Noves dianes terapèutiques en Càncer Epitelial d´Ovari. · PDF fileCurvas...
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Institut Català d'Oncologia
Noves dianes terapèutiques en
Càncer Epitelial d´Ovari.
10 de març 2015
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-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
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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
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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
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- 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
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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
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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
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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
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SUPERVIVÈNCIA A LA RECIDIVA A CÀNCER D’OVARI
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In the end almost all relapsing patients Become platinum-resistant
Influence of bev and other drugs on % platin-resistant after first line therapy!!
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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
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Gilks Human Pathol 2009
HG-SOC CCC
EC MC
LGSOC
“OVARIAN CANCER IS ERRONEOUSLY REGARDED AS A
SINGLE DISEASE”: DUALISTIC MODEL
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Institut Català d'OncologiaBanerjee S , and Kaye S B Clin Cancer Res 2013;19:961-968
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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
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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
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Abstract 5507
Curvas SLP: CT vs CPT/CDDP
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Low grade serous ovarian
carcinoma
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Lancet Oncol , Feb 2013
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Vías de señalización alteradas
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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
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Is Angiogenesis a target?
Tumor Blood Vessels
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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
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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
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Ovarian Cancer:
Key Signalling Pathways Involved in Angiogenesis
Yap TA, et al. Nat Cancer Rev 2009; 9:2583
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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.
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GOG#218
ICON-7
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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.
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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
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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
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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
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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
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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.
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Inhibidors de PARP en Càncer d´Ovari. DNA Damage Repair Pathways:
BRCAs;
FANCs CELL
DEATH
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Vías de señalización alteradas
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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.
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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
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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.
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• Primary- End Point: PFS
• Pre-specified exploratory analysis of all efficacy end-points according
to BRCA status
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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
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• 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)
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Conclusions • El factor pronòstic més important en es l´estadi de la
FIGO al diagnòstic i la cirurgia d´estadificació 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 d´ajudar-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
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Conclusions
No canvis inmediats en el tractament del càncer d´ovari però …
Futur esperançador