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Trabectedin in patients with BRCA
mutated and BRCAness phenotype
advanced ovarian cancer (AOC):
phase II prospective MITO-15 study
Lorusso D1, Ferrandina G2, Pignata S3, Sorio R4, Pietragalla A2, Mosconi A5,
Pisano C3, Mangili G6, Masini C7, Artioli G8, Narducci F9, Di Napoli M3, Rigamonti
C10, Raspagliesi F1, Scambia G2.
1 Fondazione IRCCS National Cancer Institute Milan, 2Catholic University of
Rome, 3National Cancer Institte Naples, 4CRO Aviano, 5University of Perugia,
6San Raffaele Hospital Milan, 7University of Modena and Reggio Emilia, 8
Mirano Hospital, 9Santissima Trinita’ Sora hospital. 10Pharmamar Italy.
26-30 September 2014, Madrid, Spain
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BACKGROUND
•
•
In vitro and clinical studies have reported that mutations in BRCA repair
system with functional NER machinery induce greater sensitivity to
Trabectedin.
We hypotize that Trabectedin will be an effective tretament in patients
with BRCAness phenotype, and its activity further enhanced in those
carring BRCA 1/2 mutations. Efficacy could also be affected by the
presence of different NER related germ line polymorphisms.
26-30 September 2014, Madrid, Spain
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Aim and study design
prospective phase II study
(EudraCT n: 2011-001298-17)
evaluate activity of trabectedin in patients with mutated BRCA and
BRCAness phenotype advanced ovarian cancer (AOC)
Translational sub-study:
• Assess germline mutations of BRCA 1 and 2
• Evaluate activity of trabectedin according to BRCA
and single nucleotide polymorphisms (SNPs) in
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26-30DNA
Septemberrepair
2014, Madrid,genes
Spain
(XPD, XPG and ERCC1) mutations
Patients and methods
Patients
AOC patients
BRCA mutation or BRCAness phenotype
At least 2 previous response to platinum
Stratification
Platinum resistant
(PR)
Treatment
Trabectidin 1.3 mg/m2 (3 hour iv infusion)
Every 3 weeks until progression
26-30 September 2014, Madrid, Spain
Platinum sensitive
(PS)
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Results
46 PR
100 enrolled pts
6 months
follow-up
88 evaluable pts
42 PS
N
ORR
(%)
PR (46)
15
(32.6)
PS (42)
All (88)
CR
(%)
0
PR
(%)
SD
(%)
DCR
PD
(ORR + (%)
SD) (%)
PFS
(median,
months)
OS (median,
months)
15
(32.6)
12
(26.1)
27
(58.7)
19
(41.3)
2.7
9.7
21 (50) 4 (9.5)
17
(40.5)
10
(23.8)
31
(73.8)
11
(26.2)
6**
18.5***
36 (41) 4 (9.5)
32
(36.4)
22 (25)
58*
(66)
30
(34%)
5.2
14.7
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26-30 September 2014, Madrid, Spain
ORR, overall response rate; CR, complete response; PR, partial response; DCR, disease control rate; PD, progressive disease;
PFS, progression-free survival; OS, overall survivial.. * DCR vs PD:p=0.088; **PFS PRvsPS p=0.012; ***OS PRvsPS p=0.041
Distribution of BRCA mutations in the
study population
BRCA mutation data available on 66 patients
43 wild type
12 BRCA 1 mut
11 BRCA 2 mut
34.8%
BRCA status
PR (43)
PS (42)
P value
WT
26
17
0.60
Mutated
12
11
26-30 September 2014, Madrid, Spain
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Response to trabectedin according to
BRCA mutational status
BRCA 12
N
ORR
CR+PR
(%)
DCR
(ORR+SD)
PD
WT
43
17
(39.5)
27 (62.8)* 14 (32.5)
4.5
66.7**
MUT
23
12
(52.2)
17 (73.9)
4.5
83.0
5 (21.7)
PFS
3- year
(Months) OS (%)
*P value DCR: 0.51; **P value OS: 0.041
26-30 September 2014, Madrid, Spain
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Response to trabecteding according to mutations of single
nucleotide polymorphisms (SNPs) in DNA repair genes (XPD,
XPG and ERCC1)
5 SNPs involved in NER machinery (ERCC1 C118T, ERCC1 C8092, XPG ASP1104HIS,
XPD ASP312ASN, XPD LYS751GLN) were evaluated in 75 patients.
SNPs
CR+PR+ SD (%)
PD (%)
P value
ERCC1 C118T
WT (26)
MUT (49)
16 (61.5)
33 (67.3)
8 (30.7)
14 (28.5)
0.8
ERCC1 C8092
WT (37)
MUT (38)
23 (61.3)
26 (69.3)
12 (32.4)
10 (26.3)
0.6
XPG ASP1104HIS
WT (47)
MUT (28)
30 (63.8)
19 (67.8)
15 (32)
7 (25)
0.6
XPD ASP312ASN
WT (26)
MUT (49)
15 (57.6)
34 (69.4)
9 (34.6)
13 (26.5)
0.4
16 (55)
33 (72)
11 (38)
11 (24)
0.2
XPD LYS751GLN
WT
(29)September 2014, Madrid, Spain
26-30
MUT (46)
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CONCLUSIONS
 This study shows an increased percentage of BRCA 1/2 mutations in
the BRCAness phenotype compared to published data in AOC
patients. BRCAness profile and, in particular, a history of higher
number of previous responses to platinum, is associated with
increased responses to trabectedin
 Clinical response was higher although non statistically significant in
patients carrying germline BRCA 1/2 mutations. The fact that BRCA
driven HR is not the only repair mechanism available in tumor cells,
can explain the limited sensitivity of germline BRCA mutations as
predictive factors in this study.
 In this clinical study NER polymorphisms did not correlate with
responses to trabectedin.
26-30 September 2014, Madrid, Spain
esmo.org
Next step
• Paper finalized
• Possible journals: JCO, Lancet Oncology,
Annals of Oncology
• Clinical substudies: Emesis (Dr Di Napoli),
Analisys of subsequent treatments (Dr
Salutari)
• Translational substudy: evaluation of
immoreactive signature in MITO 15 specimens
(Dr Gourley)
26-30 September 2014, Madrid, Spain
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MITO 15 Emesi
AGGIORNAMENTO
Marilena Di Napoli
Progetto di valutazione del PFS2 dopo Yondelis nei pazienti
arruolati in MITO15
CENTRI
AGGIORNAMENTI
Centro 001-Roma
Si
Centro 002-Milano
Si
Centro 011-Perugia
Si
Centro 014-Milano
Si
Centro 021-Mirano
Si
Centro 043-Catanzaro
Si
Centro 004-Roma
No
Centro 009-Ferrara
No
Centro 013-Modena
No
Centro 022- Rionero in Vulture
No
Centro 030-Napoli
No
Centro 039-Aviano
No
Centro 047-Sora
No
Centro
N° pz arruolate
N° pz sottoposte ad
ulteriore CT
N° (%)
Centro 001-Roma
21
16 (76)
Centro 002-Milano
18
13 (72)
Centro 011-Perugia
7
4 (57)
Centro 014-Milano
7
5 (71)
Centro 021-Mirano
4
4 (100)
Centro 043-Catanzaro
2
1 (50)
Patients (N°)
59
N° (%)
Next therapy
43 (73)
Not other chemotherapy
13 (22)
Screening failure
1 (2)
Not evaluable
2 (3)
Regime di chemioterapia
N° (%)
Paclitaxel settimanale
9 (20)
Cisplatino d1q21
6 (14)
Carboplatino d1q21
5 (12)
Doxorubicina Liposomiale Peghilata
d1q28
4 (9)
Ciclofosfamide p.o.
3 (7)
Gemcitabina
2 (5)
Carboplatino-Paclitaxel d1q21
2 (5)
Cisplatino intraperitoneale
1 (2)
Adriamicina
1 (2)
Cisplatino-Paclitaxel d1q21
1 (2)
Carboplatino settimanale
1 (2)
Carboplatino-Gemcitabina
1 (2)
Vinorelbina
1 (2)
Tamoxifene
1 (2)
Carboplatino-PLD d1q28
1 (2)
NV
3 (7)
Next chemotherapy
N
%
No. total patients
43
100
No. of evaluable patients
26
6
Median PFS (month)
Range
Progression event
4
(1-14)
25
Randomized phase III trial on Trabectedin (ET
743) vs clinician’s choice chemotherapy in
recurrent ovarian, primary peritoneal or fallopian
tube cancers of BRCA mutated or BRCAness
phenotype patients
MITO – 23
MITO-23: TRANSLATIONAL STUDIES
• DNA sequencing in order to evaluate
mutation/genetic aberration profile in selected
panels of genes associated to tumor sensitivity to
trabectedin.
•Evaluating the impact of altered gene and
microRNA (miRNA) expression on trabectedin
efficacy with the aim of identify which
miRNAs/genes are involved in the so called
BRCAness phenotype;
• Analysis of cellular infiltrate present on tumor
specimens of patients treated with trabectedin;
MITO - 23
TRANSLATIONAL STUDIES:
Specimens
Tumor histological blocks (FFPE material): samples will be collected at primary
surgery and/or surgery nearest to trabectedin treatment (or before trabectedin treatment by
dedicated biopsies). Storage and analysis will be centralized at Fondazione Istituto
Nazionale dei Tumori.
•Characterization of tumor infiltrate by IHC (2 slides per marker & 1 HE slide & 3
backup
slides);
•Extraction of RNA from tissue sections for miRNA/gene expression;
•Extraction of DNA from tissue sections for targeted sequencing of “Panel cancer
related
genes”.
Blood samples: Blood samples will be collected at baseline (registration), at third
cycle of treatment and at progression. Storage and analyses will be centralized at
Istituto Mario Negri, Milan. 10 ml blood sample will be taken at each time point,
centrifuged in EDTA, processed to obtain 5 ml plasma collected and stored at -20°C
or at -80°C when possible.
MITO - 23