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


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


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*


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


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


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


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


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


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


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


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.

update on breast cancer - imedexto assess the efficacy and tolerability of oral olaparib in...

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