Update on Breast Cancer - ImedexTo assess the efficacy and tolerability of oral olaparib in...
Transcript of Update on Breast Cancer - ImedexTo assess the efficacy and tolerability of oral olaparib in...
Update on Breast Cancer
William J. Gradishar, MD
Professor of Medicine
Robert H. Lurie Comprehensive Cancer Center
Feinberg School of Medicine
Northwestern University
Overview
PARP Inhibitors
Neoadjuvant Therapy in BRCA+ BC
SLNB and Auxillary Recurrence
Endocrine Therapy Studies
Metastatic Breast Cancer Therapy
– DM-1
– Neratanib
– RIBBON-1
PARP Inhibitors
PARP-1 is a key enzyme involved in repair of
single strand DNA breaks
•PARP
Inhibition of PARP-1 prevents recruitment of DNA repair enzymes leads to failure of SSB repair
-accumulation of SSBs
•XRCC1
•LigIII
•PNK 1
•pol β
During S-phase,
replication fork
is arrested at
site of SSB
Degeneration into
double strand breaks
DNA single strand
break (SSB)
damage
•Cellsurvival
•Normal cell
Deficient HR repair Increases DSB that can’t be repaired
Selective effect of PARP-1 inhibition
on cancer cells with BRCA1 mutation
Triggers activation
of HR pathway to repair DSB
•DSB in DNA
•Genomic instability and apoptosis
•BRCA-deficient cancer cell
•HR – homologous recombination; DSB – double strand break
PARP Inhibitor Mechanism of Action
O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.
1. PLATINUM CHEMOTHERAPY
Inflicts DNA damage viaadducts and DNA crosslinking
2. PARP1UPREGULATION
Base-excision repairof DNA damage
3. INHIBITION OFPARP1Disables DNAbase-excisionrepair
4. REPLICATIONFORK COLLAPSEDouble strand DNAbreak
Cell Survival Cell Death
BRCA1BRCA2
CG
CG
CG
GC
TA
ATT
A
CG
CG
TA
ATT
A
C
G
PARP1
PARP1
BSI-201
PARP1
Triple Negative BC Shares Clinical and
Pathologic Features with BRCA1-Related BC
*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44
O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.
Characteristics Hereditary BRCA1 Triple Negative/Basal-Like 1,2,3
ER/PR/HER2 status Negative Negative
TP53 status Mutant Mutant
BRCA1 status Mutational inactivation* Diminished expression*
Gene-expression pattern Basal-like Basal-like
Tumor histology Poorly differentiated
(high grade)
Poorly differentiated
(high grade)
Chemosensitivity to
DNA-damaging agents
Highly sensitive Highly sensitive
1. Perou C, et al. Nature. 2000;408:747-752. 2. Cleator S, et al. Lancet Oncology. 2007;8:235-244. 3. Sorlie T, et al. Proc Natl Acad Sci USA. 2001;98:10569-10674. 4. Miyoshi Y, et al. Int J Clin Oncol. 2008;13:395-400.
Phase II TNBC Study: Treatment Schema
O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.
RestagingEvery 2 Cycles
21-DayCycle
* Patients randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression
BSI-201 (5.6 mg/kg, IV, d 1,4,8,11)
Gemcitabine (1000 mg/m2, IV, d 1,8)
Carboplatin (AUC 2, IV, d 1,8)
Metastatic TNBCN = 120
RANDOMIZE
BSI-201: small moleculePARP inhibitor
Gemcitabine (1000 mg/m2, IV, d 1,8)
Carboplatin (AUC 2, IV, d 1,8)
BSI-201: Preliminary Efficacy Results*
O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.
Gem/Carbo
(n = 44)
BSI-201 +Gem/Carbo
(n = 42)
P-value
Objective Response Rate, n (%) 7 (16) 20 (48) .002
**Clinical Benefit Rate, n (%) 9 (21) 26 (62) .0002
* Includes patients enrolled before September 30, 2008 and patients who had a confirmed response or disease progression**Clinical Benefit Rate = CR + PR + SD ≥ 6 months
BSI-201: Conclusions
PARP1 was upregulated in most evaluated TNBC patients
BSI-201 + gemcitabine/carboplatin was well tolerated and did not potentiate chemotherapy-related toxicities
BSI-201 improved patients’ clinical outcomes
– Clinical Benefit Rate (62% vs. 21%; P = .0002)
– ORR (48% vs 16%; P = 0.002)
– Median PFS (6.9 months vs. 3.3 months; P < 0.0001)
– Median OS (9.2 months vs. 5.7 months; P = 0.0005)
Promising safety and efficacy data from this Phase II study justify further investigation of BSI-201 in a Phase III study
O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.
Phase II Study with Olaparib: Rationale
and Design To assess the efficacy and tolerability of oral olaparib in BRCA1/BRCA2
mutation carriers with breast cancer
Multicenter proof-of-concept phase II study, single-arm sequential cohort design
Tutt A, et al. ASCO 2009. Abstract 501.
Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer
(stage IIIB/IIIC/IV) after failure ≥1 prior chemotherapyfor advanced disease
Cohort 1 (enrolled first)
Olaparib 400 mg po BID (MTD)28-day cycles; n = 27
Cohort 2*
Olaparib 100 mg po BID 28-day cycles; n = 27
*Following an interim review of the emerging efficacy of each cohort, patients ongoing in 100 mg BID cohort were permitted to crossover to receive the 400 mg bid dose
MTD: determined during Phase I evaluation
Olaparib: Efficacy Results
Tutt A, et al. ASCO 2009. Abstract 501.
ITT cohort Olaparib 400 mg bid
(n = 27)
Olaparib 100 mg bid
(n = 27)
Overall Response Rate, n (%) 11 (41)* 6 (22)*
Complete Response, n (%) 1 (4) 0
Partial Response, n (%) 10 (37) 6 (22)
*An additional 1 patient in the 400 mg cohort and 3 patients in the 100 mg cohort had unconfirmed responses
Per protocol cohort 400 mg bid
(n = 26)
100 mg bid
(n = 24)
Overall Response Rate, n (%) 11 (42) 6 (25) †
Complete Response, n (%) 1 (4) 0
Partial Response, n (%) 10 (39) 6 (25)
†An additional 3 patients in the 100 mg cohort had unconfirmed responses
Olaparib: Conclusions
First report of a targeted therapy trial designed for BRCA1/BRCA2carriers with breast cancer
Single agent oral olaparib 400 mg bid has substantial activity in heavily pre-treated BRCA1/BRCA2 carriers with advanced breast cancer
– Objective response rate ITT (RECIST): 41%
– Median PFS: 5.7 months
Oral olaparib is well tolerated in BRCA1/BRCA2 carriers with a similar side effect profile to prior experience in non-carriers
Clinical proof-of-concept for targeting BRCA1/BRCA2 mutations in both breast and ovarian1,2 cancer
Neoadjuvant Therapy in BRCA+
Breast Cancer
Neoadjuvant Study: Design
Gronwald J, et al. ASCO 2009. Abstract 502.
BRCA1 Mutation Carriers
Primary Breast Cancer
Cisplatin 75mg/m2q 3wks IV x 4 cycles
SURGERY
AC
Primary Endpoint: pCR (in breast and axilla, DCIS permitted)
N = 10 25
Neoadjuvant Study: Response to
Treatment
Gronwald J, et al. ASCO 2009. Abstract 502.
Response No. %
Clinical response
Complete response 18 72
Partial response 7 28
No change 0 0
Progressive disease 0 0
Pathologic response
Complete pathologic response 18 72
Partial response 7 28
No response 0 0
Residual disease in breast
None 19 76
< 1 cm 0 0
1-5 cm 6 24
> 5 cm 0 0
Number of lymph nodes positive
0 21 84
1-3 4 16
4-9 0 0
>9 0 0
Neoadjuvant Study: Conclusions
Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancers
Choice of breast cancer treatment may be better with BRCA1 testing
Gronwald J, et al. ASCO 2009. Abstract 502.
Sentinel Lymph Node Biopsy and
Auxillary Recurrence
Omission of Axillary Therapy in Patients with
pN1mi or pN0i+ by Sentinel Node Biopsy:
the MIRROR Study
Tjan-Heijnen et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA506).
• Patients selected from the Netherlands Cancer Registry (1998-2005) (N = 3205)
• Median follow-up: 4.7 years
•Sentinel node biopsy
•only (SN only)
N = 1218
•Completion axillary
•lymph node dissection
•(cALND) N = 1314
•Axillary radiotherapy
•(axRT)
N = 148
• Patients with favorable
• primary tumor characteristics
• No indication for adjuvant
• systemic therapy
• Sentinel node procedure
• pN0, pN0(i+) or pN1mi
•N = 2680 after central pathology
review
Tjan-Heijnen et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA506).
Sentinel node
status
Axillary
therapy
N 5-yr axillary
recurrence
HR95 % CI
pN0cALND 125 1.6% 1.00 Reference
SN only 732 2.3% 1.08 0.23 – 4.98
pN0 (i+)cALND/axRT 450 0.9% 1.00 Reference
SN only 345 2.0% 2.39 0.67 – 8.48
pN1micALND/axRT 887 1.0% 1.00 Reference
SN only 141 5.0% 4.39* 1.46 – 13.24
•HR corrected for age, tumor size, grade, hormone receptor status, adjuvant systemic therapy and radiotherapy to the breast
•* Statistically significant compared to cALND/axRT
Results: Multivariate Analysis
Omission of Axillary Therapy in Patients with pN1mi or pN0i+ by Sentinel Node Biopsy:
the MIRROR Study
Tjan-Heijnen et al. J Clin Oncol 2009; 27
(suppl): 18s (abstract CRA506).
− Omission of axillary therapy appears feasible in pN0 disease
− Axillary therapy non-significantly decreased axillary
recurrence in those with pN0(i+) disease
− Axillary therapy significantly decreased axillary recurrence in
those with pN1mi disease
− Patients who received axRT showed no axillary recurrence,
although number of events was too small for statistical
analysis
− Tumor size, histological grade III, and negative ER/PgR status
were significantly predictive of 5-year axillary recurrence by
multivariate analysis
Omission of Axillary Therapy in Patients with pN1mi or pN0i+ by Sentinel Node Biopsy:
the MIRROR Study
Conclusions
Endocrine Therapy Studies:
CYP2D6 Inhibition
Tamoxifen Metabolism
Aubert RE, et al. ASCO 2009. Abstract 508.
TAMOXIFEN 4-OH-TAM
CYP2D6
CYP3A4/5 CYP3A4/5
SULT1A1UGT
SULT1A1UGT
NDM-TAM
CYP1A2CYP2C9CTYP2C19CYP2B5
CYP2B6CYP2C9CTYP2C19CYP3A
CH2
CH2O
O
H2OH2O
OH
O
CH2
CH2
O
H2O
ON
CH2
H
H2O
OH
ON
CH2
H
CYP2D6
ENDOXIFEN
Risk of breast cancer recurrence in women initiating
tamoxifen with CYP2D6 inhibitors
Aubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508).
• Retrospective cohort analysis of medical and pharmacy claims from the
Medco Health Solutions integrated database
• Primary endpoint: hospitalization for breast cancer (event-free survival)
• Median duration of overlap between CYP2D6 inhibitors and tamoxifen:
287 days
•Weak CYP2D6 inhibitor therapy use or without overlap with tamoxifen
•Moderate-severe CYP2D6 inhibitor use with tamoxifen
•(n = 945)
•(n = 359)
•(n = 1659)
Eligibility:
Continuous eligibility 6 mo prior to tamoxifen initiation
Tamoxifen naïve (6 mo negative history)
Tamoxifen duration ≥ 24 months
Medication possession ratio of ≥ 0.7
•No CYP2D6 inhibitor therapy
•(n = 355)
Risk of breast cancer recurrence in women initiating
tamoxifen with CYP2D6 inhibitors
Aubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508).
• Concomitant use of tamoxifen with moderate-severe CYP2D6 inhibitors
significantly increases the risk of breast cancer recurrence
• Moderate-potent SSRIs double the risk of recurrence, while weak SSRIs
were not associated with increased risk
N Breast cancer
recurrence
HR* P value
No CYP2D6 inhibitors 945 7.5% reference reference
Moderate/severe CYP2D6
inhibitors
407 14% 1.92 (1.36-2.73) .0002
SSRIs
Weak 137 9% 1.07 (0.79-1.45) .677
Moderate/potent 213 16% 2.20 (1.46-3.31) .0002
* HR relative to no CYP2D6 inhibitor group
Concomitant CYP2D6 inhibitor use and tamoxifen
adherence in early stage breast cancer
Dezentje et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA509).
• Retrospective pharmaco-epidemiologic study
• Databases: PHARMO, PALGA, Dutch Medical Register
• Univariate Cox regression of event-free time:
• No difference when only strong CYP2D6 inhibitors included
Inclusion criteria:
breast cancer resection
Tamoxifen use ≥ 120 days
CYP2D6 inhibitor use ≥ 60 days
Tamoxifen only
Tamoxifen + CYP2D6 inhibitor
(n = 1749)
(n = 150)(n = 3147)
CYP2D6 inhibitor
use
HR 95% CI P value
No use 1.00 reference reference
Use ≥ 60 days 0.95 0.60-1.50 0.73
Summary of concomitant CYP2D6 inhibitor use with
tamoxifen in early stage breast cancer
• Registry studies give conflicting results regarding the
effect of concomitant use on breast cancer recurrence
• CYP2D6 pharmacogenomics likely complicated;
published data on CYP2D6 genotypes inconsistent
• Possession of drug does not necessarily indicate
compliance
• Need further validation studies before
recommendations for routine use can be made
Metastatic Breast Cancer
Trastuzumab-DM1
• DM1-Derivative of maytansine:
- Naturally occurring antitumor
antibiotic
- Significant preclinical activity,
but significant clinical toxicity as
free drug
• Trastuzumab-DM1 is designed to
preferentially deliver DM1 to
HER2+ tumor cells:
- Improve therapeutic index of DM1
- Maintain biological effect of
trastuzumab
•Target-dependent cytotoxic activity
Phase II T-DM1 Study Description
A multi-institutional, open-label, single-arm Phase II US study in patients with locally confirmed HER2-positive MBC who progressed while receiving HER2-directed therapy
– Patients had received a median of 3 prior chemotherapy agents for MBC (range 1-12)
– 67/112 (60%) patients also received prior lapatinib
– T-DM1 (3.6 mg/kg) was given by IV infusion over 30-90 minutes every 3 weeks (q3w) until progression
Primary endpoint
– Objective response rate (ORR) per RECIST by independent review facility (IRF)
Krop IE, et al. ASCO 2009. Abstract 1003.
Retrospective analysis of biomarkers for response
to trastuzumab-DM1 in pretreated HER2+ MBC
Krop et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1003).
• Study objective:
− Identify biomarkers that will predict for response to T-DM1
• Study details:
− Retrospective analysis of phase II study evaluating trastuzumab-
DM1 in patients with HER2+ MBC with progression on prior HER2-
targeted therapy
− Examined HER2 (IHC, FISH, RT-PCR), HER2 extracellular
domain (ECD), HER3, PI3K mutations, PTEN loss
Efficacy
Centrally
confirmed HER2+
(n = 75)
Centrally confirmed
HER2 normal
(n = 21)
P value
ORR*
(95%CI)32% (22-43%) 5% (<1-22%) .01
PFS* 7.4 mo 2.6 mo NR
•* By independent review
Retrospective analysis of biomarkers for response
to trastuzumab-DM1 in pretreated HER2+ MBC
Krop et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1003).
• HER2-positivity by central testing was strongly correlated with
response to trastuzumab-DM1
• In patients with HER2+ disease, numerically lower response rate
in patients with either PI3K mutations or PTEN loss
• Response to trastuzumab-DM1 showed no correlation with levels
of HER2 ECD, HER2 gene copy number, or HER3 levels
PI3K mutation
or PTEN lossN
Number with
objective response
ORR (95% CI)
(%)
Yes 15 3 20 (6-45)
No 16 7 44 (20-70)
Unknown 38 14 37 (23-53.5)
•Centrally-confirmed HER2+ Patients
A Phase II Study of Trastuzumab-DM1 in
Patients With HER2+ Pretreated MBC: Efficacy
Vogel et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1017).
Tumor response nIRF ORR
% (95% CI)
IRF CBR*
% (95% CI)
All evaluable patients 112 25 (17.5-33.6) 35 (26.1-43.9)
Patients previously treated
with trastuzumab and
lapatinib
67 24 (14.3-35.4) 36 (25.2-48.2)
Patients with centrally-
confirmed HER2+ disease75 32 (22.1-43.0) 44 (33.2-55.5)
•* CBR = CR+PR+SD ≥ 6 mo
•IRF = independent review facility; ORR = overall response rate
• Median PFS = 4.9 months
A Phase II Study of Trastuzumab-DM1 in
Patients With HER2+ Pretreated MBC: Safety
Vogel et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1017).
Cardiac safety (n = 108):
No grade 3 or 4 LVEF dysfunction reported
Only 2 patients had LVEF declines below 45%
Treatment discontinuation:
83/112 discontinued (70 due to disease progression and 1 death due to progression)
5 patients discontinued due to AE, 4 that were possibly related to T-DM1
Adverse event (AE)
(n = 112)
Grade 3
(%)
Grade 4
(%)
Thrombocytopenia 4.5 3
Hypokalemia 8 0
Fatigue 4.5 0
Epistaxis 2 0
Musculoskeletal
chest pain
2 0
Dyspnea 2 1
Pleural effusion 2 0
Confusional state 0 2
Phase II results of the pan-HER inhibitor neratinib (HKI-
272) in patients with advanced breast cancer
Burstein et al. Cancer Res 2009; 69 (suppl): (abstract 37).
240 mg/day in women with stage IIIB,C or IV HER2-positive BC.
Arm A: Prior (at least 6 weeks) trastuzumab treatment
Arm B: No prior trastuzumab
Most common grade 3/4 adverse event was diarrhea
Prior
Trastuzumab
(n = 61)
No Prior
Trastuzumab
(n = 66)
Total
(n = 127)
ORR (95% CI) 26% (16-39) 56% (43-68) 42% (33-51)
Clinical benefit rate* (95% CI) 36% (24-49) 68% (56-79) 53% (44-62)
16-week PFS rate (95% CI) 60% (46-72) 77% (64-86) NR
PFS (95% CI) 23 weeks
(16-39)
40 weeks
(32-55)
NR
Phase I/II trial of neratinib (HKI-272) +
trastuzumab in advanced breast cancer
Swaby et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1004).
Stage IIIB, IIIC, or IV HER2+ BC with progression following ≥ 1 trastuzumab-containing regimen in any setting
Part 1: Neratinib 160 mg qd (n = 4), 240 mg qd (n = 4) with trastuzumab 2 mg/kg weekly (4 mg/kg loading dose)
Part 2: Neratinib 240 mg qd (n = 37) with trastuzumab 2 mg/kg weekly (4 mg/kg loading dose)
Adverse events* N (%)
All grades Grade 3/4
Diarrhea 41 (91) 7 (16)
Nausea 23 (51) 2 (4)
Anorexia 18 (40) NR
Vomiting 17 (38) 2 (4)
Asthenia 13 (29) NR
Efficacy
ORR 29%
CR 7%
PR 21%
CBR* 36%
16 wk PFS rate 45%
Median PFS 16 wks
* No significant changes in LVEF reported * CR+PR+SD ≥24wks
RIBBON-1: Study Design
Capecitabine (1000 mg/m2 BID x 14d)
Taxane (docetaxel q3w or protein-bound paclitaxel q3w)
Anthracycline-based chemotherapy (AC, EC, FAC, FEC)
Placebo or bevacizumab (15mg/kg q3w)
Robert N, et al. ASCO 2009. Abstract 1005.
Previously untreated MBC
(n = 1237)
Stratification Factors:
Disease-free interval
Previous adjuvant chemotherapy
Number of metastatic sites
Cape, T, or Anthra
Capecitabine or
Taxaneor
Anthracycline
Chemo + bevacizumab
q3w
Chemo + placebo
q3w
Optional 2nd-line
chemo + bevacizumab
TreatuntilPD
RA
ND
OM
IZE
2:1
CHOICE OF CHEMO
RIBBON-1: Exploratory Endpoint - PFS by
Chemotherapy Subgroups
Robert N, et al. ASCO 2009. Abstract 1005.
Taxane Anthra
PL
(n = 104)
BV
(n = 203)
PL
(n = 103)
BV
(n = 212)
Median PFS, mo 8.2 9.2 7.9 9.2
HR (95% CI) 0.75 (0.56-1.01) 0.55 (0.40-0.74)
P-value .0547 <.0001
PFS = PFA by investigator
RIBBON-1: Objective Response Rates
Robert N, et al. ASCO 2009. Abstract 1005.
0
10
20
40
50
60
PL
% 30
CR
PR
BV PL BV
23.6
35.437.9
51.3
CapeP = .0097
T/AnthraP = .0054
Measurable disease, (n) 161 325 177 345
Includes only patients with measurable disease at baseline.
RIBBON-1: Overall Survival
Robert N, et al. ASCO 2009. Abstract 1005.
Cape T/Anthra
PL
(n = 206)
BV
(n = 409)
PL
(n = 207)
BV
(n = 415)
% of deaths 35 30 35 34
Median OS, mo 21.2 29.0 23.8 25.2
HR (95% CI) 0.85 (0.63-1.14) 1.03 (0.77-1.38)
P-value .27 .83
1-yr survival rate (%) 74 81 83 81
P-value .076 .44
RIBBON-1: Safety Summary
Robert N, et al. ASCO 2009. Abstract 1005.
Cape Taxane Anthra
Events (%)PL
(n = 201)
BV
(n = 404)
PL
(n = 102)
BV
(n = 203)
PL
(n = 100)
BV
(n = 210)
Selected AEs* 9.0 21.8 22.5 43.8 16.0 28.1
SAEs 18.9 24.3 26.5 41.4 16.0 22.4
AEs leading to
study drug (PL or
BV) discontinuation
11.9 11.9 7.8 24.1 4.0 14.3
AEs leading to
death**2.5 1.5 3.0 2.5 3.0 1.4
*AEs previously shown to be associated with BV**Excludes AEs related to MBC progression
Conclusions
RIBBON-1 provides a third randomized Phase III trial demonstrating the efficacy and safety of combining bevacizumab, a direct VEGF inhibitor, with first-line chemotherapy for MBC
RIBBON-1 establishes the efficacy of combining bevacizumab with non-taxane chemotherapies used for first-line treatment of MBC.
The safety profile of bevacizumab in combination with these chemotherapies was consistent with that reported from prior Phase III trials.