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Immuntherapie uroonkologischer Tumore Prof. Dr. med. Viktor Grünwald Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation

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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

PCA: Ipilimumab vs. Placebo

Kantoff et al. (2010). NEJM, 363(5), 411–422.

Mutationsspektrum solide Tumore

MS Lawrence et al. Nature 2013

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.

Resistenzmechanismen

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

Was unterscheidet TKI von IO?

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

Ziel der adjuvanten Therapie

− Heilung (i.e. Gesamtüberleben)

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

NCC: adjuvante Therapie Start Q1 2017

Hochrisiko: − T2 G4− T3a G3-4− T3b-c/T4− TxN+

N=664

I°: DFS

Radiologisches Assessment

De Velasco et al. (2016). Cancer Immunology Research, 4(1), 12–17.

Erste Arbeit zur PseudoprogressionT-Zellen

Nekrose

Wolchok et al. Clin Cancer Res 2009;15(23) December 1, 2009

Urothelkarzinom

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.

1st Linie TCC: Atezolizumab(Platin-ungeeignet)

Bellmunt et al. ESMO 2016, 782PD

57%

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