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Immuntherapie uroonkologischerTumore
Prof. Dr. med. Viktor Grünwald
Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation
DisclosuresCompensated lectures:
BMS, Ipsen, Eisai, Novartis, Pfizer, Roche
Advisory: Bayer, BMS, Cerulean, Ipsen, Eisai, Novartis, Pfizer, Roche
Speaker‘s bureau:
Novartis, Pfizer
Research grants, stock shareholder:
none
Checkpunkt Blockade GU Tumore
Status Ergebnis
Nierenzellkarzinom Phase III positiv
Blasenkarzinom Phase III positiv
Prostatakarzinom Phase III negativ
Hodenkarzinom Basket Studie -
Peniskarzinom Basket Studie -
PD-L1+ als negativer Prädiktor
Das Bild kann zurzeit nicht angezeigt werden.
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 NCC GCT
PD-L1 beim Peniskarzinom
Gut diff.
Moderat diff.
Schlecht diff.
Udager et al. (2016). Annals of Oncology, 27(9), 1706–1712. http://doi.org/10.1093/annonc/mdw216
62% PD-L1+N=37
Assoziation mit fortgeschrittenem Stadium
Inflammatorisches TCC – besseres 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
PD-L1 ist nicht gleich PD-L1
Topalian et al. (2016). Nature Reviews Cancer, 16(5), 275–287. http://doi.org/10.1038/nrc.2016.36
Oncogen drivenPD-L1 expression
Oncogene PD-L1 expression +
Adaptive immunevasion
Immune cells Tumor cellsTumor cells, strong PD-L1+
PD-L1 nur im Kontext beurteilen
H&E PD-L1 TILs (CD3+)
Mansfield et al. (2016). Annals of Oncology, mdw289. http://doi.org/10.1093/annonc/mdw289
NSCLC (primary)
ZNS mets.
N=146 paired lesions, 73 cases. Discrepencies: 14% (tumor), 26% (TILs)
Immuntherapie –kein one-size-fits-all approach
CD8T cellwith
granzyme B
CD8T cell
with PD-L1expression
Immunogenic tumor
microenvironment
Nonimmunogenic tumormicroenvironment
Combination therapieswith agents that create
immunogenic tumormicroenvironment and
immune checkpoint therapy
Durable clinical benef tImmune checkpoint ther apyand 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
Bevacizumab/Atezolizumab –verbessert T-Zell-Migration
Wallin et al. (2016). Nature Communications, 7, 12624. http://doi.org/10.1038/ncomms12624
IC3 RCC Patient: PR unter ATEZO
Herbst et al. (2014). Nature, 515(7528), 563–567. http://doi.org/10.1038/nature14011
Duale Checkpoint Blockade – die zukünftige Therapie des mRCC?
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.
Erworbene Resistenz (MM)
Zaretsky et al. (2016). NEJM, NEJMoa1604958. http://doi.org/10.1056/NEJMoa1604958
IFNγ-Resistenz
− JAK1/2 mt.
MHC-I Expr.− B2M mt.
Primäre Resistenz: JAK Mutationen
Shin et al. (2016) Cancer Discovery, 1–37. http://doi.org/10.1158/2159-8290.CD-16-1223
Besseres PFS unter TKI
Motzer et al. (2015). NEJM, 150925150201006–11.Choueiri et al. (2016). Lancet Oncol, pp. 1-11.
Bessere Verträglichkeit für IO
McDermottet al. (2016). JCO, 34(8), 833–842. Motzer RJ et al. N Engl J Med, 2015; 373: 1803–13. Choueiri et al. (2016) Lancet Oncology, 17(7), 917–927. http://doi.org/10.1016/S1470-2045(16)30107-3
Immuntherapie: bessere QoL
Cella, D., Grünwald, V., Nathan, P., Doan, J., Dastani, H., Taylor, F., et al. (2016). Lancet Oncology, 17(7), 994–1003. http://doi.org/10.1016/S1470-2045(16)30125-5
Risiken der Immuntherapie: Aggravation der Erkrankung
Champiat et al. (2016). CCR.1741.2016. http://doi.org/10.1158/1078-0432.CCR-16-1741
NIVOSWITCHearly switch to PD-1i
• ccRCC• 1st line TKI for 10-
12 wks.• PR or SD• ECOG: 0-2• MSKCC: all• No intolerance
N=244
Nivolumab 3mg/kgq2Wo.
TKI continuation
R
I°: OS rate at 2 yearsII°: ORR, OS, PFS
SUNNIFORECAST Sunitinib vs. Nivolumab+Ipilimumab as First line Treatment Of Renal cell Cancer of non-
clear cell SubTypes – an international prospective randomized trial
Key Inclusion Criteria
• Metastatic or locally advanced nccRCC: papillary, chromophobe, collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), or translocation tumors and NOS
• Available tumor tissue
• Measurable disease as per RECIST v1.1
• ECOG performance status 0-2
• No prior systemic therapy for RCC
• No active CNS metastases
• No TKI contraindications
Start Date: Q3/2016Estimated Study Completion Date:Number of Sites ~30 (A, D, F, S, P)
PI: Prof. Dr. Lothar Bergmann, FrankfurtCo-Invest.: PD Dr. Peter Goebell, Erlangen
Phase II: N~284 pts.
Strata:
•Histological subtype•MSKCC score: Risk poor vs. other
• Primary Endpoint: Survival rate at 12 mths
• Key Secondary Endpoints:
• Survival rate at 6 and 18 mths
• ORR, TTP, OS, Safety, HR-QoL
• Exploratory Endpoints: biomarker e.g.PD-L1 expression of tumor, PD-1 expression of T cell subtypes etc.
R
1:1Sunitinib
50 mg PO oncedaily for 4 weeks followed
by 2 weeks off, every cycle
Nivolumab 3 mg/kg IV Ipilimumab 1 mg/kg IV
q3wfor 4 doses
then Nivolumab3 mg/kg IV q2w
Adjuvante TKI-Therapie des NCC
Ravaud et al. (2016). NEJM. http://doi.org/10.1056/NEJMoa1611406Haas et al. (2016). Lancet, 387(10032), 2008–2016. http://doi.org/10.1016/S0140-6736(16)00559-6
S-TRAC ASSUREASSURE
Unverändertes Gesamtüberleben
S-TRAC ASSURE
Ravaud et al. (2016). NEJM. http://doi.org/10.1056/NEJMoa1611406Haas et al. (2016). Lancet, 387(10032), 2008–2016. http://doi.org/10.1016/S0140-6736(16)00559-6
Erste Arbeit zur PseudoprogressionT-Zellen
Nekrose
Wolchok et al. Clin Cancer Res 2009;15(23) December 1, 2009
Systemtherapie des 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
Chemotherapie beim TCC
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.
Erstlinie Zweitlinie
ORR: 9%PFS: 3 Mo.
Langzeitüberleben unter 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.
IMvigor210:
• Inoperable locally advanced or metastatic urothelial carcinoma
• Predominantly TCC histology
• Tumor tissue evaluable for PD-L1 testinga
Cohort 2:
Platinum-treated mUC
Cohort 1 (n=119):
1L Cisplatin ineligible
Atezolizumab 1200 mg IV q3w until loss of clinical benefit
Atezolizumab 1200 mg IV q3w until RECIST v1.1 progression
Cohort 1-specific inclusion criteria
• No prior treatment for mUC (>12 mo since perioperative chemo)
• ECOG PS0–2• Cisplatin ineligibility1 based on ≥1 of the following:
• Renal impairment: GFR <60 but >30 mL/minb
• ≥Grade 2 hearing loss or peripheral neuropathy• ECOG PS2
Primary endpoint
• Confirmed ORR: RECIST v1.1 (per central IRF)
Key secondary endpoints
• DOR, PFS, OS, safety
Mod. Balar AV et al. ASCO 2016, Oral Abstract Session – Genitourinary (Nonprostate) Cancer, Abstract No. LBA4500
IRF, independent review facility; TCC, transitional cell histology, ClinicalTrials.gov ID: NCT02108652.aPD-L1 prospectively assessed by a central laboratory, with patients and investigators blinded. bCockcroft-Gault formula. 1Galsky J Clin Oncol
2011.
TCC, transitional cell carcinoma. aPatients and investigators blinded to PD-L1 ICH status. Trial Identifier: NCT02108652.1Balar ASCO 2016 [abstract LBA4500].
2Rosenberg ASCO 2016 [abstract 104].)
• Locally advanced or metastatic urothelial carcinoma
• Predominantly TCC histology
• Tumor tissue for PD-L1 testinga
Cohort 1 presented earlier this morning1
Atezolizumab 1200 mg IV q3w until loss of benefit
Cohort 1 (n=119)1L Cisplatin ineligible
Cohort 2 (n=310)Platinum-treated mUC
Cohort 2-specific inclusion criteria
• Progression during/following Platinum (no restrictions on # prior lines of therapy)
• ECOG PS 0–1• CrCl ≥30mL/min
Median follow-up: 17.5 months
(range, 0.2 to 21.1+ mo)
Co-primary endpoints:• ORR (confirmed) per RECIST v1.1 by central review• ORR per immune-modified RECIST by investigatorKey secondary endpoints• DOR, PFS, OS, safetyKey exploratory endpoints• Biomarkers (To be presented by Rosenberg et al.,
Abstract #1042)
Gesamtüberleben: Atezolizumab
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%
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
27% mit Vinflunin
22% mit BSC ca. 40%
Nivolumab (Platin-vorbehandelt)
Checkpunkt Blockade beim TCC
ATEZO1 ATEZO2 NIVO3 NIVO4 PEMBRO5 AVELU6
N 119 310 78 270 100 129
Linie CDDPungeeignet
≥2. ≥2. ≥2. CDDPungeeignet
≥2. oderCDDP ungeeignet
CR (%) 7 7 6 2 6 3
PR (%) 17 16 18 17 18 14
OS (mo.) 14.8 7.9 9.7 8.7 - -
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
SAUL Studie
Testsubstanz: Atezolizumab
Einschlusskriterien:
• Lokal fortgeschrittenes (T4, jedes N oder jedes T, N 2-3) oder metastasiertes Urothelkarzinom (M1, Stage IV) oder nicht-urotheliales Karzinom
• Zweitlinienchemotherapie geeignet
TCC: wenig aktivierende Mutationen
TCGA network. (2014). Comprehensive molecular characterization of urothelial bladdercarcinoma. Nature, 507(7492), 315–322. doi:10.1038/nature12965
Neue Ansätze zur molekularen Rx
TCGA network. (2014). Comprehensive molecular characterization of urothelialbladder carcinoma. Nature, 507(7492), 315–322. doi:10.1038/nature12965
Molekulare Therapiestudien
Substanz Inhibition Phase Mol. Stratum*
offen Ident
BEZ235 PI3K/mTOR II + - NCT01856101
Buparlisib PI3K II NR (+) NCT01551030
Dovitinib VEGFR/FGFR II + - NCT01732107
BGJ398 FGFR I/II + + NCT01004224
Nintedanib VEGFR/FGFR II + - NCT02278978
BAY1163877 FGFR I/II + + NCT01976741
LY3076226 FGFR3 mAb I + + NCT02529553
B-701 FGFR3 mAb II + + NCT02401542
Palbociclib CDK4/6 II + + NCT02334527
*Stratifizierung nach Mutation, Amplifikation, Überexpression, Aktivierung und/oder Wildtyp
www.clinicaltrials.gov
FGFR Inhibition
Testsubstanz: Erdafitinib (pan FGFR Inhibitor)
Einschlusskriterien:
• metastasiertes oder inoperables Urothelzellkarzinom (cT4b, N+ oder M+)
• progrediente Erkrankung
• FGFR mutiert
Zusammenfassung
• Adjuvante Therapie – noch kein Standard beim NCC
• Erstlinie: neuer Standard in 2017 möglich
• Zweitlinie: Nivolumab, Cabozantinib & Lenvatinib/Everolimus sind Optionen mit OS-Vorteil
• Keine Rationale in der Therapieauswahl
• PD-L1 ist kein optimaler prädiktiver Marker
• Kombinationen und Therapieoptimierung sind aktuelle Studienkonzepte