Triple Negative Breast cancer New treatment options arenowhere ?

Ofer Rotem, M.D., B.Sc. Breast Unit, Davidoff center Rabin Medical center October 2017

Case

• 6/2013 - M.D., 38 years old woman, healthy, no family Hx

Palpated mass in her right breast

• O/E & Imaging – 3cm mass in Rt breast UOQ and a 2cm mobile LN in the right axilla.

CNBx Rt breast & axilla – IDC Grade 2-3, LN-Pos

ER/PR/HER2-Neg, Ki67-40%

Systemic work-up – no evidence of Met disease

• TNBC Stage II – T2N1M0

Case

• After consulting with her surgeon, the Mrs. D refers to your clinic for Preoperative treatment.

• Mrs. D is married + 3, works as a pilot in EL-AL.

Which regimen would you prefer ?

1- DD AC Weekly Taxol

2- DD AC Taxol-Carbo

3- DD AC-Bev Taxol-Carbo-Bev

4- AC Weekly Taxol

GeparSixto: Study Design

• Randomized phase IIb study in 51 German centers

• Primary endpoint: pCR

• Secondary endpoints: RFS, DFS, OS

Pts with centrally confirmed TNBC* or HER2+ BC† with

cT2 - T4a-d or cT1 with N+

disease (N = 588)

Surgery

PMCb

Myocet 20 mg/m² Q1W + Paclitaxel 80 mg/m² Q1W

Carboplatin AUC 2‡ Q1W

q.18w

(n = 295)

PM Myocet 20 mg/m² Q1W + Paclitaxel 80 mg/m² Q1W

q.18w (n = 293)

*TNBC pts also received bevacizumab 15 mg/kg IV Q3W. †HER2+ BC pts also received trastuzumab 8 mg/kg IV (initial dose), then 6 mg/kg IV Q3D (subsequent doses) and lapatinib 750 mg QD. ‡Dose reduced to AUC 1.5 after 330 pts enrolled.

von Minckwitz G, et al. SABCS 2015. Abstract S2-04.

GeparSixto: pCR Outcomes

SABCS 2015

pCR, %

ypT0/is ypN0 PMCb PM

Odds

Ratio P Value

All pts (n = 588) 43.7 36.9 .107*

HER2+ BC (n = 273) 32.8 36.8 0.84 .6†

TNBC (n = 315)

gBRCA wild type (n = 241)*

gBRCA mutant (n = 50)*

53.2

55

65.4

36.9

36.4

66.7

1.94

2.14

0.94

.005†

.004

0.92

* Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer Secondary Analysis of the GeparSixto Randomized Clinical Trial Eric Hahnen. JAMA Oncology, Oct 2017. von Minckwitz G, et al. SABCS 2015. Abstract S2-04. von Minckwitz G, et al. Lancet Oncol. 2014;15:747-756. von Minckwitz G, et al. ASCO 2014. Abstract 1005.

*Level for significance = 0.2 †Test for interaction, P = .015

GeparSixto: DFS by gBRCA Status and Regimen in TNBC

Pts

Wit

h D

FS (

%)

BRCA wt PM BRCA wt PMCb BRCA mt PM BRCA mt PMCb

121 120

24 26

104 107

23 25

88 95 19 20

43 40

6 7

0 0 0 0

BRCA wt PM BRCA wt PMCb BRCA mt PM BRCA mt PMCb

Mos

100

80

60

40

20

0 0 12 24 36 48

BRCA1/2 Mut WT

86.3 Vs 82.5 85.3 Vs 73.5 3yDFS (%)

Non-Significant 0.53, 0.29-0.96 HR, CI

CALGB 40603

breast/axilla pCR –40603 CALGB

William M. Sikov, et al. JCO, Jan 2015

Carbo No Carbo

54% 41%

OR-1.71, p-0.0029

Bev No Bev

52% 44%

OR-1.36, p-0.057

With Bev & Carbo With Carbo With Bev Control

60% 49% 43% 39%

Carboplatin Bevacizumab

Yes No Yes No

EFS 3-year 76% 71% 75% 72%

HR 0.84 (0.58-1.22) 0.80 (0.55-1.17)

OS 3-year 81% 85% 85% 81%

HR 1.15 (0.74-1.79) 0.76 (0.49-1.19)

CALGB 40603 – EFS and OS by Factor

San Antonio Breast Cancer Symposium, December 8-12, 2015

ESMO Guidelines. 2015: Addition of carboplatin to neoadj chemotherapy in TNBC - For BRCA 1/2 or RAD mutations it is acceptable to add a platinum compound, after discussion with the patient. NCCN Guidelines version 2.2017: The NCCN panel does not recommend addition of carboplatin to neoadj standard chemotherapy for patients with TNBC outside a clinical trial setting.

ASCO 2017: I-SPY 2 Trial: Combination of Pembrolizumab Plus Standard Neoadjuvant Therapy in High-Risk Breast Cancer

ASCO 2017: I-SPY 2 Trial

• 69 pts were randomized to Pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts (25 HR+, 21 TN) have undergone surgery.

Case cont…

• Mrs. D decided she wants it all !

• 6-11.2013 - DD AC Carbo-Taxol + Bev

• 12.2013 - Rt Breast Lumpectomy + ALND

• Pathology report:

IDC Grade II, 0.5cm, LN-3/17

Next step ?

1- Adj xeloda

2- RTx and cont FU

3- NGS

4- Clinical trial – OlympiA

(In case of Germline BRCA Mut)

CREATE-X NEJM, Jun 2017

Pts 20-74 yrs of age with stage I-IIIB HER2- BC and

residual disease (non-pCR, N+) after neoadjuvant

chemotherapy* and surgery; ECOG PS 0 or 1;

no previous oral fluoropyrimidines Japan & South Korea

(N = 910)†

Capecitabine

2500 mg/m²/day PO Days 1-14

Q3W for 8 cycles‡

Hormonal therapy if ER/PgR+ (n = 455)†

Hormonal therapy if ER/PgR+

No further therapy if ER/PgR-

(n = 455)†

Stratified by ER status, age, neoadjuvant chemotherapy, use of 5-FU, institution, node status

*Anthracycline/taxane, anthracycline containing, or docetaxel/cyclophosphamide. †25 pts were removed from treatment (n = 10) and control (n = 15) arms due to failure to meet eligibility criteria. ‡IDMC recommended extension to 8 cycles following interim safety analysis of first 50 pts receiving 6 cycles.[2]

1. Toi M, et al. SABCS 2015. Abstract S1-07. 2. Ohtani S, et al. SABCS 2013. Abstract P3-12-03.

Wk 24

CREATE X

• PEP – DFS • SEP – OS, time from first day of preoperative chemotherapy to recurrence or death, safety, cost-effectiveness

• The result of the prespecified interim analysis met the PEP, so the trial was terminated.

CREATE X - TN Pts

5yDFS 70% Vs 56% 5yOS 79% Vs 70%

Case cont…

• Mrs. D was found to be BRCA1/2 WT, and decided to get Capecitabine.

• 10.2014 - Lower back pain, fatigue.

PET scan - metastatic dis – Bones, liver.

• ECOG 1

• Blood test – Normal

WWUD ?

1- NGS

2- Chemotherapy (+/- Bev)

3- PARPi

4- Immunotherapy

Immunotherapy

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Somatic mutations in cancers

Breast Cancer and mutations: Lower median rate detected compared

to the most immune-sensitive cancers but wide range of mutations detected

Alexandrov L,B. Nature 2013

Alexandrov L,B. Nature 2013

Alexandrov L,B. Nature 2013

Alexandrov L,B. Nature 2013

Luen, The Breast, 2016

TNBC - The best of what’s left...

≥2L ≥1L

Results<br />BOR per RECIST v1.1 by line of therapy

KEYNOTE 150 - An Open-Label, Single-Arm Multicenter Phase 1b/2 Study to Evaluate the Efficacy and Safety of Eribulin

Mesylate in Combination With Pembrolizumab in Subjects With Metastatic Triple-Negative Breast Cancer (mTNBC)

SABCS 2016

Case Cont… 11.2014 – Single agent Pembrolizumab. 11.2015 – Clinical and radiographic PD. NGS: Somatic BRCA1 Mut

OlympiAD – ASCO 2017 NEJM 8.2017

OlympiAD

OlympiAD

OlympiAD

No crossover

Case Cont… 12.2015– Olaparib 9.2016 – Clinical and radiographic PD. New Liver Biopsy – TN, AR > 10%

11%

TNBC subtypes comparison with intrinsic PAM50 subtypes (Unsupervised Vs supervised clustering)

374 TNBC GE profiles were subtyped using PAM50 or TNBCtype

Anti Androgen therapy

Bicalutamide Enzalutamide

Abiraterone acetate

RR-0-8%

Triple Negative Breast cancer New treatment options arenowhere/arenowhere ?