Emerging Therapies for Triple Negative Breast...

Emerging Therapies for

Triple Negative Breast Cancer

Joseph A. Sparano, MD Professor of Medicine & Women’s Health

Albert Einstein College of Medicine

Associate Chairman, Department of Oncology

Montefiore Medical Center

Bronx, New York

Overview

• Clinical Features

• Biology and Disease Classification

• Cytotoxic Therapy

• PARP Inhibitors

• Biological Agents

• Immune Checkpoint Blockade

• Clinical Trials & Novel Approaches

Triple-Negative Disease Compared with Other

Phenotypes in the California Cancer Registry Study Bauer et al. Cancer 2007: 109; 721

Parise et al. The Breast Journal 2009: 15: 593

• Population-based study

– 6370 with “triple-negative” disease compared with 44,704 “other” cases (12% of all cases)

• TNBC more likely to be associated with

– Younger age (<40): OR 1.53

– Non-Hispanic black race (OR 1.77) or Hispanic ethnicity (OR 1.23)

– Higher grade (72% grade 3)

– More advanced stage (66% >/= stage II vs. 50% ER+HER2-)

– Poorer 5 year RFI irrespective of stage

• TNBC: 76% (similar to 76% for HER2-Pos)

• HR-Pos, HER2-Neg: 94%

– Greater propensity for lung and brain mets

Annual Hazard Rate of Recurrence by Breast Cancer Subtype in E1199:

Node-Positive & High-Risk Node Negative Breast Cancer Treated with

AC-Taxane Chemotherapy Plus Endocrine Therapy

0

.00

0.0

30

.06

0.0

90

.12

0.1

5

Recu

rren

ce h

azard

ra

te

0 2 4 6 8 10 12

Years Since Randomization

ER+/PR+

HER2+

TN

Biology and

Disease Classification

Breast cancer intrinsic subtypes by gene expression profiling

Perou et al. Nature 2000; Parker et al. JCO, 2009

Luminal A Luminal B ERBB2+ Basal NormL

Smalley M. Ashworth A. Nat. Cancer Reviews 2003;3,832-844

Luminal Epithelial Cells

Low molecular wt CK 7, 8, 18 and 19

Mucin, BCL2, Hormone Receptors

Basal Cells (Myoepithelial cells)

High molecular wt CK 5, 6, 14 and 17

SMA, Calponin, p63, P-caderin

Perou C, et al. Nature 460:747-752, 2000

Terminal Duct Lobular Unit (TDLU)

Intrinsic Subtype Frequencies by ER/PgR Cut-

offs within TNBC Across 3 Adjuvant Trials: GIECAM 9906, MA5, MA12

ER/PR <1% (n=283) ER/PR <10% (n=331)

Cheang et al. ASCO 2012, abstract 1008

Biologic Basis for Poorer Outcome for

Triple Negative and/or Basal Disease

• Genomic instability

• Impaired DNA damage repair

– ATM Kinase

– CK1, claspin, EF1

• macrophage activation

• motility

• survival after colonization (ID genes)

Tommiska et al. Oncogene 2007 Nov 5 Epub

Verlinden et al. Cancer Res 2007; 67: 6574

Gupta et al. PNAS 2007; 104: 19506

XBP1 promotes TNBC by controlling the HIF1alpha pathway

• Unfolded protein response (UPR)

– adaptive response to hypoxia

– Mediated by endoplasmic reticulum (ER)-

localized membrane sensor (IRE1) and its

substrate (XBP1)

• XBP1 gene expression signature highly correlated

with HIF1-alpha and hypoxia signatures, and

associated with a poor prognosis

• XBP1 drives tumorigenicity by complexing with

HIF1-alpha and regulating expression of HIF1-

alpha targets via recruitment of RNA polymerase II

• Knockdown of of XBP1 enhances effectiveness of

cytotoxic therapy in an MDA 231 xenograft model

Chen et al. Nature 2014

BRCA Mutations & TNBC

• Up to 20% of unselected patients

• Up to 50% of patients with a strong

family history

• 50% of mutation carriers don’t have a

strong family history

Gonzalez-Angulo et al. JCO 2011

Bayraktar et al. BCRT 2011

BRCA1-Deficient Cells are Hypersensitive to Cisplatin

Tassone P et al. Br J Cancer 2003; 88:1285-1291

BRCA-deficient cell line – HCC1937

BRCA Proficient - MCF-7 (ER-pos) & MDA-MB-231 (ER/PR-Neg)

TNBC Subtypes 21 publicaly available gene expression breast cancer datasets, 587 TNBCs

Basal-like 1 (BL1): Cell-cycle, proliferation and

DNA damage response genes

Basal-like 2 (BL2): Growth factor signaling (EGF,

MET, Wnt/β-catenin, IGF1R)

Immunomodulatory (IM): Immune cell & cytokine

signaling (overlap with medullary signature)

Mesenchymal (M): Cell motility and differentiation

(Wnt, ALK, TGF-β)

Mesenchymal stem-like (MSL): Similar to M, but

increased growth factors signaling, low

proliferation, enrichment of stem cell genes

Luminal androgen receptor (LAR): Enriched in

hormonally-regulated pathways, androgen

receptor signaling. Displays luminal expression

patterns (molecular apocrine carcinomas)

Copyright © 2011, American Society for Clinical Investigation

Lehmann BD, et al. Journal of

Clinical Investigation, 2011

Are the Subtypes Clinically Relevant? Maybe

• Basal Cisplatin

• LAR Bicalutamide

• Mesenchymal-like

Src inhibition

Cytotoxic Therapy

Gem/Carbo (GC) (N= 258)

Gemcitabine 1000 mg/m2 IV d 1, 8 Carboplatin AUC2 IV d 1, 8

21-day cycles

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

R

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)

Study Design: Multi-center, randomized open-label Phase III Trial

Schema

Crossover allowed

to GCI following

Disease Progression* (central review)

N = 519

*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

0 2 4 6 8 10 12 14 16

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Months Since Study Entry

Pro

bab

ilit

y o

f P

rogre

ssio

n F

ree

Surv

ival

No. at risk

GC 258 171 116 63 38 18 6 1 0

GCI 261 187 138 83 53 11 2 0 0

No. at risk

GC 258 239 214 181 151 99 38 11 0

GCI 261 248 230 204 169 111 52 15 0

Efficacy Endpoints – ITT population

0 2 4 6 8 10 12 14 16

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Pro

bab

ilit

y o

f S

urv

ival

Months

Pre-specified alpha = 0.04

PFS GC

(N=258)

GCI

(N=261)

Median PFS, mos

(95% CI)

4.1 (3.1, 4.6)

5.1 (4.2, 5.8)

HR (95% CI) 0.79 (0.65, 0.98)

p-value 0.027

Pre-specified alpha = 0.01

OS GC

(N=258)

GCI

(N=261)

Median OS, mos

(95% CI)

11.1 (9.2, 12.1)

11.8 (10.6, 12.9)

HR (95% CI) 0.88 (0.69, 1.12)

p-value 0.28

Relation Between BRCA Mutation Status and

Response to Neoadjuvant Platinum Trial Characteristics Regimen No. pCR

Byrski BRCA1+mut carriers Not-platinum-based 90 14 (16%)

BRCA1+mut carriers CDDP 75mg/m2 x4 12 10 (83%)

Silver Sporadic TNBC

(not BRCA1+mut

carriers)

CDDP 75mg/m2 x4 26 4 (15%)

BRCA1mut carriers CDDP 75mg/m2 x4 2 2 (100%)

Ryan Sporadic TNBCs

(not BRCA1+mut

carriers)

CDDP 75mg/m2 x4 +

bevacizumab 15 mg/kg

q3wk x3

51 8 (16%)

Byrski, JCO 2009; Silver JCO 2009: Baselga ESMO 2010; Isakoff SABCS 2010

PrECOG 0105 Schema PI: Melinda Telli, MD

Every 21 days x 6 cycles

n = 80

Definitive

Surgery

Assess

Pathologic

Response

Carboplatin AUC 2 D 1, 8

Gemcitabine 1000 mg/m2 D 1, 8

Iniparib 5.6 mg/kg D 1, 4, 8, 11

Newly

Diagnosed

Stage I-IIIA (T 1cm by MRI)

Triple-negative (ER/PR ≤ 5%)

or

BRCA1/2

mutation

Primary Endpoint: Pathologic complete response (pCR) [no invasive disease in breast + axilla]

Secondary Endpoint: Correlation of gene expression profiles & gene copy number with response

Results ITT population

Pathologic Response (n=80)

All patients

*******

n = 80

BRCA 1/2

wild-type

n = 61

BRCA 1/2

mutant

n = 19

TN & BRCA

1/2 mutant

n = 16

pCR [RCB 0]; n (%) 29 (36%) 20 (33%) 9* (47%) 9* (56%)

90% CI 27–46 23–44 27-68 33-77

RCB 0/1; n (%) 45 (56%) 31 (51%) 14 (74%) 12 (75%)

90% CI 46-66 40-62 52-89 52-91

* One BRCA1 carrier had bilateral TNBC & achieved pCR in both breasts

Target: lower bound of 90% exact binomial CI pCR rate exceeds 25%

87.5% power to detect 15% absolute improvement from 25% to 40% in pCR rate (binomial test with 1-sided alpha level of 5%)

Homologous Recombination Deficiency

(HRD) Assay

Goal:

To detect a genomic HR deficiency ‘footprint’ in a tumor caused by various defects in the HR pathway

Potential to identify non-BRCA1/2 mutation carriers with ‘BRCA-like’ cancers who may benefit from DNA repair targeted treatment strategies

Assay development:

Association of genomic patterns of loss of heterozygosity (LOH) & HR deficiency assessed in ovarian cancer

Major Finding:

LOH regions of intermediate size were observed more frequently in tumors with defective BRCA1 or BRCA2

HRD Score = Count of the # of LOH regions of intermediate size (> 15 Mb and < whole chromosome) observed in the tumor genome

Abkevich V, et al. British Journal of Cancer, 2012

Rate of Favorable Response (RCB 0/1)

by HRD Score

p = 0.0001

Telli ML, Timms K, Hartmann A-R, Ford JM, et al. SABCS 2012; abstract PD09-04

HRD score

Non-responders

BRCA1/2 intact responders

BRCA1/2 mutant responders

Antitubulins Bind to Different Sites on Tubulin

Taxus brevifolia

Paciific yew tree

Paclitaxel

Taxus baccata

European yew tree

Docetaxel

Myxobacteria

Sorangium

cellulosum

Ixabepilone Eribulin

Marine sponge

Halichondria

okidai

Vinorelbine

Catharanthus

roseus

Rosy periwinkle

•Paclitaxel, docetaxel, and epothilone B bind

to subunits at inside surface

Vincas binds to

(+) ends and

along sides Eribulin binds

to (+) ends

31

0.0

0.2

0.4

0.6

0.8

1.0

PFS by Treatment

ER Positive, PgR Positive

Months

PF

S P

rob

ab

ilit

y

0 6 12 18 24 30

PB

P

P < 0.0001

Medians: 7, 14.1

0.0

0.2

0.4

0.6

0.8

1.0

PFS by Treatment

ER Negative, PgR Negative

Months

PF

S P

rob

ab

ilit

y

0 6 12 18 24 30

PB

P

P < 0.0001

Medians: 4.7, 8.6

E2100: Weekly paclitaxel alone or plus bevacizumab as first-line

therapy for metastatic breast cancer – outcomes by ER/PR expression

P P+B

All 17% 34%

Measurable

(79%)

17% 41%

P P+B

All 23% 37%

Measurable

(46%)

30% 51%

ER/PR Negative

ER and/or PR Positive

Phase III Trials of Capecitabine With or Without

Ixabepilone in Anthracycline and Taxane Pretreated or

Resistant Advanced Breast Cancer

Thomas ES, et al. J Clin Oncol. 2007;25:5210-5217; Sparano J, et al. J Clin Oncol. 2010;28:3256-6263.

Ixabepilone

40 mg/m2 day 1 q3w

Capecitabine

2000 mg/m2 days 1-14 q3w

Capecitabine

2500 mg/m2 days 1-14 q3w

Eligibility criteria:

• Locally advanced or

metastatic breast

cancer

• CA163-046 Trial:

– Anthracycline-

pretreated or

resistant

– Taxane-resistant

• CA163-048 Trial:

– Anthracycline-

pretreated

– Taxane-pretreated

R

A

N

D

O

M

I

Z

E

Resistance criteria for CA163-046:

Progression / recurrence:

(Neo)adjuvant: < 6 months anthracycline,

< 12 months taxane

Metastatic: < 3 months anthracycline,

< 4 months taxane

Capecitabine ± Ixabepilone in

Triple Negative MBC

Rugo H, et al. SABCS 2008. Abstract 3057.

Pooled triple negative subgroup (n = 443)

Efficacy Ixa + Cape

(n = 191)

Cape

(n = 208)

ORR 31% 15%

CR 3% 1%

PR 28% 14%

Median PFS 4.2 mo 1.7 mo

HR 0.63

P value < 0.0001

Median OS 10.3 mos

(n = 213)

9.0 mos

(n = 230)

HR 0.87

P value 0.18

Selected

Grade 3/4

AEs

Ixa + Cape

(n = 209)

Cape

(n = 226)

Neutropenia 70% 8%

Febrile

neutropenia

4% < 1%

Leukopenia 63% 5%

Peripheral

neuropathy

23% < 1%

Hand-foot

syndrome

14% 16%

Fatigue 11% 3%

Eribulin Study 301

• Global, randomized, open-label phase III trial (Study 301)

• Stratification:

Capecitabine 1250 mg/m2 BID orally

Days 1-14, q21 days

Eribulin mesylate 1.4 mg/m2 2- to 5-min IV

Day 1 & 8 q21 days

Randomization 1:1

Co-primary endpoint

• OS and PFS

• Secondary

endpoints

• Quality of life

• ORR

• Duration of response

• 1-, 2- and 3-year survival

• Tumor-related symptom

assessments

• Safety parameters

• Population PK

Patients (N = 1102)

Locally advanced or

MBC • ≤ 3 prior

chemotherapy

regimens (≤ 2 for

advanced disease)

• Prior anthracycline

and taxane in

(neo)adjuvant setting

or for locally

advanced or MBC

Kaufman PA, et al. SABCS December 7, 2012. Abstract S6-6.

Overall 0.879 (0.770, 1.003) 15.9 14.5

HER2 status

Positive 0.965 (0.688, 1.355) 14.3 17.1

Negative 0.838 (0.715, 0.983) 15.9 13.5

ER status

Positive 0.897 (0.737, 1.093) 18.2 16.8

Negative 0.779 (0.635, 0.955) 14.4 10.5

Triple negative

Yes 0.702 (0.545, 0.906) 14.4 9.4

No 0.927 (0.795, 1.081) 17.5 16.6

Subgroup HR (95% CI) Eribulin Capecitabine

Median (months)

ITT population

Overall Survival By Receptor Status

0.2 0.5 1.0 2 5

N = 755

N = 449

N = 284

Favors eribulin Favors capecitabine

Kaufman et al, SABCS– December 7, 2012 Kaufman PA. et al, SABCS December 7, 2012. Abstract S6-6.

PARP Inhibitors

DNA Damage Repair Pathways

Base

excision

repair

Single-

strand

breaks

(SSBs)

PARP

Double-

strand

breaks

(DSBs)

Recombination

repair

ATM

BRCA DNA-PK

HR NHEJ

Type of

damage:

Repair

pathway:

Repair

enzymes:

Bulky

adducts

Insertions

& deletions

O6-

alkylguanine

Nucleotide-

excision

repair

Mismatch

repair

Direct

reversal

XP,

polymerases MSH2,

MLH1 AGT

Poly (ADP-ribose) Polymerase (PARP)

DNA binding

domain Catalytic Domain

PARP homology domain

PARP-1

Automodification

domain

• Nuclear protein – 3 functional domains

– Amino terminal: DNA binding

– Automodification: autoribosylation (protein-protein interactions)

– C-terminal: catalytic domain – transfer ADP-ribose from NAD+ to protein

acceptors, forming pADPr (2x higher charge density than DNA)

• DNA damage

– PARPs recruited to altered DNA, catalytic activity ↑ up to 500-fold

– pADPr localization to DNA and recruitment of proteins (eg, XRCC1)

which assemble and activate DNA base excision repair

– NAD+ and ATP depletion contribute to cell death

44

History of Poly(ADP-ribose) Polymerase (PARP) as a Therapeutic Target Chambon et al. Nature Cancer Reviews 2010

• Discovery of PARP

– 1963: Nuclear enzymatic activity that synthesizes an adenine containing

RNA-like polymer (Chambon et al)

– 1966-67: Confirmed by others, identified as PARP (Nishizuka et al)

• Discovery of PARP Function

– 1979: PARP activated by DNA strand breaks (Juarez-Salinas et al)

– 1980: PARP participates in DNA repair (Durkacz et al)

– 1986: PARP1 hyperactivation leads to NAD+ and ATP depletion after

DNA damage & metabolic cell death (parthanotos) (Berger et al)

– 2000: PARP knockouts confirm role in DNA repair (Shall et al)

• Discovery of PARP Inhibitors

– 1980: PARP inhibitors enhance alkylators (Durkacz et al)

– 2005: PARP inhibitors toxic to BRCA deficient cells (Bryant et al, Farmer

et al)

46

Chambon et al. Biochem Biophsyic Res Comm, 1963; Nishizuka et al l. JBC, 1968; Juarez-Salinas, Nature,

1979, Durkacz et al. Nature, 1980; Berger et al, BBRC, 1986; Shall et al. Mut Res, 2000; Bryant et al, Naure

2005, Farmer et al. Nature, 2005;

PARP Inhibitors

BSI-201 (Iniparib) AG014699

ABT-888 (Veliparib)

CEP-6800

NN

N

ONH2

NH

F NH

NH

O

NH

O

R1

R2

NH

NH

NH2

O

O

Olaparib

All share 3-aminobenzamide ring

Benzamide Inhibitors

3-aminobenzamide

Cell

survival

Base Excision Repair

Synthetic Lethality: Selective effect of PARP-1 inhibition on cancer

cells with BRCA1 or BRCA2 mutation

Homologous Recombination

DNA Damage

PARP

Inhibitor

BRCA

Mutation

Cancer

cell death

PARP Inhibitors In Development

Compound Other names Phase

Olaparib (AZ) KU0059436, AZD2281 III

Veliparib (AbbVie) ABT888 III

Rucaparib (Clovis) PF01367338 , AG014699 I/II

Niraparib (Tesaro) MK4827 III

BMN-673 (BioMarin) II & III

CEP-9722 (Cephalon) I

E7016 (Eisai) I

PARP Inhibitors - single agent development in

BRCA mutation associated breast cancer

Best response (ITT) Olaparib 400 bid

(n=27)

Olaparib 100 bid

(n=27)

CR 1 (4%) 0

PR 10 (37%) 6 (22%)

SD 12 (44%) 12 (44%)

PD 4 (15%) 9 (33%)

Median PFS 5.7 mo 3.8 mo

Tutt, Lancet 2010 MRD 141-144 days

Olaparib Not Effective in Sporadic TNBC

Olaparib 400 mg po BID

Gelmon et al, Lancet Oncol 2011

Phase III OLympiAD (OLaparib in Advanced Disease)

Metastatic breast

cancer & BRCA

mutation carrier

Prior anthra/taxane

0-2 prior for MBC

No prior platinum

Physician’s choice

(capecitabine, vinorelbine, eribulin)

Olaparib

Primary endpoint: PFS (no cross-over)

Secondary: OS, PFS2

Planned sample size: 310 patients

Nearly identical studies planned with niraparib (BIG/EORTC) and BMN-673 (Industry-sponsored)

Adjuvant Olaparib in Localized Breast

Cancer and BRCA Mutation Carriers

Randomise 1:1

Double blind

N=1320

Olaparib 300 mg

BID x

12 months

Placebo

X 12 months

IDF

S

•Adjuvant ER-positive group will be added after pilot safety data with endcorine therapy

•Primary endpoint: IDFS

•HR 0.7 (CV=0.81), 90% power, 5% significance level, approx 330 events required

• assumes consistent treatment effect (HR=0.7) across patient groups

• N=1320 (25% maturity), assuming 4 years recruitment, IDFS analysis estimated approx

5.5 to 6 years from FSI

•Study being managed by BIG & NRG/Alliance

Post neoadjuvant BRCA TNBC,

Non-PathCR

Assumptions:

- Control arm 3 year EFS ~ 60%

Post adjuvant TNBC

Node positive disease

Node neg & T ,> 2cm

Assumptions:

-Control arm 3 year EFS ~ 75%

Dis

tan

t DF

S; O

S

Phase I-II Trials of Veliparib in BRCA-Mutation

Associated Metastatic Breast Cancer

Somlo et al. ASCO 2014; Abstract 1021

Recommended phase II dosing:

• Veliparib monotherapy: 400 mg PO BID continuously

• Veliparib + carboplatin : 150 mg PO BID days 1-14 + carbo AUC5 q3 wks

Paclitaxel + Trastuzumab* +

New Agent A

Paclitaxel + New Agent C

Patient is on Study

Paclitaxel+ Trastuzumab

Paclitaxel + Trastuzumab* +

New Agent B

Paclitaxel

Paclitaxel + New Agent E

AC

AC HER 2 (+)

HER 2 (–)

Randomize

Randomize

Surgery

Surgery

Learn and adapt from each patient as

we go along

Paclitaxel + New Agent F

Paclitaxel + Trastuzumab* +

New Agent C

Paclitaxel + New Agent D

Paclitaxel + New Agent GH

MRI

Residual

Disease

(Pathology)

Key

I-SPY 2 TRIAL Design:

Learn, Drop, Graduate, and Replace Agents Over Time

I-SPY 2: Veliparib/Carboplatin Graduates in TNBC

SIGNATURE

Estimated pCR Rate (95% probability interval)

Probability

Veliparib +

Carbo is

Superior to

Control

Predictive

Probability of

Success in

Phase 3 Veliparib/

Carbo

Concurrent

Control

All HER2- 33%

(22-43%)

22%

(10-35%) 92% 55%

HR+/HER2- 14%

(4-27%)

19% (6-35%)

28% 9%

HR-/HER2- 52% (35-69%)

26% (11-40%)

99% 90%

Rugo et. al. SABCS 2013

Veliparib Phase III Trials in Breast Cancer

• Phase III Randomized Placebo-Controlled Trial of

Carboplatin and Paclitaxel with or without the PARP

Inhibitor Veliparib (ABT-888) in Metastatic or Locally

Advanced Unresectable BRCA-Associated Breast Cancer

• Phase III Randomized, Placebo-Controlled, Double-Blind,

Study Evaluating Safety and Efficacy of the Addition of

Veliparib Plus Carboplatin Versus the Addition of

Carboplatin to Standard Neoadjuvant Chemotherapy

Versus Standard Neoadjuvant Chemotherapy in Subjects

With Early Stage Triple Negative Breast Cancer (TNBC)

Clinical Trials with PARP Inhibitor BMN673

Phase III: Open-Label, Randomized, Parallel, 2-Arm, Study of

BMN 673 versus Physician’s Choice in Germline BRCA Mutation

Subjects with Locally Advanced and/or Metastatic Breast Cancer,

Who Have Received No More than 2 Prior Chemotherapy

Regimens for Metastatic Disease

Phase II: A 2-Stage, 2-Cohort Study of BMN 673 Administered to

Germline BRCA Mutation Subjects with Locally Advanced and/or

Metastatic Breast Cancer

• Cohort 1: previously responded to a platinum-containing

regimen for metastatic disease with disease progression > 8

weeks following the last dose of platinum

• Cohort 2: Received > 2 prior chemotherapy regimens and

who have had no prior platinum therapy for metastatic

disease

Biological Agents

BALI-1 Trial Cisplatin Cisplatin +

Cetuximab

No. 58 115

Response Rate 10.3% 20% P=0.11

Median PFS 1.5 mo. 3.7 mo. HR 0.67, p=0.03

Median OS 9.4 mo. 12.4 mo. HR 0.82, p=0.31

Baselga et al. J Clin Oncol. 2013 Jul 10;31(20):2586-92.

Miles et al. Ann Oncol 2013, 7/25/13 ahead of print

Median PFS 9.2 vs. 6.7 mo.

HR 0.64 (95% CI 0.58,

0.71) ORR: 49% vs. 32%,

p<0.0001

Paclitaxel 90mg/m2 weekly

x 3 q4 weeks /

Placebo 10 mg/kg q2w

Paclitaxel 90 mg/m2 weekly x 3 q4 weeks /

Bevacizumab 10 mg/kg q2w

Confirmatory Study Schema: MERiDiAN

Co-Primary Endpoints: PFS (All Patients) , PFS (VEGF high subset)

Secondary Endpoints: OS; ORR; Symptoms/QoL; Safety

MBC, HER2-Negative Chemo-naïve

N=480

Stratification

• VEGF-A (low/high) • Adjuvant therapy (yes/no) • Hormonal status (ER +/-) R

A N

D O

M I Z

E D

Immune Checkpoint Blockade

Loi et al.. J Clin Oncol 2013; 31: 860

Adams et al. JCO 2014

Systematic Review & Metaanalysis of TILs and Response to Neoadjuvant Chemotherapy

San Antonio Breast Cancer Symposium 2013 Murali Janakiram, MD

• Methods:

– 1147 reports in Pubmed, ASCO abstracts (2009 -2012), & Embase between 1/91-5/13

– 7 studies including 1641 patients met inclusion criteria

• Results:

– TIL ratio classified as either high or positive was associated with a significantly higher likelihood of achieving a pCR/near pCR after NAC

– Effect was driven mainly by a difference in in ER negative tumors and Her2 positive tumors

Subtype N Noof

studies

pCR% OR 95%CI

TILlow TILhighAll 1641 7 12.5% 28.6% 3.68 1.93–7.01

ER-/PR- 403 4 23.6% 41.3% 4.04 2.16–7.57Her2+ 326 3 16.9% 23.4% 5.61 1.80-17.47ER/PR+ 558 2 5.6% 11.5% 2.17 0.95–4.98

Reference Trials N (Subtype)

pCR Rates and TILs

Issa-Nummer, PLOSone 2013

Prospective Validation

GeparQuinto 313

(HER2-)

14.3% (<60% TILs)

36.6% (≥60% TILs)

Denkert, SABCS 2013

Prospective validation

GeparSixto 314

(TNBC)

TNBC (+Carbo)

45.7% (<60% TILs)

73.8% (≥60% TILs)

TNBC (-Carbo)

33.9% (<60% TILs)

42.6% (≥60% TILs)

Presented by: Shaveta

Vinayak, M.D., M.S.

Relationship Between TILs and Response to Neaodjuvant Therapy

“Cancers associated with BRCA1 mutations … showed more lymphocytic infiltrate (P for trend <.0001)…”

Presented by: Sridhar Ganesan, MD, PhD

WHY DOES AN IMMUNE INFILTRATE PREDICT FOR

SENSITIVITY TO CHEMOTHERAPY ?

1. CHEMOTHERAPY REVERSES IMMUNE TOLERENCE AND

INDUCES EFFECTIVE IMMUNE RESPONSE.

2. IMMUNE INFILTRATE IS A MARKER OF AN UNDERLYING

DNA REPAIR DEFECT

3. CHEMOTHERAPY KILLS LYMPHOCYTES , DEPRIVING

TUMOR CELLS OF GROWTH FACTORS (“lymphocyte

addiction”)

Immune Checkpoint Blockage as a Therapeutic Strategy

Ribas et al. NEJM 2012

B7 Family Expression in Triple Negative Breast Cancer

Unpublished data. Courtesy of X. Zang, Albert Einstein College of Medicine.

Topalian et al. NEJM 2012

Clinical Trials and

Novel Approaches

Genomic Sequencing vs. Gene Expression

Whole Exome Sequencing – 1% Genome

Coding regions only

Whole Genome Sequencing –100% Genome (22,000 genes)

Exons (coding), Introns (non-coding), & Intergenic Regions

Targeted Sequencing – 0.003% Genome

200-400 exons – potentially actionable mutations

Gene Expression Profiling

7 (BCI), 21 (Oncotype), 50 (PAM50), 70 (Mammaprint), others

Poor risk proflles identify patients with ER-pos, HER2 neg

disease & 0-3 pos nodes who derive greatest chemo benefit

Non-coding RNA

DNA methylation

Histone modfications

Researc

h &

D

iscovery

Clin

ica

l P

ractice

Proteomics

Presented by: Joseph A. Sparano, MD

Distribution of Mutations in TCGA

by Breast Caner Subtype

Presented by: Joseph A. Sparano, MD

427 Enrolled 407 MBC Bx 299 Genomics

195 Druggable Lesions 55 Genomic-driven Rx

SAFIR 01 Molecular-Driven Study Flow

(13%)

Andre F, et al. Lancet Oncol 2014

Most Activating Mutations are Rare

AURORA Initiative

Zardavas et al. BJC 2014

NCI MATCH • Molecularly profile 3000 patients with PD after Rx

– Multianalyte validated targeted NGS assay in CLIA lab

– Identify 1000 patients with tumors that have mutations

and/or amplifications in pathways targetable by existing

agents

• Assignment to receive targeted agents/regimens

– Commercial or experimental agents

– Phase II design for each agent with OR/PFS endpoint

– Rule based algorithms

• Level 1: FDA approved different tumor

• Level 2: Data from clinical trials in similar molecular abnormality

• Level 3: Plausible preclinical evidence that drug works against a

given tumors with a given molecular abnormality

Presented by: Joseph A. Sparano, MD

Barriers to Clinical Application

• Technical and Logical Gaps

– Tissue access & purity (eg, stroma, inflammation)

– Limited access to novel agents /combinations

• Biological Barriers

• Tumor heterogeneity

» Intra-cellular (multiple mutations)

» Inter-cellular (multiple clones)

» Stromal and immune effects

• Driver vs. passenger mutations

» Few “addictive”

» Most are uncommon/rare

• Clonal evolution

» Intrinsic/acquired resistance

» Need for combinations

Tumor Heterogeneity

A

B

C

B

C Drug A

B

B

B B

C

C

C

Clonal Evolution

A A

A

Driver vs. Passenger

Conclusions – Treatment of TNBC • Predictive biomarkers

– Evaluate for BRCA mutation – NCCN guidelines vs. population screen?

– Clinical utility of genomic sequencing uncertain

• Cytotoxic therapy

– Taxanes & platinum combinations have modest activity in MBC

– Capecitabine less effective than eribulin in MBC

– Platinums improve pCR rates as neoadjuvant therapy – effect of breast

conservation and recurrence unknown

• PARP Inhibitors

– Multiple ongoing trials will define role in mutation-associated and

sporadic TNBC

• Biologics

– Bevacizumab improves response and PFS, not survival – predictive

biomarkers needed - use limited due to rescinded FDA approval

– Anti-EGFR directed agents have modest activity & skin/GI toxicity