triple negative advanced breast cancer systemic therapy€¦ · triple negative advanced breast...

Triple Negative Advanced Breast CancerSystemic Therapy

Giuseppe Curigliano MD, PhDUniversity of Milano and European Institute of Oncology

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Outline

• Targeting TNBC by subtypes• Immunotherapy “Hype or Hope?”• New antibody drug coniugates

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Clinical Heterogeneity of TNBC

Subtype Gene expression profile ClinicalBasal-like 1 high Ki-67; DNA damage response BRCA-associatedBasal-like 2 GF pathways Higher pCRImmunomodulatory Immune genesMesenchymal Cell motility Lower DDFSMesenchymal stem-like Cell motility; claudin-lowLuminal androgen receptor Steroid pathways Apocrine features,

higher LRF; PI3Kmut5th

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Metastatic triple-negative breast cancer


higher LRF; PI3Kmut5t

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OlympiAD

M=metastatic breast cancer, HER2=human epidermal growth factor 2, TNBC=triple negative breast cancer, TPC=treatment of physician’s choice, OS=overall survival, PFS=progression-free survival, PFS2=progression-free survival 2, ORR=objective response rate, HRQoL=health-related quality of life, FSI=first subject in, RECiST= Response Evaluation Criteria in Solid Tumors, ER=oestrogen receptor, PR=progresterone receptor, ECOG PS= Eastern Cooperative Oncology Group Performance Status, gBRCAm=germline BRCA mutation; po=oral1. https://clinicaltrials.gov/ct2/show/NCT02000622; 2. Robson et al. Poster OT1-1-04, San Antonio Breast Cancer Symposium 2014; 3. AZ data on file (2017), 4. Robson et al. N Engl J Med. 2017; 377:523-533

Olaparib300mg*po bid

Treatment of Physician’s

Choice (TPC)Capecitabine, eribuline and vinorellbine

• gBRCAm mBC

• TNBC or HER2-negative, ER/PR positive

• ≤2 prior chemotherapy lines for mBC

• Previous treatment must include anthracycline and taxane

• Hormone receptor positive (HR+) disease progressed on ≥1 endocrine therapy, or not suitable

• 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 0-1

• At least one lesion that can be assessed by RECIST v1.1

Randomise 2:1N=3024

Stratification by2

• Prior chemotherapy regimens for metastatic breast cancer

• Hormonal receptor (HR) status

• Prior platinum therapy

Primary endpoint

• PFS (RECIST 1.1, Independent Review)

Secondary endpoints

• OS

• PFS2

• ORR

• PFS, PFS2 and OS based on Myriad gBRCAm status

• HRQoL (EORTC-QLQ-C30)

• Safety and tolerability

FSI May 20143

Global Study in 19 countries and approximately 141 sites1

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https://en.wikipedia.org/wiki/Response_Evaluation_Criteria_in_Solid_Tumors

Robson et al. N Engl J Med. 2017; 377:523-533

Patient characteristics

Olaparib n=205n (%)

TPCn=97n (%)

Totaln=302n (%)

Median age (min, max) 44 (22, 76) 45 (24, 68) 44 (22, 76)

Male 5 (2.4) 2 (2.1) 7 (2.3)

ECOG PS0 148 (72.2) 62 (63.9) 210 (69.5)

1 57 (27.8) 35 (36.1) 92 (30.4)

Race

White 134 (65.4) 63 (64.9) 202 (66.9)

Asian 66 (32.2) 28 (28.9) 94 (31.1)

Other 5 (2.4) 6 (6.2) 11 (3.6)

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Olaparib n=205n (%)

TPCn=97n(%)

Totaln=302n (%)

Received previous chemotherapy for mBC

Yes 146 (71.2) 69 (71.1) 215 (71.2)

No 59 (28.8) 28 (28.8) 87 (28.8)

Hormonal receptor statusHR+ 103 (50.2) 49 (50.5) 152 (50.3)

TNBC 102 (49.8) 48 (49.5) 150 (49.7)

Received prior platinum therapy for breast cancer

Yes 60 (29.3) 26 (26.8) 86 (28.4)

No 145 (71) 71 (73) 216 (71.5)



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Olaparibn=205n (%)

TPCn=97n(%)

Totaln=302n (%)

Number of metastatic sites

1 46 (22.4) 25 (25.8) 71 (23.5)

2 or more 159 (77.6) 72 (74.2) 231 (76.5)

Sites of metastatic lesions

Bone & locomotor only

16 (7.8) 6 (6.2) 22 (7.3)

CNS 17 (8.3) 8 (8.2) 25 (8.3)

BRCA mutation status

BRCA1 117 (57.1) 51 (52.6) 168 (55.6)

BRCA2 84 (41.0) 46 (47.4) 130 (43.0)

Both 4 (1.9) 0 4 (1.3)

De novo metastatic BC 26 (12.7) 12 (12.4) 38 (12.6)

Progressive disease at randomisation 159 (77.6) 73 (75.3) 232 (76.8)

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Olaparibn=205n (%)

TPCn=97n(%)

Totaln=302n (%)

Received prior endocrine therapy*†

Adjuvant/neoadjuvant 71 (68.9) 36 (73.5) 107 (70.4)

Metastatic 66 (64.1) 28 (57.1) 94 (61.8)

Total 97 (94.2) 45 (91.8) 142 (93.4)

Lines of previous cytotoxic chemotherapy for metastatic breast cancer

0 68 (33.2) 31 (32.0) 99 (32.8)

1 80 (39.0) 42 (43.3) 122 (40.4)

2 57 (27.8) 24 (24.7) 81 (26.8)

Received prior platinum therapy for BC†

Metastatic 43 (21.0) 14 (14.4) 57 (18.9)

Adjuvant/neoadjuvant 15 (7.3) 7 (7.2) 22 (7.3)

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Olaparib

n=205 n(%)

TPC

n=97 n (%)

Total

n=302 n (%)

Full analysis set (randomised, ITT) 205 (100) 97 (100) 302 (100)

Patients who received study treatment 205 (100) 91 (93.8) 296 (98.0)

Number who received olaparib 205 (100) - 205 (67.9)

Number who received capecitabine - 41 (42.3) 41 (13.6)

Number who received eribulin - 34 (35.1) 34 (11.3)

Number who received vinorelbine - 16 (16.5) 16 ( 5.3)

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Safety


21

17

18

18

12

21

7

15

22

50

23

15

26

35

1

9

1114

16

16

17

20

21

27

29

30

40

58

0 25 755075 50 25Adverse events (%)

NauseaAnemiaVomitingFatigueNeutropeniaDiarrheaHeadacheCough

Decreased appetitePyrexiaIncreased ALTIncreased ASTHand-foot syndrome

Olaparib 300 mg bd (N=205)Chemotherapy TPC (N=91)

Decreased white blood cells

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Safety


2

2

3

0

1

3

1

10

26

4

0

1

1

2

2

2

3

3

9

16Anemia

Fatigue

Neutropenia

Increased AST

Hand-foot syndrome

Dyspnea

Decreased platelet count

Leukopenia

0 25 755075 50 25

Headache

Adverse events (%)

Olaparib 300 mg bd (N=205)Chemotherapy TPC (N=91)

Decreased white blood cells

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Progression free survival


17783

15946

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

bab

ility

of

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gre

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n-f

ree

su

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al

Time from randomisation (months)

14121086420 16 18 20 22 24 26 28

234

408

6911

9421

10725

15444

20597

214

111

41

31

21

10

00

214

367

6111

7313

10024

12929

20188

111

111

31

21

10

10

OlaparibTPC

Number of patient’s at risk Median PFS was improved by 69% with olaparib treatment compared to standard of care

chemotherapy

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

Olaparib 300 mg bd (N=205)

TPC (N=97)

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Response rate


Olaparib TPC

Response Evaluable Population, n 167 66

ORR, n (%) 100 (59.9) 19 (28.8)

Complete Response, n (%) 15 (9.0) 1 (1.5)

Partial Response, n (%) 85 (51.0) 18 (27.3)

Median Duration of Response, months (95%CI) 6.4 (2.9-9.7) 7.1 (3.2-12.2)

Median Time to Onset of Response, days 47 45

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Summary of efficacy data


– OlympiAD showed a statistically significant improvement in PFS*

(HR=0.58 (95% CI 0.43-0.80), p=0.0009) with a median PFS of 7.0 months

in the olaparib arm compared to 4.2 months in the TPC arm

– Treatment with olaparib increased PF2, demonstrating a continued and

consistent clinical benefit beyond progression with olaparib (HR: 0.57,

95% CI 0.40-0.83, p=0.0033)

– Median OS in the olaparib arm was 19.3 months compared to 17.1

months in the TPC arm, (HR= 0.9 (95% CI 0.66-1.23)); the difference did

not reach statistical significance p=0.51

– Patients treated with olaparib had a significantly better HRQoL

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Talazoparib

BRCA=breast cancer susceptibility gene; CR=complete response; ECOG=Eastern Cooperative Oncology Group; HA=alternate hypothesis; H0=null hypothesis; ORR=objective response rate; PR=partial response; QD=once daily; RECIST=Response Evaluation Criteria in Solid Tumors; 3L=third-line.

Turner NC, et al. Abstract 1007. ASCO 2017.

Patients with advanced breast cancer with germline BRCA mutation

• ECOG ≤ 1• Measurable disease

by RECIST v1.1

Cohort 1 (Prior Platinum)n=49

PR or CR to last platinum-containing regimen for metastatic disease with disease

progression >8 weeks following the last dose of platinum

Cohort 2 (3L+, No Prior Platinum)n=35

3 or more prior cytotoxic regimens for metastatic disease

No prior platinum for metastatic disease

Phase 2, 2-Stage, 2-Cohort Study

Talazoparib

Primary Endpoint

•Confirmed ORR by central independent radiology facility using RECIST v1.1

Secondary Endpoints

•Clinical benefit rate lasting ≥24 weeks

•Duration of response

•Progression-free survival

•Overall survival

•Safety

2-stage design for each cohort separately:• Stage 1: enrollment of 35 patients in each

cohort• If ≥ 5 responses seen in 1 cohort Stage 2:

enrollment of 35 patients• Designed to compare HA 30% versus H0 15%

response rate (90% power; alpha=0.05)

Note: enrollment discontinued at 84 pts

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Talazoparib

Turner NC, et al. Abstract 1007. ASCO 2017.

Cohort 1 Cohort 2

*

**

*

*

**

*

BRCA1+

BRCA2+

Unknown

BRCA1+

BRCA2+

Overall ORR for BRCA1=23% and for BRCA2=33%

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EMBRACA: Study DesignPatients with locally advanced or metastatic HER2-negative breast cancer and a germline BRCA1 or BRCA2mutation*†

Stratification factors:

• Number of prior chemo regimens (0 or ≥1)

• TNBC or hormone receptor positive (HR+)

• History of CNS mets or no CNS mets

Talazoparib1 mg PO daily

Physician's choice of therapy (PCT)‡:

capecitabine,eribulin,

gemcitabine,or vinorelbine

R2:1

*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.CNS=central nervous system; EORTC=European Organisation for Research and Treatment of Cancer; HER2=human epidermal growth factor receptor 2; mets=metastases; PO= by mouth; 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.

Litton J, et al. N Engl J Med 2018; 379:753-763.

Primary endpoint• Progression-free survival by

RECIST by blinded central review

Key secondary efficacy endpoints• Overall survival (OS)

• Objective response rate (ORR) by investigator

• Safety

Exploratory endpoints• Duration of response (DOR) for

objective responders

• Quality of life (QoL; EORTC QLQ-C30, QLQ-BR23)

Treatment (21-day cycles) continues until progression or

unacceptable toxicity

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TALA(n=287)

Overall PCT(n=144)

Age, median (range), y 45 (27.0-84.0) 50 (24.0-88.0)

<50 y, no. % 182 (63.4) 67 (46.5)

Gender, % female 98.6 97.9

ECOG = 0 / 1 / 2, % 53.0 / 44.0 / 2.0 58.0 / 40.0 / 1.0

Measurable disease by investigator, no. (%) 219 (76.3) 114 (79.2)

History of CNS metastasis, no. (%) 43 (15.0) 20 (13.9)

Visceral disease, no. (%) 200 (69.7) 103 (71.5)

Hormone receptor status, no. (%)

TNBC 130 (45.3) 60 (41.7)

HR+ 157 (54.7) 84 (58.3)

BRCA status, no. (%)

BRCA1+ 133 (46.3) 63 (43.8)

BRCA2+ 154 (53.7) 81 (56.3)

Disease free interval (initial diagnosis to aBC) <12 months

108 (37.6) 42 (29.2)


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TALA(n=287)

Overall PCT(n=144)

Patients, no (%)

Prior adjuvant/neoadjuvant therapy 238 (82.9) 121 (84.0)

Prior hormonal therapy 161 (56.1) 77 (53.5)

Prior platinum therapy 46 (16.0) 30 (21.0)

No. of prior cytotoxic regimens for aBC

0 111 (38.7) 54 (37.5)

1 107 (37.3) 54 (37.5)

2 57 (19.9) 28 (19.4)

≥3 12 (4.2) 8 (5.6)

aBC=advanced breast cancer; PCT=physician’s choice of therapy; TALA=talazoparib.


Litton J, et al. N Engl J Med 2018; 379:753-763.5t

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Safety


TALA(n=286)

Overall PCT(n=126)

All Grade Grade 3 Grade 4 All Grade Grade 3 Grade 4

No. of patients with ≥1 AE, no. (%)

194 (67.8)

140

(49.0)17 (5.9) 63 (50.0) 29 (23.0) 19 (15.1)

Anemia151

(52.8)

110

(38.5)2 (0.7) 23 (18.3) 5 (4.0) 1 (0.8)

Neutropenia 99 (34.6) 51 (17.8) 9 (3.1) 54 (42.9) 25 (19.8) 19 (15.1)

Thrombocytopenia 77 (26.9) 32 (11.2) 10 (3.5) 9 (7.1) 2 (1.6) 0

Lymphopenia 21 (7.3) 9 (3.1) 0 4 (3.2) 0 1 (0.8)

Febrile neutropenia 1 (0.3) 0 1 (0.3) 1 (0.8) 0 1 (0.8)

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Safety


TALA(n=286)

Overall PCT(n=126)

All Grade Grade 3 Grade 4 All Grade Grade 3 Grade 4

No. of patients with ≥1 nonhematologic AE, no. (%) 282 (98.6) 91 (31.8) 123 (97.6) 48 (38.1)

Fatigue 144 (50.3) 5 (1.7) 0 54 (42.9) 4 (3.2) 0

Nausea 139 (48.6) 1 (0.3) 0 59 (46.8) 2 (1.6) 0

Headache 93 (32.5) 5 (1.7) 0 28 (22.2) 1 (0.8) 0

Alopecia 72 (25.2) ‒ ‒ 35 (27.8) ‒ ‒

Vomiting 71 (24.8) 7 (2.4) 0 29 (23.0) 2 (1.6) 0

Diarrhea 63 (22.0) 2 (0.7) 0 33 (26.2) 7 (5.6) 0

Constipation 63 (22.0) 1 (0.3) 0 27 (21.4) 0 0

Decreased appetite 61 (21.3) 1 (0.3) 0 28 (22.2) 1 (0.8) 0

Back pain 60 (21.0) 7 (2.4) 0 20 (15.9) 2 (1.6) 0

Dyspnea 50 (17.5) 7 (2.4) 0 19 (15.1) 3 (2.4) 05th

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Progression free survival


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Overall survival


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Response rate


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Summary of efficacy data

– Talazoparib resulted in prolonged progression-free survival vs physician’s

choice of therapy by blinded central review HR: 0.54 (95% CI: 0.41,

0.71); P<0.0001

– Overall survival is immature (51% of projected events); HR: 0.76 (95% CI:

0.54, 1.06); P=0.105

– Global Health Status/Quality of Life showed overall improvement from

baseline

– Talazoparib was generally well tolerated, with minimal nonhematologic

toxicity and few adverse events resulting in treatment discontinuation


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Cisplatin in basal like 1

RANDOMISE(1:1)

Docetaxel (D)100mg/m2 q3w, 6 cycles

Carboplatin (C)AUC 6 q3w, 6 cycles

ER-, PgR-/unknown & HER2- or known BRCA1/2Metastatic or recurrent locally advanced

Exclusions include:• Adjuvant taxane in ≤12 months• Previous platinum treatment• Non-anthracyclines for MBC

A Priori subgroup analyses:• BRCA1/2 mutation• Basal-like subgroups (PAM50 and IHC) • Biomarkers of HRD

On progression, crossover if appropriate

On progression, crossover if appropriate

Carboplatin (C)AUC 6 q3w, 6 cycles

Docetaxel (D)100mg/m2 q3w, 6 cyclesn-376

BRCA1/2 = 9%/12%

Tutt A et al, 2108

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Cisplatin in basal like 1

59/188 (31.4%)

67/188(35.6%)

0 20 40 60 80 100

Carboplatin

Docetaxel

% with OR at cycle 3 or 6 (95% CI)

Tutt, 2018

Absolute difference (C-D)-4.2% (95% CI -13.7 to 5.3)

Exact p = 0.44

Randomised treatment - all patients (N=376)

21/92*(22.8%)

23/90*(25.6%)

0 20 40 60 80 100

Carboplatin(Crossover=Docetaxel)

Docetaxel(Crossover=Carboplatin)

% with OR at cycle 3 or 6 (95% CI)

Absolute difference (D-C)-2.8% (95% CI -15.2 to 9.6)

Exact p = 0.73

Crossover treatment - all patients (N=182)

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Cisplatin in BRCA mutated

17/25(68.0%)

6/18(33.3%)

0 10 20 30 40 50 60 70 80 90 100

Carboplatin

Docetaxel

Percentage with OR at cycle 3 or 6 (95% CI)

29

Absolute difference (C-D)34.7% (95% CI 6.3 to 63.1)

Exact p = 0.03

Germline BRCA 1/2 Mutation (n=43)

Interaction: randomised treatment & BRCA 1/2 status: p = 0.01

0 20 40 60 80 100

Carboplatin

Docetaxel

Percentage with OR at cycle 3 or 6 (95% CI)

No Germline BRCA 1/2

Mutation (n=273)

Absolute difference (C-D)-8.5% (95% CI -19.6 to 2.6)

Exact p = 0.16

36/128(28.1%)

53/145(36.6%)

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Subsets of triple-negative breast cancer



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Role of TILs in TNBC

19%

9%

TIL high2

Ob

jecti

ve R

esp

on

se

Rate

(%

)

10%

20%

30%

0%

6.4%

1.9%

Pembrolizumab(Cohort A: >2nd line)

Atezolizumab

TIL low

39.1%

8.7%

TIL lowTIL high

Pembrolizumab(Cohort B: 1st line)

4%

TIL high2TIL low

Schmid P, et al. AACR 2017; Adams S, et al ASCO 2017, Loi, ESMO 2017

Different levels by source of sample (archival vs new)

and organ site sampled: LN>lung>liver

Metastatic breast cancer is a low TIL disease

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PD-L1 Expression (ICH) As a Predictive Biomarker

Plots include patients with ≥1 evaluable postbaseline assessment (n = 143 for cohort A, n = 50 for cohort B).

1. Adams S, et al. ASCO Annual Meeting; Jun 2-6, 2017; Chicago, IL; Abstr 1088.

-100

-80

-60

-40

-20

0

20

40

60

80

100

Ch

ang e

F ro

mB

ase

l ine,

%

-100

-80

-60

-40

-20

0

20

40

60

80

100

Ch

an

ge

Fr o

mB

as el

i ne

,%

Cohort A (N = 170): Previously Treated,

Regardless of PD-L1 Expression

Cohort B (N = 52)1: Previously Untreated,

PD-L1 Positive

ORR:4.6% ORR:23.1%

All patients responding are still alive Median TTR:3.0moMedian duration of response: 6.3mo

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Activity of immune-checkpoint inhibitors monotherapy in TNBC

• Modest activity• Impressive

outcomes in those with response

• PDL1+ and 1st

line enriches for responsive tumors

From Emens LA, CCR 2018

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Chemotherapy Induces Multiple Immunomodulatory Changes in the Tumor Microenvironment That May Influence the Effectiveness of Immunotherapy

Tumor cells

Immature dendritic

cells

Tumor antigens

Increased antigen release

Tumor antigens

Upregulation of PD-L1

PD-L1

Upregulation of immunogenic cell surface markers

MHC

Changes influencing the effectiveness of

immunotherapy

Primed dendritic cell

TNF-ɑ

M1 cell

M1, tumor-associated macrophage; MHC, major histocompatibility complex; TNF-ɑ, tumor necrosis factor alpha

1. Daly ME, et al. J Thorac Oncol. 2015;10(12):1685-1693. 2. Kaur P, et al. Front Oncol. 2012;2:191; 3. Deng L, et al. J Clin Invest. 2014;124(2):687-695.

Cytotoxic T cell

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Activity of immune-checkpoint inhibitors in combination with CT

From Emens LA, CCR 2018

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Atezolizumab and nabpaclitaxel

Primary endpoints = safety, ORR

Key eligibility criteria:

• Metastatic or inoperable TNBC

• 0-2 prior lines of chemo

Atezo + Nab pac:

Atezolizumab 800 mg IV D1, 15 q28

+ Nab paclitaxel 125 mg/m2 IV D1, 8, 15 q28

N=33

Note: serial biopsy cohort had lead-in nab paclitaxel alone, atezolizumab added C1D15

Adams S et al, JAMA Oncol 2018

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Atezolizumab and nabpaclitaxel

Key findings:

Activity in 1st and 2nd+ lines

Activity in PDL1+ and –

7 patients with prolonged (> 1y) duration on ICI alone or no Rx

Adams S et al, JAMA Oncol 2018

ORR PFS

1st L 54% 9m

2nd+ L 30% 5m

PDL1+ 41% 22m

PDL1- 33% 11m

OS 15mExploratory biomarker studies window chemo alone: No effect on immune

microenvironment No ↓ atezo-induced T-cell

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Pembrolizumab and eribulin

Primary endpoints = safety, ORR

Tolaney S et al, SABCS 2017

Key eligibility criteria:

• Metastatic or inoperable TNBC

• 0-2 prior lines of Rx for advanced TNBC


• 1st line (62%) vs 2nd+ line (38%)

• PD-L1 status on IHC (PDL1+ 46%)

Pembro + eribulin:

Pembrolizumab 200 mg IV D1 q21

+ Eribulin 1.4 mg/m2 IV D1, 8 q21

N=107

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Pembrolizumab and eribulin

Tolaney S et al, SABCS 2017

Key findings:

Activity in 1st and 2nd+ lines

Activity in PDL1+ and –

Long duration in those that respond

1st line

2nd+ line

DoR (n=28): > 6m 54%, > 12m 14%

OS 18m

ORR PFS

1st L 29% 5m

2nd+ L 22% 4m

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Atezolizumab and nab-Paclitaxel in mTNBC

Schmid P, et al. N Engl J Med. 2018 Nov 29;379(22):2108-2121

• Co-primary endpoints were PFS and OS in the ITT and PD-L1+ populationsd

– Key secondary efficacy endpoints (ORR and DOR) and safety were also evaluated

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).

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


• 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 permittedRECIST v1.1 PD

or toxicityR

1:1

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Is nab-Paclitaxel the ideal partner?DRUG EFFECT ON IMMUNE SYSTEM

Doxorubicin

Induces immunogenic cell deathIncreases proliferation of CD8 T cellsStimulates antigen presentation by DCsStimulates MCP1 and M6PR

CyclophosphamideInduces immunogenic cell deathSuppressed Treg inhibitory functions and restoration of the proliferative capacity of effector T cells and NK cell cytotoxicity

TaxanesEnhance T-cell and NK-cell functionIncrease recruitment of TILIncrease efficacy of immunostimulatory agents

GemcitabineReduce the number of myeloid suppressor cells Increase the antitumor activity of CD8(+) T cells and activated NK cells

Platinum saltsInduces immunogenic cell deathIncreases MHC I complexInhibits PD-L2

DC, dendritic cells; MHC, major histocompatibility complex; NK, natural killer

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Statistical design


• Primary PFS analysis (PFS tested in ITT and PD-L1+ populations)

• First interim OS analysis (OS tested in ITT population, then, if significant, in PD-L1+ population)

a α recycled if PFS/ORR testing is significant. Hazard ratio (HR)/P value–stopping boundaries are dependent on the OS analysis timing.

Atezo + nab-P vs Plac + nab-P

α = 0.05

PFS (primary)α = 0.01

OSa

• Interim• Primary (α ≥ 0.04)

OS in ITT population

OS in PD-L1+ population

1. PFS in ITT population

α = 0.005

3. ORR in ITT population

α = 0.001

4. ORR in PD-L1+ population

α = 0.001

2. PFS in PD-L1+ population

α = 0.005

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Patients


Data cutoff: 17 April 2018. a Race was unknown in 12 patients in the Atezo + nab-P arm and 15 in the Plac + nab-P arm. b Of n = 450 in each arm. c ECOG PS before start of treatment was 2 in 1 patient per arm. d Of n = 450 in the Atezo + nab-P arm and n = 449 in the Plac + nab-P arm arm.

CharacteristicAtezo + nab-P

(N = 451)Plac + nab-P

(N = 451)

Median age (range), y 55 (20-82) 56 (26-86)

Female, n (%) 448 (99%) 450 (100%)

Race, n (%)a

White 308 (68%) 301 (67%)

Asian 85 (19%) 76 (17%)

Black/African American 26 (6%) 33 (7%)

Other/multiple 20 (4%) 26 (6%)

ECOG PS, n (%)b,c

0 256 (57%) 270 (60%)

1 193 (43%) 179 (40%)

Prior (neo)adjuvant treatment, n (%)

284 (63%) 286 (63%)

Prior taxane 231 (51%) 230 (51%)

Prior anthracycline 243 (54%) 242 (54%)

CharacteristicAtezo + nab-P

(N = 451)Plac + nab-P

(N = 451)

Metastatic disease, n (%) 404 (90%) 408 (91%)

No. of sites, n (%)d

0-3 332 (74%) 341 (76%)

≥ 4 118 (26%) 108 (24%)

Site of metastatic disease, n (%)

Lung 226 (50%) 242 (54%)

Bone 145 (32%) 141 (31%)

Liver 126 (28%) 118 (26%)

Brain 30 (7%) 31 (7%)

Lymph node onlyd 33 (7%) 23 (5%)

PD-L1+ (IC), n (%) 185 (41%) 184 (41%)

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Safety


• 1 grade 5 AESI per arm (both treatment related):

– Atezo + nab-P: autoimmune hepatitis

– Plac + nab-P: hepatic failure

• All hypothyroidism AESIs were grade 1-2; none led to discontinuation

– Atezo + nab-P: 17%

– Plac + nab-P: 4%

• Pneumonitis was infrequent with only 1 grade 3-4 event in the Atezo + nab-P arm

– Atezo + nab-P: 3%

– Plac + nab-P: < 1%

• Hepatitis rates were balanced

AESI, adverse event of special interest. Data cutoff: 17 April 2018. a Baskets of preferred terms according to medical concepts. b All events of photophobia. c Includes all AESIs occurring in ≥ 1% of patients in either arm.

AESI, n (%)a

Atezo + nab-P (n = 452)

Plac + nab-P (n = 438)

Any Grade Grade 3-4 Any Grade Grade 3-4All 259 (57%) 34 (8%) 183 (42%) 19 (4%)

Important AESIs

Hepatitis (all) 69 (15%) 23 (5%) 62 (14%) 13 (3%)Hepatitis (diagnosis) 10 (2%) 6 (1%) 7 (2%) 1 (< 1%)

Hepatitis (lab abnormalities) 62 (14%) 17 (4%) 58 (13%) 12 (3%)

Hypothyroidism 78 (17%) 0 19 (4%) 0

Hyperthyroidism 20 (4%) 1 (< 1%) 6 (1%) 0

Pneumonitis 14 (3%) 1 (< 1%) 1 (< 1%) 0Meningoencephalitisb 5 (1%) 0 2 (< 1%) 0

Colitis 5 (1%) 1 (< 1%) 3 (1%) 1 (< 1%)

Adrenal insufficiency 4 (1%) 1 (< 1%) 0 0

Pancreatitis 2 (< 1%) 1 (< 1%) 0 0Diabetes mellitus 1 (< 1%) 1 (< 1%) 2 (< 1%) 1 (< 1%)Nephritis 1 (< 1%) 0 0 0

Other AESIsc

Rash 154 (34%) 4 (1%) 114 (26%) 2 (< 1%)Infusion-related reactions 5 (1%) 0 5 (1%) 0

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Primary PFS analysis: ITT population

NE, not estimable. Data cutoff: 17 April 2018. Median PFS durations (and 95% CI) are indicated on the plot. Median follow-up (ITT): 12.9 months.

0 3 6 9 12 15 18 21 24 27 30 33Months

No. at risk:Atezo + nab-P 451 360 226 164 77 34 20 11 6 1 NE NE

Plac + nab-P 451 327 183 130 57 29 13 5 1 NE NE NE

Atezo + nab-P (N = 451)

Plac + nab-P (N = 451)

PFS events, n 358 378

1-year PFS(95% CI), %

24%(20, 28)

18%(14, 21)

7.2 mo(5.6, 7.5)

5.5 mo(5.3, 5.6)

100

80

60

40

20

0

Pro

gre

ssio

n-f

ree

su

rviv

al

Stratified HR = 0.80(95% CI: 0.69, 0.92)

P = 0.0025


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Primary PFS analysis: PD-L1+ population

Data cutoff: 17 April 2018.

0 3 6 9 12 15 18 21 24 27 30 33Months

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

Pro

gre

ssio

n-f

ree

su

rviv

al

Stratified HR = 0.62(95% CI: 0.49, 0.78)

P < 0.0001



PFS events, n 138 157

1-year PFS(95% CI), %

29%(22, 36)

16%(11, 22)


As opposed to what is observed in melanoma and lung cancer, there is NO tail of the PFS curve in TNBC

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aThe 31% figure is for all tumors; the ORR was 37% in nonsquamous tumors and 12% in squamous cases. In PDL-1 negative cases, ORR was 14% in nonsquamous tumors and 0% in squamous tumors. bThisstudy concerned squamous cell carcinomas only. cThese authors also used the anti-PD-1 monoclonal M3 in their immunohistochemical analysis. dIHC score 3, ≥10% TIICs positive; IHC score 2–3, ≥5% TIICspositive; IHC score 1–2–3, ≥1% TIICs positive.

PD-L1 Expression (ICH) As a Predictive Biomarker

Kerr KM, et al. J Thorac Oncol. 2015;10(7):985-989. IHC, immunohistochemistry; Rx, treatment; TIICs, tumor infiltrating immune cells

DrugBiomarkerAntibody Rx Line

Definition of “Positive” (%) N Positive (%)

Positive Predictive Outcome

ORR % IHC Positive Cases

ORR % IHC Negative Cases

Nivolumab Dako 28-8 1st ≥5 in >100 cells 59 Yes 31a 10

Nivolumab Dako 28-8 ≥2nd ≥5, ≥1 49, 56 No 15, 13 14, 17

Nivolumab + Ipilimumab

Dako 28-8 1st ≥5 in >100 cells 42 No 19 14

Nivolumab Dako 28-8 ≥2nd ≥5 33b Yes 24 14

Nivolumab 5H1c ≥2nd ≥5, alsostudied TIICs

67 Yes No data for lung No data for lung

Pembrolizumab Dako 22C3 Any“Strong” ≥50, “Weak” 1-49

25, 70 Yes, Yes 37, 17 9

Pembrolizumab Dako 22C3 1st ≥5, ≥1 ? Yes 47, 26 ?

MPDL3280A Roche Ventana, SP142 ≥2nd ≥10d, ≥5, ≥1 TIICs 13, 28, 56 Yes 83, 46, 31 18, 18, 20

MEDI-4736 Roche Ventana, SP263 ≥2nd Data not available 41 Yes 25 3

Dedicated Different

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Primary PFS analysis


Characteristic Patients

All 902

Baseline liver metastases Yes 244No 658

Prior taxane use Yes 461No 441

PD-L1 status PD-L1+ (IC1/2/3) 369PD-L1– (IC0) 533

Age group 18-40 y 11441-64 y 569≥ 65 y 219

ECOG PSb 0 5261 372

Baseline disease status Locally advanced 88Metastaticc 812

No. of metastatic sites 0-3c 673> 3c 226

Brain metastases Yes 61No 841

Lung metastases Yes 468No 434

Prior (neo)adjuvant chemo Yes 570No 332

0.81 (0.70, 0.93)

0.80 (0.62, 1.04)0.79 (0.66, 0.94)

0.80 (0.65, 0.97)0.81 (0.66, 1.00)

0.64 (0.51, 0.80)0.95 (0.79, 1.15)

0.79 (0.53, 1.16)0.84 (0.70, 1.01)0.69 (0.51, 0.94)

0.78 (0.64, 0.94)0.82 (0.66, 1.03)

0.66 (0.40, 1.09)0.82 (0.71, 0.96)

0.76 (0.64, 0.91)0.89 (0.67, 1.17)

0.86 (0.50, 1.49)0.80 (0.69, 0.93)

0.87 (0.72, 1.07)0.74 (0.60, 0.91)

0.85 (0.71, 1.03)0.72 (0.57, 0.92)

0,2 2

Hazard Ratio (95% CI)a

P + nab-P betterA + nab-P better 1

Stratification factors

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Interim OS analysis: ITT populationa

Data cutoff: 17 April 2018. Median OS durations (and 95% CI) are indicated on the plot. Median follow-up (ITT): 12.9 months.a For the interim OS analysis, 59% of death events had occurred. b Significance boundary was not crossed.

0 3 6 9 12 15 18 21 24 27 30 33 36Months

No. at risk:Atezo + nab-P 451 426 389 337 271 146 82 48 26 15 6 NE NE

Plac + nab-P 451 419 375 328 246 145 89 52 27 12 3 1 NE

21.3 mo(17.3, 23.4)

17.6 mo(15.9, 20.0)

100

80

60

40

20

0

Ove

rall

surv

ival

Stratified HR = 0.84(95% CI: 0.69, 1.02)

P = 0.0840b

Atezo + nab-P (N = 451)

Plac + nab-P (N = 451)

OS events, n 181 208

2-year OS(95% CI), %

42%(34, 50)

40%(33, 46)


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Interim OS analysis: PD-L1+ population

Data cutoff: 17 April 2018. Median OS durations (and 95% CI) are indicated on the plot. a Not formally tested.

25.0 mo(22.6, NE)

15.5 mo(13.1, 19.4)

100

80

60

40

20

0

Ove

rall

surv

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0 3 6 9 12 15 18 21 24 27 30 33 36Months

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



OS events, n 64 88

2-year OS(95% CI), %

54%(42, 65)

37%(26, 47)


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• Numerically higher and more durable responses were seen in the Atezo + nab-P arm

– Differences were not significant based on α level = 0.1% (ITT: P = 0.0021; PD-L1+: P = 0.0016)

• The CR rate was higher in the Atezo+ nab-P arm vs the Plac + nab-P arm

– ITT population: 7% vs 2%

– PD-L1+ patients: 10% vs 1%

Secondary efficacy endpoints

0

10

20

30

40

50

60

70

ITT A-nabPx

ITT P-nabPx

PD-L1+A-

nabPx

PD-L1+P-

nabPx

OR

R (

%)

ITTa PD-L1+b

56%

46%

59%

43%

49%

44%

49%

42%

7% 10%CR:

PR:

Atezo + nab-P

Plac + nab-P

Atezo + nab-P

Plac + nab-P

DOR, median(95% CI), mo

7.4(6.9, 9.0)

5.6(5.5, 6.9)

8.5(7.3, 9.7)

5.5(3.7, 7.1)

No. of ongoing responses, n (%)c 78 (31%) 52 (25%) 39 (36%) 19 (24%)


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• A positive study for IO in TNBC: this brings breast cancer into the immunotherapy era

• Subset data for PDL1 expression show clear benefit, which means we have to figure out how best to test tumors

• There is a “missing arm” in the study: atezolizumab alone. Might that be a good option for certain subset?

• What can we learn from other tumor types where IO is established?

• Roadmap: Single agent vs combination therapy with chemotherapy in highly immunogenic selected patients? Chemotherapy followed by consolidation treatment with IO?

Discussion

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• Endpoints: should we be more focused on OS than on PFS ?

• Other tumor types (ER+, HER2+) are they as likely to be susceptible? BRCA mutated?

• Neoadjuvant setting: pCR with PD1/PDL1 inhibitors not the ideal endpoint: new data are expected with the potential of biomarker discovery

Discussion

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Is immunotherapy transformative in TNBC?

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PARP inhibitors and IO

Patients with OC or TNBCPatients with OC (target n = 48) or TNBC (target n = 48)

RP2D

Dose level 1Niraparib 200 mg + pembrolizumab 200 mg

Dose level 2Niraparib 300 mg + pembrolizumab 200 mg

Endpoint assessment

Endpoint assessment

Phase I Phase II

Konstantinopoulos PA, et al. Ann Oncol. 2017;28(Suppl 5): Abstract 1143PD.

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PARP inhibitors and IO

Konstantinopoulos PA, et al. Ann Oncol. 2017;28(Suppl 5): Abstract 1143PD.

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Phase 1b Study of docetaxel + PF-

03084014 in Triple-negative Breast Cancer

PF-03084014

Notch pathway

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Luminal Androgen Receptor: Bicalutamide

Bicalutamide 150mg dailyER/PR(-)

(IHC ≤10%)LABC/MBC

AR+ DAKO Ab >

10%

• Primary endpoint = CBR24 (CR + PR + SD > 24 weeks)

Gucalp et al CCR 2013

Screened patients 12% AR+ (mostly TNBC)

Clinical Benefit Rate = 19% (95% CI 7-39%)

All SD

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Luminal Androgen Receptor: Abiraterone• MBC ER/PR ≤10% • 138 screened 38% AR+ (≥10%)

• Primary Endpoint = CBR24

• N = 30 evaluable patients• ~ 2.5 prior lines Rx• ~ 50% visceral mets

• Most common, related AEs: • fatigue (18%)• HTN (12%)• hypokalemia (9%)• nausea (6%)

Bonnefoi et al, Ann Onc 2016

Median PFS 2.8m

CBR24 = 20% (95%CI: 8-39%)

1 confirmed CR

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Luminal Androgen Receptor: Enzalutamide

Enzalutamide 160 mg dailyER/PR/HER2 (-) LABC/MBC

AR+ Ventana

> 0%

• Primary endpoint = CBR16 (CR + PR + SD > 16) weeks)Screened patients 79% AR+ (55% by 10% cutoff)

• Median 1 prior Rx

Evaluable (n=75 AR > 10%)

CBR16 35% (24-46%)

CBR24 29% (20-41%)

RR 8%

SAE 29%

0 8 16 24 33 41 49 6164

100

80

60

40

20

0

PFS

(%

)

PFS 14.7 weeks95% CI: 8.1, 19.3

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Luminal Androgen Receptor

64

PREDICT AR−

0 8 16 24 32 40 52Time (weeks)

PREDICT AR− PREDICT AR+Total, n (%) 62 (53%) 56 (47%)CBR16, %

(95% CI)n

11%(5, 21)n = 7

39%(27, 53)n = 22

CBR24, %(95% CI)n

6%(2, 16)n = 4

36%(24, 49)n = 20

CR or PR, %n

3%n = 2

9%n = 5

Active

Confirmed CR or PR

0–1 Prior Lines2+ Prior Lines

PREDICT AR+

0 8 16 24 32 40 52 64Time (weeks)

Traina et al, ASCO 2015

Gene expression classifier created = “PredictAR”(Basal-, apocrine+, etc to identify LAR)

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Luminal Androgen Receptor

64

56

62

53

55

49

46

45

37

42

27

40

24

32

13

15

6

11

6

3

2

Data cutoff 1Jul2015

ITT = intent to treat; mOS = median survival; CI = confidence interval; .

Patients at risk

PREDICT AR+

PREDICT AR−

0

80

40

20

n = 118

PREDICT AR−

mOS 32.3 weeks

(95% CI: 20.7, 48.3)

PREDICT AR+

mOS 75.6 weeks

(95% CI: 51.6, 91.4)

0 8 16 24 33 41 49 61 64

Weeks

100

60

Ov

era

ll S

urv

ival (%

)

85

ITT Population

NCT01889238

PREDICT AR+ mOS 18.0 monthsPREDICT AR – mOS 7.5 months

Courtesy of J. Cortes, ECCO 20155t

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Antibody drug conjugated

1. Yardley DA, et al. J Clin Oncol. 2015;33(14):1609-1619. 2. Forero-Torres A, et al. Cancer Res. 2017;77(4_Suppl): Abstract P6-12-04. 3. Bardia A, et al. J Clin Oncol. 2017;35(19):2141-2148.

ADCs GlembatumumabVedotin1

LadiratuzumabVedotin2

SacituzumabGovitecan3

Other name CDX-011 SGN-LIV1A IMMU-132

Target gpNMB LIV-1 Trop-2

Tumor expression ~40% 71% 88%

Cytotoxin MMAE MMAE SN-38

Single-agent activity (ORR)

28% 37% 30%

Registrational trials

METRIC1st-3rd line

Active arm in ISPY-2Phase II trial 2018

ASCENT≥3rd line

ABT 414: depatuxizimab mafodotin, targets EGFR linked to MMAF

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Glembatumumab Vedotin in GPNMB+ TNBC

GPNMB, glycoprotein NMB

Yardley DA, et al. J Clin Oncol. 2015;33(14):1609-1619.

Metastatic triple negative BC

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Phase II Trial Sacituzumab Govitecan

Median DoR 7.6 months

Med PFS 5.5 months

Met TNBC 3/4/5th-Line Phase II

CT, computed tomography; MRI, magnetic resonance imaging

Bardia A, et al. Presented at: San Antonio Breast Cancer Symposium;

December 5-9, 2017: San Antonio, Texas.>90% TNBCs express Trop-2

Metastatic triple negative BC

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• Chemotherapy is still a standard for many patients

• PARP inhibitors standard in BRCA carriers (will work in somatically inactivated?)

• AR inhibitors: may be in very well selected population

• I-O: is it transformative? Eventually in more immunogenic tumors (enrichment by PD-L1 and TILs)

Conclusions

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• Select the right partner and validate studies with the same backbone

• Demonstrate bioactivity and not MTD

• Metastatic breast cancer is not always the right setting

• Neoadjuvant and Post-neoadjuvant can be more informative

Conclusions

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Thank You

Giuseppe Curigliano MD, [email protected]

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mailto:[email protected]

triple negative advanced breast cancer systemic therapy€¦ · triple negative advanced breast...

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