Transcript ASCO Breast Cancer Symposium

Immunotherapy
Update
Elizabeth A. Mittendorf, MD, PhD
Associate Professor
Department of
Breast Surgical Oncology
Immunotherapy
• Treatment to
stimulate or
modulate the
immune system to
fight disease
Couzin-Frankel J. Science 2013;342:1432-1433
Dizon DS, et al. J Clin Oncol 2016;34:987-1011
Immunogenic Tumors
Mutational Load
Lawrence MS et al. Nature 2013;499:214-218
Immunotherapy in Breast Cancer?
• Breast tumors express multiple putative TAA
– HER2, MUC-1
ECD
TMD
ICD
I I S A VV G I L
GP2-peptide vaccine (aa 654-662)
MHC Class I : HLA-A2
Stimulate CD8 + T cells
KI FGSLAFL
GVGS PYVSRLLGI CL
E75-peptide vaccine (aa 369-377)
AE37-peptide vaccine (aa 776-790)
MHC Class I : HLA-A2 & HLA-A3
MHC Class II : multi-allele
Stimulate
CD8+
T cells
Stimulate CD4+ T cells
Immunotherapy in Breast Cancer?
• Passive immune strategies with α-HER2
antibodies has led to survival benefits
Trastuzumab
EGFR (HER1)
P <.001
HER2
Perez EA et al. J Clin Oncol 2011;29:3366-3373
HR=0.52 (95% CI: 0.45-0.60)
TIL in Breast Tumors
• BIG 02-98
• N=2009 node positive
breast cancer samples
• TIL identified on pretreatment H&E sections
P<.001
– Evaluated stromal and
intratumoral TIL
– LPBC = ≥ 50%
lymphocyte infiltration
Loi S, et al. J Clin Onc 2013; 31:860-867
Prognostic Value of TIL
All Patients
HER2+
Loi S, et al. J Clin Onc 2013; 31:860-867
ER+/HER2-
TNBC
Prognostic Value of TIL
• N=991 TNBC pts
• 6 randomized adjuvant tx
trials
• 90% had at least 1% sTIL
• Average value of sTIL = 20%
• Each 10% ↑ in sTIL was
associated with:
– 14% relative ↓ in IDFS events
– 17% relative ↓ in deaths
Loi S, et al. SABCS 2015
Predictive Value of TIL
No lymphocytic infiltrate
pCR: 3-7%
Lymphocyte predominant
pCR: 40-42%
Denkert C, et al. J Clin Onc 2010; 28:105-113
Breast cancer is
immunogenic……
Is there a role for
immunotherapy?
Immunotherapy
• Checkpoint blockade
• Adoptive cellular therapy
–Antigen-specific T cells
–CAR+ T cells
• Vaccines
Immunotherapy
• Checkpoint blockade
• Adoptive T cell therapy
–CAR+ T cells
• Vaccines
T-Cell Response
Mellman I et al. Nature; 2011;480:480-89
Novel agents in clinical trials
PD-L1 in TNBC
PD-L1
Log2
TCGA
P<0.001
Non-TNBC
(n=716)
TNBC
(n=120)
Mittendorf EA, et al. Cancer Immunol Res, 2014;2:361-370
CD8+ T cells
Pembrolizumab (α-PD-1)
KEYNOTE-012:
Triple-Negative Breast Cancer Cohort
• Recurrent or metastatic
ER–/PR–/HER2– breast
cancer
• ECOG PS 0-1
• PD-L1+ tumora
• No systemic steroid
therapy
• No autoimmune disease
(active or history of)
• No active brain metastases
•
•
•
Pembro
10 mg/kg
Q2W
Complete Response
Discontinuation
Permitted
Partial Response or
Stable Disease
Treat for 24 months
or until progression
or intolerable
toxicity
Confirmed
Progressive Diseaseb
Discontinue
PD-L1 positivity: 58% of all patients screened had PD-L1-positive tumors
Treatment: 10 mg/kg IV Q2W
Response assessment: Performed every 8 weeks per RECIST v1.1
Nanda R, et al. J Clin Oncol, 2016 May 2 [Epub ahead of print]
Treatment Response
• Response assessed by RECIST v1.1
• Overall response rate
5 (18.5%)
• Best overall response
–
–
–
–
–
Complete response
Partial response
Stable disease
Progressive disease
No assessment
1 (3.7%)
4 (14.8%)
7 (25.9%)
12 (44.4%)
3 (11.1%)
Nanda R, et al. J Clin Oncol, 2016 May 2 [Epub ahead of print]
Time to and Durability of Response
• Median follow-up duration:
9.9 months (range, 0.4-15.1)
• Median time to response:
18 weeks (range, 7-32)
a
Best overall response • Median duration of response :
Responder
CR
not reached (range, 15 to 40+
Nonresponder
PR
PD after CR, PR, or SD
weeks)
SD
Last dose
Treatment ongoing
PD
Nanda R, et al. J Clin Oncol, 2016 May 2 [Epub ahead of print]
Pembrolizumab
KEYNOTE-028:
ER+/HER2- Breast Cancer Cohort
• ER+/HER2- tumors
• Locally advanced or
metastatic disease
• Failure of or inability to
receive standard therapy
• ECOG PS 0 or 1
• ≥ 1 measurable lesion
• PD-L1 positivity
•
•
•
Complete or partial
response or stable
disease
Treat for 24 mnths
or until progression
or intolerable
toxicity
Complete or partial
response or stable
disease
Discontinue
pembrolizumab
Pembro
10 mg/kg
Q2W
PD-L1 positivity: assessed on archival or newly obtained core or excisional biopsy using 22C3 antibody clone.
Positivity defined as membranous PD-L1 expression in ≥1% of tumor cells or any staining in stroma
Treatment: 10 mg/kg IV Q2W
Response assessment: Performed every 8 weeks for 6 weeks then every 12 weeks per RECIST v1.1
Rugo H, et al. SABCS 2015
KEYNOTE-028
•
•
•
•
Patients screened
Samples evaluable
PD-L1+
Patients treated
261
248
48
25
19.4%
PD-L1+
– 14 withdrew consent
– 5 inadequate organ function
– 4 other
Rugo H, et al. SABCS 2015
Treatment Response
Antitumor Activity (n=25)
n (%)
95% CI
3 (12)
2.5-31.2
0
0-13.7
Partial response
3 (12)
2.5-31.2
Stable disease
4 (16)
4.5-36.1
Clinical benefit rate*
5 (20)
6.8-40.7
Progressive assessment
15 (60)
38.7-78.9
No assessment†
3 (12)
2.5-31.2
Overall response rate
Complete response
* CBR = CR + PR + SD for ≥ 24 weeks
† patients who d/c therapy before 1st post-baseline scan
Rugo H, et al. SABCS 2015
Avelumab (anti-PD-L1)
JAVELIN (phase Ib cohort expansion)
Patients
Dosing
• Histologically confirmed LABC or
MBC refractory to or progressing
after SOC therapy
•
•
•
≤3 prior lines of cytotoxic therapy
Must have received prior taxane and
anthracycline
Bx or surgical specimen collected
within 90d of first dose of avelumab
• Unselected for ER/PR/HER2
molecular subtype
• Unselected for PD-L1 expression
• ECOG PS 0-1 and estimated life
expectancy of > 3 months
Avelumab
10mg/kg IV Q2W
until progression
Select
Assessments
• Safety and
tolerability
• BOR by
RECIST 1.1
• PD-L1
expression
status by IHC
at various cutoffs
Dirix L, et al. SABCS 2015
JAVELIN
HR+/HER2n=72
HER2+
N=26
TNBC
N=58
ORR
2 (2.8%)
1 (3.8%)
5(8.6%)
PD-L1+ tumor cells
evaluable cases
≥1% cut-off
≥5% cut-off
≥25% cut-off
56
31 (55%)
4 (7%)
1 (2%)
21
15 (71%)
5 (24%)
0
48
33 (69%)
13 (27%)
2 (4.2%)
≥10% immune cell “hotspots”
2/56 (7%)
1/21 (5%)
9/48 (29%)
•
•
•
•
8/156 (5.1%) responders
5/8 (62.5%) of responders had TNBC
Among 5 TNBC responders, 4 (80%) had PD-L1+ immune cells (“hotspots”)
PD-L1 expression by immune cells was associated with response to avelumab
• 4/12 (33.3%) of patients with “hotspots” responded
• 3/124 (2.4%) of patients without “hotspots” responded
Dirix L, et al. SABCS 2015
PD-1/PD-L1 Pathway
• Response to
anti-PD-1 or
anti-PD-L1
therapy requires:
–PD-L1 expression
–Presence of T cells
Loi S, et al. J Clin Onc 2013; 31:860-867
Strategies to Augment T Cell
Infiltrate
• Chemotherapy
–“immunogenic cell death”
• Radiation
• Cryoablation
• Drugs stimulating an innate immune
response (i.e. TLR, STING agonists)
• Vaccines
Strategies to Augment T Cell
Infiltrate
• Chemotherapy
–“immunogenic cell death”
• Radiation
• Cryoablation
• Drugs stimulating an innate immune
response (i.e. TLR, STING agonists)
• Vaccines
Atezolizumab + nab-Paclitaxel
• Combination of checkpoint inhibitors and chemotherapy may
be synergistic
Jeong Kim, Genentech, unpublished data
Atezolizumab + nab-Paclitaxel
• Efficacy evaluable population; N=24
Best Overall
Response
1L
(n=9)
2L
(n=8)
3L+
(n=7)
All patients
(n=24)
ORR
(95% CI)
67%
(30, 93)
25%
(3, 65)
29%
(4, 71)
42%
(22, 63)
CR
PR
11%
78%
0
75%
0
43%
4%
67%
SD
11%
25%
29%
21%
PD
0
0
29%
8%
Adams S, et al. ASCO 2016
Targeting PD-L1 in TNBC
enroll
nab-paclitaxel q3wk
Atezolizumab
N=37 to detect ↑ in rate of pCR or RCB-I from 5% to 20%
Primary endpoint:
• Determine safety of MPDL3280A in combination with nab-paclitaxel
• pCR/RCB-I rate
Secondary endpoint:
• DFS
PIs: Jennifer Litton, MD and Elizabeth Mittendorf, MD, PhD
Atezolizumab
to complete 6 mo of
treatment
blood
•
surgical
specimen
blood
•
blood
tissue biopsy
blood
•
•
surgery
adriamycin
cyclophosphamide
q3wk x 4
Strategies to Augment T Cell
Infiltrate
• Chemotherapy
–“immunogenic cell death”
• Radiation
• Cryoablation
• Drugs stimulating an innate immune
response (i.e. TLR, STING agonists)
• Vaccines
Cryo-Immunotherapy in Breast
Cancer
2. Immunogenic cell death
1. Tumor cryoablation
5. Distant tumor lysis
3. Ag processing and presentation
4. Ag recognition
Ipilimumab
NCT010502592 PI: Heather McArthur MD, MPH
Memorial Sloan Kettering Cancer Center
Cryo-Immunotherapy
• N=19
• Cryoablation →
ipilimumab
• No study-attributed
grade 3 or 4 AEs
• Immune correlates
– ↑ T cell proliferation
– ↑ IFN-γ production
Diab A, et al. SABCS 2013
Page D, et al. SABCS 2014
Strategies to Augment T Cell
Infiltrate
• Chemotherapy
–“immunogenic cell death”
• Radiation
• Cryoablation
• Drugs stimulating an innate immune
response (i.e. TLR, STING agonists)
• Vaccines
Vaccines
• Inject an antigen
that stimulates a
specific immune
response
• Lymphocytes –
B cells and T cells
Vaccine Platforms
•
•
•
•
•
•
Dendritic cell vaccines
Whole tumor cell vaccines
Recombinant protein
Peptide vaccines
DNA vaccines
Recombinant viral vectors
Peptide Vaccines
• Use antigenic
peptides derived
from tumor
associated
antigens (TAA)
• Stimulate peptidespecific immune
regulators
Peptide Vaccines
• Pros:
•
•
•
•
Simple to construct
Easy to manufacture large scale
Inexpensive
Exportable to the community
Vaccines for Solid Tumors
• Hypothesis:
Cancer vaccines
will be more
effective in a
minimal disease
(adjuvant) setting
HER2
Extracellular Domain
(aa 1-652)
ECD
Trans Membrane Domain
(aa 653-675)
TMD
Intracellular Domain
(aa 676-1255)
ICD
I I S A VV G I L
GP2-peptide vaccine (aa 654-662)
MHC Class I : HLA-A2
Stimulate CD8 T cells
KI FGSLAFL
GVGS PYVSRLLGI CL
E75-peptide vaccine (aa 369-377)
AE37-peptide vaccine (aa 776-790)
MHC Class I : HLA-A2 & HLA-A3
MHC Class II : multi-allele
Stimulate CD8 T cells
Stimulate CD4 T cells
HER2-Derived Peptide Vaccine
• E75
– 9 aa peptide from extracellular domain
– Immunodominant epitope of HER2
– MHC class I peptide → stimulated CD8+ T cells
– High affinity for HLA-A2 /A3
GM-CSF
E75
HER2/neu
Trial Objectives
• Determine safety, dosing (phase I)
• Determine safety, optimal dosing,
and clinical efficacy (phase II)
• Primary endpoint: disease-free
survival at 18 months, extended to 60
months
• Monitor immune response
Inclusion Criteria
• Histologically confirmed breast
cancer
• Node positive or high-risk node
negative
• Completed SOC surgery,
chemotherapy and radiation
• Immunocompetent
• Any level of HER2 (IHC 1+, 2+, 3+)
E75 Phase I/II Trial
Vaccine
Control
n=108
n=79
Age (median)
57
53
0.49
Node Positive
49%
56%
0.37
Tumor Size (T2-T4)
30%
39%
0.51
Histologic Grade 3
41%
38%
0.85
ER/PR negative
31%
18%
0.03
HER2 overexpression
31%
25%
0.53
Chemotherapy
76%
73%
0.70
Mittendorf EA et al. Ann Oncol 2014;25:1735-1742
p value
Percent of Vaccinated
Patients
Safety and Toxicity
Grade of Maximum Toxicity
Local Toxicity
Systemic Toxicity
Mittendorf EA et al. Ann Oncol 2014;25:1735-1742
In Vivo Immune Response: DTH
P<.001
Orthogonal Mean (mm)
P<.001
Normal
Saline
E75
Pre-Vaccination
Mittendorf EA et al. Ann Oncol 2014;25:1735-1742
Normal
Saline
E75
Post-Vaccination
Vaccine Induced E75 CTL
%E75 CD8+ T cells
(mean dimer index)
4.00
3.50
P=0.09
3.00
Did Not Recur
2.50
Recurrence
2.00
1.50
Recurrence above the mean: 1/30 (3%)
1.00
Mean R6 Dimer =0.63
0.50
0.00
Patient
Recurrence below the mean: 8/56 (14%)
Schneble EJ et al. Immunotherapy 2014;6:519-531
Fraction Surviving Disease Free
DFS – 60 mo f/u
89.7%
80.2%
P=.08
Vaccinated (n=108)
Control (n=79)
Time (months)
Mittendorf EA et al. Ann Oncol 2014;25:1735-1742
Fraction Surviving Disease Free
DFS – Optimal Dosing
94.6%
87.1%
80.2%
P=.05*
Optimally dosed (n=37)
Suboptimally dosed (n=71)
Control (n=79)
Time (months)
Mittendorf EA et al. Ann Oncol 2014;25:1735-1742
Phase III Study Schema: PRESENT (Prevention of Recurrence in
Early Stage Node-Positive Breast Cancer with Low to
Intermediate HER2 Expression with NeuVax Treatment)
Interim
analysis by Endpoint DFS
at n=139
DSMB at
n=70 events events/36 mos.
Study Population
Adjuvant Breast cancer
(BC) patients, n=700,
randomized 1:1
• Node positive (NP),
HLA A2/A3+, low and
intermediate HER2
expression
E75 + GM-CSF
• Achieve CR with
standard of care (SOC)
• Stratified by Stage (IIAIIIA), Type of Surgery,
Hormone Receptor and
Menopausal status
• Single dose level of
GM-CSF +/- E75
Placebo
+ GM-CSF
Dosing
by Month
1
2
3
4 5
6
+ 1 booster
dose every
6 months
thereafter
+ Dosing to
disease
progression or
36 months
PI: E.A. Mittendorf
HER2
Extracellular Domain
(aa 1-652)
ECD
Trans Membrane Domain
(aa 653-675)
TMD
Intracellular Domain
(aa 676-1255)
ICD
I I S A VV G I L
GP2-peptide vaccine (aa 654-662)
MHC Class I : HLA-A2
Stimulate CD8+ T cells
KI FGSLAFL
GVGS PYVSRLLGI CL
E75-peptide vaccine (aa 369-377)
AE37-peptide vaccine (aa 776-790)
MHC Class I : HLA-A2 & HLA-A3
MHC Class II : multi-allele
Stimulate
CD8+
T cells
Stimulate CD4+ T cells
GP2
• 9aa peptide from transmembrane domain
• MHC class I peptide → stimulates CD8+ T cell
response
• Subdominant epitope
• Immunogenic
– In vitro cytotoxicity
– Epitope spreading to GP2 in patients vaccinated with E75
• Phase I trial demonstrated safe and capable of
stimulating HER2-specific immune response
Mittendorf EA et al. Cancer 2006;106:2309-2317
Carmichael M et al. Cancer 2010;116:292-301
GP2 – Phase II Trial
• Hypothesis: The GP2+GM-CSF vaccine will ↓
recurrence rates when administered in the adjuvant
setting after completion of SOC therapy
• Inclusion criteria
– Histologically confirmed breast cancer
– Node-positive or high-risk node-negative
– Any level of HER2 expression (IHC 1+, 2+, or 3+)
– HLA-A2+
– NED after SOC therapy
GP2 – Phase II Trial
GP2+GM-CSF
Randomize
• NP or highrisk NN
• HER2 IHC
1+, 2+ or
3+
• HLA-A2+
• NED after
SOC
therapy
GM-CSF only
National PI: E Mittendorf, M.D., Ph.D.
Clinicopathologic Characteristics
Controls
N=91
51
P value
Age (median)
Vaccinated
N=89
51
Node positive
57%
66%
0.23
Grade 3
57%
57%
1.00
Tumor ≥ 2 cm
56%
57%
1.00
ER/PR negative
38%
34%
0.63
HER2 overexpression
57%
55%
0.88
Mittendorf EA, et al. ASCO Breast Cancer Symposium 2014
0.96
Toxicity
80
GP2+GM-CSF
70
GM-CSF only
% of Subjects
60
50
40
30
20
10
0
Grade 0 Grade 1 Grade 2 Grade 3 Grade 0 Grade 1 Grade 2 Grade 3
Local
Mittendorf EA, et al. ASCO Breast Cancer Symposium 2014
Systemic
In Vivo Immune Responses
GP2+GM-CSF
GM-CSF only
18
Orthogonal Mean (mm)
16
14
12
10
8
6
4
2
0
Pre-vaccination
Post-vaccination
*p<0.05
Mittendorf EA, et al. ASCO Breast Cancer Symposium 2014
DFS Per Treatment
93.5%
85.0%
57% RRR
Log Rank
p = 0.168
Vaccine Group
n= 83
A2+ Controls
n= 87
Mittendorf EA, et al. ASCO Breast Cancer Symposium 2014
DFS – HER2+ Patients
100%
88.8%
Log Rank
p = 0.077
Vaccine Group
n= 48
A2+ Controls
n= 50
Mittendorf EA, et al. ASCO Breast Cancer Symposium 2014
Mechanisms of Synergy
• ADCC → ↑ CD8+ T cell response
• Broad stimulation of HER2-specific
immunity
–CD4+ T cell response
–Antibody response
• ↑ antigen availability/presentation
Phase II Trial of Combination
Immunotherapy with E75+GM-CSF and
Trastuzumab in high-risk HER2+ Breast
Cancer Patients
Study Sponsors:
Department of Defense
Galena Biopharma
High-risk HER2+ Breast Cancer
• Did not achieve a
pCR after
neoadjuvant
chemotherapy +
HER2-targeted
therapy
• Upfront surgery
patients that are path
node-positive
– ≥ 4+ LN
– 1-3+ LN if HR
negative
Neoadjuvant Therapy
Study
TECHNO
N
217
Regimen
EC→taxol +
Tz
Results
3-yr DFS from
randomization
pCR = 88%
no pCR = 73%
MD Anderson (2009)
142
Included a taxane,
anthracycline and
concomitant Tz
3-yr RFS from
date of diagnosis
pCR = 96%
no pCR = 80%
MD Anderson (2013)
229
Included a taxane,
anthracycline and
concomitant Tz
5-yr RFS from
date of diagnosis
pCR = 96%
no pCR = 79%
Adjuvant Therapy
BCIRG-006
3222
Randomized to:
AC-T
AC-T + Tz
TCH
5-yr DFS
NN
NP
ACTH
TCH
≥4+
LN
93%
80%
73%
90%
78%
72%
Schema
18-24 weeks
Neoadjuvant Chemo
Surgery
Must enroll before 3rd
dose of trastuzumab
maintenance therapy
18-24 weeks
Study Population
• Primary resected
HER2+ breast
cancer (upfront
surgery) with node
positive disease
• HER2+ breast
cancer patients not
achieving a pCR
after neoadjuvant
chemotherapy*
• HLA-A2/3+
Adjuvant Chemo
Surgery
*neoadjuvant chemotherapy regimen must include trastuzumab
and at least four cycles (12 weeks) of taxane-containing therapy
^inoculations to begin with 3rd dose of trastuzumab maintenance
therapy
Trastuzumab +
E75+GM-CSF^
Trastuzumab +
GM-CSF^
Endpoints
• Primary
– Compare invasive DFS between treatment
groups
• Secondary
– Distant RFS
– Assess local and systemic toxicities
– Evaluate in vivo and in vitro immune
responses
Conclusions
• Breast cancer is an immunogenic
tumor
• Multiple ongoing trials are evaluating
immunotherapy strategies
• Combinations are the likely way
forward
• Appropriate strategy will be dictated
by the stage of disease
Acknowledgements
–
–
–
–
–
–
–
George E. Peoples, MD
Sathibalan Ponniah, PhD
Karen Arrington, RN
Shalece Barrow, RN
Susie Newman, RN
G. Travis Clifton, MD
Erika Schneble, DO
Julia Greene, MD
Acknowledgements
Surgical Oncology
Breast Medical Oncology
Research Staff
Lab
Kelly Hunt, MD
Catherine Akay, MD
Gildy Babiera, MD
Isabelle Bedrosian, MD
Shon Black, MD
Abigail Caudle, MD
Carlos Barcenas, MD
Gabriel Hortobagyi, MD
Nuhad Ibrahim, MD
Jennifer Litton, MD
Stacy Moulder, MD
Lee Murray, MD
Debu Tripathy, MD
Vicente Valero, MD
Holly Simmons, RN
Daniel Thorp, RN
Annie Toms, RN
Sharell Cornett-Risher
Mikki Talley
Gheath Alatrash, DO, PhD
Jeffrey Molldrem, MD
Victor Gall, MD
Anne Philips, PhD
Na Qiao, PhD
Protocol Team
Funding Sources
Benjamin Smith, MD
Lisa Kelly
Jason Love
David Welch
Kristen Weaver
Welela Tereffe, MD
Wendy Woodward, MD, PhD
Advocates
NIH/NCI
DoD
SSO
Komen for the Cure
Nancy Owens Memorial
Foundation
Henry M. Jackson Foundation
R. Lee Clark Fellows Program
Sarah DeSnyder, MD
Richie Ehlers, MD
Barry Feig, MD
Elizabeth FitzSullivan, MD
Rosa Hwang, MD
Henry Kuerer, MD, PhD
Anthony Lucci, MD
Funda Meric-Bernstam, MD
Makesha Miggins, MD
Merrick Ross, MD
Jessica Suarez, MD
Alastair Thompson, MD
Radiation Oncology
Pathology
Yun Wu, MD, PhD
Nadine Eidman
Jeannie Frazier
Lourdes Hernandez
Carla Leslie
Dorothy Patterson
Susan Rafte
Delia Stroud
MD Anderson Faculty Scholar
Injecting Hope