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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
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)
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
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
Immunotherapy of urothelial cancers
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
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
Immunotherapy of urothelial cancers
Immune checkpoint Inhibitors: Introduction
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.
Immunotherapy of urothelial cancers: 2nd line Atezolizumab
Immunotherapy of urothelial cancers: 2nd line Atezolizumab
Immunotherapy of urothelial cancers: 2nd line Atezolizumab
Immunotherapy of urothelial cancers: 2nd line Atezolizumab
Immunotherapy of urothelial cancers: 2nd line Atezolizumab
Immunotherapy of urothelial cancers: 2nd line Atezolizumab
Immunotherapy of urothelial cancers: 2nd line pembrolizumabModule 5
Immunotherapy of urothelial cancers: 2nd line pembrolizumabModule 5
Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Immunotherapy of urothelial cancers: 2nd line pembrolizumabModule 5
Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Immunotherapy of urothelial cancers: 2nd line pembrolizumab
Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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%
Immunotherapy of urothelial cancers pembrolizumab
Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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]
Immunotherapy of urothelial cancersfirst line chemotherapy (cisplatin ineligle patients)
Maria de Santis et al, JCO 2012, 30, 191-199
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%
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
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
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
Immunotherapy of urothelial cancers
Immune checkpoint InhibitorsIgG antibodies and their Fc regions
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
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
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%
Immunotherapy of urothelial cancers part 2Module 6: biomarkers for chemotherapy
TCGA, Nature, 2014
Urothelial Cancer is a molecularly heterogeneous disease
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
Comprehensive Molecular Characterization ofMuscle-Invasive Bladder Cancer
A. Gordon Robertson et al. Cell 2017
Immunotherapy of urothelial cancers
Tom Powles, Kate Smith, Arnulf Stenzl, Jens Bedke European Urology 2017.03.047
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
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
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
Immunotherapy of prostate cancerselection of patients
Immunotherapy of prostate cancerselection of patients
Radboudumc experience: Nivolumab in MSI high & sanctuary sites
PSMA - PET scan
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
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