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Immunotherapy for Metastatic Triple Negative Breast Cancer Sylvia Adams, MD Associate Professor of Medicine Breast Cancer and Cancer Immunotherapy Programs New York University School of Medicine

Immunotherapy for Metastatic Triple Negative Breast Cancer

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Page 1: Immunotherapy for Metastatic Triple Negative Breast Cancer

Immunotherapy for Metastatic

Triple Negative Breast Cancer

Sylvia Adams, MD

Associate Professor of Medicine

Breast Cancer and Cancer Immunotherapy Programs

New York University School of Medicine

Page 2: Immunotherapy for Metastatic Triple Negative Breast Cancer

Disclosures

No relevant financial conflicts

Global Principal Investigator, Keynote-086

Steering Committee Member, Impassion-130

Page 3: Immunotherapy for Metastatic Triple Negative Breast Cancer

FDA approvals for immune checkpoint antibodies

8/5/16 Pembrolizumab met H&N ca

Breast Cancer?

10/19/16 Atezolizumab met NSCLC

Page 4: Immunotherapy for Metastatic Triple Negative Breast Cancer

Presented by: Shaveta Vinayak, M.D., M.S. Adams et al, J Clin Oncol 2014

Breast Tumor-Infiltrating Lymphocytes (TIL)

iTILs

sTILs

Page 5: Immunotherapy for Metastatic Triple Negative Breast Cancer

Immune Response against Cancer

CD4+

T cell

CD8+

T cell

Tumor bed Tumor bed

CD8+

T cell

CD8+

T

cell

CD4+

T cell

CD4+

T cell CD40

CD4+

T cell

CTLA-4 CD137

OX40 PD-1

PD-L1 CD80 CD86

DEC-205

Ag

Release of Cancer Antigens &

Antigen presentation

T cell priming and activation

T cell trafficking, tumor

infiltration, recognition and killing

Page 6: Immunotherapy for Metastatic Triple Negative Breast Cancer

Presented by: Shaveta Vinayak, M.D., M.S. Adams et al, J Clin Oncol 2014

Breast Tumor-Infiltrating Lymphocytes (TIL)

iTILs

sTILs

Page 7: Immunotherapy for Metastatic Triple Negative Breast Cancer

TIL in breast cancer- the

subtype matters

Loi S, et al. J Clin Oncol 2013

Luen, et al, Breast, 2016

Stanton, Adams, Disis. Jama

Onc 2016

Page 8: Immunotherapy for Metastatic Triple Negative Breast Cancer

500 patients with TNBC

Median age: 49 years (24-85), 59% positive LN

Adjuvant treatment with anthracycline/taxane

Median follow-up 10.6 years.

Baseline surgical sample assessed on H&E section,

TIL graded in deciles

Higher sTIL were associated with better prognosis:

For every 10% increment in sTIL:

•14% reduction of risk for recurrence or death (P=0.02)

•18% reduction of risk for distant recurrence (P=0.04)

•19% reduction of risk of death (P=0.01)

Prognostic value retained in multivariate model

sTIL are prognostic in TNBC treated with

adjuvant chemotherapy: E2197 and E1199

0%

80%

Page 9: Immunotherapy for Metastatic Triple Negative Breast Cancer

Randomized Ph III BIG 02-98 ECOG 2197 and

1199

FINHER Gustave Roussy

Trial A CMF, AC

CMF

AC-T, AC, AT Docetax or

Vinorelb FEC

CAF/CEF vs none

256 TNBC 481 TNBC 134 TNBC 199 TNBC

8-year f/u 10.6- year f/u 5.2- year f/u 12.7-year f/u

all LN pos 59% LN pos 89% LN pos 43% LN pos

Methods REMARK & pre-specified analysis

H&E full section, analyzed in deciles (continuous) and categorical (LPBC vs not)

sTIL per 10% DFS

univariate OS

HR 0.84 (p=0.02) HR 0.86 (p=0.02) HR 0.79 (p=0.03) n/a

HR 0.82 (p=0.02) HR 0.81 (p=0.01) HR 0.80 (p=0.08) HR 0.89 (p=0.1)

sTIL per 10% DFS

multivariate OS

HR 0.85 (p=0.02) HR 0.84 (p=0.005) HR 0.77 (p=0.02) n/a (DFS)

HR 0.83 (p=0.02) HR 0.79 (p=0.003) HR 0.81 (p=0.14) HR 0.85 (p=0.04)

sTIL are a robust prognostic biomarker in TNBC

Summary of prospective studies ~ level I evidence

Loi S, et al. J Clin Oncol 2013, Adams S, et al, J Clin Oncol 2014

Loi S, et al. Ann Oncol 2014, Dieci MV, et al, Ann Oncol 2015

Page 10: Immunotherapy for Metastatic Triple Negative Breast Cancer

• Stromal TIL in 80% of TNBC, ~ 10% are lymphocyte-predominant (more

lymphocytes than tumor cells)

• Pre-existing TIL indicative of an endogenous adaptive anti-tumor immune

response and determine survival

• Consensus guidelines for evaluation of TIL in breast cancer published by

our group

Target and harness the immune system to improve cure rates in

TNBC

TNBC is immunogenic - Implications

Salgado et al, 2014, Annals of Oncology

Page 11: Immunotherapy for Metastatic Triple Negative Breast Cancer

Immune checkpoint inhibitors are drugs

– often made of antibodies – that re-

invigorate an immune attack on cancer

cells.

Programmed death 1 (PD-1) receptor

and its ligand PD-L1 are expressed in

the tumor and TILs to protect against

immune destruction (‘inhibitory’)

Anti PD-1/PD-L1 antibodies can block

that these inhibitory pathways, restoring

functional killer T cells.

The PD-1:PD-L1 Pathway– Immune checkpoints

Page 12: Immunotherapy for Metastatic Triple Negative Breast Cancer

Anti-PD-1, Nanda, SABCS 2014/JCO 2016

N=32, heavily pretreated

IHC >1% in tumor or stroma, 58% of screened

MK-3475 at 10 mg/kg q 2 weeks (Keynote-012)

•Acceptable safety (6/32 G3 or higher)

•Median follow-up: 9.9 months

•ORR 18.5% (5/27), including 1 CR

•Responses durable, with the median response

duration not reached (range, 15 to 40+ weeks) and 3

of 5 responders on treatment for ≥11 mos

•Median time to response: 18 weeks (q 8 scans)

•Median time on study: 8.5 weeks

PD-1/PD-L1 Blockade in metastatic PD-L1-positive TNBC

Anti-PD-L1, Emens, SABCS 2014/AACR2015

N=21

IHC >5% immune cells, 23% of screened patients

MPDL3280A at 15-20 mg/kg q 3 weeks

• Acceptable safety (1/12 G3)

• Median follow-up: 40 wks

• ORR 19% (4/21), including 1 CR

• Responses durable, median duration of responses

not yet reached (range 18+ to 56+ weeks),

• Median time to response: 6 weeks (q 6 scans)

• Median time on study: 9 weeks

Page 13: Immunotherapy for Metastatic Triple Negative Breast Cancer

KEYNOTE-086:

Pembrolizumab Monotherapy for Metastatic TNBC

• Primary Endpoint:

– ORR (RECIST 1.1) in first line PD-L1+BC

– ORR (RECIST 1.1) in 2+ line BC

– Safety, tolerability

• Secondary Endpoints:

– PFS, DOR, OS

1L PD-L1-positive

mTNBC n=80 Pembrolizumab 200 mg IV q 3 weeks

Pembrolizumab 200 mg IV q 3 weeks

2+L mTNBC n=160

Conditional expansion

in PD-L1-positive

Adams, et al, TIP, SABCS 2015

Page 14: Immunotherapy for Metastatic Triple Negative Breast Cancer

SWOG S1418/NRG BR006

RPhIII Pembrolizumab for Residual TNBC post NAC

• Hypothesis:

– Pembrolizumab reduces IDFS by 33% c/w observation alone

• Primary Endpoint:

– Invasive DFS in PD-L1-positive and overall cohort

• Secondary Endpoints:

– Toxicity

– OS

– DRFS

– QOL (PROMIS, PRO-CTCAE forms, inflammatory markers)

– Tissue banking

Pembrolizumab 200 mg IV q 3 weeks x 1y

Observation

TNBC with >/=1 cm

residual invasive breast

cancer or any + LN after

neoadjuvant chemotherapy

N=1000

PIs: Pusztai/Mamounas

• Registration:

– Central PD-L1 testing

• Stratification:

– Nodal stage ypNo vs ypN+

– Residual tumor >2 vs < 2cm

– PD-L1 pos vs neg

– Prior adjuvant chemo yes vs no

1:1

Page 15: Immunotherapy for Metastatic Triple Negative Breast Cancer

15

• Cytotoxic chemotherapy can maintain clinical stability with these highly aggressive

tumors as well as lower tumor burden, a known predictive factor for immunotherapy

success

• Preclinical data for synergy of chemo- and immunotherapy

• Immune effects of paclitaxel can be harnessed

Can increase TIL in neoadjuvant setting (Demaria et al., 2001).

Enhances antigenicity of cancer cells by increasing the expression of MHC class I molecules.

Reduce local immunosuppressive mechanisms such as intratumoral MDSCs, transforming

growth factor β (TGF-β), IL-10 and regulatory T cells (reviewed in Zitvogel et al 2013).

Can increase PD-L1 expression (Gong et al 2011).

• Nab-paclitaxel does not require steroid premedication, FDA-approved for metastatic

breast cancer.

PD-1:PD-L1 Blockade Combined with Chemotherapy

Rationale

Adams et al, ASCO 2016

Page 16: Immunotherapy for Metastatic Triple Negative Breast Cancer

16

Rationale:

• Cytotoxic chemotherapy can maintain clinical stability with these highly aggressive

tumors as well as lower tumor burden, a known predictive factor for immunotherapy

success

• Preclinical data for synergy of chemo- and immunotherapy

• Immune effects of paclitaxel can be harnessed

• Nab-paclitaxel does not require steroid premedication, FDA-approved for metastatic

breast cancer

Main eligibility:

• Up to two cytotoxic regimens for metastatic TNBC, no taxane within 6 months

• Measurable disease, biopsy-accessible

Treatment:

• Nab-paclitaxel (125 mg/m2 IV over 30 minutes on Days 1, 8, and 15 q 28 days).

• Atezolizumab (MPDL3280A, 800 mg flat dose) every 2 weeks (Days 1 and 15 q 28

days), starting with cycle 2 for serial biopsies

Objectives:

• Primary: safety and tolerability,

• Secondary: PK, RR and PD, tissue correlates

Phase Ib Nab-paclitaxel with atezolizumab (a PD-L1)

Adams et al, ASCO 2016

Page 17: Immunotherapy for Metastatic Triple Negative Breast Cancer

17

• 32 patients enrolled

• All 32 patients who received ≥ 1 dose of atezolizumab were evaluable for safety (data

cutoff date of January 14, 2016)

• No unusual toxicities observed above what is expected for the single agents

• All patients experienced ≥ 1 adverse event (AE) of any cause

• No deaths related to study treatment

• Fatigue and pyrexia frequent

• Neutropenia, thrombopenia, anemia, neuropathy

• 1 patient with new onset Type I diabetes

• 1 patient discontinued atezolizumab after prolonged asymptomatic Grade 2 AST

elevation

• 6 patients discontinued nab-paclitaxel due to a treatment-related AE: n = 1:

peripheral sensory neuropathy (Grade 1), asthenia (Grade 2), fatigue (Grade 2),

pneumonia (Grade 3), n = 2 for peripheral neuropathy (1 each Grade 2 and 3)

Phase Ib Nab-paclitaxel with atezolizumab (a PD-L1)

Safety

Adams et al, ASCO 2016

Page 18: Immunotherapy for Metastatic Triple Negative Breast Cancer

18

• 32 patients enrolled

• Best overall response by RECIST 1.1

• 2 patients experienced a decrease in tumor burden after

an initial increase or the appearance of new lesions (irPR)

• 2/15 at NYU NED at 2 years, off abraxane >1 year

• PFS data are not mature, median DOR not been reached

• Median overall survival not mature: NE (95% CI, 8.0-NE)

• Planned evaluation of modulators of PD-L1 expression

• RPIII ongoing

Phase Ib Nab-paclitaxel with atezolizumab (a PD-L1)

Preliminary efficacy

Adams et al, ASCO 2016

BORR 1L (n = 13) All Patients (n = 32)

Confirmed ORR 46% (19-75) 38% (21-56)

CR 8% 3%

PR 38% 34%

SD 38% 44%

PD 15% 16%

By line of therapy:

Page 19: Immunotherapy for Metastatic Triple Negative Breast Cancer

• Baseline levels of TILs showed a trend with increased response

• PD-L1 expression?

• HR deficiency, MMR, mutational load?

TILs as a percentage of total tumor area.

Adams S, et al. ASCO 2016

PD-1:PD-L1 Blockade Combined with Chemotherapy

Predictive markers?

Page 20: Immunotherapy for Metastatic Triple Negative Breast Cancer

Response/Pseudoprogression to Atezolizumab/Nab-Paclitaxel

Adams S, et al. ASCO 2016

Page 21: Immunotherapy for Metastatic Triple Negative Breast Cancer

IMpassion130 (WO29522) Randomized Phase 3 trial:

Front-line Metastatic TNBC

• Primary Endpoint:

– PFS (RECIST 1.1) and OS

• Secondary Endpoints:

– PFS (mRECIST), ORR, DOR, HRQoL

• Key efficacy populations:

– ITT and PD-L1+

• FDA-registration trial

1L mTNBC n=900

(1:1; double-blinded)

Atezolizumab 840 mg q2wk +

Nab-paclitaxel 100 mg/m2 qwk 3/4 wks

Placebo q2wk +

Nab-paclitaxel 100 mg/m2 qwk 3/4 wks

Stratification factors:

Liver mets: Y/N

Prior Taxane: Y/N

PD-L1 IHC (IC 1/2/3)

Emens, Adams, et al, TIP, SABCS 2015

Page 22: Immunotherapy for Metastatic Triple Negative Breast Cancer
Page 23: Immunotherapy for Metastatic Triple Negative Breast Cancer

NYU 15-00441:

PhII Pembrolizumab and Nab-paclitaxel in mBC

• Primary Endpoint:

– Safety run in in first 12 patients

– ORR in TNBC

• Secondary Endpoints:

– PFS (mRECIST), DOR, OS

– ORR in HR+

– Predictive biomarkers

• Tumor biopsy baseline, after abraxane

alone and after combination

• Serum, PBMC, stool baseline, p c 2, 4

1L-3L metastatic BC

- TNBC n=30

- HR+/HER2- n=20

Nab-paclitaxel 100 mg/m2 d1, d8 q 3w

+

Pembrolizumab 200 mg q3w (added

with second cycle)

Eligibility:

Measurable disease

Serial biopsy-accessible tumor

Up to 2 prior chemoRx lines for mBC

Taxane washout 3 months

No active brain metastases

No pneumonitis

Metaplastic BC

Emens, Adams, et al, TIP, SABCS

2015

PI: Adams

Clinicaltrials.gov NCT# 02752685

Page 24: Immunotherapy for Metastatic Triple Negative Breast Cancer

For TIL-rich tumors:

Therapies targeting immune inhibitory pathways which are often also increased

For Non-infiltrated tumors: Interventions to trigger innate immune activation, T cell priming and effector T cell trafficking

Immunotherapeutic Approaches based on

Tumor Microenvironment

CD4+

T cell

CD8+

T cell

Tumor bed Tumor bed

CD8+

T cell

CD8+

T

cell

CD4+

T cell

CD4+

T cell CD40

CD4+

T cell

CTLA-4 CD137

OX40 PD-1

PD-L1 CD80 CD86

DEC-205

Ag

Release of Cancer Antigens &

Antigen presentation Vaccines, RT, chemo, TLR agonists

T cell priming and activation CTLA-4, OX40, HD IL-2, IL-7

T cell trafficking, tumor

infiltration, recognition and killing

Page 25: Immunotherapy for Metastatic Triple Negative Breast Cancer

Summary

1. Subsets of breast cancer are immunogenic.

2. The anti-tumor immune response has prognostic significance, with level

I evidence that TIL predict survival in TNBC. It also predicts

chemotherapy efficacy in the neoadjuvant setting.

3. There are compelling reasons why immunotherapies should be studied

in breast cancer, but specific to subtype.

4. Several modalities (TLR agonists, radiotherapy, trastuzumab etc) can be

harnessed to TIL-poor into TIL+ tumors.

5. Immune checkpoint blockade is emerging as highly promising strategy in

breast cancer. Combination studies are ongoing to improve response

rates. > 100 studies available nationally (see www.clinicaltrials.gov).

Page 26: Immunotherapy for Metastatic Triple Negative Breast Cancer

Thank you!

NYU Langone

Bellevue