Immunotherapy of Urothelial Cancer/Prostate Cancer 10 years experience

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1 Immunotherapy of Urothelial Cancer/Prostate Cancer 10 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

2 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)

Sources: 1. J Bellmunt et al EJC suppl 2016: 14(1): 1-20. 2. BCAN: Bladder cancer Advocacy Network: www. Bcan.

118,365 diagnosed in 2012 400K + living with bladder cancer 5th most common cancer 39,522 died in 2012

3 Sources: 1. J Bellmunt et al EJC suppl 2016: 14(1): BCAN: Bladder cancer Advocacy Network: www. Bcan.org Immunotherapy of urothelial cancers Module 1: Diagnosis and incidence of urothelial cancer In Europe 118,365 diagnosed in K + living with bladder cancer 5th most common cancer 39,522 died in 2012 Statistics are human beings with the tears wiped away. 50% - 80% recurrence rate 4th most common in men 11th most common in women

4 Immunotherapy of urothelial cancers Exogenous Schistosomiasis Tobacco Phenacetin metabolites Cytostatics (Cyclophosphamides)? Sweeteners (Saccharin,cyclamate) Pelvic radiation Blackfoot disease (Taiwan) A. Fangchi (Chinese herb) Endogenous Chronic irritations (catheters) /Toxins Chronic inflammation Industrial Aniline dyes Benzene derivatives (aromatic amines) Paints, oils, gasoline Trytophan metabolites Nitrosamines

5 Immunotherapy of urothelial cancers

6 Immunotherapy of urothelial cancers Albert Calmette The Tuberculosis vaccine was invented in 1921 Attenuated form of the Mycobacterium bovis Produces local inflammatory reaction which will lead to stimulation of the T-cell function to destroy Superficial bladder cancer Cammile Guerin

7 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 in7 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

8 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

9 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, tumourinfiltrating lymphocyte. Teng MWL et al. Cancer Res. 2015;75;

10 Immunotherapy of urothelial cancers: 2nd line Atezolizumab

11 Immunotherapy of urothelial cancers: 2nd line Atezolizumab

12 Immunotherapy of urothelial cancers: 2nd line Atezolizumab

13 Immunotherapy of urothelial cancers: 2nd line Atezolizumab

14 Immunotherapy of urothelial cancers: 2nd line Atezolizumab

15 Immunotherapy of urothelial cancers: 2nd line Atezolizumab

16 Immunotherapy of urothelial cancers: 2nd line pembrolizumab Module 5

17 Immunotherapy of urothelial cancers: 2nd line pembrolizumab Module 5 Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

18 Immunotherapy of urothelial cancers: 2nd line pembrolizumab Module 5 Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

19 Immunotherapy of urothelial cancers: 2nd line pembrolizumab Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

20 Immunotherapy of urothelial cancers: 2nd line pembrolizumab OS in all patients OS in patients with PD-L1 CPS 10% Adapted from: Fradet Y et al. ASCO Analysis cut-off date: 26 October a Based 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). b One-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 Chicago IL, June 1 5, Abstract 4521.

21 Immunotherapy of urothelial cancers pembrolizumab Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

22 Immunotherapy of urothelial cancers pembrolizumab OS by best overall response (CR + PR) [n=87] Adapted from: Fradet Y et al. ASCO Analysis cut-off date: 26 October CI, confidence interval; CR, complete response; HR, hazard ratio; OS, overall survival; PR, partial response. Fradet Y et al. ASCO Chicago IL, June 1 5, Abstract 4521.

23 Immunotherapy of urothelial cancers first line chemotherapy (cisplatin ineligle patients) Maria de Santis et al, JCO 2012, 30,

24 Immunotherapy of urothelial cancers part 2 Module 3: first line chemotherapy (Response Rate) Best Overall Response Rate Gemcitabine/ Carboplatin Complete Response 3% Partial Response 38% Stable Disease 33% Progressieve Disease 15% Others 11% Maria de Santis et al, JCO 2012, 30,

25 Immunotherapy of urothelial cancers first line Pembrolizmab (cisplatin ineligible): Phase II Overall Survival Analysis cut-off date: 30 November OS, overall survival. 1. Vuky J et al. ASCO Chicago IL, June 1 5, Abstract 4524; 2. Balar AV et al. Lancet Oncol 2017;pii:S (17) Adapted from: Vuky J et al. ASCO 2018.

26 Immunotherapy of urothelial cancers first line Pembrolizmab (cisplatin ineligible): Phase II Response, n (%) 95% CI Objective response, n (%) 107 (29) Complete response 30 (8) Partial response 77 (21) Stable disease, n (%) 67 (18) Progressive disease, n (%) 156 (42) No assessment, n (%) 31 (8) Not evaluable, n (%) 9 (2) Adapted from: Vuky J et al. ASCO ORR was 24% in the total population in the primary analysis (analysis cut-off date: 1 September 2016) 2 Analysis cut-off date: 30 November Vuky J et al. ASCO Chicago IL, June 1 5, Abstract 4524; 2. Balar AV et al. Lancet Oncol 2017;pii:S (17) Adapted from: Vuky J et al. ASCO 2018.

27 Immunotherapy of urothelial cancers first line Pembrolizmab (cisplatin ineligible): Phase II PDL-1 CPS scoring and response rate EMA restricts use of anti-pd-1 drugs for bladder cancer Balar AV et al. Lancet oncology 2017:11; , updated Vuky J et al, ASCO 2018 Abstract 4524

28 Immunotherapy of urothelial cancers Immune checkpoint Inhibitors IgG antibodies and their Fc regions

29 Immunotherapy of urothelial cancers Module 3: Immune checkpoint Inhibitors Different IgG antibodies and different effects Anti-CTLA-4: in vivo based rationale Intra-tumoral Depletion of T-regs

Immunotherapy of urothelial cancers IgG1 wt Curetech Anti-PD-1 Merck/Pfizer Avelumab IgG4 hinge mutant BMS Anti-PD-1 Merck Anti-PD-1 ADCC intact Potential to deplete activated T cells and TILs and

30 Immunotherapy of urothelial cancers IgG1 wt Curetech Anti-PD-1 Merck/Pfizer Avelumab IgG4 hinge mutant BMS Anti-PD-1 Merck Anti-PD-1 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 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 at clinically relevant doses Courtesy of Dr. Herbst

31 Immunotherapy of urothelial cancers apd-1 apd-l1 NIVOLUMAB PEMBROLIZUMAB ATEZOLIZUMAB DURVALUMAB AVELUMAB IgG4 IgG4 Modified IgG1 Modified IgG1 IgG1 NO or modified ADCC / ADCP Infusion Related Reactions 3% ADCC / ADCP IRR 18%

32 TCGA, Nature, 2014 Immunotherapy of urothelial cancers part 2 Module 6: biomarkers for chemotherapy Urothelial Cancer is a molecularly heterogeneous disease

33 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 expression Mutational 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

34 Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer A. Gordon Robertson et al. Cell 2017

35 Immunotherapy of urothelial cancers Tom Powles, Kate Smith, Arnulf Stenzl, Jens Bedke European Urology

36 Anti-PD-1/ anti-pdl-1 nivolumab Immunotherapy of prostate cancer combination therapy combined with Vaccines (eg Prostvac) remarks nivolumab ipilimumab Neoantigen DNA vaccine, Prostvac, Biomarker driven, Immunogenic signature, enzalutamide pembrolizumab Olaparib, docetaxel, enzalutamide Phase III planned pembrolizumab DNA vaccines, Radium-223, ADX , CPI-444 atezolizumab Radium-223,Sipuleucel-T, Enzalutamide Phase III study enzalutamide avelumab Durvalumab Sipuleucel-T Tremulimumab Regn2810 Ipilimumab (intraprostatic) + stereotactic RT

37 Prostate cancer immunogenic subtypes identified by WGS 15-25% of patients have an immunogenic molecular signature 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 signature 1 12% have BRCAness Enrichment of aberrations in htmb tumours MMR genes (MSH6, MSH2, MLH1) Non-synonymous variants in POLE Recurrent frameshift mutations 2 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 1. Wu YM et al. Cell 2018; 173(7): /11/ Kim T-M et al. Cell 2013;155(4):

38 Immunotherapy of prostate cancer selection of patients MICROSATELLITE INSTABILITY IN PROSTATE CANCER AND RESPONSE TO IMMUNE CHECKPOINT BLOCKADE WASSIM ABIDA ET AL. ASCO 2018 ABSTRACT 5020

39 Immunotherapy of prostate cancer selection of patients

40 Immunotherapy of prostate cancer selection of patients Radboudumc experience: Nivolumab in MSI high & sanctuary sites PSMA - PET scan

41 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

THE SEARCH FOR BIOMARKERS IN BLADDER CANCER

THE SEARCH FOR BIOMARKERS IN BLADDER CANCER CDDP and IO WORLD ALEJO RODRÍGUEZ-VIDA MD PhD Consultant Medical Oncologist Associate Professor Hospital del Mar, Barcelona November 23 rd 2018 DISCLOSURE OF