TNBC: What’s new…Déjà vu All Over Again?

Lucy R. Langer, MD MSHSCompass Oncology - SABCS 2016 Review

February 21, 2017

The problem with TNBC…

1. Generally more aggressive 2. ONLY chemotherapy3. No other proven targets

In 2014…

1.Subtyping TNBC2.Platinums3.PARP-inhibitors4.Clinical Trials

What’s new in 2016?

1. Prevention of TNBC2. More on TNBC

subtyping3. AR, a potential new

target4. “BRCA”-ness5. Tumor infiltrating

lymphocytes & a brief word on the PD-1 inhibitors

Prevention

Prevention

HER-2 Strategies

• DCIS trastuzumab trials• Lapatinib in mouse, now

being evaluated in women• VADIS trial: HER2 peptide

vaccineDHEA: omega-3 fatty acids

statins

PolyphenonE(active agent in green tea)

retinoids

Metformin

What’s new in 2016?

1. Prevention of TNBC2. More on TNBC

subtyping3. AR, a potential new

target4. “BRCA”-ness5. Tumor infiltrating

lymphocytes & a brief word on the PD-1 inhibitors

Triple Negative Subtyping

70-80% Basal-like20-30% Luminal/AR type

What’s new in 2016?

1. Prevention of TNBC2. More on TNBC

subtyping3. AR, a potential new

target4. “BRCA”-ness5. Tumor infiltrating

lymphocytes & a brief word on the PD-1 inhibitors

6. Neoadjuvant and post-neoadjuvant

Luminal/AR type TNBC

Enriched in hormonal pathways, like the Androgen Receptor

HER2-enriched, even though HER2 ‘negative’

Bicalutamide, a prostate drug, no benefit

Enzalutamide, some benefit predicted by Predict-AR

Lapatinib shows possible benefit

What’s new in 2016?

1. Prevention of TNBC2. More on TNBC

subtyping3. AR, a potential new

target4. “BRCA”-ness5. Tumor infiltrating

lymphocytes & a brief word on the PD-1 inhibitors

Basal-Like TNBC

Most BRCA1 breast cancers are Basal-Like

Basal-Like breast cancers have DNA repair defects like BRCA1

Carboplatin shows some promise in BRCA+ cancers

Parp inhibitor Olaparib shows effect in BRCA+ cancer

HRD test not predictive of BRCA-ness

What’s new in 2016?

1. Prevention of TNBC2. More on TNBC

subtyping3. AR, a potential new

target4. “BRCA”-ness5. Tumor infiltrating

lymphocytes & a brief word on the PD-1 inhibitors

What about PD-1?

10-15% of TNBC falls into the ‘immunomodu-latory’ subtype

Enriched immune processes, TILs

Higher expression of PDL-1

Atezolizumab(Tecentriq) + nab-paclitaxel

PembrolizumabAwaiting RCTs

Conclusions… TNBC subtyping tools are

nearly ready

TNBC is chemo-sensitive, biomarkers such as Basal/non, TILs, and HRD signature are emerging

Many promising new drugs exist and are being tested (AR blockers, lapatinib, immune modulators, etc)

What’s new in 2016?

1. Prevention of TNBC2. More on TNBC

subtyping3. AR, a potential new

target4. “BRCA”-ness5. Tumor infiltrating

lymphocytes & A brief word on the PD-1 inhibitors

Neoadjuvant therapy in TNBC• GeparSixto: Phase II chemo/bev +/- carbo

- 36.9% vs 53.2% pCR, slight incr DFS• CALGB 40603: Phase II chemo+/-bev+/- carbo

- 41% vs. 64% pCR, no DFS or OS benefit at 5 years• What increase in pCR is needed to translate into DFS or OS?

Post-neoadjuvant treatment trialsJapan: CREATE-X trial

- Capecitabine vs. obs/endocrine- Benefit appears limited to TNBC, requires HIGH chemo doses

• PAM50 Analysis basal-like has worse prognosis in non-pCR group

ECOG-ACRIN EA1131- Phase III, platinum vs. obs in Basal TNBC

SWOG 1418- Phase III pembrolizumab for TNBC post-neo or adjuvant

CREATE-X: Study Design

Preplanned interim analysis of a randomized, open-label phase III study[1]

Primary endpoint: DFS

Secondary endpoints: OS, time from first day of preoperative chemotherapy to recurrence or death, safety, cost-effectiveness

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(N = 910)†

Capecitabine2500 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)†

Slide credit: clinicaloptions.com

Stratified by ER status, age, neoadjuvantchemotherapy, 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: 5-Yr EfficacyCapecitabine achieved significantly higher 5-yr DFS and OS in HER2-

BC pts with residual disease

Slide credit: clinicaloptions.com

Characteristic, %

Capecitabine

(n = 440)

No Capecitabin

e(n = 445)

HR (95% CI) P Value

5-yr DFS 74.1 67.7 0.70 (0.53-0.93) .00524

5-yr OS 89.2 83.9 0.60 (0.40-0.92) < .01

Toi M, et al. SABCS 2015. Abstract S1-07.

CREATE-X: DFS by Subgroup

Slide credit: clinicaloptions.comToi M, et al. SABCS 2015. Abstract S1-07.

Subgroup HR(95% CI)

Total (N = 885) 0.70 (0.53-0.93)

Age < 50 yrs (n = 531) ≥ 50 yrs (n = 354)

0.72 (0.50-1.03)0.68 (0.45-1.04)

Hormone receptor status Positive (n = 561) Negative (n = 296)

0.84 (0.57-1.23)0.58 (0.39-0.87)

Node stage ypN0 (n = 345) ypN1 (n = 339) ypN2 or 3 (n = 199)

0.88 (0.48-1.62)0.54 (0.36-0.83)0.82 (0.52-1.29)

Path grade by NAC 0-1b (n = 482) 2-3 (n = 385)

0.63 (0.45-0.88)0.84 (0.52-1.34)

Subgroup HR(95% CI)

Total (N = 885) 0.70 (0.53-0.93)

Taxane-containing NAC Yes (n = 849) No (n = 36)

0.70 (0.53-0.93)0.87 (0.12-6.24)

5-FU–containing NAC Yes (n = 529) No (n = 356)

0.74 (0.52-1.04)0.65 (0.42-1.02)

Nationality Japanese (n = 599) Korean (n = 286)

0.74 (0.53-1.02)0.63 (0.37-1.05)