Sylvia Adams, MD, medical oncologist, and associate professor at the NYU School of Medicine, discusses the latest research including the role of immunology in the treatment of triple negative metastatic breast cancer. This webinar was hosted on October 19, 2016.
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Immunotherapy for Metastatic Triple Negative Breast Cancer
1. 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
3. FDA approvals for immune
checkpoint antibodies
8/5/16 Pembrolizumab met H&N ca
Breast
Cancer?
10/19/16 Atezolizumab met NSCLC
4. Presented by: Shaveta Vinayak, M.D., M.S. Adams et al, J Clin Oncol 2014
Breast Tumor-Infiltrating Lymphocytes (TIL)
iTILs
sTILs
5. 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 cellCD40
CD4+
T cell
CTLA-4CD137
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
6. Presented by: Shaveta Vinayak, M.D., M.S. Adams et al, J Clin Oncol 2014
Breast Tumor-Infiltrating Lymphocytes (TIL)
iTILs
sTILs
7. 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
8. 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%
9. 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
10. • 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. 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:
19. • 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?
23. 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
PI: Adams
Clinicaltrials.gov NCT# 02752685
24. 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 cellCD40
CD4+
T cell
CTLA-4CD137
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
25. 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).