Management of triple negative breast cancer in 2019

1. Management of TNBC
Mohamed Abdulla M.D.
Prof. of Clinical Oncology - Cairo University
Director of KOSC Advisory Board
Vice President of KASO
KIOW 4th Edition
Corinthia Hotel – Khartoum
Saturday 17/11/2018

2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Mundipharma, MSD, Ely Lilly, Sanofi-
Genzyme.
• No conflict of interest.
• This presentation does not relate to any product of commercial
interest in particular.
Speaker Disclosures

3. The Simple View:
Three Subtypes of Breast Cancer
ChemotherapyEndocrine therapy Anti-HER2 therapy
HER2, human epidermal growth factor receptor 2; HR, hormone receptor
HR +ve
60 – 70%
HER 2 +ve
15 – 20%
TNBC
15 – 20%

4. Key characteristics of TNBC
• TNBC = ER, PR &
Her2 neu
NEGATIVE
• 10% to 17% of
all breast
carcinomas
• TNBC patients
are generally
younger than
the overall
BC population
• Related to
Hereditary BC
• Significantly
more aggressive
than other
molecular BC
subtypes
• Relapse pattern
• Short disease-free
interval
• Increased incidence
in visceral mets
(74%)
• CNS mets in 46% of
cases
BC
TNBC
TNBC
Boyle P. Ann Oncol. 2012; Anders CK, et al. Clin Breast Cancer. 2009

5. Survival data for different metastatic breast cancer subtypes with triple negative breast cancer (TNBC) faring the
worst (SEER, 2017)
Associated with poor outcomes!
Key characteristics of TNBC

6. Current Treatment Options for Metastatic
TNBC
• Sequential single-agent chemotherapy is the preferred
approach for most pts with metastatic TNBC
– Combination chemotherapy can be used for pts
requiring more rapid response but does not improve OS
Taxanes
Paclitaxel
Nab-paclitaxel
Docetaxel
Anthracyclines
Doxorubicin
Pegylated liposomal
doxorubicin
Epirubicin
Antimetabolites
Capecitabine
Gemcitabine
Other Microtubule
Inhibitors
Vinorelbine
Eribulin
Ixabepilone
Platinum Agents
Carboplatin
Cisplatin
ZeichnerSB, et al. Breast Cancer (Auckl). 2016
• Patients should generally remain on a regimen until best
response, disease progression, or significant toxicity

8. Challenges with TNBC in Daily Practice:
1. Aggressive disease with dismal outcome.
2. Younger age group.
3. Absence of Target to be attacked for decades.
4. Heterogeneous disease (No one size to fit all).
5. The cross talk between TNBC and Hereditary BC.
6. Controversial approach for neoadjuvant, adjuvant and
metastatic sittings.
7. How to apply the identified back-stage molecular players
into therapeutic platform.

9. NEOADJUVANT SYSTEMIC THERAPY
TNBC

10. Neoadjuvant Therapy:
• Direct assessment of in vivo response.
• pCR in TNBC > HR+ HER2- BC (30% vs 7%).
• Highest pCR in Basal-Like 1 (> 50%).
• pCR  +ve long term outcome.
• Growing interest in platinum compounds.
von Minckwitz et al. J Clin Oncol 2012;30:1796–804. Masuda et al. Clin Cancer Res 2013;19:5533–40. Liedtke et al. J Clin
Oncol 2008;26:1275–81. Cortazar et al. Lancet 2014;384:164–72.

14. Guidelines:
Lebert et al. Curr Oncol. 2018 Jun;25(S1):S142-S150

15. ADJUVANT SYSTEMIC THERAPY
TNBC

16. CREATE – X TRIAL
69.8%
56.1%
78.8%
70.3%

17. 1025 TNBC

18. Guidelines:
Lebert et al. Curr Oncol. 2018 Jun;25(S1):S142-S150

19. METASTATIC SYSTEMIC THERAPY
TNBC

20. Challenges & Factors Affecting
Treatment Choice:
• Relapse is common with TNBC in 1st 2 years.
• Re-biopsy of metastatic site for discordance.
• Factors Affecting Treatment Choice:
1. Tumor burden.
2. Rate of disease progression.
3. Performance status.
4. Previous treatment received.
5. Patient’s preference.

22. Trying to move away from ONE Size fits all!
TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ Breast Cancer
Pts with ER-, PgR
unknown, and HER2-
or BRCA1/2+
metastatic or
recurrent LABC
(N = 376)
Carboplatin AUC6 Q3W
x 6 cycles (n = 188)
Docetaxel 100 mg/m2 Q3W
x 6 cycles (n = 188)
For both arms,
crossover upon
progression allowed
Median PFS, Mos Carbo Doc
BRCA1/2 mutated
6.8 4.8
BRCA1/2 not mutated
3.1 4.6
Carboplatin + BRCA1/2 mutated
Carboplatin + BRCA1/2 not mutated
Docetaxel + BRCA1/2 mutated
Docetaxel + BRCA1/2 not mutated
Tutt A, et al. SABCS 2014. Abstract S3-01.

23. Guidelines:
Lebert et al. Curr Oncol. 2018 Jun;25(S1):S142-S150

24. BETTER UNDERSTANDING OF THE
BIOLOGY
Can revolutionize the disease outcome!

25. DNA Repair –
A Process Essential to Cell Survival
• Each cell sustains 10,000 to 30,000 episodes of DNA
damage per day
• 5 basic types of DNA damage-repair pathways
How long is a piece of DNA?
DNA length per cell 2 meters
Cells per human 2 ˣ 1013
DNA length per human 4 ˣ 1013 meters
Distance from the earth to the sun 1.49 ˣ 1011 meters
Number of return trips to the sun 134

26. BRCA Genes:
Basic Knowledge
Eukaryotic Genome
Constant StressEndogenous Exogenous
Continuous Damage
Continuous Repair
Misrepair Perfect Repair No Repair
Mutations Apoptosis
Tumor Suppressor Genes
Peter J.O’Donovan and David M.Livingston. Carcinogenesis vol.31 no.6 pp.961–967, 2010
BRCA1 & BRCA2
• DNA Repair
• Control of Cell Cycle Checkpoints
• Control of Mitotic Activity

27. BRCA Genes: Basic Knowledge
DNA Repair
NHEJR HR
1 2 1 2
Peter J.O’Donovan and David M.Livingston. Carcinogenesis vol.31 no.6 pp.961–967, 2010
G0, G1,
Early S
Late S,
G2

28. Presented By Elizabeth Swisher at 2015 ASCO Annual Meeting
Risk of Breast Cancer for Women with
BRCA1 & 2 Mutations:
King, Science, New York Breast Cancer Study, 2003

29. Breast Cancer with BRCA Mutations:
Poor Prognosis
1. Early onset of disease  more years of lost life.
2. High prevalence of poorly differentiated, high grade and highly
proliferative lesions  more common in BRCA1 mutation cases.
3. Higher prevalence of HR –ve and TNBC.
4. Altered sensitivity to systemic agents:
•  to platinum and PARP inhibitors.
•  to taxanes.
5. Chemotherapy for early small tumors might improve the
outcome.
Rijnsburger et al. JCO 2010;28:5265
Lee et al. Breast Cancer Res Treat 2010;122:11.
Hemel & Domchek. Hematol Oncol Clin North Am 2010; 24:799.

30. Breast Cancer with BRCA Mutation:
Systemic Therapy: PARP Inhibitors:
Wild BRCA 1/2
PARP
REPAIR/APOPTOSIS
SYNTHETIC
LETHALITY

31. Aim and study design
Olaparib vs TPC in BRCA-mutated metastatic breast cancer
Olaparib
300mg*po bid
Treatment of
Physician’s
Choice
FSI May 2014
Status: Ongoing but not recruiting
Patients
• BRCA-mutated MBC
• TNBC or HER2-negative,
ER/PR-positive
• ≤2 prior chemotherapy lines
• Previous treatment must include anthracycline and
taxane
• If patients have received platinum therapy there
should be:
• No evidence of progression during treatment in
the advanced setting
• At least 12 months since (neo)adjuvant treatment
and randomisation
• ECOG PS 0 or 1
• At least one lesion that can be assessed by RECIST
Randomise 2:1
Approximate
N=310
Stratification by
• Prior chemotherapy regimens for
metastatic breast cancer
• Hormonal status
• Prior platinum therapy
Primary endpoint
• PFS (RECIST 1.1,
Independent Review)
Secondary endpoints
• OS
• PFS2
• ORR
• PFS, PFS2 and OS
based on gBRCAm
status
• HRQoL (EORTC-QLQ-
C30)
• Safety and tolerability
Global Study in 19 countries and
approximately 190 sites
ClinicalTrials.gov. NCT02000622.; Robson M, et al. Poster presented at San Antonio Breast Cancer Symposium; 9–13 December, 2014
* tablet formulation (2 tablets twice daily)

32. Olaparib treatment significantly improved PFS assessed by BICR
compared to TPC1
BICR: blind independent centralised review - FAS; Maturity rate: 234/302=77%
Stratified log rank test, stratified by previous chemotherapy for MBC (yes/no) and HR+ versus TNBC. 2 sided p value
1. Robson et al. N Engl J Med. 2017; Epub ahead of print; 2. AZ data on file (2017)
The risk of progression or death over the course of the study was reduced by over 40%1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Probabilityofprogression-free
survival
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Time from randomisation (months)
Olaparib
Chemotherapy
Number of patient’s at risk
205 201 177 159 154 129 107 100 94 73 69 61 40 36 23 21 21 11 11 11 4 3 3 2 2 1 1 1 0
97 88 83 46 44 29 25 24 21 13 11 11 8 7 4 4 4 1 1 1 1 1 1 1 1 0 0 0 0
Olaparib 300 mg bd (N=205)
TPC (N=97)
Median PFS was improved by 69% with
olaparib treatment compared to standard of
care chemotherapy2
Olaparib TPC
n 205 97
Events (%) 163 (79.5%) 71 (73.2%)
Median (m) 7.0 4.2
HR = 0.58
95 % CI (0.43,0.80)
p=0.0009
PFS free at 6m (%) 54.1 32.9
PFS free at 12m (%) 25.9 15.0

33. Risk of progression was also reduced in olaparib treated patients
with HR+ disease and TNBC compared to TPC1
Patients with HR+
MBC2
Patients with
TNBC2
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Probabilityofprogression-freesurvival
0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Olaparib 300 mg bd (N=103)
Chemotherapy (N=49)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Probabilityofprogression-freesurvival
0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Olaparib 300 mg bd (N=102)
Chemotherapy (N=48)
Olaparib TPC
n 102 48
Events (%) 81 (79.4) 40 (83.3)
Median(m) 5.6 2.9
HR= 0.43
95% CI (0.29, 0.63)
Olaparib TPC
n 103 49
Events (%) 82 (79.6) 31 (63.3)
Median(m) 8.3 5.1
HR= 0.82
95% CI (0.55, 1.26)
1. Robson et al. N Engl J Med. 2017; Epub ahead of print; 2. AZ data on file (2017)

34. PFS results was observed across all pre-specified subgroups
with olaparib treatment compared with TPC1
All patients
Prior chemotherapy for metastatic breast cancer
Yes
No
Receptor status
ER and/or PgR positive
ER and PgR negative
Prior platinum for breast cancer
Yes
No
Measureable versus non-measurable disease
Measureable
Non-measurable
Progressive disease at time of randomization
Yes
No
BRCA mutationtype
BRCA1
BRCA2
Age (years)
<65
≥65
Region
Asia
Europe
North and SouthAmerica
Race
Whit
e
Other
0.58 (0.43 to 0.80)
0.65 (0.47 to 0.91)
0.56 (0.34 to 0.98)
0.82 (0.55 to 1.26)
0.43 (0.29 to 0.63)
0.67 (0.41 to 1.14)
0.60 (0.43 to 0.84)
0.58 (0.43 to 0.80)
0.57 (0.30 to 1.12)
0.60 (0.43 to 0.83)
0.72 (0.41 to 1.30)
0.54 (0.37 to 0.79)
0.68 (0.45 to 1.07)
0.65 (0.49 to 0.88)
Not calculated
0.57 (0.34 to 0.97)
0.71 (0.48 to 1.08)
0.39 (0.22 to 0.73)
0.67 (0.48 to 0.95)
0.51 (0.32 to 0.85)
119 (81.5) : 51(73.9)
44 (74.6) : 20(71.4)
82 (79.6) : 31(63.3)
81 (79.4) : 40(83.3)
50 (83.3) : 21(80.8)
113 (77.9) : 50(70.4)
139 (84.2) : 56(77.8)
24 (60.0) : 15(60.0)
127 (79.9) : 53(72.6)
36 (78.3) : 18(75.0)
94 (82.5) : 41(82.0)
64 (76.2) : 30(66.7)
154 (79.4) : 67(72.0)
9 (81.8) : 4(100.0)
46 (78.0) : 21(75.0)
77 (79.4) : 34(75.6)
40 (81.6) : 16(66.7)
109 (81.3) : 47(74.6)
54 (76.1) : 24(70.6)
Hazard ratio (95%
CI)
Olaparib : TPC, n (%)
163 (79.5) : 71(73.2)
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Olaparib better TPCbetter
NC
1. Robson et al. N Engl J Med. 2017

35. At the final DCO median overall survival in the olaparib arm was 19.3
months compared to 17.1 months in the TPC arm1
• The difference did not reach statistical significance HR = 0.9 (95% CI: 0.66, 1.23) p=0.513
Olaparib 300 mg bd (N=205)
TPC (N=97)
Probabilityofoverallsurvival
1.0
0.0
0.9
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
205
97
199
85
178
74
146
62
124
48
92
40
55
30
23
15
11
5
6
2
0
0
N at risk
Olaparib
TPC
Time from randomization (months)
OlympiAD was not powered to
show an OS benefit1
• At final OS data cut-off;
• 13% of patients in the
olaparib arm and 0% on
the TPC arm remained
on study treatment
• 19% of patients
received olaparib for
more than 18 months
• Median treatment
duration in the olaparib
arm was double that in
the TPC arm at 7.6 and
3.5 months respectively
1. Robson et al. AACR, 2018

36. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to
physician’s choice of therapy in patients with advanced breast
cancer and a germline BRCA-mutation
Jennifer K. Litton, Hope S. Rugo, Johannes Ettl, Sara Hurvitz,
Anthony Gonçalves, Kyung-Hun Lee, Louis Fehrenbacher, Rinat Yerushalmi, Lida A.
Mina, Miguel Martin, Henri Roché, Young-Hyuck Im, Ruben G. W. Quek, Iulia Cristina
Tudor, Alison L. Hannah, Wolfgang Eiermann, Joanne L. Blum
Litton JK et al. SABCS, 2017

37. Talazoparib (BMN673) Phase III trial : EMBRACA
Primary endpoint
• Progression-free survival by RECIST by
blinded central review
Key secondary efficacy endpoints
• Overall survival (OS)
• ORR by investigator
• Safety
Exploratory endpoints
• Duration of response (DOR) for objective
responders
• Quality of life (QoL; EORTC QLQ-C30,
QLQ-BR23)
Phase 3, international, open-label study randomized
431 patients in 16 countries and 145 sites
Abbreviations: CNS, central nervous system; EORTC, European Organisation for Research and Treatment of Cancer; HER2, human epidermal growth factor receptor 2; mets, metastases; PO, orally (peros);
QLQ-BR23, Quality of Life Questionnaire breast cancer module; QLQ-C30, Quality of Life Questionnaire Core 30; R, randomized; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1;
TNBC, triple-negative breast cancer.
*Additional inclusion criteria included: no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease; prior treatment with a taxane and/or anthracycline unless medically
contraindicated.
†HER2-positive disease is excluded. ‡Physician's choice of therapy must be determined prior to randomization.www.clinicaltrials.gov
(NCT01945775)
Patients with locally advanced or metastatic
HER2-negative breast cancer and a germline
BRCA1 or BRCA2 mutation*†
Stratificationfactors:
• Number of prior chemo regimens (0 or ≥ 1)
• TNBC or hormone receptor positive (HR+)
• History of CNS mets or no CNS mets
Talazoparib
1 mg PO daily
Physician's choice of
therapy (PCT)‡:
capecitabine, eribulin,
gemcitabine, or
vinorelbine
R
2:
1
Treatment (21-day cycles)
continues until progressionor
unacceptable toxicity
Litton JK et al. SABCS, 2017

38. Talazoparib (BMN673) Phase III trial : EMBRACA_PFS
• At a median follow-up of 11.2 months, Median progression-free survival (PFS) was 8.6 months (95% CI, 7.2-9.3) with
talazoparib compared with 5.6 months (95% CI, 4.2-6.7) with physician’s choice of therapy (HR, 0.54; 95% CI, 0.41-0.71; P
<.0001).
Litton JK et al. SABCS, 2017

39. Talazoparib (BMN673) PIII EMBRACA_PFS Subgroup
PFS:CNSMetastasesSubgroup
Litton JK et al. SABCS, 2017
Breast cancer brain metastases show increased levels of genomic aberration-based
homologous recombination deficiency scores relative to their corresponding
primary tumors. Ann Oncol. 2018

40. Immune-associated
(IM) TNBC
Immune
Checkpoint
inhibitors
Basallike (BL)
TNBC
PARPi in
gBRCAm
HER2-enriched (HER2e) TNBC
Luminal/apocrine (LA)
TNBC
AR antagonists
Mesenchymallike (ML)
TNBC
PI3K/mTOR
inhibitors
Lehmann’s classification
PAM50/claudin-low classification
Le Du F. Oncotarget. 2015;6:12890-12908.

41. CLINICAL DATA ON THE USE OF
IMMUNE CHECKPOINT INHIBITORS
FOR PATIENTS WITH MTNBC

42. Is breast cancer immunogenic?
High TILs correlate with improved survival in node positive TNBC
TIL effect is linear: the more TILs the better you do: OS: 0.83 (95%CI: 0.71-0.98) p=0.015
Loi et al, JCO 2013; Loi et al Annals of
Oncology 2014

43. KEYNOTE-086: Antitumor Activity of
Pembrolizumab
Cohort A (N = 170): Previously Treated
mTNBC
Cohort B (N = 84): Previously Untreated mTNBC,
PD-L1 Positive
Adams et al 2018

44. IMpassion130 study design
IC, tumour-infiltrating immune cell; TFI, treatment-free interval. a ClinicalTrials.gov: NCT02425891. b
Locally evaluated per ASCO–College of American Pathologists (CAP) guidelines. c Centrally evaluated per
VENTANA SP142 IHC assay (double blinded for PD-L1 status). d Radiological endpoints were investigator
assessed
(per RECIST v1.1). Schmid P, et al. IMpassion130
ESMO 2018 (LBA1_PR) http://bit.ly/2DMhayg
Co-primary endpoints were PFS and OS in the ITT and PD-L1+ populations
Key secondary efficacy endpoints (ORR and DOR) and safety were also evaluated
Key IMpassion130 eligibility criteriaa:
• Metastatic or inoperable locally advanced TNBC
‒ Histologically documentedb
• No prior therapy for advanced TNBC
‒ Prior chemo in the curative setting, including taxanes,
allowed if TFI ≥ 12 mo
• ECOG PS 0-1
Stratification factors:
• Prior taxane use (yes vs no)
• Liver metastases (yes vs no)
• PD-L1 status on IC (positive [≥ 1%] vs negative [< 1%])c
Atezo + nab-P arm:
Atezolizumab 840 mg IV
‒ On days 1 and 15 of 28-day cycle
+ nab-paclitaxel 100 mg/m2 IV
‒ On days 1, 8 and 15 of 28-day cycle
Plac + nab-P arm:
Placebo IV
‒ On days 1 and 15 of 28-day cycle
+ nab-paclitaxel 100 mg/m2 IV
‒ On days 1, 8 and 15 of 28-day cycle
Double blind; no crossover permitted
RECIST v1.1 PD
or toxicity
R
1:1

45. Primary PFS analysis: PD-L1+
population
Data cutoff: 17 April 2018. Schmid P, et al. IMpassion130 ESMO 2018 (LBA1_PR) http://bit.ly/2DMhayg
0 3 6 9 12 15 18 21 24 27 30 33
Months
No. at risk:
Atezo + nab-P 185 146 104 75 38 19 10 6 2 1 NE NE
Plac + nab-P 184 127 62 44 22 11 5 5 1 NE NE NE
7.5 mo
(6.7, 9.2)
5.0 mo
(3.8, 5.6)
100
80
60
40
20
0
Progression-freesurvival
Stratified HR = 0.62
(95% CI: 0.49, 0.78)
P < 0.0001
Atezo+ nab-P
(n = 185)
Plac+nab-P
(n = 184)
PFS events,
n
138 157
1-year PFS
(95% CI),
%
29%
(22, 36)
16%
(11, 22)

46. Interim OS analysis: PD-L1+ population
25.0 mo
(22.6, NE)
15.5 mo
(13.1, 19.4)
100
80
60
40
20
0
Overallsurvival
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
No. at risk:
Atezo + nab-P 185 177 160 142 113 61 36 22 15 9 5 NE NE
Plac + nab-P 184 170 147 129 89 44 27 19 13 6 NE NE NE
Stratified HR = 0.62
(95% CI: 0.45, 0.86)a
Atezo+ nab-P
(n = 185)
Plac+nab-P
(n = 184)
OS events, n 64 88
2-year OS
(95% CI),
%
54%
(42, 65)
37%
(26, 47)

47. TAKE HOME MESSAGE:
• TNBC is a heterogeneous collection of molecularly distinct disease
subtypes with widely differing natural histories
• TNBC is often associated with genomic instability and is
particularly sensitive to platinum salts, especially when associated
with BRCA mutations
• Several promising novel antibody drug conjugates and targeted
therapies are in late-stage development
• PARP inhibitors have clinically important activity in breast cancers
associated with a germline BRCA mutation
• Checkpoint inhibitors have shown activity in TNBC. Patient
selection remains challenging
• Combination approaches are likely to be necessary for activity
in the majority of patients

48. Thank You