Evolving Strategies for Enhancing the Impact of Immunotherapy in Breast Cancer
Hope S. Rugo, MD, FASCO
Professor of Medicine
Director, Breast Oncology and Clinical Trials Education
University of California San Francisco Comprehensive Cancer Center
TILS in Breast Cancer
• High TILS are more frequent in TNBC (30%)>HER2 (19%)>luminal tumors (13%)
• Correlate with grade but not other CP factors
• High TILS predictive of:
• DFS and OS in TN early stage breast cancer
• pCR in TN and HER2+ breast cancer
• Improved DFS and OS in untreated largely node negative TNBC (>30%)
• International consensus scoring recommendations see www.tilsinbreastcancer.org
Salgado, Denkert et al, 2014 Ann Oncol
Denkert et al 2016 Modern Path
Loi et al, JCO 2019; TILs images from www.tilsinbreastcancer.org
Park et al, Ann Oncol 2019
0% TILS 30% TILS
80% TILS
Checkpoint Inhibitor Monotherapy: Line of Therapy MattersAgent Subtype N ORR ORR (PD-L1+)*
Pembrolizumab• Single agent (Keynote-012)• Single agent (Keynote-028)• Single agent (Keynote-086-A)• Single agent (Keynote-086-B)• Plus trastuzumab (PANACEA)
TNBCER+
TNBCTNBCHER2+
3225
1708458
18.5%12.0%
5.7% (PD-L1+)21.4%
18.5%12.0%5.7%
21.4%15.0%
Atezolizumab• Single agent• Single agent (expanded)
TNBCTNBC
21115
19.0%10.0%
IL (n=21): 26%; >2L (n=91): 6%
19.0%13.0%
Avelumab• Single agent (Javelin) All
ER+/HER2-HER2+TNBC
168723858
4.8%2.8%3.8%8.6%
33.3%NRNR
44.4%
*Studies used different antibodies and cutoffs for PD-L1 positivity
Nanda et al, JCO 2016; Rugo et al, CCR 2018; Dirix et al, BCRT 2017; Loi et al, SABCS 2017; Emens et al, JAMA Onc 2019; Adams et al, Ann Onc 2019
Immunologic Differences Between Primary and
Metastatic Tumor Samples
Percent TIL counts in full
sections and TMAs.
PD-L1 + rates (≥1%
stromal or tumor cells)Change in PD-L1 status
between the primary and
metastatic cohorts.
Szekely, et al (Pusztai), Ann Oncol 2018
Monotherapy: Overall Survival by RECIST in First-Line Setting Atezolizumab Pembrolizumab
Adams et al, Ann Onc 2019; Emens et al, Jama Onc 2019
N=84Median OS: 18 mo
N=116Median OS: 17.6mo
Augmenting the Cancer
Immunity Cycle
Chen DS and Mellman I. Immunity 2013;39:1-9
◆ Co-primary endpoints were PFS and OS in the ITT and PD-L1+ populationsd
– Key secondary efficacy endpoints (ORR and DOR) and safety were also evaluated
IMpassion130 study design
Schmid P, et al. NEJM 2018, ASCO 2019
IC, tumour-infiltrating immune cell; TFI, treatment-free interval. a ClinicalTrials.gov: NCT02425891. b Locally evaluated per ASCO–College of American Pathologists (CAP)
guidelines. c Centrally evaluated per VENTANA SP142 IHC assay (double blinded for PD-L1 status). d Radiological endpoints were investigator assessed
(per RECIST v1.1).
Key IMpassion130 eligibility criteriaa:
• Metastatic or inoperable locally advanced TNBC
‒ Histologically documentedb
• No prior therapy for advanced TNBC
‒ Prior chemo in the curative setting, including
taxanes, allowed if TFI ≥ 12 mo
• ECOG PS 0-1
Stratification factors:
• Prior taxane use (yes vs no)
• Liver metastases (yes vs no)
• PD-L1 status on IC (positive [≥ 1%] vs negative [< 1%])c
Atezo + nab-P arm:
Atezolizumab 840 mg IV
‒ On days 1 and 15 of 28-day cycle
+ nab-paclitaxel 100 mg/m2 IV
‒ On days 1, 8 and 15 of 28-day cycle
Plac + nab-P arm:
Placebo IV
‒ On days 1 and 15 of 28-day cycle
+ nab-paclitaxel 100 mg/m2 IV
‒ On days 1, 8 and 15 of 28-day cycle
Double blind; no crossover permittedRECIST v1.1
PD or toxicityR1:1
Rugo et al. Abstract 6571
IMpassion130 PD-L1 IHC
https://bit.ly/30OmOqz
PD-L1 IC status by SP142 predicts PFS and OS
benefit with atezolizumab + nab-paclitaxel1,2
(41% positive by SP142)
A + nP, atezolizumab + nab-paclitaxel; HR, hazard ratio; ITT, intention to treat; OS, overall survival; P + nP, placebo + nab-paclitaxel; PFS, progression-free survival.
PD-L1 IC+: PD-L1 in ≥ 1% of IC as percentage of tumour area assessed with the VENTANA SP142 assay.
NCT02425891. Stratification factors: prior taxane use, liver metastases and PD-L1 IC status. Co-primary endpoints in ITT and PD-L1 IC+: PFS and OS.
Clinical cutoff date: 2 January 2019.
1. Schmid, ASCO 2019. 2. Schmid et al., submitted.
PopulationMedian OS HR
(95% CI)A + nP P + nP
PD-L1 IC+ 25.0 mo 18.0 mo0.71
(0.54, 0.93)
PD-L1 IC- 19.7 mo 19.6 mo0.97
(0.78, 1.20)
PopulationMedian PFS HR
(95% CI)A + nP P + nP
PD-L1 IC+ (41%) 7.5 mo 5.3 mo0.63
(0.50, 0.80)
PD-L1 IC- (59%) 5.6 mo 5.6 mo0.93
(0.77, 1.11)
A + nP (IC+, n = 185)
P + nP (IC+, n = 184)
A + nP (IC-, n = 266)
P + nP (IC-, n = 267)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 420 3 6 9 12 15 18 21 24 27 30 33 36 39 42
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
Overa
ll S
urv
ival (%
)
Pro
gre
ssio
n-F
ree S
urv
ival (%
)
MonthsMonths
Immune-Related Adverse Events
Schneeweiss, Rugo et al, ASCO 2019
AESI = adverse event of special interest
Immune-Mediated AESI Requiring Systemic Corticosteroids
Most Clinically Relevant AESI by Grade
Rugo et al. Abstract 6571
IMpassion130 PD-L1 IHC
https://bit.ly/30OmOqz
Efficacy in PD-L1 IC+
PFS OS
Pri
mary
Meta
sta
tic
PD-L1 status in primary vs metastatic tissues
a Evaluable population (n = 901). PD-L1 IC+: PD-L1 in ≥ 1% of IC as percentage of tumour area assessed with the VENTANA SP142 assay.
HRs adjusted for prior taxanes, presence of liver metastases, age and ECOG PS. No major differences were observed for clinical benefit in samples collected within 61 days of randomization or
beyond that period (Emens, et al, manuscript in preparation).
Atezolizumab + nab-paclitaxel
Placebo + nab-paclitaxel
HR, 0.61 (95% CI: 0.47, 0.81)
HR, 0.55 (95% CI: 0.32, 0.93)
HR, 0.79 (95% CI: 0.57, 1.09)
HR, 0.69 (95% CI: 0.46, 1.03)S
urv
ival (%
)
Surv
ival (%
)S
urv
ival (%
)
Surv
ival (%
)
Months
MonthsMonths
Months
44%
36%
0% 20% 40% 60%
Primary tissue (62%)
Metastatic tissue (38%)
P = 0.014
43%
51%
43%
13%
30%
48%
36%
0% 20% 40% 60%
Breast (64%)
Lymph node (12%)
Lung (6%)
Liver (5%)
Soft tissue (4%)
Skin (2%)
Other (6%)
PD-L1 IC+
PD-L1 status by
primary vs metastatic tissuea
PD-L1 status by anatomical locationa
PD-L1 IC+▪ Median time of sample collection to randomization: 61 days
Rugo et al. Abstract 6571
IMpassion130 PD-L1 IHC
https://bit.ly/30OmOqz
▪ Intensity of PD-L1 staining did not impact clinical outcome (1 – 3+) (Emens et al, SABCS2018)
▪ Central testing of VENTANA PD-L1 SP142, DAKO 22C3 and VENTANA PD-L1 SP263
IHC assays performed according to the respective package insertsa
▪ PD-L1 IC algorithm (SP142 and SP263)
− Presence of discernible PD-L1 staining of any intensity in IC covering ≥ 1% of tumour area occupied by
TC, associated intratumoural and continuous peritumoural stroma
▪ PD-L1 CPS algorithm (22C3)
− Number of PD-L1–stained cells (TC, lymphocytes and macrophages) divided by the total number of viable
TC, multiplied by 100
▪ BEP population: 614 patients (68% of ITT) with samples tested with the 3 PD-L1 assays
− Prevalence of PD-L1 IC+ status according to SP142 was higher in the BEP (46%) than the ITT (41%).
All other evaluated baseline characteristics were balanced between BEP and ITT
− PFS outcome with A + nP in the BEP slightly overperformed compared with PFS outcome in the ITT
Comparison of PD-L1 Assays:
Exploratory post hoc IMpassion130 substudy
CPS, combined positive score; TC, tumour cells. a Using respective platforms. b SP142: 5 pathologists trained for TNBC; 22C3: 2 pathologists trained for non-TNBC; SP263: 3 pathologists trained for non-TNBC.
Rugo et al. Abstract 6571
IMpassion130 PD-L1 IHC
https://bit.ly/30OmOqz
SP142 (IC 1%)
and SP263 (IC 1%)
OPAc 69%
PPA 98%
NPA 45%
SP142 (IC 1%)
and 22C3 (CPS 1)
OPAc 64%
PPA 98%
NPA 34%
PD-L1 IHC assays: prevalence and
analytical concordance
NPA, negative percentage agreement; OPA, overall percentage agreement; PPA, positive percentage agreement.a > 97% of SP142+ samples included in 22C3+ or SP263+ samples. b Compared with 41% in ITT (Schmid, New Engl J Med 2018).c ≥ 90% OPA, PPA and NPA required for analytical concordance.
SP142-
22C3-
(18%)
SP142+
22C3+
(45%)a
SP142-
22C3+
(36%)
SP142+
22C3-
(1%)
SP142-
SP263+
(30%) SP142-
SP263-
(24%)
SP142+
SP263+
(45%)a
PD
-L1+
Cases
PD-L1+
prevalence
SP142+
SP263-
(1%)
46%
81%
75%
0%
20%
40%
60%
80%
100%
SP142 (IC ≥ 1%)
22C3 (CPS ≥ 1)
SP263 (IC ≥ 1%)
b
Rugo et al. Abstract 6571
IMpassion130 PD-L1 IHC
https://bit.ly/30OmOqz
Population PFS OS
SP142+
22C3+(45%; 279/614)
SP142-
22C3+(36%; 218/614)
SP142-
22C3-(18%, 111/614)
Median OS, mo HR
(95% CI)A + nP P + nP ∆
27.3 18.0 9.3 0.71 (0.52, 0.98)
Median PFS, mo HR
(95% CI)A + nP P + nP ∆
8.3 3.9 4.4 0.60 (0.46, 0.78)
Clinical outcomes in BEP subpopulations
defined by SP142 (IC 1%) and 22C3 (CPS 1)13
Double positive: SP142 IC ≥ 1%, 22C3 CPS ≥ 1; single positive: SP142 IC < 1%, 22C3 CPS ≥ 1; double negative: SP142 IC < 1%, 22C3 CPS < 1.
HR adjusted for prior taxanes, presence of liver metastases, age and ECOG PS.
7.3 5.6 1.7 0.81 (0.61, 1.09) 21.3 21.8 −0.5 0.92 (0.64, 1.31)
5.5 5.6 −0.1 1.00 (0.66, 1.51) 14.7 19.6 −4.9 1.08 (0.67, 1.76)
Double
positives
Single
positives
Double
negatives
Surv
ival (%
)
Surv
ival (%
)
Months
Months
Months
Months
Surv
ival (%
)
Surv
ival (%
)
Surv
ival (%
)
Surv
ival (%
)
Months Months
Rugo et al. Abstract 6571
IMpassion130 PD-L1 IHC
https://bit.ly/30OmOqz
In this post hoc exploratory biomarker sub-study of the IMpassion130 trial
▪ Clinical activity was observed in the SP142 PD-L1 IC+ subgroup, regardless of whether
the sample was from the primary tumour or metastatic tissue
▪ With overall percentage agreements of 64% (22C3) and 69% (SP263), the analytical
concordance was subpar (< 90%) and the assays are not equivalent
− 22C3 (CPS ≥ 1) and SP263 (IC ≥ 1%) PD-L1 assays identified a larger patient population
of which SP142+ (IC ≥ 1%) is a subgroup
▪ The clinical benefit in 22C3+ and SP263+ subgroups was driven by the SP142+ subgroup
− The SP142 assay identified patients with the smallest HR point estimates and
longest median PFS and OS from atezolizumab + nab-paclitaxel
▪ At the present time, the SP142 assay at IC >1% cutoff is the approved diagnostic test used
to identify patients with mTNBC most likely to benefit from the addition of atezolizumab to
nab-paclitaxel
Conclusions
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
Time, monthsNo. at risk
312 224 154 112 76 57 031 6
310 233 163 108 75 48 021 6
Pembro
Chemo
OS
, %
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
No. at risk
203 151 109 76 51 40 020 3
202 152 102 66 42 27 012 3
Pembro
Chemo
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
No. at risk
96 79 57 41 26 23 011 1
98 80 54 36 23 12 04 1
Pembro
Chemo
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
No. at risk
57 50 39 28 21 18 08 1
52 41 29 20 13 6 02 0
Pembro
Chemo
Events
HR
(95% CI) P
77.1% 0.78
(0.57-1.06)
0.057
88.8%
Events
HR
(95% CI) P
84.2% 0.86
(0.69-
1.06)
0.073
90.6%
Events HR (95% CI)
85.3% 0.97(0.82-1.15)
88.1%
Events HR (95% CI)
70.2% 0.58 (0.38-0.88)
92.3%
OS in the ITT, CPS ≥1 and CPS ≥10 populations were primary endpoints; OS in the CPS ≥20 population was an exploratory endpoin t. Data cutoff date: April 11, 2019
KEYNOTE 119: Phase III Pembrolizumab vs. Chemo in 2L/3L TNBC: OS by PD-L1 CPS
ITT
N=622
CPS ≥1
CPS ≥10 CPS ≥20
Median (95% CI)
12.7 mo (9.9-16.3)
11.6 mo (8.3-13.7)
Median (95% CI)10.7 mo (9.3-12.5)
10.2 mo (7.9-12.6)
Median (95% CI)
14.9 mo (10.7-19.8)
12.5 mo (7.3-15.4)
Median (95% CI)
9.9 mo (8.3-11.4)
10.8 mo (9.1-12.6)
Cortes et al, ESMO 2019
65%
31% 18.5%
0 10 20 30 400
10
20
30
40
50
60
70
80
90
100
Time, monthsNo. at risk
312 154 76 31 0
203 109 51 20 0
All
CPS 1
OS
, %
CPS 10
CPS 20
96 57 26 11 0
57 39 21 8 0
0 10 20 30 400
10
20
30
40
50
60
70
80
90
100
Time, monthsNo. at risk
310 163 75 21 0
202 102 42 12 0
All
CPS 1
OS
, %
CPS 10
CPS 20
98 54 23 4 0
52 29 13 2 0
OS by PD-L1 CPS: Role of high score?
Data cutoff date: April 11, 2019.
ChemoPembro
Cortes et al, ESMO 2019
I-SPY ™ | The right drug. The right patient. The right time.™
pCR is a highly significant predictor of EFS and DRFS
17
I-SPY2 TRIAL
EFS DRFSOVERALL
Yee et al SABCS 2018
Event Free Survival by pCR & non-pCR by SubtypeI-SPY2 TRIAL
Yee et al., SABCS 2018
pCR is a Great Early Endpoint
I-SPY2: Pembrolizumab Graduated for Efficacy in HER2-Negative Cohorts
Current I-SPY2 Immunotherapy Arms:• Pembolizumab x 8, extended through AC• Olaparib/Durvalumab/Pac -> AC• SD101/paclitaxel/pembrolizumab -> AC
Nanda et al, ASCO 2017
SD-101:TLR9 agonist (30 nucleotide
phosphorothioate oligodeoxynucleotide with
juxtaposed CpG motifs)
aMust consist of at least 2 separate tumor cores from the primary tumor. bCarboplatin dose was AUC 5 Q3W or AUC 1.5 QW.cPaclitaxel dose was 80 mg/m2 QW.
dDoxorubicin dose was 60 mg/m2 Q3W.eEpirubicin dose was 90 mg/m2 Q3W.fCyclophosphamide dose was 600 mg/m2 Q3W.
KEYNOTE-522 Study Design (NCT03036488)
Stratification Factors:• Nodal status (+ vs -)• Tumor size (T1/T2 vs T3/T4)• Carboplatin schedule (QW vs Q3W)
Key Eligibility Criteria
• Age ≥18 years
• Newly diagnosed TNBC of
either T1c N1-2 or T2-4 N0-2
• ECOG PS 0-1
• Tissue sample for PD-L1
assessmenta
Neoadjuvant Treatment 1
(cycles 1-4; 12 weeks)
Neoadjuvant Treatment 2
(cycles 5-8; 12 weeks)
Adjuvant Treatment
(cycles 1-9; 27 weeks)
Carboplatinb +
Paclitaxelc
Doxod/Epirubicine+
Cyclophosphamidef
Pembrolizumab 200 mg Q3W
84% PD-L1+
Pembrolizumab 200 mg Q3W
Placebo
81% PD-L1+
Placebo
R
2:1
Neoadjuvant Phase Adjuvant Phase
Carboplatinb +
Paclitaxelc
Doxod/Epirubicine +
Cyclophosphamidef
S
U
R
G
E
R
Y
Neoadjuvant phase: starts from the first neoadjuvant treatment and ends after definitive surgery (post treatment included)
Adjuvant phase: starts from the first adjuvant treatment and includes radiation therapy as indicated (post treatment included)
PD-L1 + defined by CPS >1
Schmid et al, ESMO 2019
Pathological Complete Response at IA1Total N=1174; pCR in 1st 602 pts, P value boundary for significance 0.003
aEstimated treatment difference based on Miettinen & Nurminen method stratified by randomization stratification factors. bPD-L1 assessed at a central laboratory using the PD-L1 IHC
22C3 pharmDx assay and measured using the combined positive score (CPS; number of PD-L1–positive tumor cells, lymphocytes, and macrophages divided by total number of tumor
cells x 100); PD-L1–positive = CPS ≥1. Data cutoff date: September 24, 2018 – after last patient enrolled
0
10
20
30
40
50
60
70
80
90
100
ypT0/Tis ypN0
pC
R,
% (
95
% C
I)
Primary Endpoint: ypT0/Tis ypN0
64.8%
51.2%
Δ 13.6 (5.4–21.8)a
P=0.00055
0
10
20
30
40
50
60
70
80
90
100
PD-L1–Positive PD-L1–Negative
pC
R,
% (
95
% C
I)
By PD-L1 Statusb: ypT0/Tis ypN0
68.9%
54.9%
Δ 14.2 (5.3–23.1)a
45.3%
30.3%
Δ 18.3 (–3.3–36.8)a
260/401 103/201 230/334 90/164 29/64 10/33
Pembro + Chemo
Placebo + Chemo
Event-Free Survival at IA2: 1st Interim AnalysisP value boundary for significance 0.000051 (HR<0.4)
aPrespecified P value boundary of 0.000051 not reached at this analysis (the first interim analysis of EFS). IA2: If pCR hypothesis successful at IA1, pCR will not be formally tested at IA2
HR (CI) analyzed based on a Cox regression model with treatment as a covariate stratified by randomization stratification fac tors. Data cutoff April 24, 2019; 24 mo after last pt enrolled
0 3 6 9 12 15 18 21 24 270
10
20
30
40
50
60
70
80
90
100
Months
EF
S, %
No. at Risk784 780 666 519 242376 073 2765390 386 337 264 116186 035 1380
91.3%
85.3%
EventsHR
(95% CI)
Pembro + Chemo/Pembro 7.4% 0.63a
(0.43-0.93)Placebo + Chemo/Placebo 11.8%
Immune related Aes:
• 14.1 vs 2.1% grade 3-5
Discontinuation of any drug:
• 9.5 vs 2.6% 9% events with median FU 15.5 months
Immune-Mediated AEs and Infusion Reactions in Combined Phases: IA2
0
10
20
30
40
50
60
70
80
90
100
Inc
ide
nc
e, %
a1 patient from pneumonitis.
Considered regardless of attribution to treatment or immune relatedness by the investigator. Related terms included in additi on to preferred terms listed. Data cutoff date: April 24, 2019.
Immune-Mediated AEs and Infusion Reactions With Incidence ≥10 Patients
1-2
Grade
3-5
Pembro Arm
Placebo Arm
Pembro Arm(N = 781)
Placebo Arm(N = 389)
Any grade 42.3% 21.3%
Grade 3-5 14.1% 2.1%
Led to death 0.1%a 0
Led to discontinuation of any drug
9.5% 2.6%
17.7
11.614.9
5.7 5.5
1.05.1
1.8 2.70
1.9 1.5 1.8 0.8 1.8 0.3 1.7 1.0 1.4 0.5
*Tissue: FFPE, fresh frozen;
Liquid biopsies: full blood; plasma, serum;
GeparNUEVO Study Design
12 weeks*
Su
rge
ry
Nab-Pac
+DurvalumabN=174
TNBC
Stratum:TILs
(low/med/high)C
linic
al re
sp
on
se
R
Durvalumab
Placebo
2 weeks
Co
re b
iop
sy Nab-Pac
+PlaceboECx4
+Placebo
ECx4
+Durvaluma
b
8 weeks
Window of opportunity
until amendment
Durvalumab
(0.75g) 1.5g d1q28 nab-Paclitaxel 125mg/m²
weekly
Epirubicin 90mg/m²;
Cyclophosphamide 600mg/m² d1q14
Loibl et al, Ann Oncol 2019
Subgroup Analysis of the Window Cohort(Overall pCR 52.4% vs 44.2%; Adjusted OR 1.53, p 0.182)
61.0%
41.4%
0%
10%
20%
30%
40%
50%
60%
70%
80%
Durvalumab Placebo
P=0.052
37.9%
50.0%
0%
10%
20%
30%
40%
50%
60%
70%
80%
Durvalumab Placebo
P=0.515
Window (N=117) No window
(N=57)
N=59 N=58 N=29 N=28
pCR +carbo/pac pCR + pac pCR + IO carbo/pac delta
Meta-analysis Poggio et al 2018
52.1%
KN522
N=1174
51.2% ITT 64.8% (pembro) 13.6%
ISPY2 20% 60%(pembro/no carbo) NA
GeparNeuvo
ITT
N=174
44.2% 53.4%(durva/no
carbo/nab-pac)
9.2%
GeparNeuvo
window
N=117
ITT 41.4% ITT 61% 19.6%
KN173 N=80
window
Single arm ITT 60% (pembro) NA
pCR Rates Across IO Studies
Courtesy of Sherene Loi; adapted
Stage I/II high TIL/PD-L1 patients do very well
Should we personalize treatment based on TILS?
50-67% 56-71%
Do All Patients with Early Stage TNBC Need Immunotherapy?
81-89% 86-93%
91-97% 95-99%
N=2210 early stage TNBC patients treated with AC-T;
Loi et al, JCO 2019
Ongoing Phase III Trials with IO in TNBC
Neoadjuvant/adjuvant
• Atezolizumab
• Impassion 31 (n=204)
• Nab-pac AC or EC
• NeoTRIPaPDL1 (n=272)
• Nab-pac/Carbo (no post-op IO)
• NSABP B59/GeparDouze (n=1520)
• Pac/carbo AC/EC
• Pembrolizumab
• EFS Keynote 522
Adjuvant
• Atezolizumab• Impassion 30 (n=2300)
• Pac AC/EC
• Avelumab• A-Brave (n=335)
• Adjuvant and post NAC high risk: avelumab alone
• Pembrolizumab• SWOG S1418/NRG BR006 (n=1000)
• Post NAC: Pembro vs Obs x 1 yr
Metastatic:• Keynote 355: Pembro + gem/carbo or paclitaxel/nab-P• Impassion 131: Atezo + paclitaxel • Impassion 132: Atezo + gem or carbo or capecitabine
Improving the response to immunotherapy
Turning cold tumors hot
TONIC Trial
Radiotherapy 3x 8 Gy
Doxorubicin2x 15 mg IV
Cyclophosphamide2 weeks 50 mg daily
Cisplatin2x 40 mg/kg IV
ControlNo induction
Randomization
anti-PD1
2 weeks
anti-PD1
anti-PD1
anti-PD1
anti-PD1
biopsy + blood biopsy + blood biopsy + blood
8 weeks
Voorwerk et al, Nat Medicine 2019
Anti-PD1: Nivolumab
7 patients who died within 6 weeks of nivolumab are not included
Biomarkers in the TONIC Trial
TONIC stage II: randomized to doxorubicin lead-in or no lead-in
InCITe: Innovative Combination Immunotherapy for Metastatic Triple Negative BC
TBCRC 047
A multicenter, multi-arm TBCRCstudy funded by the Breast Cancer Research Foundation
PI: Hope S. Rugo; Co-PI: Ingrid Mayer
Metastatic TNBC• Measurable disease
• No more than 3 prior metastatic lines of chemotherapy• Known PD-L1 status
• Prior IO allowed
Tumor biopsy
Blood collection
Utomilumab
Binimetinib
PF04518600
Binimetinib + Avelumab
Utomilumab + Avelumab
PF04518600 + Avelumab
Tumor biopsy
Blood collection
15 day lead-in1 Cycle=4 weeksTumor assessments & PRO q 8 wks
Blood collection (at
8 weeks and at PD)
Novel agent 1: Binimetinib, a MEK inhibitor
Novel agent 2: Utomilumab, a 4-1BB agonist
Novel agent 3: PF04518600, an OX40 agonist
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PARP Inhibition May Enhance Immune Surveillance Through Multiple Mechanisms
Topacio and Mediola trials indicate safety combining PARPi with IO: subset analysis unclear (Domchek, Vinayak, SABCS 2018)
MEDIOLA:SchemaforThirdStage
PI:Domchek,OT3-5-03,SABCS2018
Enhancing Efficacy of Immunotherapy:Paclitaxel/Atezolizumab plus Ipatasertib
The combination of (nab-)paclitaxel, ipatasertib and atezolizumab not approved for triple-negative breast cancer, investigational use. AKT, protein kinase B; CI, confidence interval; IV, intravenous; ORR, objective response rate; PD, progressive disease; PD-L1, programmed death-ligand 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha;PR, partial response; SD, stable disease; SLD, sum of longest diameters; TNBC, triple-negative breast cancer. Schmid P, et al. AACR 2019 (Abstract CT049).
ORR 73% (95% CI = 53, 88)
- PD-L1+: 82%
- PD-L1–: 75%
- PIK3CA/AKT+: 71%
- PIK3CA/AKT–: 82%
A phase III trial is planned
Enhancing the Efficacy of Immunotherapy
• Most studies in breast are studying CPI; a small number of trials are evaluating vaccines and adoptive T-cell therapy
Adams et al, JAMA Onc 2019
Immune-Related AEs
Postow et al: NEJM. 2018Cancer Treatment Reviews 45 (2016) 7–18
Awareness, provider and patient education, early intervention is critical
Case History
• 40 year old woman
• Stage II TNBC treated with AC/T and radiation
• No germline mutation
• 1.5 years later routine CXR picks up nodular density
• CT: multiple pulmonary nodules
• FNA+ TNBC
• Treatment
• Capecitabine: stabilitization then increase in one nodule at 10 weeks
• Pembrolizumab on single agent >2nd line trial
Outcome• CT scans: reduction in lung nodules
• After a trip to Mexico 3 months after starting pembrolizumab, developed diarrhea that improved then worsened after a brief antibiotic course
• Colonoscopy with blind biopsy revealed inflammatory changes consistent with immune colitis
• With loperamide, up to 3 loose stools/day
• Treated with oral budesonide with complete resolution of symptoms
• CT scan at 8 months: one residual 1 cm nodule RUL, no FDG avidity
• SBRT to single nodule
• 4.5 years after starting pembrolizumab, remains NED on occasional budesonide
• Immunotherapy comes of age in breast cancer!
• Checkpoint blockade + chemotherapy
• IMpassion130: Defining a subset of patients with mTNBC who benefit!
• Regulatory approval for atezolizumab + nab-paclitaxel as first line therapy for PD-L1+
(IC) mTNBC
• Survival benefit > PFS benefit suggests change in tumor microenvironment and host
response
• Keynote 522: success in treating earlier line independent of PD-L1 positivity?
• Await EFS results next year
• Novel combination strategies offer great promise
• Role in HER2+ and ER+ disease also being actively explored
Conclusions
The Dawn of Immunotherapy for Breast Cancer!
Thank you!