Renal Cell (RCC) andBladder Carcinoma (TCC)
Prof. Dr. med. Viktor Grünwald
Klinik für Hämatologie, Hämostaseologie, Onkologie und
Stammzelltransplantation
DisclosuresCompensated lectures:
BMS, Ipsen, Eisai, Novartis, Pfizer, Roche
Advisory: Astac Zeneca, Bayer, BMS, Cerulean, Ipsen, Eisai, Novartis, Pfizer, Roche
Research grants: Astra Zeneca, BMS, MSD, Pfizer, Novartis
Stock shareholder :none
Checkpoint Blockade in GU Cancer
Carinoma Status outcome
Renal cell Phase III positive
Urothelial Phase III positive
Prostate Phase III negative
Germ cell Basket study -
Penile Basket study -
PD-L1 – a negative predictor
Gevensleben et al. (2016). CCR, 22(8), 1969–1977. Thompson et al. Proc Natl Acad Sci USA 2004;101:17174–9. Cierna et al. (2016). Annals of Oncology, 27(2), 300–305.
PCA RCC GCT
Don‘t be too advanced for the field: Sipuleucel-T in PCA
Kantoff et al. (2010). NEJM, 363(5), 411–422. Fong et al. (2014). JNCI Journal of the National Cancer Institute, 106(11)
HR 0,78 (0,61-0,98)P=0,03
PCA: Ipilimumab vs. Placebo
Kantoff et al. (2010). NEJM, 363(5), 411–422.
Mutational load of GU cancers varies
MS Lawrence et al. Nature 2013
...so does immune cell infiltration
Mandal, R., Senbabaoglu, Y., Desrichard, A., Havel, J. J., Dalin, M. G., Riaz, N., et al. (2016). JCI Insight, 1(17), e89829. http://doi.org/10.1172/jci.insight.89829
Immunotherapy –not a one-size-fits-all approach
CD8T cellwith
granzyme B
CD8
T cellwith PD-L1
expression
Immunogenic tumor
microenvironment
Nonimmunogenic tumormicroenvironment
Combination therapies
with agents that create
immunogenic tumor
microenvironment and
immune checkpoint therapy
Durable clinical benef tImmune checkpoint ther apy
and durable clinical benef t
CD8T cell
with CD45ROexpression
CD8T cell
CD4T cell
Tumorcell
with PD-L1expression
BA
Sharma & Allison. The future of immune checkpoint therapy. (2015). The future of immune checkpoint therapy. Cancer
Immunology Immunotherapy, 1–7.
hot tumor
single agent
cold tumor
combination
OS-benefit for Nivolumab in 2nd line
Motzer RJ et al. N Engl J Med, 2015; 373: 1803–13.
Plimack et al. KCS 2016
2-year-Follow-up
...but, only minor improvement in PFS
Motzer et al. (2015). NEJM, 150925150201006–11. http://doi.org/10.1056/NEJMoa1510665.
44% received treatment beyond progression for nivolumab, and 46% for everolimus
Geonomic profile differs by line in mRCC (ctDNA analysis)
Pal et al. (2017). European Urology. http://doi.org/10.1016/j.eururo.2017.03.046
What about combinations in RCC?
Immunogenic cell death – the goalof combinations with RTX or CTX
Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L., & Kroemer, G. (2017). Nature Reviews. Immunology, 17(2), 97–111. http://doi.org/10.1038/nri.2016.107
Immunotherapy – a matter ofcombinations?
Salama, A. K. S., & Moschos, S. J. (2016). Annals of Oncology, mdw534. http://doi.org/10.1093/annonc/mdw534
death-ligand 1; VEGF, vascular endothelial growth factor.
Res. 2008; McDerm
ott, J ClinOncol. 2016; W
allin. Nat Comm
un. 2016.
g the Balance Toward Anti-Cancer Imm
unity
ombined VEGF/PD-L1 Blockade
Atezolizumab
Atezolizumab
Bevacizumab
Sunitinib
Anti-Cancer Imm
unity
McDerm
ott D, et al. IMm
otion150 bioma
Bevacizumab/Atezolizumab –improved T-cell-migration
Wallin et al. (2016). Nature Communications, 7, 12624. http://doi.org/10.1038/ncomms12624
IC3+ RCC Patient: PR with atezolizumab
Herbst et al. (2014). Nature, 515(7528), 563–567. http://doi.org/10.1038/nature14011
ATEZO-BEV: PFS (ITT)
Atezo, atezolizumab; Bev, bevacizumab.a P values are for descriptive purposes only and not adjusted for multiple comparisons.
Stratified HR
(95% CI)P Valuea
Atezo + bev vs
sunitinib
1.00
(0.69, 1.45)0.982
Atezo vs
sunitinib
1.19
(0.82, 1.71)0.358
Atezolizumab + bevacizumab
Atezolizumab
Sunitinib
Atezo + bev: 11.7 mo (8.4, 17.3)
Atezo:6.1 mo
(5.4, 13.6)Sunitinib:8.4 mo (7.0, 14.0)
McDermott et al. ASCO GU 2017: 431
Dual Checkpoint Blockade – a future was of treatment?
Hammers et al. ASCO 2015 #4516. Hammers et al. ESMO 2016: 1062P
IPI3 +
NIVO1
IPI1 +
NIVO3
ORR 40% 40%
PD 17% 17%
PFS 6,6 Mo. 9,1 Mo.
Efficacy of dual checkpointinhibition in mRCC
Hammers et al. ESMO 2016: 1962P
VEGF inhibition triggers PD-L1 expression
Liu et al. Cancer Immunol Res; 3(9); 1–12.
100
Cha
ng
e in b
aselin
e (
%)
Time since first dose (weeks)
80
60
40
20
-20
-40
-60
-80
-100
120 36 48 60 72 84
1st occurrence of new lesion
24
0
120 36 42 48 54 6024 6630186 120 36 48 60 9624 72 84
SU+NIVO pretreated(n=13)
SU+NIVO Rx-naive (n=15)
PAZ+NIVO pretreated(n=19)
Amin et al. ASCO 21014: #5010
ORR: 52% (n=17/33)
PFS: 49 wks.
ORR: 45% (n=9/20)
PFS: 31 wks
Do we have proper marker forpatient selection?
Checkmate-025:
PD-L1 is not predictive for nivolumab
Motzer RJ et al. N Engl J Med, 2015; 373: 1803–13
Res.2012; Herbst, Nature2014; Powles, SITC
2015; Fehrenbacher, Lancet2016.
iptome M
ap of Angiogenesis and Imm
une-Associatedn RCC Tum
ors
mm
une,
entation
Myeloid
mm
ation
McDerm
ott D, et al. IMm
otion150 bioma
genesis
PD-L1 IHC
(e.g., CD34, KDR, VEGFA)
(e.g. CD8A, IFNG, PSMB8)
(e.g. IL6, PTGS2, IL8)
signature: VEGFA, KDR, ESM1, PECAM
1, ANGPTL4, CD34.
� median expression, Angiogenesis Low: < m
edian expression.
bDem
onstrated Improved PFS in Angiogenesis
HighSogenesis
LowSubset
Sunitinib
HR95%
CI
isw)
0.31(0.18, 0.55)
Atezolizumab + Bevacizum
ab
HR95%
CI
Angiogenesis
(High vs Low)0.90
(0.54, 1.51)
AtezolizuH
Angiogenesis
(High vs Low)
0.7
High (n = 44)
Low (n = 45)
Sunitinib
High (n = 45)
Low (n = 43)
Atezolizumab + Bevacizum
abAtezolizu
McDerm
ott D, et al. IMm
otion150 bioma
ature: CD8A, EOMES, PRF1, IFNG, CD274.
edian expression, T-effector Low: < median expression.
umab and Bevacizum
ab Demonstrated Im
proved PFStinib in the T-Effector HighSubset
Atezo+ be
Atezo(n =
Sunitinib (n
T-effector High
Atezo+ bev(n =
46)
Atezo(n = 40)
Sunitinib (n = 46)
T-effector Low
HR (95% CI)
T-effector LowT-effector High
Atezo+ bev
vs sunitinib1.41 (0.84, 2.36)
0.55(0.32, 0.95)
Atezovs sunitinib
1.33(0.76,2.33)
0.85 (0.50, 1.43)
McDerm
ott D, et al. IMm
otion150 bioma
Res.2012; Herbst, Nature2014; Powles, SITC
2015; Fehrenbacher, Lancet2016.
iptome M
ap of Angiogenesis and Imm
une-Associatedn RCC Tum
ors
PD-L1 IHC
PD-L1 IHC
IC0IC1
IC2IC3
-32
-2-1
10
T-effector HighSubpopulation
T-effector High
Myeloid Inflam
mation
Low
T-effector Hi
Myeloid Inflam
ma
McDerm
ott D, et al. IMm
otion150 bioma
nature: CD8A, EOMES, PRF1, IFNG, CD274.
ession, Low: < median expression.
n of Bevacizumab to Atezolizum
ab is Associated With
ed Benefit in T-effector High/Myeloid Inflam
mation
HighSu
T-effector HighMyeloid
Hig
Atez
Atez
Suni
T-effector HighMyeloid
Low
Atezo+ bev(n =
23)
Atezo(n = 23)
Sunitinib (n = 19)
McDerm
ott D, et al. IMm
otion150 biomar
on
ssed ORR.
orrelates With PFS in Gene Expression Subgro
h 44
Low n = 41
High n = 42
Lown = 4
% %
10%16%
33%
17%
High n = 44
Low n = 42
High n = 41
Low n = 44
High n = 45
Low n = 40
High n = 43
Low n = 42
Angiogenesis SignatureT-effector Signature
nitinibSunitinib
AtezoAtezo
Atezo+ bev
Atezo+ b
9%12%
12%14%
12%
29%
20%5%11%
5%
20%
10%5%
2%
24%25%
McDerm
ott D, et al. IMm
otion150 bioma
What about response?
Depth of remission isprognostic in RCC (TKI-era)
Grünwald V et al. ESMO 2013, Amsterdam, #2702; EUR UROL 2015
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 10 20 30 40 50 60
Su
rviv
al
Pro
ba
bil
ity
Time (Months)
Median OS (m)
–100% to –60% (n=283) 54.53
–60% to –30% (n=547) 26.38
–30% to 0% (n=1155) 16.56
0% to +20% (n=390) 10.36
≥20% (n=156) 7.33
No post-baseline scan (n=218) 1.97
CM025: OS according to bestresponse at 4 mo.
Motzer et al. ASCO 2016
QoL-responders gain OS-benefit
HR-QoL responders (2 pts..):
• NIVO (55%) > EVE (37%)
• Faster with NIVO (4.7 mo. vs.
NR)
Cella et al. ASCO 2016 #4549
Conclusion RCC
• GU-cancers are immunogenic
• Nivolumab has improved 2nd line treatment in RCC
• Depth of remission is prognostic with targeted therapies
in RCC
• Combinations may improve efficacy
• Gene signatures may guide future choice of therapy
Urothelial Carcinoma
Systemic therapy in TCC
1st Linie- Cisplatin/Gemcitabine
- (DD-MVAC)
2nd Linie- Vinflunine
- Taxane- (Ifosfamide)
1st Linie: frail- Carboplatin/Gemcitabine
- Gemcitabine- Taxane
Bellmunt et al. ESMO Guidelines Working Group. (2014, September). Annals of Oncology. http://doi.org/10.1093/annonc/mdu223
VICTOR: UK-real worldretrospective Data for vinflunine
Hussain et al. (2017), International Journal of Oncology, 50(3), 768–772. http://doi.org/10.3892/ijo.2017.3847
Chemotherapy in mTCC
Bellmunt et al. (2012). JCO, 30(10), 1107–1113. Bellmunt et al. (2009). JCO, 27(27), 4454–4461. http://doi.org/10.1200/JCO.2008.20.5534
ORR: 44%OS: 12,7 Mo.PFS: 7,6 Mo.
1st line 2nd line
ORR: 9%PFS: 3 Mo.
Long-term survival with CTX
PCG1
n=312GC1
n=314GC2
n=203MVAC2
n=202MVAC3
n=129DD-MVAC3
n=134
PFS (mo.) 7.6 8.3 7.7 8.3 8.2 9.1
2y-PFS rate - - 14% 18% 12 25
5y-PFS rate - - 10% 11% - -
OS (mo.) 15.8 12.7 14 15.2 14.1 15.5
2y-OS rate - - 25% 31% 25 35
5y-OS rate 17%* 16%* 13% 15% 10%§ 14%§
1Bellmunt et al. (2012). JCO, 30(10), 1107-11132van der Maase et al. (2005). JCO, 23(21), 4602–4608.3Sternberg et al. (2001). JCO, 19(10), 2638–2646.
Inflammatory TCC –association with better OS
Bellmunt et al. (2015). Annals of Oncology, mdv009. doi:10.1093/annonc/mdv009
TIMC: tumor infiltrating monocytic cells
12 mo.
23 mo.
PD-L1+ TIMC analysed
Checkpoint inhibitors in mTCC
Massard et al. (2016). JCO, 34(26), JCO679761–3125. Apolo et al. (2017). JCO, 2016.71.679. Balar et al. ESMO 2016. Sharma et al. ASCO 2016: 4501.
Durvalumab Avelumab
-100
-80
-60
-40
-20
0
20
40
60
80
100
C h a
n g e F r
o m B
a s e l i n
e , %
20% increase
30% decrease
52% experienced a decrease in target lesions
PembrolizumabNivolumab
PD-L1
PD-1
Activity of PD-(L)1i in mTCC
ATEZO1 ATEZO2 NIVO3 NIVO4 PEMBRO5 AVELU6 DURVA7
N 119 310 78 270 100 129 61
Line CDDP unfit ≥2. ≥2. ≥2. CDDP unfit ≥2. or
CDDP unfit
≥2. or
CDDP unfit
CR (%) 7 7 6 2 6 3 -
PR (%) 17 16 18 17 18 14 31
OS (mo.)
14.8 7.9 9.7 8.7 - - -
FDA license ✓ ✓ ✓ ✓ ✓ ✓ ✓
1Balar et al. ASCO 2016 #4500. 2Dreicer et al.ASCO 2016 #4515. 3Sharma et al. ASCO 2016 #4501. 4Galsky et
al. ESMO 2016 LBA31. 5Balar et al. ESMO 2016 LBA32. 6Patel ESMO 2016: 2534. Massard et al. (2016). JCO,
34(26), JCO679761–3125.
1st Linie TCC: Atezolizumab(IMvigor210): CDDP-unfit
Bellmunt et al. ESMO 2016, 782PD
57%
1st line CDDP-unfit: chemotherapy
De Santis et al. (2012). JCO, 30(2), 191–199. De Santis et al. (2015). Annals of Oncology, mdv609.
approx. 38%
phase II 2011-2012: Vinflunine-doublet (GEM or CARBO)ORR: 44 vs. 29%PFS: 5.9 vs. 6.1 mo.OS: 12.8 vs. 14.0 mo. (P=0.86)
2001-2008OS:8.1 vs. 9.3 mo.
IMvigor210: platinum-failure
Loriot et al. ESMO 2016: 783P
IC0/1 n=210
IC2/3n=100
Alle Pts.N=310
OS; Mo.
(95% CI)
6,7
(5,4-8,0)
11,9
(9,0-NE)
7,9
(6,7-9,3)
12-Mo. OS 31% 50% 37%
Atezolizumab
approx.. 38%
All treated patients
No. at RiskAll treated patients
PD-L1 <1%
PD-L1 ≥1%
PD-L1 ≥1%
Median OS, Months (95% CI)a
All treated 8.74 (6.05–NR)
PD-L1 <1% 5.95 (4.30–8.08)
PD-L1 ≥1% 11.30 (8.74–NR)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15
Overa
ll S
urv
ival (P
rob
ab
ilit
y)
Months
PD-L1 <1%
aSimilar results were seen using the 5% PD-L1 tumor expression cutoff; NR, not reached
265 198 148 63 5 0143 101 69 26 2 0122 97 79 37 3 0
Galsky et al. ESMO 2016: LBA31
approx.. 40%
Nivolumab (Platinum-failure)
OS in 2nd line with chemotherapy
Bellmunt et al. (2009). JCO, 27(27), 4454–4461. http://doi.org/10.1200/JCO.2008.20.5534Bellmunt et al. (2013). Annals of Oncology, 24(6), 1466–1472. http://doi.org/10.1093/annonc/mdt007
27% Vinflunine
22% BSC
Atezolizumab: similar outcome by line of Rx
Perez-Garcia et al. ASCO GU 2017: 323
2nd line TCC KN45 (OS)
Bellmunt et al. (2017). NEJM, 376(11), 1015–1026. http://doi.org/10.1056/NEJMoa1613683
CTX Dealers choice:DocetaxelPaclitaxelVinflunine
PFS: Pembrolizumab vs. CTX
Bellmunt et al. (2017). NEJM, 376(11), 1015–1026. http://doi.org/10.1056/NEJMoa1613683
KN45: adverse events
Bellmunt et al. (2017). NEJM, 376(11), 1015–1026. http://doi.org/10.1056/NEJMoa1613683
KN-45: better HR-QoL with PD-1i
Bellmunt et al. ASCO GU 2017: 282
DOR: longer with pembrolizumab
Bellmunt et al. (2017). NEJM, 376(11), 1015–1026. http://doi.org/10.1056/NEJMoa1613683
What about enrichment?
Durvalumab (mixed cohort)
Powles et al. ASCO GU 2017: 286
Previous therapy: 91%
ORR: 20%PFS: 2.2 mo.OS: 14.1 mo.
Durvalumab in mTCC
Massard et al. (2016). JCO, 34(26), JCO679761–3125. http://doi.org/10.1200/JCO.2016.67.9761
Avelumab in mTCC (mixed cohort)
Apolo et al. (2017). JCO, 2016.71.679. http://doi.org/10.1200/JCO.2016.71.6795
1st line chemotherapy: 1-year-OS rate
approx.60%
van der Maase et al. (2005). JCO, 23(21), 4602–4608.
Treatment effect or independentprognostic factor?
Rosenberg et al. Lancet 2016
Treatment failure occurs despiteenrichment for IC2/3+ TCC
Rosenberg et al. Lancet 2016
Response to atezolizumab shown in IC2/3+ patients according to RECIST defined responses
50%
Are we missing something?
Risks of immunotherapy: hyperprogression
Champiat et al. (2016). CCR.1741.2016. http://doi.org/10.1158/1078-0432.CCR-16-1741
Conclusion TCC
• Chemotherapy-efficacy is limited
• PD-(L)1 inhibitors are active irrespective of prior therapy
• Petter outcome in PD-L1+ TCC
• Phase III data indicate survival benefit (pembrolizumab)
• But, atezolizumab without improvement...