab

ility

of

p

rogr

ess

ion

-fre

e s

urv

ival

Time from randomization (months)

Hazard ratio 0.35, (95% CI, 0.25–0.49); P<0.00001

Randomized treatment

Placebo Olaparib 400 mg bid monotherapy

• Statistically significant PFS improvement (HR 0.35, P<0.00001) • Interim OS analysis: HR=0.94; 95% CI, 0.63–1.39; P=0.75( 29.7 mos vs 29.9 mos)

Ledermann J et al. N Engl J Med 2012;366:1382–1392

8.4 mos

4.8 mos


• Retrospective testing of blood and archival tumor samples was performed for all consenting patients

• BRCA1/2 mutation status was determined for 254/265 (96%) patients:

– 136 (51.3%) patients had a known deleterious BRCA1/2 mutation* (BRCAm dataset):

• 92pts( 68%): BRCA-1 mut

• 43 pts ( 32%): BRCA-2 mut

• 1 pte had a mutation in both: BRCA-1,2

– 118 (44.5%) patients were defined as BRCA1/2 wild type (BRCAwt)†

– 11 (4.2%) patients had neither a tumor nor a germline result available

*Germline and/or somatic mutation; †wild-type group includes patients with no known BRCA1/2 mutation or a variant of unknown significance (a non-deleterious mutation)


Conclusions • El factor pronòstic més important en es léstadi de la

FIGO al diagnòstic i la cirurgia déstadificació òptima.

• La gran majoria de pacients reben QT adjuvant.

• La gran majoria de pacients recauràn i moriran.

• Les QTs i els nous fàrmacs amb un diagnòstic molecular precís harien dájudar-nos a millorar la qualitat de vida, la SLP i la SG de les nostres pacients.

ESTUDIS CLINICS I SIGNATURES PRONOSTIQUES I PREDICTIVES DIRIGIDES A FER UNA MEDICINA PERSONALITZADA


Conclusions

No canvis inmediats en el tractament del càncer d´ovari però …

Futur esperançador

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