Immunotherapy of Urothelial Cancer/Prostate...
Transcript of Immunotherapy of Urothelial Cancer/Prostate...
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Immunotherapy of Urothelial Cancer/Prostate Cancer10 years experience
Prof Winald R. Gerritsen
Radboud University Medical Center
Department of Medical Oncology
Nijmegen, the Netherlands
Adjunct Professor
Johns Hopkins Sidney Kimmel Cancer Center
Baltimore, USA
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Disclosures last five years
Speaker fees
Astellas (personal), Bayer (institute), MSD (institute), ESMO (institute)
Advisory boards
Amgen (personal), Bayer (institute), Bristol-Myers Squibb (institute),
Curevac (personal), Dendreon (personal), IMS Health/iQVia (institute),
Janssen-Cilag (institute), Merck (MSD) (institute),
Morphosys (institute), Sanofi (personal),
Research grants
Astellas (institute), Bayer (institute), Janssen-Cilag (institute), Sanofi (institute)
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Immunotherapy of urothelial cancers
Module 1: Diagnosis and incidence of urothelial cancer In Europe
39,522 died in 2012
118,365 diagnosed in 2012
400K + living with bladder
cancer
most common
cancer 5th
most common
in men
4thmost
common in women
11th50% - 80% recurrence
rate
“Statistics are human beings with the tears wiped away.”
Sources: 1. J Bellmunt et al EJC suppl 2016: 14(1): 1-20. 2. BCAN: Bladder cancer Advocacy Network: www. Bcan.org
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Immunotherapy of urothelial cancers
Exogenous
Schistosomiasis
Tobacco
Phenacetin metabolites
Cytostatics (Cyclophosphamides)
? Sweeteners (Saccharin,cyclamate)
Pelvic radiation
Blackfoot disease (Taiwan)
A. Fangchi (Chinese herb)
Industrial
Aniline dyes Benzene
derivatives (aromatic
amines)
Paints, oils, gasoline
Endogenous
Chronic irritations (catheters)
/Toxins Chronic inflammation
Trytophan metabolites
Nitrosamines
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Immunotherapy of urothelial cancers
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Immunotherapy of urothelial cancers
Cammile GuerinAlbert Calmette
The Tuberculosis vaccine was invented in 1921
Attenuated form of the Mycobacterium bovis
Produces local inflammatory reaction which willlead to stimulation of the T-cell function to destroySuperficial bladder cancer
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Immunotherapy of urothelial cancers
Bacillus Calmette Guerin (BCG)
• 1975 – deKernion – treated isolated melanoma in bladder with intravesical BCG
• 1976 – Morales – first successful use of intravesical BCG for superficial TCC– Devised original protocol for induction
• 6 doses because Frappier strain packaged in 6 vials
• 120 mg/dose because tolerated by intradermal
• Weekly instillation because adverse effects <1 week
• 1978 – Morales treated 10 patients and BCG reduced/eradicated tumor recurrences in 7
• 2 randomized controlled trials – SWOG (Lamm) and MSKCC conducted and confirmed reduced tumor recurrences compared to TURBT alone
• 1990 – FDA approved intravesical BCG
• sources: HERR ET AL. J UROL2008: NCI presentation:Agarwal
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Immunotherapy of urothelial cancers
Immune checkpoint Inhibitors: Introduction
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Immunotherapy of urothelial cancers
Immune checkpoint Inhibitors: Introduction
APC, antigen presenting cell; MDSC, myeloid derived suppressor cell; M2, M2 macrophage; PD-L1, programmed cell death ligand 1; TCR, T cell receptor; TH1, T helper 1; TIL, tumour-infiltrating lymphocyte. Teng MWL et al. Cancer Res. 2015;75;2139–2145.
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Immunotherapy of urothelial cancers: 2nd line Atezolizumab
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Immunotherapy of urothelial cancers: 2nd line Atezolizumab
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Immunotherapy of urothelial cancers: 2nd line Atezolizumab
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Immunotherapy of urothelial cancers: 2nd line Atezolizumab
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Immunotherapy of urothelial cancers: 2nd line Atezolizumab
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Immunotherapy of urothelial cancers: 2nd line Atezolizumab
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Immunotherapy of urothelial cancers: 2nd line pembrolizumabModule 5
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Immunotherapy of urothelial cancers: 2nd line pembrolizumabModule 5
Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Immunotherapy of urothelial cancers: 2nd line pembrolizumabModule 5
Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Immunotherapy of urothelial cancers: 2nd line pembrolizumab
Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Immunotherapy of urothelial cancers: 2nd line pembrolizumab
Analysis cut-off date: 26 October 2017. aBased on Cox regression model with treatment as a covariate stratified by ECOG PS (0/1 vs 2), liver metastases (yes vs no), haemoglobin level (<10 vs ≥10 g/dL), and time from completion of chemotherapy (<3 vs ≥3 months). bOne-sided P value based on stratified log-rank test.
CI, confidence interval; CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival; PD-L1, programmed death ligand 1.Fradet Y et al. ASCO 2018. Chicago IL, June 1–5, 2018. Abstract 4521.
Adapted from: Fradet Y et al. ASCO 2018.
OS in all
patients
OS in patients
with PD-L1
CPS ≥10%
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Immunotherapy of urothelial cancers pembrolizumab
Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Immunotherapy of urothelial cancers pembrolizumab
Analysis cut-off date: 26 October 2017.
CI, confidence interval; CR, complete response; HR, hazard ratio; OS, overall survival; PR, partial response.Fradet Y et al. ASCO 2018. Chicago IL, June 1–5, 2018. Abstract 4521.
Adapted from: Fradet Y et al. ASCO 2018.
OS by best overall response (CR + PR) [n=87]
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Immunotherapy of urothelial cancersfirst line chemotherapy (cisplatin ineligle patients)
Maria de Santis et al, JCO 2012, 30, 191-199
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Immunotherapy of urothelial cancers part 2Module 3: first line chemotherapy (Response Rate)
Maria de Santis et al, JCO 2012, 30, 191-199
Best Overall Response Rate
Gemcitabine/Carboplatin
Complete Response 3%
Partial Response 38%
Stable Disease 33%
Progressieve Disease 15%
Others 11%
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Immunotherapy of urothelial cancersfirst line Pembrolizmab (cisplatin ineligible): Phase II
Analysis cut-off date: 30 November 2017.
OS, overall survival.1. Vuky J et al. ASCO 2018. Chicago IL, June 1–5, 2018. Abstract 4524; 2. Balar AV et al. Lancet Oncol 2017;pii:S1470–2045(17)30616–2. Adapted from: Vuky J et al. ASCO 2018.
Overall Survival
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Immunotherapy of urothelial cancersfirst line Pembrolizmab (cisplatin ineligible): Phase II
Adapted from: Vuky J et al. ASCO 2018.
Analysis cut-off date: 30 November 2017.
1. Vuky J et al. ASCO 2018. Chicago IL, June 1–5, 2018. Abstract 4524; 2. Balar AV et al. Lancet Oncol 2017;pii:S1470–2045(17)30616–2.
Response, n (%) 95% CI
Objective response, n (%) 107 (29) 24.3–33.8
Complete response 30 (8) 5.5–11.4
Partial response 77 (21) 16.8–25.3
Stable disease, n (%) 67 (18) 14.3–22.4
Progressive disease, n (%) 156 (42) 37.1–47.4
No assessment, n (%) 31 (8) 5.8–11.7
Not evaluable, n (%) 9 (2) 1.1–4.6
Adapted from: Vuky J et al. ASCO 2018.
▪ ORR was 24% in the total population in the primary analysis (analysis cut-off date: 1 September 2016)2
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Immunotherapy of urothelial cancersfirst line Pembrolizmab (cisplatin ineligible): Phase II
Balar AV et al. Lancet oncology 2017:11;1483-1492, updated Vuky J et al, ASCO 2018 Abstract 4524
PDL-1 CPS scoring and response rate
EMA restricts use of anti-PD-1 drugs for bladder cancer
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Immunotherapy of urothelial cancers
Immune checkpoint InhibitorsIgG antibodies and their Fc regions
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Immunotherapy of urothelial cancers
Module 3: Immune checkpoint InhibitorsDifferent IgG antibodies and different effects
Anti-CTLA-4: in vivo based rationale
Intra-tumoral Depletionof T-regs
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Immunotherapy of urothelial cancers
†at clinically relevant doses
IgG1 wt
Curetech Anti-PD-1
Merck/Pfizer Avelumab
ADCC intact ➔
Potential to deplete activated T cells
and TILs and diminish activity
Blocks PD-1/PD-L2 interaction in lungs
➔
Potential for autoimmune pneumonitis
IgG4 hinge mutant
BMS Anti-PD-1
Merck Anti-PD-1
40% reduced ADCC†➔
Potential to deplete activated T
cells and TILs and diminish
activity
Blocks PD-1/PD-L2 interaction
in lungs ➔
Potential for autoimmune
pneumonitis
Courtesy of Dr. Herbst
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Immunotherapy of urothelial cancers
IgG4
NIVOLUMAB PEMBROLIZUMAB ATEZOLIZUMAB DURVALUMAB AVELUMAB
aPD-1 aPD-L1
Modified IgG1IgG4
ModifiedIgG1
IgG1
NO or modified ADCC / ADCPInfusion Related Reactions ≈3%
ADCC / ADCPIRR≈18%
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Immunotherapy of urothelial cancers part 2Module 6: biomarkers for chemotherapy
TCGA, Nature, 2014
Urothelial Cancer is a molecularly heterogeneous disease
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Immunotherapy of urothelial cancers
Response on chemotherapy:ERCC2 mutations (Liu et al, Jama Oncol 2016)
ATM, RB1, FANCC (DNA mismatched repair) (Plimack et al, Eur Urol 2015)
Response on immunotherapy:PDL-1/PDL-2 expressionMutational load (Davarpanah et al, 2017)
MDSC presence Curr Clin Opinion
Tregs
Response on Herceptin therapy:HER2/neu expression (Powles et al, JCO 2017)
Response on mTOR inhibitors:mutations in PI3K/AKT/mTOR pathway (Kortyglu et al, Clin Genit Cancer 2015)
Response on FGFR3:FGFR3 mutation (Joerger et al, ESMO 2016)
AR expression
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Comprehensive Molecular Characterization ofMuscle-Invasive Bladder Cancer
A. Gordon Robertson et al. Cell 2017
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Immunotherapy of urothelial cancers
Tom Powles, Kate Smith, Arnulf Stenzl, Jens Bedke European Urology 2017.03.047
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Immunotherapy of prostate cancercombination therapy
Anti-PD-1/anti-PDL-1
combined with remarks
nivolumab Vaccines (eg Prostvac)
nivolumab ipilimumab Neoantigen DNA vaccine, Prostvac, Biomarker driven,Immunogenic signature, enzalutamide
pembrolizumab Olaparib, docetaxel, enzalutamide Phase III planned
pembrolizumab DNA vaccines, Radium-223, ADX531-142, CPI-444
atezolizumab Radium-223,Sipuleucel-T, Enzalutamide Phase III study enzalutamide
avelumab Sipuleucel-T
Durvalumab Tremulimumab
Regn2810 Ipilimumab (intraprostatic) + stereotactic RT
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09/11/20181. Wu YM et al. Cell 2018; 173(7): 1770–1782.2. Kim T-M et al. Cell 2013;155(4):858-868.
❖ 7.7% have hTMB (>10 mut/Mb)• 6.7% of patients have a
hTMB /MSI signature• 1% of patients have BRCA
inactivation❖ 6.7% of patients have CDK12
biallelic inactivation and tandem duplication signature1
❖ 12% have BRCAness
Prostate cancer immunogenic subtypes identified by WGS
Enrichment of aberrations in hTMB tumours • MMR genes (MSH6, MSH2, MLH1)• Non-synonymous variants in POLE• Recurrent frameshift mutations2 in relevant
genes including ACVR2A, JAK1 and TGFBR2 • Aberrations in known prostate cancer drivers
ZFHX3, PALB2• Novel potential (immuno)suppressive genes
TTK, CIC, ZFP36L2, EPA1, KMT2C, SETD1B, ZMYM3 and others
15-25% of patients have an immunogenic molecular signature
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Immunotherapy of prostate cancerselection of patients
MICROSATELLITE INSTABILITY IN PROSTATE CANCER AND RESPONSE TO IMMUNE CHECKPOINT BLOCKADE
WASSIM ABIDA ET AL. ASCO 2018 ABSTRACT 5020
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Immunotherapy of prostate cancerselection of patients
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Immunotherapy of prostate cancerselection of patients
Radboudumc experience: Nivolumab in MSI high & sanctuary sites
PSMA - PET scan
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Conclusions
Urothelial cancers:• First and second line: immune checkpoint inhibitors• First line (platinum ineligible): restricted use based on PDL-1 expression• Different mode of action• NGS data become more important
Prostate cancer:• New immunotherapy trials• 20-25% eligible for immunotherapy, especially MSI high• Be aware of sanctuary sites