The Expert Thoughts

(1)

Point of View on Triple Negative

Ida Paris

Day Hospital for Female Cancers Department of Woman

and Child Health

(2)

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?

(3)

(4)

Where do we come from?

(5)

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

(6)

(7)

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

(8)

Embraca phase III study - PFS

(9)

• 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

(10)

The problem of VUS

Nik-Zainal, Nature, 2016

(11)

(12)

(13)

Checkpoint inhibitors

(14)

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

(15)

What news?

(16)

Antibody Drug Coniugate: Trojan Horse Story

(11

^th

-12

^th

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

(17)

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

(18)

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- Trop- 2

2

Nagayama et al, Target Oncol, 2017

(19)

(20)

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

(21)

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

(22)

• 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

(23)

Breakthrough Therapy status from FDA in metastatic TNBC in Feb 2016

Bardia A, SABCS

Sacituzumab (IMMU132) in TNBC: Survival

(24)

(25)

Neoadjuvant chemotherapy in TNBC

(26)

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

(27)

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

(28)

(29)

(30)

(31)

(32)

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

(33)

≧ 10%

≦10%

(34)

(35)

(36)

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

(37)