Immunotherapy of Urothelial Cancer/Prostate …regist2.virology-education.com/presentations/2018/ICPAD/...Immunotherapy of urothelial cancers: 2nd line pembrolizumab Analysis cut-off

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


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



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


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


Immune checkpoint Inhibitors: Introduction


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 pembrolizumabModule 5


Presented By Joaquim Bellmunt at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care



Immunotherapy of urothelial cancers: 2nd line pembrolizumab


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


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


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


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


Immune checkpoint InhibitorsIgG antibodies and their Fc regions


Module 3: Immune checkpoint InhibitorsDifferent IgG antibodies and different effects

Anti-CTLA-4: in vivo based rationale

Intra-tumoral Depletionof T-regs


†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


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


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


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



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

Immunotherapy of Urothelial Cancer/Prostate …regist2.virology-education.com/presentations/2018/ICPAD/...Immunotherapy of urothelial cancers: 2nd line pembrolizumab Analysis cut-off

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