Triple Negatif Meme Kanserinde Birinci Basamak Kemoterapi

Triple Negatif Meme Kanserinde Birinci Basamak Kemoterapi

Triple Negatif
Meme Kanserinde Birinci Basamak
Kemoterapi Sonrası Seçenekler
Dr. Alper SEVİNÇ
Gaziantep Üniversitesi Onkoloji Hastanesi
13 Mayıs 2016, Antalya
Ajanda
• TNMK Genel Bilgiler
• PARP İnhibitörleri
• İmmüno-Onkolojik Yaklaşımlar
Meme Kanseri
Alt Sınıfları
TNMK
Heterojen
Yapısı
Dissecting the Heterogeneity of TNBC
CK5/6, CK17
Metzger-Filho et al, JCO 2012
“Triple Negative”  “Basal-like”
“Triple Negative”
Immunohistochemistry profile
ER-, PR-, HER2(cyclin D1-, CK5/6/17+, EGFR+, vimentin+, nestin+…)
Gene Expression Profile
Not all Triple Negative Breast Cancers are Basal Subtype ….
Nielsen et al al. CCR, 2004
“Triple negatif” meme kanserinin doğal süreci
Basal/TN
Basal/TN
Copyright ©2003 by the National Academy of Sciences
Sorlie et al PNAS 2003
TNMK: Uzak Nüks
1-3 Yıl
Peak of recurrence
• TN: 1 to 3 years
• Non-TN: steady risk over time
Dent R, et al. Clin Cancer Res 2007
Metastatik Triple Negatif Meme Kanseri
Kemoterapi Seçenekleri
Davis SL, et al. Ther Med Oncol 2014
DNA Tamir Mekanizması
DNA DAMAGE
Environmental factors
(UV, radiation, chemicals)
Normal physiology
Cell Death
(DNA replication, ROS)
Chemotherapy
(alkylating agents, antimetabolites)
Radiotherapy
Single Strand Breaks
• Nucleotide excision repair
• Base excision repair
MAJOR DNA REPAIR
PATHWAYS
Replication Lesions
• Base excision repair
• PARP1
• PARP1
Double Strand Breaks
• Non-homologous end-joining
• Homologous recombination
• BRCA1/BRCA2
• Fanconi anemia pathway
• Endonuclease-mediated repair
DNA Adducts/Base Damage
• Alkyltransferases
• Nucleotide excision repair
• Base excision repair
• PARP1
Helleday et al. Nature Reviews. 2008; 8:193
BiPar Sciences Confidential
TNMK
PARP-1 Upregulation
Normal
Normal
IDC
ER+
ERPR+
PRHER2+
HER2ER+/PR+/HER2+
ER-/PR-/HER20%
IDC subtype
2.90%
30.2%
22.9%
55.6%
23.1%
45.0%
29.2%
70.0%
20.0%
80.0%
20%
40%
60%
80%
100%
% PARP1 Upregulation*
* Defined by percentage of samples exceeding the 95% UCL of normal tissue distribution.
O’Shaughnessy J. TNBC 101
Research To Practice Webinar, 2010.
Triple Negatif Meme Kanserinde Birinci Basamak
Kemoterapi Sonrası Seçenekler
Poly (ADP-Ribose)
Polymerase (PARP)
Inhibitörleri
Faz II-İniparib
Iniparib Faz II
BRCA+
20 Centers in US
Patients
• ≥18 years
• HER2-negative breast
cancer with a germline
BRCA mutation
• Up to 2 prior
chemotherapy (neo
adjuvant and adjuvant)
• ECOG PS 0 or 1
• Prior therapy of cisplatin,
carboplatin, gemcitabine
or a PARP inh.
excluded
Randomise
1:1
Gemcitabi
ne+Carbo
platin+
Iniparib
(61)
N≈123
Gemcita
bine+Ca
rboplatin
(62)
Primary
endpoint
Clinical
Benefit
Rate
(CBR)
Second
ary
endpoin
ts
ORR
PFS
OS
Faz II
A Randomized Phase III Study of Iniparib
(BSI-201) in Combination with Gemcitabine
and Carboplatin in Metastatic Triple
Negative Breast Cancer (mTNBC)
Joyce O’Shaughnessy,1,2,3 Lee Schwartzberg4,5 Michael A. Danso,3,6 Hope Rugo,7
Kathy Miller,8 Denise Yardley,9,10 Robert W. Carlson,11 Richard Finn,12 Eric
Charpentier,13 Sunil Gupta,13 Monica Freese,13 Anne Blackwood-Chirchir,14 and Eric
P. Winer15
Iniparib: TNMK
Study Design: Multi-center, randomized open-label Phase III Trial
N = 519
Gem/Carbo (GC)
Study Population:
• Stage IV TNBC
• ECOG PS 0–1
• Stable CNS metastases allowed
• 0-2 prior chemotherapies for mTNBC
• Randomization stratified by prior
chemo in the metastatic setting:
• 1st-line (no prior therapy)
• 2nd/3rd-line (1-2 prior therapies)
(N= 258)
Gemcitabine 1000 mg/m2 IV d 1, 8
Carboplatin AUC2 IV d 1, 8
Crossover allowed
to GCI following
Disease Progression*
(central review)
21-day cycles
R
Gem/Carbo + Iniparib (GCI)
(N= 261)
Gemcitabine - 1000 mg/m2 IV d 1, 8
Carboplatin - AUC2 IV d 1, 8
Iniparib - 5.6 mg/kg IV d 1,4,8,11
21-day cycles
*Prospective central radiology review of progression required prior to crossover
96% (n=152) of progressing patients crossed over to GCI at time of primary analysis
NCT00938652
ITT Popülasyonda Fark Saptanmadı
2-3 Sıra Alanlarda Fark Var
2nd / 3rd -line = 43% patients (222/519)
PFS
GCI 4.2 mos (3.8, 5.7)
0.9
GC
2.9 mos (1.9, 4.1 )
HR=0.67 (0.5, 0.92); 169 events
0.8
0.7
0.6
0.5
0.4
GCI 10.8 mos (9.7,13.1)
0.9
GC
8.1 mos (6.6, 10)
HR=0.65 (0.46, 0.91); 132 events
0.7
0.6
0.5
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
0
0
No. at
risk
GC
GCI
1.0
0.8
Probability of Survival
Probability of Progression Free Survival
1.0
OS
2
4
6
8
10
12
14
16
0
2
4
6
Months
109
113
61
81
42
59
19
32
9
18
8
10
12
14
16
Months
5
4
1
0
0
0
0
0
109
113
96
107
84
98
68
86
54
70
29
47
11
24
2
9
0
0
Oleparib Çalışmaları
Studies evaluating olaparib in
breast cancer
Faz II
•
Study 8 / ICEBERG
Study 20
Study 42
(Tutt A, et al. Lancet. 2010)
(Gelmon KA, et al. Lancet. Oncol. 2011)
(Kaufman B, et al. J Clin Oncol. 2015)
Locally advanced/metastatic BRCAm
breast cancer (n=54)
• Olaparib 400mg bid (n=27)
• Olaparib 100mg bid (n=27)
• Advanced metastatic or recurrent
breast cancer (n=26)
• BRCA (n=10) Non-BRCA (n=16)
• Olaparib 400mg bid
• Advanced BRCAm solid tumours,
(n=298);
breast cancer (n=62)
• Olaparib 400mg bid
Tutt A, et al. Lancet. 2010;376:235–244; Kaufman B, et al. J Clin Oncol. 2015;33:244–250; Gelmon KA, et al. Lancet Oncol. 2011;12:852–861
Study 8
Patients (N=54)
• Locally advanced or metastatic
breast cancer
• Confirmed germline BRCA1 or
BRCA2 mutation
• ≥1 measurable lesion according
to RECIST
• Received ≥1 chemotherapy
regimen
• ECOG PS 0–2
Cohort 1 (n=27)
Olaparib
400mg bid (MTD*)
Treatment was not
randomly assigned
Cohort 2 (n=27)
Olaparib
Primary endpoint
• ORR
Secondary endpoints
• Clinical benefit rate
• PFS
• Duration of response
• Safety & tolerability
100mg bid**
*MTD, maximum tolerated dose determined during Phase I evaluation
**Following an interim review of the emerging efficacy of each cohort, patients ongoing in the 100mg bid cohort were permitted to
escalate to the 400mg twice daily dose after a repeat RECIST response assessment
Tutt A, et al. Lancet. 2010;376:235–244
Study 8
Efficacy: Best % change from
baseline
The median best percentage change (reduction)
both BRCA1
and(range
BRCA2
carriers
in Responses
tumour sizeseen
from in
baseline
was –30%
–100%
to 27%)
Best % change from baseline
100
80
Olaparib 400mg bid
cohort
60
40
20
0
–20
–40
–60
–80
–100
Tutt A, et al. Lancet. 2010;376:235–244
Increasing tumour
shrinkage
BRCA1
BRCA2
Study 8
Efficacy: PFS
Median PFS was
5.7 months
withfor
olaparib
400mg
Kaplan-Meier
curves
of PFS
ITT population
Freedom from progression, %
and 3.8 months with olaparib 100mg
100
Median PFS (95% CI)
Olaparib 400mg: 5.7 months (4.6, 7.4)
Olaparib 100mg: 3.8 months (1.9, 5.5)
90
80
70
60
50
40
30
20
10
0
0
50
No. of patients at risk
400mg: 27
26
100mg: 27
24
Tutt A, et al. Lancet. 2010;376:235–244
100
150
200
250
300
350
400
450
6
0
5
0
1
0
0
0
PFS, days
22
16
17
10
13
4
8
0
BRCA vs Non-BRCA
Study 20
• To determine the role of BRCA mutations on the efficacy and safety of olaparib in
women with advanced ovarian or breast cancer
• Phase II, multicentre, open-label, non-randomised study in six centres in Canada
Breast cancer patients (N=26)
• Confirmed advanced metastatic
or recurrent BC
•
•
Triple negative OR known
BRCA-mutated BC
Primary endpoint
• ORR (RECIST)
Olaparib
400mg bid
Life expectancy of >16 weeks
•
ECOG PS ≥2
•
Been tested for or willing to
undergo BRCA1 and BRCA2
mutation testing
Gelmon KA et al. Lancet Oncol. 2011;12:852–861
Stratification by
presence of BRCA1 or
BRCA2 mutation or not
Secondary endpoints
• Disease-control rate
• % change from baseline
in target-tumour size
• PFS
Study 20
Best % change from baseline
100
80
Breast BRCA
Breast non-BRCA
60
40
20
0
–20
–40
–60
–80
–100
Gelmon KA et al. Lancet Oncol. 2011;12:852–861
PFS: 3.6 ay
Studies evaluating Olaparib
in Breast Cancer
Phase II
•
Study 8 / ICEBERG
Study 20
Study 42
(Tutt A, et al. Lancet. 2010)
(Gelmon KA, et al. Lancet. Oncol. 2011)
(Kaufman B, et al. J Clin Oncol. 2015)
Locally advanced/metastatic BRCAm
breast cancer (n=54)
• Olaparib 400mg bid (n=27)
• Olaparib 100mg bid (n=27)
• Advanced metastatic or recurrent
breast cancer (n=26)
• BRCA (n=10) Non-BRCA (n=16)
• Olaparib 400mg bid
• Advanced BRCAm solid tumours,
(n=298);
breast cancer (n=62)
• Olaparib 400mg bid
Phase III
Tutt A, et al. Lancet. 2010;376:235–244; Kaufman B, et al. J Clin Oncol. 2015;33:244–250; Gelmon KA, et al. Lancet Oncol. 2011;12:852–861
ClinicalTrials.gov identifier NCT020000622.
Assessment of the efficacy and safety of
olaparib monotherapy versus physicians’
choice chemotherapy in the treatment of
metastatic breast cancer patients with
gBRCA1/2 mutations
ClinicalTrials.gov identifier NCT020000622.
Aim and study design
Olaparib vs TPC in BRCA-mutated metastatic breast cancer
Patients
•
BRCA-mutated MBC
•
TNBC or HER2-negative,
ER/PR-positive
•
•
•
Global Study in 19 countries
and approximately 190 sites
Suitable for 1st, 2nd or 3rd line single
agent chemotherapy
Previous treatment must include
anthracycline and taxane
If patients have received platinum
therapy there should be:
• No evidence of progression during
treatment in the advanced setting
• At least 12 months since
(neo)adjuvant treatment and
randomisation
•
ECOG PS 0 or 1
•
At least one lesion that can be
assessed by RECIST
* tablet formulation (2 tablets twice daily)
Olaparib
300mg*po bid
Randomise 2:1
Approximate
N=310
Treatment of
Physician’s
Choice
Stratification by
• Prior chemotherapy regimens for
metastatic breast cancer
• Hormonal status
• Prior platinum therapy
Primary endpoint
• PFS (RECIST 1.1,
Independent Review)
Secondary endpoints
• OS
• PFS2
• ORR
• HRQoL
• Development of a
companion diagnostic
• PK
• Safety and tolerability
FSI May 2014
Status: Recruitment completed
ClinicalTrials.gov. NCT020000622. Available from https://clinicaltrials.gov/ct2/show/NCT02000622?term=NCT02000622&rank=1. [Last accessed: December,
2015]; Robson M, et al. Poster presented at San Antonio Breast Cancer Symposium; 9–13 December, 2014; San Antonio, Texas. Poster number OT1-1-04
Country coverage
Europe & Middle East
N. America
USA
Latin America
Mexico
Peru
Bulgaria
Czech Republic
France
Hungary
Italy
Poland
Romania
Spain
Switzerland
Turkey
UK
Russian
Federation
Asia Pacific
China
Japan
Republic of
Korea
Taiwan
ClinicalTrials.gov. NCT020000622. Available from https://clinicaltrials.gov/ct2/show/NCT02000622?term=NCT02000622&rank=1. [Last accessed: December,
2015]
Phase I Trial of Cisplatin/Vinorelbine with PARP
Inhibitor ABT-888 (Veliparib) in Metastatic Breast
Cancer
Patients with
metastatic TNBC
and/or BRCA
mutation
associated breast
cancer
Cisplatin 75 mg/m2
IV Day 1
Vinorelbine 25 mg/m2
Days 1,8
Veliparib Days 1-14
Dose escalation
every 21 days
Rodler E et al, SABCS 2011, abstract P1-17-04
Phase I Trial of Cisplatin/Vinorelbine with ABT-888
(Veliparib)
Maximum Tumor Response (%) from Baseline
• 36 patients
enrolled to
date
• Currently at
dose level 7 of
veliparib
Gelişmekte Olan PARP İnhibitörleri
PARP Inhibitors in Development
Agent
Company
Route
Current Trials
Rucaparib
Clovis
IV/Oral
BRCA+, post-neoadjuvant
TNBC +cisplatin
Olaparib
AstraZeneca
Oral
BRCA+
Veliparib
Abbott
Oral
BRCA+, TNBC +
paclit/carbo
Iniparib
BSI-201
BiPar/Sanofi-Aventis
IV
Dose escalation
LT673
(2011)
Biomarin
Oral
-
INO-1001
Inotek
IV
-
MK4827
Merck
Oral
-
CEP-9722
Cephalon
Oral
-
E7016
Eisai
Oral
-
Plummer R BCR 2011 vol. 13 (4) pp. 218. with edits
Meme Kanseri Patogenezi:
İmmün Mekanizmalar
Hanahan D, Cell. 2011
T Hücre Hedefleri
Aktivatör vs İnhibitör
Mellman I. Nature 2011
PD-1/PD-L1 inhibisyonu
T-hücresini aktive ediyor
Sznol M. Clin Cancer Res. 2013
Phase Ib KEYNOTE-012: Pembrolizumab in
PDL-1+ Advanced TNBC
Pts with recurrent
or metastatic
ER/PgR-/HER2-,
PD-L1+ BC
(N = 32)
Pembrolizumab
10 mg/kg
q2w
CR
Discontinuation
permitted
PR or SD
Treat for 24 mos
or until PD or intolerable
toxicity
PD
Discontinue
• Pembrolizumab: anti–PD-1 antibody with high affinity for receptor
– Provides dual ligand blockage of PD-L1 and PD-L2
– No cytotoxic activity (ADCC/CDC)
– Clinical activity in multiple tumor types, recent approval in melanoma
Nanda R, et al. SABCS 2014. Abstract S1-09.
%44.4
Pembrolizumab in Advanced TNBC
(KEYNOTE-012): Toxicity
Adverse Events in ≥ 5%, %
N = 32
Any Grade
Grade 3-5
Arthralgia
18.8
0
Fatigue
18.8
0
Myalgia
15.6
0
Nausea
15.6
0
ALT increased
6.3
0
AST increased
6.3
0
Diarrhea
6.3
0
Erythema
6.3
0
Headache
6.3
3.1 (1 patient)
Potentially immune-related AEs (regardless of attribution): pruritus (n = 3; all grade 1/2),
hepatitis (n = 1; grade 3), hypothyroidism (n = 1; grade 2)
Nanda R, et al. SABCS 2014. Abstract S1-09.
Pembrolizumab in Advanced TNBC
(KEYNOTE-012): Conclusions
• Pembrolizumab safe, tolerable in heavily
pretreated,
PD-L1–positive advanced TNBC
• ORR: 18.5%
• Durable responses
– Median DOR: not reached (range: 15-40+ wks)
– 3 responding pts on treatment for ≥ 11 mos
• Phase II study in advanced TNBC planned for
2015
Nanda R, et al. SABCS 2014. Abstract S1-09.
TNMK-Kılavuzlar
• NCCN:
• ESMO:
• St Gallen:
No specific algorithm
No specific algorithm
No specific algorithm
How to improve the outcome of
TNBC?
• Adjuvant setting
CLINICAL
• Neoadjuvant setting
TRIALS!!!
• Metastatic setting
– Anthra plus Taxanes
– Anthra plus Taxanes
–
–
–
–
–
Re-biospy
Bevacizumab
Platinum salts
Eribulin
PARP inhibitörleri
Vaka
TB-Öğretim Üyesi Eşi (Yrd. Doç)
Beyin Metastazı sonrası YBÜ ihtiyacı olursa
müdahale istemedi…
Şubat 2015 BRCA +
Oleparib kolu (Karşı kol Eribulin)
1.Ayda %30
2. Ayda %20
16. Ayda %10 regresyon
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