Systemic therapy in Metastatic Triple Negative …...Systemic therapy in Metastatic Triple Negative...

Systemic therapy in MetastaticTriple Negative Breast Carcinoma

Giuseppe Curigliano, MD, PhDUniversity of Milano and Istituto Europeo di Oncologia

Milano, Italia

Disclosures

◆ Board Member : Ellipses

◆ Consultant: Lilly, Novartis, Seattle Genetics, Roche-Genentech

◆ Research grants to my Institute : MSD, Astra Zeneca

◆ Speakers bureau: Pfizer, Lilly, Novartis, Roche-Genentech, Samsung, Celltrion

◆ Stock ownership: None

• Triple negative breast cancer as an heterogeneous disease

• ABC Guidelines

• Tackling the diversity of triple negative breast cancer

• Conclusions

Outline

TNBC: An heterogeneous disease

• Invasive Ductal Carcinoma high grade

• Invasive Lobular Carcinoma high grade, pleomorphic

• High grade neuroendocrine

• Metaplastic, high grade

• Myoepithelial carcinoma

• Medullary

• Apocrine

• Adenoid-cystic

• Metaplastic, low grade

Poor prognosis

Goodprognosis

Triple negative disease

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; PI3Kmut

ESMO ABC 4 Guidelines, Cardoso F et al, Annals of Oncology 2018

ABC 4 Guidelines

?

(01)

(00)

(43)

(44)

2.2%

0.0%

97.7%

Total # of votes:

1. YES:

2. NO:

3. ABSTAIN:

For non-BRCA-associated triple negative ABC, there are no data supporting different or specific CT recommendations. Therefore, all CT recommendations for HER-2 negative disease also apply for triple negative ABC.(LoE: 1 A)

BRCA mutated TNBC


higher LRF; PI3Kmut

BRCA mutated TNBC

A PARP inhibitor (olaparib or talozaparib) is a reasonable treatment option for patients with BRCA-associated triple negative or luminal (after

progression on endocrine therapy) ABC, previously treated with an anthracycline with/without a taxane (in the adjuvant and/or metastatic

setting), since its use is associated with a PFS benefit, improvement in QoL and a favorable toxicity profile.

OS results are awaited. It is unknown how PARP inhibitors compare with platinum compounds in this setting and their efficacy in truly platinum-resistant tumors.

(LoE/GoR: I/B) (80%)

ESMO ABC 4 Guidelines, Cardoso F et al, Annals of Oncology 2018

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

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)

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 receptorstatus

HR+ 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)





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)



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)



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)

Safety


21

17

18

18

12

21

7

15

22

50

23

15

26

35

1

9

11

14

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

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 (%)


Chemotherapy TPC (N=91)

Decreased white blood cells

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

pro

gre

ssio

n-f

ree

su

rviv

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


TPC (N=97)

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

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

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

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)


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.



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)

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) 0

Progression free survival


Overall survival


Response rate


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


RANDOMISE

(1:1)

Docetaxel (D)

100mg/m2 q3w, 6 cycles

Carboplatin (C)

AUC 6 q3w, 6 cycles

ER-, PgR-/unknown & HER2- or known BRCA1/2

Metastatic 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 appropriateOn progression,

crossover if appropriate

Carboplatin (C)

AUC 6 q3w, 6 cyclesDocetaxel (D)

100mg/m2 q3w, 6 cyclesn-376

BRCA1/2 =

9%/12%

Tutt A et al, 2108

Carboplatin in BRCA mutant

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)


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)

31

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 10 20 30 40 50 60 70 80 90 100

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%)


Carboplatin or PARP inhibitors?

Talazoparib / Olaparib Carboplatin

Number of patients 287 205 43 out of 376

BRCA 1 43.6% 57% 9%

BRCA 2 56.7% 41% 12%

Toxicities Hematological Emesis, neuropathy, nephrotoxicity

PR rates 60% 68%

Estimated costs of the treatment for 6 courses

$ 28.000 E 360

Carboplatin or PARP inhibitors?

Talazoparib / Olaparib Carboplatin

Number of patients 287 205 43 out of 376

BRCA 1 43.6% 57% 9%

BRCA 2 56.7% 41% 12%

Toxicities Hematological Emesis, neuropathy, nephrotoxicity

PR rates 60% 68%

Estimated costs of the treatment for 6 courses

$ 28.000 E 360


higher LRF; PI3Kmut

PDL-1 positive

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.

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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

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

Activity of immune-checkpoint inhibitors and CT

From Emens LA, CCR 2018

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

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 permittedRECIST v1.1 PD

or toxicityR

1:1

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


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)


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%)


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 AESIsHepatitis (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%) 0Hyperthyroidism 20 (4%) 1 (< 1%) 6 (1%) 0Pneumonitis 14 (3%) 1 (< 1%) 1 (< 1%) 0Meningoencephalitisb 5 (1%) 0 2 (< 1%) 0Colitis 5 (1%) 1 (< 1%) 3 (1%) 1 (< 1%)Adrenal insufficiency 4 (1%) 1 (< 1%) 0 0Pancreatitis 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


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)


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


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


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. bThis study 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% TIICs positive; 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

Drug

Biomarker

Antibody 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 +

IpilimumabDako 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, also

studied TIICs67 Yes No data for lung No data for lung

Pembrolizumab Dako 22C3 Any“Strong” ≥50,

“Weak” 1-4925, 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

Primary PFS analysis

CharacteristicPatient

s

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


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)


OS events, n 181 208

2-year OS(95% CI), %

42%(34, 50)

40%(33, 46)


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

ival

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)


• 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%)


OS analysis: ITT population

OS analysis: PD-L1+ population

Clinical Heterogeneity of TNBC


higher LRF; PI3Kmut

Bicalutamide 150 mg 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

Bicalutamide

• 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

Abiraterone

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

Enzalutamide

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)

Enzalutamide

56

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

Overa

ll S

urv

ival

(%)

85

ITT Population

NCT01889238

PREDICT AR+ mOS 18.0 months

PREDICT AR – mOS 7.5 months

Courtesy of J. Cortes, ECCO 2015

Enzalutamide

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

Glembatumumab Vedotin in GPNMB+ TNBC

GPNMB, glycoprotein NMB

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

Phase I I T rial Sacitu zumab Go vitecan

Median DoR 7.6 mon thsMed PF S 5.5 mon ths

Met T NB C 3/4/5 th -Line Pha se II

CT , com p u ted t o mo g raph y; M RI, mag netic r es o n ance imag ing

Bardi a A , e t a l. P re s e nt e d a t: S a n A nt onio Brea s t Canc e r S y mpos ium;

Dec e mbe r 5 -9 , 2 0 1 7 : S a n A nt onio, Te x a s .>90% TNBC s ex pres s Trop -2

• Chemotherapy is still a standard for many patients

• Molecular subtypes cannot be used in clinical practice

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

• Atezolizumab and nabpaclitaxel a new standard in PD-L1 positiveTNBC

• AR inhibitors: may be in very well selected population

Conclusions

Thank You

Giuseppe Curigliano MD, PhD

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