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A personal view on PDL1 & TILs in TNBCIs a combined TIL-PDL1 analysis in TNBC the new narrative in daily practice?
Roberto Salgado
Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium
Division of Research, Peter Mac Callum Cancer Centre, Melbourne, Australia
Disclosures• Advisory Board role for BMS, Roche.
• Research funding by Roche, Puma, Merck.
• Travel and congress-registration support by Roche, Merck, Astra Zeneca.
• Member of an advisory group to the Belgian Government onreimbursement of assays in genomics and pathology.
• I have no financial conflicts of interest related to TILs.
• I have no financial conflicts of interests related to the current workpresented.
• Chair of The International Immuno-Oncology Biomarker Working Group(www.tilsinbreastcancer.org)
Taking a new biomarker into daily practice should be in agreement between pathologists,
oncologist, patients and industry
Higher levels in HER2+ and TNBC
Loi et al, JCO 2013; Ann Oncol 2014
TNBC, TILs AND PROGNOSIS
Pooled individual patient data analysis from 2148 early-stage TNBC treated with anthracycline-based adjuvant CT showed significant predictive value of sTILs for iDFS, dDFS, and OS
dDFS
OS
Loi S, et al. JCO 2019
Model to predict risk of distant recurrence at 5 years (%) by TILs & nodal status by tumor size and age
www.tilsinbreastcancer.org
Clinical Guidelines
• St. Gallen 2019: The Panel recommended that TILs be routine characterized in TNBC because of its prognostic value. However, data are inadequate to recommend TILs as a test to guide neo-adjuvant treatment choices in TNBC, as treatments are largely governed by stage.
= similar in ESMO 2019 BC Guidelines
How to use TILs as a prognostic factor in TNBC?= actually determining TILs at the moment of diagnosis
• Examples:• T1a,b,c- high vs low TIL- how well do they do WITHOUT chemotherapy? Can
we withhold chemo in high TIL TNBC T1a,b N0?
• High TIL Node negative and N1-3 – can we get away with less chemo- 4 cyclesAC for example vs 6 cycles
How do TILs affect stage?
Intrinsic prognostic value of tumor infiltrating lymphocytes (TILs)
in early-stage triple negative breast cancer (TNBC) not treated with adjuvant chemotherapy
A pooled analysis of 4 individual cohorts
Ji Hyun Park †, Sarah Flora Jonas†, Guillaume Bataillon†, Carmen Criscitiello†,
Roberto Salgado, Sherene Loi, Giuseppe Viale, Hee Jin Lee, Maria Vittoria Dieci, Sung-Bae Kim,
Anne Vincent-Salomon, Giuseppe Curigliano ◦, Fabrice Andre ◦, Stefan Michiels◦*.
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
Multivariable Cox Analyses (adjusted)iDFS (events 173) D-DFS (events 118) OS (events 107)
Stromal TILs (per 10%) 0.90 (0.83-0.98) p=0.02 0.86 (0.77-0.95) p=0.01 0.88 (0.79-0.98) p=0.02
Age* (yrs) 1.01 (0.99-1.02) p=0.31 1.03 (1.01-1.05) p=0.01 1.03 (1.01-1.05) p=0.01
Histologic grade, II vs I 1.69 (0.70-4.08) p=0.024 3.17 (0.74-13.60) p=0.12 2.74 (0.63-11.87) p=0.018
III vs I 2.74 (1.13-6.63) p=0.003 5.77 (1.34-24.83) p=0.02 5.14 (1.19-22.22) p=0.03
Tumor size* (cm) 1.26 (1.13-1.41) p<0.0001 1.25 (1.12-1.40) p<0.001 1.27 (1.12-1.43) p<0.001
Positive nodes 1.06 (1.03-1.10) p<0.001 1.07 (1.03-1.10) p<0.001 1.11 (1.06-1.15) p<0.00001
Radiotherapy 0.56 (0.39-0.83) p<0.01 0.55 (0.35-0.88) p<0.01 0.46 (0.28-0.75) p<0.01
* TILs, tumor size and age treated as continuous variables
iDFS (events 173)ΔX
2** p valueD-DFS (events 118)ΔX
2 ** p valueOS (events 107)ΔX
2** p value
CP+ sTILs vs CP 3.35 p=0.012 9.63 p<0.01 5.96 p=0.015
** Likelihood ratio test between univariate and multivariate model
Further Excellent Outcomes In pStage I tumors5Y: 91% 5Y: 97% 5Y: 98%3Y: 93% 3Y: 97% 3Y: 99%
Absolute benefit of chemo could be minimal in this group!
95-10095-10084-96 89-96 95-99 97-100
TILs assessment is gaining importance as a prognosticmarker. High TILs are associated with a better outcomeand a better response to neoadjuvant therapy in Triple-negative and HER2 positive breast carcinomas (Level 1Bevidence). TILs have strong prognostic value inimproving estimates of distant recurrence-free survival ,disease-free and overall survival in early-stage TNBCtreated with standard adjuvant/neoadjuvantchemotherapy (Level 1B evidence). This is based on anevaluation by pathologists using H&E stained glass slidesat time of diagnosis (pre-treatment and in the residualdisease post neoadjuvant chemotherapy). The presenceand the extent of TILs in invasive breast carcinomas varygreatly from one tumour to another. Their quantificationis feasible on H&E tissue sections during diagnosisprocedure and follows internationalrecommendations. Clinical utility (treatment allocation)is under investigation. TILs should be considered as astratification factor in clinical trials and be included instudies involving or evaluating prognosis. Inquantifying TILs, the international consensus scoringrecommendations are recommended (seewww.tilsinbreastcancer.org).
2019 WHO/IARC on TILs
Clinical Guidelines
• St. Gallen 2019: The Panel recommended that TILs be routine characterized in TNBC because of its prognostic value. However, data are inadequate to recommend TILs as a test to guide neo-adjuvant treatment choices in TNBC, as treatments are largely governed by stage.
= similar in ESMO 2019 BC Guidelines
The NarrativeDo Oncologists want to know?
• TILs can be assessed in a reproducible manner by Pathologists.
• Pathologists only need a microscope and a HE and can be trained using afreely available training-tool (www.tilsinbreastcancer.org).
• The scoring can be done at the moment of making a diagnosis.
• Stage I TNBC with high TILs have excellent 5-year survival, irrespective oftreatment, so I expect oncologist will start to ask it once the papers are out.
• So, if TILs are one day used for prediction for ICI, the pathologist hasalready scored them for prognostic reasons in the primary sample. This canhelp in PDL1-assessment.
TNBC, TILs, PDL1 AND PREDICTION
Clinical trial evidence regarding immune-checkpoint blockade therapies in a variety oftumour types (including breast tumours) is rapidlyevolving. Monoclonal antibodies targeting thePD1/PDL1 pathway or CTLA-4 are thought tofunction by removing the inhibition of theantitumour immune response. Early data from thephase III IMpassion130 clinical trial suggest thatimmunohistochemical PDL1 expression on > 1% ofimmune cells in metastatic TNBC is predictive ofimprovements in progression-free survival andoverall survival when first-line atezolizumab isadded to protein-bound paclitaxel (nab-paclitaxel).The use of approved and validated antibodiesand their corresponding organ-specific scoringsystems is recommended if testing is performed.However, the field is rapidly evolving, and otherbiomarkers may emerge that prove to beimportant for prediction of response tocheckpoint inhibitors.
2019 WHO/IARC on PDL1
Relationship Between Tumor-Infiltrating Lymphocytes and Response to Pembrolizumab + Chemotherapy as Neoadjuvant Treatment for Triple-Negative Breast Cancer: Phase 1b KEYNOTE-173 Trial
1Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia; 2Centre for Experimental Medicine, Barts Cancer Institute, London,
UK; 3Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 4Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic
of Korea; 5Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 6Yonsei University College of Medicine, Seoul, Republic of
Korea; 7Seoul National University College of Medicine, Seoul, Republic of Korea; 8Ramon y Cajal University Hospital, Madrid, Spain; 9Karolinska University
Hospital, Stockholm, Sweden; 10Kliniken Essen-Mitte, Essen, Germany; 11National Cancer Centre, Singapore; 12Merck & Co., Inc., Kenilworth, NJ, USA
S Loi,1 P Schmid,2 J Cortés,3 YH Park,4 E Muñoz-Couselo,3 S-B Kim,5 J Sohn,6
S-A Im,7 E Holgado,8 T Foukakis,9 S Kuemmel,10 R Dent,11 A Wang,12 G Aktan,12
V Karantza,12 R Salgado1
Objective
To evaluate the association of stromal TIL (sTIL) levels and PD-L1 expression
with pCR and ORR in patients treated with pembrolizumab + chemotherapy
(taxane ± platinum-based) as neoadjuvant treatment for TNBC
sTIL Levels by Response
Data cutoff date was May 31, 2018.aOne-sided Wald test P-values from logistic regression adjusted for tumor size.
ResponderNonresponder ResponderNonresponder
ResponderNonresponder ResponderNonresponderP=0.0097a
AUROC (90% CI) = 0.676 (0.547–0.806)
P=0.0039a
AUROC (90% CI) = 0.779 (0.667–0.891)
P=0.0085a
AUROC (90% CI) = 0.690 (0.564–0.817)
P=0.0262a
AUROC (90% CI) = 0.745 (0.618–0.872)
PD-L1 CPS by Response
Data cutoff date was May 31, 2018.aOne-sided Wald test P-values from logistic regression adjusted for tumor size.
ResponderNonresponder
ResponderNonresponderResponderNonresponder
ResponderNonresponder
P=0.0286a
AUROC (90% CI) = 0.611 (0.481–0.741)
P= 0.0127a
AUROC (90% CI) = 0.658 (0.532–0.784)
P=0.0115a
AUROC (90% CI) = 0.713 (0.594–0.832)
P=0.0494a
AUROC (90% CI) = 0.719 (0.591–0.847)
P o s it iv e N e g a t iv e
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
TIL
Le
ve
l, %
aWilcoxon rank sum (one sided). Red font indicates statistical significance. bSpearman’s rank correlation testIn the left figure, Box = 25th and 75th percentiles; line = median; whiskers = 1.5IQR. Data cutoff date: Nov 10, 2017.
Relationship Between sTIL Levels and PD-L1 CPS Scores
≥1
140
10%(5-35)
53
3%(1-5)
<1
n
Median (IQR)
CPS ≥1 vs <1
Significant Correlation
Between sTIL levels and
PD-L1 CPS
• Cohort A:
rho = 0.404; P < 0.001b
• Cohort B:
rho = 0.375; P = 0.001b
• Combined cohorts:
rho = 0.451; P < 0.001b
PD-L1 CPS vs sTIL Level
LN
Non-LN
0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
P D -L 1 C P S
TIL
Le
ve
l, %
A BRegression linesb
Cohort A
Cohort B
Combined cohorts<0.001a
esmo.org
OVERALL SURVIVAL IN KATE2 (NCT02924883): A PHASE 2 STUDY OF PD-L1 INHIBITOR
ATEZOLIZUMAB + TRASTUZUMAB EMTANSINE (T-DM1) VS PLACEBO + T-DM1 IN PREVIOUSLY TREATED HER2-POSITIVE ADVANCED BREAST
CANCERLeisha A. Emens,1 Francisco Esteva,2 Mark Beresford,3 Cristina Saura,4 Michelino De Laurentiis,5
Sung-Bae Kim,6 Seock-Ah Im,7 Yifan Wang,8 Aruna Mani,9 Jigna Shah,9 Haiying Liu,9 Sanne de Haas,10 Monika Patre,10 Sherene Loi11
1University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA; 2Perlmutter Cancer Center at NYU Langone Medical Center, New York, NY; 3Royal United Hospital, Bath, UK; 4Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO),
Barcelona, Spain; 5IRCCS Istituto Nazionale Tumori Fondazione Pascale, Napoli, Italy; 6Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 7Seoul National University Hospital, Seoul, Korea; 8Roche (China) Holding Ltd, Shanghai, China; 9Genentech, Inc., South San Francisco, CA; 10F. Hoffmann-La Roche, Basel, Switzerland; 11Peter
MacCallum Cancer Centre, Melbourne, Australia
Access slides at: https://bit.ly/2NGiaqZ
Atezolizumab + T-DM1 Placebo + T-DM1
Patients with OS event, n (%) 11 (19.3) 8 (29.6)
Median OS (mo) NE NE
Stratified HR (95% CI) 0.55 (0.22–1.38)
1-year survival rate (%) 94.3 87.9
Atezolizumab + T-DM1 Placebo + T-DM1
Patients with OS event, n (%) 21 (27.6) 12 (28.6)
Median OS (mo) NE NE
Stratified HR (95% CI) 0.88 (0.43–1.80)
1-year survival rate (%) 85.1 89.7
11 December 2018 cutoff date
Ove
rall
Su
rviv
al (%
)
100
80
60
40
20
00 3 6 9 12 15 18 21 24 27
Time (mo)
Ove
rall
Su
rviv
al (%
)
100
80
60
40
20
00 3 6 9 12 15 18 21 24 27
Time (mo)
T-DM1 + Atezolizumab (n=57)
T-DM1 + Placebo (n=27)
Censored
T-DM1 + Atezolizumab (n=76)
T-DM1 + Placebo (n=42)
Censored
• In the PD-L1 IC+ subgroup, the 1-year OS rate was numerically higher in the atezolizumab + T-DM1 arm than in the placebo + T-DM1 arm
CI, confidence interval; HR, hazard ratio; IC, tumour-infiltrating immune cell; NE, not
estimable; OS, overall survival.
KATE2: OS IN PD-L1 IC+ AND PD-L1 IC− SUBGROUPS
OS in PD-L1 IC+ Subgroup (IC 1/2/3) OS in PD-L1 IC− Subgroup (IC 0)
57
27
56
23
54
23
52
22
49
21
45
18
33
15
18
6
9
2
56
26
56
25
55
23
54
23
54
23
52
23
52
21
50
21
49
19
45
19
44
18
37
16
27
11
23
8
17
5
13
4
2T-DM1 + Atezolizumab
T-DM1 + Placebo
No. of Patients at Risk
76
42
73
41
68
38
64
36
62
33
56
29
45
20
26
10
12
6
75
41
74
41
71
40
68
39
67
38
66
37
64
34
64
33
62
32
59
29
54
27
49
21
39
18
33
15
25
9
21
8
4
1
T-DM1 + Atezolizumab
T-DM1 + Placebo
No. of Patients at Risk
Access slides at: https://bit.ly/2NGiaqZ
IC, tumour-infiltrating immune cell, IHC, immunohistochemistry;
Teff; T effector cell; TIL, tumour infiltrating lymphocyte.
ALL BIOMARKERS OF T CELL ACTIVATION/QUANTITY WERE ENRICHED IN THE PD-L1 IC+ SUBGROUP
PD-L1 proteina vs PD-L1 gene
expression
a PD-L1 protein was measured by IHC.b The Teff signature included PD-L1, IFNγ, CXCL9, GZMB, and CD8A.c TILs were scored according to www.tilsinbreastcancer.org; The median for stromal TILs was 5%.
PD-L1 protein vs CD8 gene
expression
PD-L1 protein vs Teff signatureb
gene expression
PD-L1 protein vs TILsc
PD
-L1
RN
A
2
0
–2
–4
IC0 IC1/2/3
PD-L1 IHC
IC0 IC1/2/3
PD-L1 IHC
IC0 IC1/2/3
PD-L1 IHC
IC0 IC1/2/3
PD-L1 IHC
CD
8R
NA
2
0
–2
Te
ff S
ign
atu
re
2
1
0
–1 TIL
(%
)
80
60
40
20
–2
0
Access slides at: https://bit.ly/2NGiaqZ
KATE2: OS BY OTHER IMMUNE BIOMARKER SUBGROUPS IS CONSISTENT WITH PD-L1 IC+ SUBGROUP DATA
CI, confidence interval; HR, hazard ratio; OS, overall survival; TIL, tumour-infiltrating cell; Teff,
T effector cell.
Baseline Risk Factors
All Patients
PD-L1 RNA Expression
≤Median
>Median
CD8A RNA Expression
≤Median
>Median
Teff Signature
≤Median
>Median
TILs
<5%
≥5%
n
69
25
23
26
22
26
22
25
40
Events
20
9
7
11
5
9
7
5
13
1-Year
Survival (%)a
89.0
86.5
89.7
87.1
89.5
87.1
89.5
100
83.5
T-DM1 + Placebo
(n=69)
n
133
48
49
47
50
47
50
45
80
Events
32
14
11
11
14
12
13
13
17
1-Year
Survival (%)a
89.0
84.5
89.6
84.8
89.4
86.7
87.6
84.2
90.8
T-DM1 + Atezolizumab
(n=133)
HR (95% CI)
0.74 (0.43–1.30)
0.77 (0.33–1.78)
0.57 (0.22–1.49)
0.46 (0.20–1.07)
1.09 (0.39–3.04)
0.64 (0.27–1.53)
0.70 (0.28–1.75)
1.43 (0.51–4.01)
0.55 (0.26–1.12)
T-DM1 +
Atezolizumab
Better
T-DM1 +
Placebo
Better
0.01 0.1 1 10 100
a One-year survival is included since median OS was not estimable in most subgroups.
Access slides at: https://bit.ly/2NGiaqZ
• 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 phase III study design
Schmid P, et al. IMpassion130.
ESMO 2018 (abstract 2056).
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
Interim OS analysis: PD-L1+ population (41% ITT)
Schmid P, et al. IMpassion130.
ESMO 2018 (abstract 2056).Data cutoff: 17 April 2018. Median OS durations (and 95% CI) are indicated on the plot. a Not formally tested.
25.0 mo(22.6, NE)
15.5 mo(13.1, 19.4)
100
80
60
40
20
0
Overa
ll s
urv
iva
l
0 3 6 9 12 15 18 21 24 27 30 33 36Months
No. at risk:Atezo + nab-
P 185 177 160 142 113 61 36 22 15 9 5 NE NE
Plac + nab-P 184 170 147 129 89 44 27 19 13 6 NE NE NE
Stratified HR = 0.62
(95% CI: 0.45, 0.86)a
Atezo + nab-P
(N = 451)
Plac + nab-P
(N = 451)
OS events, n 64 88
2-year OS
(95% CI), %
54%
(42, 65)
37%
(26, 47)
BEP (TILs): n = 893. Cutoff of 10% was used to distinguish low vs intermediate/high levels of TILs (Denkert Lancet Oncol2018).a 2x2 Fisher’s exact test.
Stromal TILs predicted PFS benefit, but not OS benefit
39
• TILs+ were enriched for PD-L1 IC+ (P < 0.0001) but PD-L1 IC+ were not enriched for TILs+ (P = ns)a
• Patients with TILs+ tumors only derived clinical benefit if their tumors were also PD-L1 IC+
Emens LA, et al. IMpassion130 biomarkers.
SABCS 2018.
PD-L1 IC+
41%
TILs+32%
20% 21% 11%
TILs–/PD-L1 IC+ (n = 176)HR (95% CI) P value
PFS 0.74 (0.54, 1.03) 0.07OS 0.65 (0.41, 1.02) 0.06
TILs+/PD-L1 IC+ (n = 190)HR (95% CI) P value
PFS 0.53 (0.38, 0.74) ≤ 0.005OS 0.57 (0.35, 0.92) 0.02
TILs+/PD-L1 IC– (n = 94)HR (95% CI) P value
PFS 0.99 (0.62, 1.57) 0.97OS 1.53 (0.76, 3.08) 0.24
• Be aware of subgroup-analysis, comparing variables scored using different scoring-methods.• TILs scored as a continous variable, compared with PDL1 scored a categorical variables is not appropriate. This applies also to
comparing or pooling different antibodies that were scored using different methods. Stromal TILs should be assessed as a continuous variable on its own.
Underpowered and methodologically suboptimal
esmo.org
PERFORMANCE OF PD-L1 IMMUNOHISTOCHEMISTRY
ASSAYS IN UNRESECTABLE LOCALLY ADVANCED OR
METASTATIC TRIPLE-NEGATIVE BREAST CANCER:
POST HOC ANALYSIS OF IMPASSION130
Hope S. Rugo,1 Sherene Loi,2 Sylvia Adams,3 Peter Schmid,4 Andreas Schneeweiss,5 Carlos H. Barrios,6
Hiroji Iwata,7 Véronique Diéras,8 Eric P. Winer,9 Mark M. Kockx,10 Dieter Peeters,10 Stephen Y. Chui,11
Jennifer C. Lin,11 Anh Nguyen Duc,11 Giuseppe Viale,12 Luciana Molinero,11 Leisha A. Emens13
1University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA; 2Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; 3NYU Langone Medical Center, New York, NY, USA; 4Barts Cancer Institute, Queen Mary University London, London, UK; 5University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany; 6Centro de Pesquisa Clínica, HSL, PUCRS, Porto Alegre, Brazil; 7Aichi Cancer Center Hospital, Nagoya, Japan; 8Department of Medical Oncology, Centre Eugène Marquis, Rennes, France; 9Dana-Farber Cancer Institute, Boston, MA, USA; 10HistoGeneX NV, Antwerp, Belgium; 11Genentech, Inc., South San Francisco, CA, USA; 12University of Milan, European Institute of Oncology IRCCS, Milan, Italy; 13University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
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
41NPA, 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
Population PFS OS
SP142
IC ≥ 1%: 46%
(285/614)
22C3
CPS ≥ 1: 81%
(497/614)
SP263
IC ≥ 1%: 75%
(460/614)
Median OS, mo HR
(95% CI)A + nP P + nP ∆
27.3 17.9 9.4 0.74 (0.54, 1.01)
Median PFS, mo HR
(95% CI)A + nP P + nP ∆
8.3 4.1 4.2 0.60 (0.47, 0.78)
Clinical outcomes in PD-L1+ populations per SP142 (IC 1%), 22C3 (CPS 1) and SP263 (IC 1%)
42
HR adjusted for prior taxanes, presence of liver metastases, age and ECOG PS.
7.5 5.4 2.1 0.68 (0.56, 0.82)
Atezolizumab + nab-paclitaxel
Placebo + nab-paclitaxel
7.5 5.3 2.2 0.64 (0.53, 0.79)
21.6 19.2 2.4 0.78 (0.62, 0.99)
22.0 18.7 3.3 0.75 (0.59, 0.96)
Surv
ival (%
)
Surv
ival (%
)
Months
Months
Months
Months
Su
rviv
al (%
)
Surv
ival (%
)
Surv
ival (%
)
Su
rviv
al (%
)
Months Months
PD-L1
Status n
Median sTILs
(IQR)
SP142+
SP263+274
10%
(5-20)
SP142-
SP263+177
5%
(2-7)
SP142-
SP263-146
3%
(1-5)
sTILs (% tumour stroma)
PD-L1
Status n
Median sTILs
(IQR)
SP142+
22C3+274
10%
(5-20)
SP142-
22C3+214
5%
(2-7)
SP142-
22C3-109
3%
(1-5)
▪ Within the 22C3+ or SP263+ subgroups, SP142+ patients had numerically higher sTIL counts compared with SP142- patients
sTILs in PD-L1 subgroups defined by SP142 and 22C3 or SP263
IQR, interquartile range; sTIL, stromal tumour-infiltrating lymphocyte.** P < 0.01; **** P < 0.0001 by Kruskal-Wallis multiple comparisons test.Similar results were observed with CD8 IHC staining.
SP142 (IC 1%) and 22C3 (CPS 1) SP142 (IC 1%) and SP263 (IC 1%)
sTILs (% tumour stroma)
**
********
**
********
43
TILs correlate with response to immune checkpoint-inhibition.
PDL1 correlates with TILs.
PDL1 correlates -almost- always with response to immune checkpoint-inhibition, in TNBC.
Considering that:• TILs can be assessed in a reproducible manner by Pathologists.
• Pathologists only need a microscope and a HE and can be trained using a freely available training-tool (www.tilsinbreastcancer.org).
• The scoring can be done at the moment of making a diagnosis.
• Stage I TNBC with high TILs have excellent 5-year survival, irrespective of treatment, so I expect oncologist will start to ask it once the papers are out. Challenge me!
• TILs are associated with prediction.
• PDL1 is associated with prediction.
• If pathologists score TILs already in their daily practice, for prognostic purposes, this information is already present in the report if needed for selection for ICI, in a combination with PDL1, at term.
• If the patients with metastasis, I believe that pathologists can use any antibody, as long as it is well validated, and is used in conjunction with TILs, as if there are no TILs, PDL1 IC will be negative, and if there are many TILs, probably it may not matter that much wich AB is used, as long as it is validated.
Do Oncologists want to know? Should we as an oncology-pathology community start to inform and train the pathology-community on this combined narrative?
EQA to optimise TIL and PDL1 estimation in Breast Cancer for prognosis and therapy response prediction
Start early 2020
Dr. Roberto Salgado, chair of the International Immuno-Oncology Working Group (TILs-WG), co-chaired with Sherene Loi, Carsten Denkert, Stefan Michiels. Co-leads of this project: Hugo Horlings, Netherlands Cancer Institute; Siziopikou Kalliopi, Northwestern University, US; John Bartlett, Canada/UK (Biobank), Giuseppe Floris, UZ Leuven.
Prof. Dr. Els Dequeker, KU Leuven
Inne Nauwelaers, KU Leuven
In conclusion
Taking a new biomarker into daily practice should be in agreement between pathologists,
oncologist, patients and industry
I do believe that, based on common sense and evidence, PDL1 and TILs should be assessed together in TNBC.
What do you think?
Manuscripts in preparation
Sherene Loi, Peter Savas, David Moore, Crispin Hiley, Maise Al-Bakir,Charles Swanton, Stephen Luen, Jeannette, Sylvia Adams, SandraDemaria, Sunil Badve, Giuseppe Floris, Christine Desmedt, Iris, Leonie,Jan, Marleen, Hugo, Stefan, Fabrice, Beppe V., TIL-WG, Carsten Denkert,Sybille, Fraser, Elia, Jorge RF, Mark R, David R., Federico R., Lajos P.,David S., Zuzana, Torsten, John B., Rim K., Tracy L., Ken Emancipator, JonJ., Luciana M., Ian Cree, Giancarlo, Maria Vittoria, etc…
Acknowledgments to the TIL-WG and ourindustry colleagues from IARC, Merck, Astra,Genentech/Roche, etc…
