ESMO-2021-presentation-galsky-cisplatin-related-immunomodulation-and-efficacy-with-atezolizumab-cis.pdf

poster

1. Cisplatin-related immunomodulation
and efficacy with atezolizumab
+ cisplatin-vs carboplatin-based
chemotherapy in metastatic
urothelial cancer
Matthew D. Galsky,
1
Xiangnan Guan,
2
Romain Banchereau,
2
Li Wang,
3,4
Jun Zhu,
3,4
Haocheng Yu,
4
Deepali Rishipathak,
2
Emma Hajaj,
5
Rebecca H. Herbst,
5
Ian D. Davis,
6
Enrique Grande,
7
Aristotelis Bamias,
8
Maria De Santis,
9
JoséÁngel Arranz,
10
Eiji Kikuchi,
11
Jingbin Zhang,
12
Chooi Lee,
13
Xiaodong Shen,
2
Peter C. Black,
14
Sanjeev Mariathasan
2
1
Icahn School of Medicine at Mount Sinai/Tisch Cancer Institute, New York, NY, USA;
2
Genentech Inc, South San
Francisco, CA, USA;
3
Icahn School of Medicine at Mount Sinai, New York, NY, USA;
4
Sema4, a Mount Sinai Venture,
Stamford, CT, USA;
5
Immunai, New York, NY, USA;
6
Eastern Health Clinical School, Monash University and Eastern
Health, Melbourne, Australia;
7
MD Anderson Cancer Center Madrid, Madrid, Spain;
8
National & Kapodistrian
University of Athens, Athens, Greece;
9
Charité Universitätsmedizin, Department of Urology, Berlin, Germany, and
Medical University of Vienna, Department of Urology, Vienna, Austria;
10
Gregorio Maranon Hospital, Madrid, Spain;
11
St. Marianna University School of Medicine, Kawasaki, Japan;
12
Hoffmann- La Roche Limited, Mississauga, ON,
Canada;
13
Roche Products Limited, Welwyn Garden City, UK;
14
Vancouver Prostate Centre, University of British
Columbia, Vancouver, BC, Canada

2. https://bit.ly/3jB8jRR @MattGalskyGalsky M. IMvigor130 cisplatin biomarkers. Abstract 4107. Content of this presentation is copyrighted toand the responsibility of the author. Permission is required for re- use.
Disclosures: Matthew D. Galsky
•Research funding:
−AstraZeneca, Bristol Myers Squibb, Dendreon, Genentech, Merck and Novartis
•Advisory board/consultant:
−AstraZeneca, Basilea, Bristol Myers Squibb, Dragonfly, EMD Serono, Genentech, GlaxoSmithKline, Janssen, Merck,
Numab, Pfizer, Rappta Therapeutics, Seattle Genetics and UroGen
2

3. https://bit.ly/3jB8jRR @MattGalskyGalsky M. IMvigor130 cisplatin biomarkers. Abstract 4107. Content of this presentation is copyrighted toand the responsibility of the author. Permission is required for re- use.
Favours Arm C (pbo + plt/gem)Favours Arm A (atezo + plt/gem)
Arm A Arm C
OS HR (95% CI)n
mOS,
mo n
mOS,
mo
All 45116.140013.4 0.85 (0.72, 1.00)
Cis 13721.613614.6 0.73 (0.54, 0.98)
Carbo 31414.326413.0 0.91 (0.74, 1.10)
Immunomodulatory effects may underlie favourable
outcomes with cisplatin ±atezo vs carboplatin ±atezo in mUC
•Cisplatin, but not carboplatin, achieves
durable control of mUC in a subset of
patients
1
•Atezo + cisplatin- based chemo was
associated with better efficacy than
atezo + carboplatin- based chemo in an
exploratory subset analysis from
IMvigor130
2
•Together, these findings raise the
hypothesis that cisplatin may be
associated with specific favourable
immunomodulatory effects
Atezo, atezolizumab; carbo, carboplatin; chemo, chemotherapy; cis, cisplatin;
gem, gemcitabine; mOS, median OS; mUC, metastatic urothelial cancer.
1. Galsky MD. 2. Galsky MD. AACR 2021. Abstract 5253.J Clin Oncol.2011;29:2432- 8.
2
Arm C: placebo
+ plt (cis or carbo)
+ gem
Arm A: atezo
+ plt (cis or carbo)
+ gem
Arm B: atezo
monotherapy
Phase III IMvigor130 study (N=1213)
•
Locally advanced or metastatic UC
•No prior systemic therapy for mUC
OS by investigator’s choice of platinum
2
3

4. https://bit.ly/3jB8jRR @MattGalskyGalsky M. IMvigor130 cisplatin biomarkers. Abstract 4107. Content of this presentation is copyrighted toand the responsibility of the author. Permission is required for re- use.
Favours IC0/1Favours IC2/3
mOS, mo OS HR
(95% CI)IC0/1IC2/3
Atezo +
cis/gem 19.5NR
0.46
(0.25, 0.83)
carbo/gem13.916.6
0.85
(0.61, 1.17)
Pbo +
cis/gem 12.827.9
0.51
(0.30, 0.86)
carbo/gem13.014.0
1.00
(0.71, 1.42)
IMvigor130: OS by PD-L1 status and chemo
Arm A Arm C
PD-L1 expression on tumour-infiltrating immune cells was assessed from
archival pre- treatment tumour samples (VENTANA SP142 assay): IC0/1,
PD-L1–expressing immune cells on <5% of the tumour area; IC2/3, ≥5% of
the tumour area.
CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survival.
Effects of cisplatin ±atezo on OS are most prominent
in patients with PD-L1 IC– high tumours
4
0 6 12 18 24 30 36 42
IC0/1 (n=102)
IC2/3 (n=34)
0
20
40
60
80
100
Overall survival
Time, months
Arm C: pbo
+ cis/gem
IC0/1(n=241)
IC2/3(n=73)
Overall survival
Time, months
0 6 12 18 24 30 36 42
0
20
40
60
80
100
Arm A: atezo
+ carbo/gem
0 6 12 18 24 30 36 42
IC0/1(n=207)
IC2/3(n=57)
0
20
40
60
80
100
Overall survival
Time, months
Arm C: pbo
+ carbo/gem
0 6 12 18 24 30 36 42
0
20
40
60
80
100
Overall survival
Arm A: atezo
+ cis/gem
Time, months
IC0/1(n=102)
IC2/3(n=35)

5. https://bit.ly/3jB8jRR @MattGalskyGalsky M. IMvigor130 cisplatin biomarkers. Abstract 4107. Content of this presentation is copyrighted toand the responsibility of the author. Permission is required for re- use.
scRNAseq
b
No. of samples
C1D1 C3D1 Total no.
Arm A: atezo + cis/gem 14 14 28
Arm A: atezo + carbo/gem 24 24 48
Arm C: pbo + cis/gem 17 17 34
Arm C: pbo + carbo/gem 16 16 32
Total no. 71 71 142
Does cisplatin vs carboplatin show evidence of
immunogenic cell death?
•Neoadjuvant MIBC cohort
c
: To study cis-related changes in the tumour
microenvironment, gene expression data from 113 paired pre-/post-
neoadjuvant cis/gem-treated samples were also analysed
IMvigor130 PBMC analyses
a
Immunogenic cell death
a
Only patients with evaluable samples at both C1D1 and C3D1 are included.
b
Includes gene set enrichment analysis (Hallmark pathways).
c
Includes samples from an MIBC non- trial cohort
1,2
MIBC, muscle- invasive bladder cancer.
1. Seiler R. Eur Urol. 2017;72:544- 54. 2. Seiler R. Clin Cancer Res. 2019;25:5082- 93.
5
CRT/HSPexposure
Inflammation response
IFNα/IFNγresponse
TNF-αsignaling via NFκ B

6. https://bit.ly/3jB8jRR @MattGalskyGalsky M. IMvigor130 cisplatin biomarkers. Abstract 4107. Content of this presentation is copyrighted toand the responsibility of the author. Permission is required for re- use.
•IMvigor130: Cis-vs carbo-treated
patients showed on-treatment
enrichment of TNF-α signallingvia
NFĸB, inflammatory response
gene sets and interferon response
gene sets across immune cell
clusters
•Neoadjuvant cohort: TNFα
signaling via NFĸB was also
enriched in paired tumoursamples
(post-vs pre-cis/gem)
Cisplatin vs carboplatin leads to gene
expression changes suggestive of
induction of innate and adaptive
immunity
Heatmaps include pathways significant in ≥3 cell types, with manual
ordering (IMvigor130). Asterisks (*) in heatmap cells indicate significance
defined by a false discovery rate <0.05. Ten cells per sample were required.
6
Gene sets
B, naive
B, non -naive
CD4, naive
CD4, non -naive
CD4, helper
CD4, T
reg
CD8, naive
CD8, non -naive
NK
Innate T
Monocytes
MDSC
B, naive
B, non -naive
CD4, naive
CD4, non -naive
CD4, helper
CD4, T
reg
CD8, naive
CD8, non -naive
NK
Innate T
Monocytes
MDSC
Arm A (C3D1 vs C1D1):
atezo + cis/gem
vs atezo + carbo/gem
Arm C (C3D1 vs C1D1):
pbo + cis/gem
vs pbo + carbo/gem
−log
10P
adj
10
5
0
−5
−10
TNFA_SIGNALING_VIA_NFKB
IL2_STAT5_SIGNALING
INFLAMMATORY_RESPONSE
INTERFERON_ALPHA_RESPONSE
INTERFERON_GAMMA_RESPONSE
ALLOGRAFT_REJECTION
IL6_JAK_STAT3_SIGNALING
MYC_TARGETS_V1
G2M_CHECKPOINT
P53_PATHWAY
MITOTIC_SPINDLE
APOPTOSIS
HYPOXIA
OXIDATIVE_PHOSPHORYLATION
KRAS_SIGNALING_UP
ANDROGEN_RESPONSE
MTORC1_SIGNALING

7. https://bit.ly/3jB8jRR @MattGalskyGalsky M. IMvigor130 cisplatin biomarkers. Abstract 4107. Content of this presentation is copyrighted toand the responsibility of the author. Permission is required for re- use.
Conclusions
•In this exploratory analysis from IMvigor130, PD-L1 IC2/3 status was associated with longer OS
in cisplatin-but not carboplatin- treated patients with mUC
•Cisplatin-vs carboplatin- based chemo was associated with increased innate and adaptive
immune gene expression—both in circulating immune cells in patients with mUC enrolled in
IMvigor130 and in the TME in a neoadjuvant cisplatin + gemcitabine– treated MIBC cohort
•These data suggest that cisplatin + gemcitabine enhances anti-tumourimmunity, particularly
when combined with atezolizumab (i.e., as seen when comparing IMvigor130 Arms A and C),
potentially through the induction of immunogenic cell death
•These data may provide fundamental insights regarding the mechanisms underlying durable
disease control achieved in the subset of patients with mUC treated with cisplatin- based chemo
±atezolizumab
7

8. https://bit.ly/3jB8jRR @MattGalskyGalsky M. IMvigor130 cisplatin biomarkers. Abstract 4107. Content of this presentation is copyrighted toand the responsibility of the author. Permission is required for re- use.
Acknowledgements
•The patients and their families
•The investigators and clinical study sites
•This study is sponsored by F. Hoffmann- La Roche Ltd
•Medical writingassistance for this oral presentation was provided by Ashley J. Pratt, PhD,
of Health Interactions and funded by F. Hoffmann- La Roche Ltd
8