Update on Breast Cancer William J. Gradishar, MD Professor of - - PowerPoint PPT Presentation

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
• f 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

• Cell

survival

• Normal cell

Deficient HR repair Increases DSB that can’t be repaired

Selective effect of PARP-1 inhibition

• n cancer cells with BRCA1 mutation

Triggers activation

• f 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 via adducts and DNA crosslinking

• 2. PARP1

UPREGULATION Base-excision repair

• f DNA damage
• 3. INHIBITION OF

PARP1 Disables DNA base-excision repair

• 4. REPLICATION

FORK COLLAPSE Double strand DNA break

Cell Survival Cell Death

BRCA1 BRCA2 CG CG CG GC TA AT T A CG CG TA AT T 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.

Restaging Every 2 Cycles

21-Day Cycle

* 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 TNBC N = 120 RANDOMIZE

BSI-201: small molecule PARP 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 chemotherapy for 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) 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) 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/BRCA2

carriers 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/m2 q 3wks IV x 4 cycles S U R G E R Y 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 Progressive disease Pathologic response Complete pathologic response 18 72 Partial response 7 28 No response Residual disease in breast None 19 76 < 1 cm 1-5 cm 6 24 > 5 cm Number of lymph nodes positive 21 84 1-3 4 16 4-9 >9

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 HR 95 % CI pN0 cALND 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 pN1mi cALND/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 SULT1A1 UGT SULT1A1 UGT NDM-TAM

CYP1A2 CYP2C9 CTYP2C19 CYP2B5 CYP2B6 CYP2C9 CTYP2C19 CYP3A CH2 CH2 O O H2O H2O OH O CH2 CH2 O H2O O NCH2 H H2O OH O N 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
• r 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
• f HER2 ECD, HER2 gene copy number, or HER3 levels

PI3K mutation

• r PTEN loss

N Number with

• bjective 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 n IRF 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+ disease 75 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 Fatigue 4.5 Epistaxis 2 Musculoskeletal chest pain 2 Dyspnea 2 1 Pleural effusion 2 Confusional state 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

• r

Taxane

• r

Anthracycline Chemo + bevacizumab q3w Chemo + placebo q3w Optional 2nd-line chemo + bevacizumab Treat until PD RANDOMIZE 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.

10 20 40 50 60 PL % 30 CR PR BV PL BV 23.6 35.4 37.9 51.3 Cape P = .0097 T/Anthra P = .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.