Tumores Triple negativo.

Estado del arte: investigación y futuro próximo

Emilio AlbaUGCI Oncología Integral

Hospital Universitario Regional y Virgen de la Victoria

Departamento de Medicina. Universidad de Málaga

IBIMA

TOPICS

� What do we talk about when we talk about metastatic TN

breast cancer?

� The platinum salts question

� PARP inhibitors

� Immunotherapy

� The AR way

� Conclusions

TOPICS

� What do we talk about when we talk about metastatic TN

breast cancer?

� The platinum salts question

� PARP inhibitors

� Immunotherapy

� The AR way

� Conclusions

Non Concordance Primary/Metastasis

Regarding IHC Subtype

Thompson AM, 2010 39%

Dieci MV, 2012 23%

Amir E, 2012 38%

Martínez de Dueñas E, 2014 26%

TOPICS

� What do we talk about when we talk about metastatic TN

breast cancer?

� The platinum salts question

� PARP inhibitors

� Immunotherapy

� The AR way

� Conclusions

Predictors of response to cisplatin therapy

in triple-negative/basal-like tumors

Silver, D. P. et al. J Clin Oncol; 28:1145-1153 2010

Copyright © American Society of Clinical Oncology

pCR Rates by Treatment and According to HR

Deficiency Status (ypT0 ypN0)

Gunter von Minckwitz et al. ASCO 2015

Telli ML et al. J Clin Oncol 2015

Platinum+ GEM versus

Paclitaxel+Gem

Xi-Chun Hu, JZ et al. Lancet Oncology 2015.

Carboplatin vs Docetaxel in Advanced TNBC or

BRCA1/2+ BC (TNT): ORR

Tutt A, et al. SABCS 2014. Abstract S3-01.

All Pts

(n = 376)

C→D D→C

Crossover*

(All pts; n = 182)

BRCA1/2

Mutation

(n = 43)

No BRCA1/2

Mutation

(n = 273)

0

10

20

30

40

50

60

70

80

90

Re

spo

nse

at

Cy

cle

3 o

r 6

(%

)

31.4%

35.6%

22.8%25.6%

P = .44

P = .73

68.0%

33.3%

P = .03

28.1%

36.6%

P = .16

Carboplatin

Docetaxel

Crossover

*Excludes those with no first progression or not starting crossover treatment.

No difference in RR in BRCA1 methylated

or BRCA1 mRNA silenced tumors

PFS improved in platinum-treated BRCA1

mutant TNBC; not BRCA1 methylated TNBC

Platinum salts and lehmann subtypes

BL1 vs LAR, p=0,048

BL1 vs resto de subtipos, p=0,027

% R

Cp

(n=5) (n=3) (n=8) (n=4) (n=4) (n=2) (n=5)

TOPICS

� What do we talk about when we talk about metastatic TN

breast cancer?

� The platinum salts question

� PARP inhibitors

� Immunotherapy

� The AR way

� Conclusions

Olaparib in BRCA-deficient Metastatic

Breast Cancer: Results

Tutt A et al. J Clin Oncol 2009;27(18S):803s (abstr CRA501)

ITT cohort400 mg BID

N = 27100 mg BID

N = 27

ORR 11 (41%) 6 (22%)

CR 1 (4%) 0

PR 10 (37%) 6 (22%)

Median PFS5.7 mo

(4.6-7.4)3.8 mo

(1.9 – 5.6)

Best percent change from baseline in target lesions by

genotypeMedian 3 prior lines of therapy

Objective Response Rate

(by RECIST)

Gelmon KA et al. Lancet Oncology 2011.

Efficacy Endpoints

Overall Survival (OS) – ITT Population

With permission from O’Shaughnessy J et al. Proc ASCO 2011;Abstract 1007

Pro

ba

bil

ity

of

Su

rviv

al

Prespecified alpha = 0.04

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 2 4 6 8 10 12 14 16

OS

GC

(N = 258)

GCI

(N = 261) HR p-value

Median OS 11.1 mos 11.8 mos 0.88 0.28

BROCADE: Study Design

Mod. Han HS et al. SABCS 2016, General Session 2, Abstract No. S2-05 17

*Carboplatin/Paclitaxel administered on D3, 21-day cycle; †28-day cycle; Patients were treated until progression or unmanageable toxicity. If both Carboplatin and Paclitaxel or if TMZ was discontinued, Placebo/Veliparib was discontinued;

AUC, area under the concentration-time curve; BID, twice daily; D, day; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PgR, progesterone receptor; Q, every; TMZ, Temozolomide.

Locally recurrent or metastatic breast cancer with deleterious BRCA1/2 mutationN=290 (86 sites, 20 countries)

R

1:1:1

Veliparib 120 mg D1–7 BID + Carboplatin AUC 6/Paclitaxel 175 mg/m²

Q3W*N=97

Placebo+ Carboplatin AUC 6/Paclitaxel 175 mg/m²

Q3W*N=99

Veliparib 40 mg D1–7 BID + TMZ 150 to 200 mg/m² QD, D1-5†

N=94

Stratification factors for randomization• ER and PgR status (positive or negative)• Prior cytotoxic therapy (yes or no)• ECOG status (0–1 or 2)

Veliparib + TMZ results were presented separately; December 9, 2016, 7.30 AM – 9.30 AMSABCS program number: P4-22-02

Demographics and Baseline Characteristics

Mod. Han HS et al. SABCS 2016, General Session 2, Abstract No. S2-05 18

*Positive in either primary site or metastasis; †Status missing for 2 patients in the Placebo + C/P and 3 patients in the Veliparib + C/P arm; HER2, human epidermal growth factor receptor 2.

Characteristic, n (%)Placebo +

C/PN=99

Veliparib + C/P

N=97

Median age, years (range) 46 (24–66) 44 (25–65)

ER/PgR status

ER negative and PgR negative 43 (43.4) 40 (41.2)

ER positive and/or PgR positive 56 (56.6) 57 (58.8)

HER2 overall status*

Negative 92 (92.9) 94 (96.9)

Positive 7 (7.1) 3 (3.1)

TNBC 42 (42.4) 40 (41.2)

Non-TNBC 57 (57.6) 57 (58.8)

BRCA1 mutation positive 53 (53.5) 51 (52.6)

BRCA2 mutation positive 46 (46.5) 44 (45.4)

ECOG status

0–1 93 (93.9) 92 (94.8)

2 6 (6.1) 5 (5.2)

Characteristic, n (%)Placebo +

C/PN=99

Veliparib + C/P

N=97

Number of prior regimens of cytotoxic therapy (any setting)

0 23 (23.2) 19 (19.6)

1 42 (42.4) 47 (48.5)

2 25 (25.3) 24 (24.7)

>2 9 (9.1) 7 (7.2)

Measurable disease at baseline †

Yes 81 (83.5) 73 (77.7)

No 16 (16.5) 21 (22.3)

Number of metastaticsites

No metastases 5 (5.1) 4 (4.1)

1 38 (38.4) 39 (40.2)

2 28 (28.3) 30 (30.9)

3 18 (18.2) 13 (13.4)

≥4 10 (10.1) 11 (11.3)

Improved tumor response with

addition of veliparib

Placebo + C/PVeliparib + C/P

Months Since RandomizationNo. at Risk

Placebo + C/P

Veliparib + C/P

98

95

82

80

61

60

35

38

20

22

8

13

4

4

0

2

0

1

Pro

babi

lity

of

Pro

gres

sion

-Fre

e S

urvi

val

Placebo + C/P

N=98

Veliparib + C/P

N=95HR p value*

Median PFS, months (95% CI)

12.3 (9.3–14.5)

14.1 (11.5-16.2)

0.789 (0.536–1.162)

0.231

Progression-Free Survival

Mod. Han HS et al. SABCS 2016, General Session 2, Abstract No. S2-05 20

*From Cox proportional hazard model, stratified by ER/PgR status and prior cytotoxic therapy use.Efficacy population includes all randomized patients who had a deleterious BRCA1/2 mutation per the core lab. CI, confidence interval; HR, hazard ratio.

Median (95% CI) PFS, Veliparib + TMZ: 7.4 (5.9–8.5) months; HR=1.858 (1.278–2.702), p=0.001. (SABCS program number: P4-22-02)

TOPICS

� What do we talk about when we talk about metastatic TN

breast cancer?

� The platinum salts question

� PARP inhibitors

� Immunotherapy

� The AR way

� Conclusions

Distribution of molecular subtypes of breast cancer by PD-L1 protein expresion level

in pooled cases from the SEARCH and NEAT studies

Ali HR et al. Ann Oncol 2015

KEYNOTE 012

Nanda R et al. J Clin Oncol 2016.

MPDL3280A: Summary of EfficacyEfficacy-evaluable patients (n=21) with TNBC in Phase

la expansion

IC2/3 patients, na ORR

(95%CI)

24-Wekk PFS

(95%CI)

2119%

(5-42)

27%

(7-47)

• Responses included 2 CRs (1 IC3 and 1 IC2) and 2 PRs (IC2

- 3 of 4 responses were ongoing.

• 3 patients recorded as PD appeared to experience

pseudoprogression, with durable shrinkage of target and new

lesions.

a ICO/1 patients not yet evaluable for efficacy

IHC IC3 (≥ 10% of ICs PD-L1+), IHC IC2 (≥ 5% to <10% of ICs PD-L1+)

Investigator-assessed confirmed ORR per RECIST v1.1.

Efficacy population includes patients dosed by July 21, 2014

Atezolizumab + Nab -Paclitaxel in mTNBC: Phase Ib Study Design� GP28328: a multicenter, multicohort phase Ib study; arm F includes pts with TNBC

(metastatic or unresectable, locally advanced)[1,2]

� Primary endpoint: safety and tolerability

� Secondary endpoints: response per RECIST v1.1 (ORR, DoR, PFS) and immune-modified response criteria; pharmacokinetics, biomarker analyses

Slide credit: clinicaloptions.com1. Adams S, et al. ASCO 2016. Abstract 1009. 2. ClinicalTrials.gov: NCT01633970.

Atezolizumab (800 mg) + nab-paclitaxel (125 mg/m2), as long as

clinical benefit received;Nab-paclitaxel for

at least 4 cycles, unless disease progression or unacceptable toxicity; if

discontinued, atezolizumab as

monotherapy

Pts with TNBC≤ 2 previous

systemic cytotoxicsECOG PS 0/1;

no CNS cancer or untreated/active

CNS metastases;available tumor

sample

++ +

++

++ +

++

++ +

++

Atezolizumab Nab-paclitaxel

SafetyCohort(n = 8)

B

-+ +

++

++ +

++

++ +

++

B BB

Cycle 1, Day 1 Cycle 2, Day 1 Cycle 3, Day 1 (weeks)

Serial BiopsyCohort(n = 24)

Atezolizumab Nab-paclitaxel

Cycle 1, Day 1 Cycle 2, Day 1 Cycle 3, Day 1

Atezolizumab + Nab -Paclitaxel in mTNBC: Efficacy (Secondary Endpoints)

� Among 12 responders, 6 (50%) remain on atezolizumab; 1 for > 17 mos

� Median DoR not reached; PFS and OS data not yet mature

� Responses observed in pts regardless of PD-L1 expression level; trend toward increase in baseline TILs for responding pts

Slide credit: clinicaloptions.comAdams S, et al. ASCO 2016. Abstract 1009.

Best Overall Response (RECIST v1.1)

First Line(n = 13)

Second Line(n = 9)

Third Line+(n = 10)

All(N = 32)

Confirmed ORR, % (95% CI) 46 (19-75) 22 (3-60) 40 (12-74) 38 (21-56)

CR, % 8 0 0 3

PR, % 38 22 40 34

SD, % 38 67 30 44

PD, % 15 0 30 16

Missing or not estimable, % 0 11 0 3

Median DoR, mos (range) NE (2.9 to 11.5+) NE (9.1 to 13.1+) NE (1.9+ to 5.6+)

Ongoing clinical trials with anti-bodies directed

against PD-1/PD-L1 to treat breast cancer

Hartkopf AD et al. Breast Care 2016.

TOPICS

� What do we talk about when we talk about metastatic TN

breast cancer?

� The platinum salts question

� PARP inhibitors

� Immunotherapy

� The AR way

� Conclusions

Antiandrogens in TNBC

Cortés J et al, 2015 Enzalutamide mOS: 12 m

Gucalp A et al, 2013 Bicalutamide CBR: 19%

Traina TA et al, 2015 Enzalutamide CBR: 35%

Bonnefoi H et al, 2016 Abiraterone CBR: 20%

Overview of relevant molecular alterations

in triple-negative breast cancer

Denkert C et al. The Lancet 2016.

Conclusions

� TNBC is a title of convenience rather than a biologicalentity.

� HRD: platinum salts/ iPARP/HDCHT/Immuno

� LAR: HT?