Point of View on Triple Negative

Ida Paris Day Hospital for Female Cancers

Department of Woman and Child Health

Chemotherapy for TNBC

• Bevacizumab

• Eribulin

• Capecitabine

• Vinorelbine

• Ixabepilone

• Gemcitabine

• Liposomal doxorubicin

• Albumin bound-paclitaxel

Duration of response usually short, with rapid relapse Toxicity major

issue clinically

Where do we come from?

Where do we come from?

Whole genome sequence of 560 BC:

-93 protein-coding cancer genes;

-high mutation frequencies in non-

coding regions

-elevated mutation rates without driver

mutations

Three rearrangement signatures,

characterized by tandem duplications

or deletions, appear associated with

defective HR-based DNA repair

No two patients share the

same set of drivers

Nik-Zainal, et al. Nature, 2016

Parp-i and BC

Phase III OlympiAD Cohort 1

Prior

Platinum

(n = 48)

Cohort 2

3L+, No Prior

Platinum

(n = 35)

Total

(N = 83)

Objective response rate

(ORR), % (95% CI)

21 (10-35) 37 (22-55) 28 (18-39)

Best OR, % (n°)

Complete response 4 (2) 0 2 (2)

Partial response 17 (8) 37 (13) 25 (21)

Stable disease 38 (18) 51 (18) 43 (36)

Progressive disease 38 (18) 11 (4) 27 (22)

Not evaluable 4 (2) 0 2 (2)

Phase II ABRAZO, Talazoparib

50% TNBC

35% TNBC

Phase III BROCADE 3 (Vel) and BRAVO (Nirap)- Trials Ongoing

Phase II rand. Brocade

Embraca phase III study - PFS

• Olaparib is the first PARP inhibitor to show benefit over standard therapy for germline BRCA mutated metastatic breast cancer in a phase III trial;

• Control arm of OlimpiAD evaluated non-DNA damaging CHT • The olaparib performance compared to platinum is unknown • Cross resistance to platinum and PARPi is awaited • What do we do at PD on platinim/PARPi? • Trial results with other PARP inhibitors are awaited

Questions

The problem of VUS

Nik-Zainal, Nature, 2016

Checkpoint inhibitors

Considerations

• Relationship with PD-L1 positivity is unclear

• Best response when administered in first line

• Checkpoint inhibitors in combination with CHT present

toxicity profile look like these of the single agent

• Biomarkers remain elusive: recognize that immunologic

aspects of the Tumor Microenvironment vary during

progression of disease

What news?

Antibody Drug Coniugate: Trojan Horse Story

(11th-12th Century BC):

After a fruitless 10-year siege, the Greeks constructed a huge wooden

horse, and hid a select force of men inside. The Trojans pulled the

horse into their city. That night the Greek force crept out of the horse

and opened the gates for the rest of the Greek army. The Greeks

entered and destroyed the city of Troy, ending the war.

Homer, Odyssey 8.492–495

Payload

・Highly potent

・Microtubule

inhibitors

-Auristatins

-Maytansines

・DNA damaging

agents

-Calicheamicin

-Duocarmycins

- SN-38

F

a

b

Fc

Antibody

・High affinity

and specificity

to tumor

antigen

・ Efficient

internalization

・ Reduced

immunogenicity

Components of ADC

Linker

・Stable in the blood

stream

・Capable of releasing

payload once internalized

・Cleavable linker

・Non-cleavable linker

Nagayama, Target Oncol,

2017

Selective delivery of toxic payload

Degradatio

n of ADCs

in the

lysosome

1. Binding of an ADC

to antigen 2. Internalization to

the early endosome

3.

4. Release and action

of payload

Clathrin

5. Apoptosis of

the cancer cell H +

H +

Trop-

2 Trop-

2

Nagayama et al, Target Oncol, 2017

Targeting markers for selective delivery of potent

agents

Sacituzumab

Govitecan

(IMMU132) -

ADC Targeting trop-2 • Trop-2/EGP-1 is a pan-epithelial cancer

antigen

• Related to but distinct from EGP-2 (aka

EpCAM).

• Trop2e is seen in all BC subtypes,

including TNBC.

• Trop2e correlates with the expression of

genes involved in cell epithelial

transformation, adhesion, and proliferation

Vidula N et al. ASCO, 2017

Trop-2 antigen

Novel linker and

ADC construct

Glucuronidation site

protected while bound

to IgG Internalization

into Trop-2-

positive cells

Inhibit topo-1

Inhibit DNA

replication and repair

Apoptosis

Sacituzumab Govitecan (IMMU-132): Mechanism of Action

• Median onset of response = 1.9

months

• Median duration of response = 8.9

months

ORR=30%

88% Trop-2 IHC staining

Median lines of CHT= 5 (range 1-12)

Phase Ib-II – Response to Sacitumumab in TNBC

Breakthrough Therapy status from FDA in

metastatic TNBC in Feb 2016 Bardia A, SABCS

Sacituzumab (IMMU132) in TNBC: Survival

Neoadjuvant chemotherapy in TNBC

Survival by pCR in TNBC patients

All pCR do well

Non-pCR do

not do well

especially if

TNBC

Liedtke C et al, J Clin Oncol, 2008

Neoadjuvant Carboplatin for TNBC

von Minckwitz, Lancet Oncol 2014; Sikov, JCO, 2015; Rugo HS, NEJM, 2016

Summary of recent randomized trials

Study Design N

pCR

Control Platinum

GeparSixto;

von Minckwitz

nplDox/Pac/Bev

+/- wCb (AUC1.5) X 18 wks

315 42.7% 53.2%

ALLIANCE 40603

2x2 design ; Sikov

wPac x12+ ddACx4 +/- Cb

(AUC 6) +/- bev

433 41% 54%

ISPY2 ; Rugo wPac+/-Cb/veliparib ACx4 71 26% 51%

Both GeparSixto and CALGB 40603 included Bev along with Cb

and I Spy included PARPi

Chemotherapy-resistant TNBC: what can we do?

To evaluate the association of cfDNA tumor fraction and copy

number alterations with metastatic survival in TNBC

Stover DG, J Clin Oncol, 2018

Cell-free DNA tumor fraction (TFx)>10% is associated with worse outcome

≧ 10%

≦10%

Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA damaging agents

Birkbak NJ, et al. Cancer Discov, 2012

telomeric chromosome aberrations

in the tumor genome, NtAI, predicts

sensitivity to platinum treatment

determination of

copy number