Kemoterapi idag Immunterapi i morgon?

Kemoterapi idag Immunterapi i morgon? -systemisk behandling av metastaserad sjukdom Anders Ullén Karolinska Sjukhuset

Kemoterapi idag Immunterapi i morgon? State of the art systemisk behandling idag Immunterapi Introduktion Genomgång av aktuella studiedata 1st line, 2nd + line Biverkningar Biomarkörer Utvecklingslinjer

Hur behandlar vi? Vad har vi att ta hänsyn till? Metastaserad Urinblåscancer är en kemoterapikänslig sjukdom

Hur behandlar vi? Vad har vi att ta hänsyn till? Metastaserad Urinblåscancer är en kemoterapikänslig sjukdom - Njurpåverkan? - Relativt åldrad patientgrupp - Ofta rökare - Ofta komorbiditet - Olika histopatologier - Varierande sjukdomsaggresivitet

Hur behandlar vi? Vad har vi att ta hänsyn till? > 90 % från övergångsepitel (TCC, transitional cell carcinoma) 6-8 % skivepitelcancer adenocarcinom småcelliga sarkom lymfom

Cisplatin nyckelcytostatika -Ta CH s bild.

Cisplatin- fit respektive unfit?

Cisplatin- fit resp. unfit vad avses?

Unfit = Cisplatin-ineligible Performance status: Nedsatt njurfunktion: Co-morbiditet:

Unfit = Cisplatin-ineligible Performance status: ECOG/WHO 2, Karnofsky < 80 % Nedsatt njurfunktion: GFR < 60 ml/min Co-morbiditet: NYHA Class III - IV hjärtsvikt Grad 2 hörselnedsättning Grad 2 perifer neuropati

Cisplatin fit - 1st line

Cisplatin fit - 1st line Metotrexat-Vinblastine-Adriamycin-Cisplatin (MVAC) MVAC CR (%) 25+11 PR (%) 43 Median OS (months) 14.8 5-year survival rate (%) 17 Jämför OS = ca 4-6 mån obehandlad (Sternberg et al 1989 Cancer, Bajorin et al 1999 JCO)

Cisplatin fit - 1st line Gemcitabine-Cisplatinum vs. MVAC - Overall Survival von der Maase H, J Clin Oncol. 17:3068-3077, 2000 and 2005

Cisplatin fit - 1st line Gemcitabine-Cisplatinum vs. MVAC - Toxicitet von der Maase H, Hansen SW, Roberts JT et al. J Clin Oncol. 17:3068-3077, 2000,2005.

Cisplatin fit - 1st line Gemcitabine-Cisplatinum vs. MVAC - Toxicitet Toxicitet GC MVAC Infektion (grad 3-4) 3% 15% Mucosit (grad 3-4) 1% 22% Diarrée (grad 3-4) 3% 8% Alopecia (grad 3) 11% 55% Anemi (grad 3-4) 27% 18% Trombocytopeni (grad 4) 29% 13% Neutropeni (grad 4) 30% 65% Neutropen feber 2% 14% Neutropen sepsis 1% 12% Cytostatika relaterad död 1% 3% von der Maase H, Hansen SW, Roberts JT et al. J Clin Oncol. 17:3068-3077, 2000,2005.

Cisplatin fit - 1st line Gemcitabine-Cisplatinum vs. MVAC - Toxicitet Toxicitet GC MVAC Infektion (grad 3-4) 3% 15% Mucosit (grad 3-4) 1% 22% Diarrée (grad 3-4) 3% 8% Alopecia (grad 3) 11% 55% Anemi (grad 3-4) 27% 18% Trombocytopeni (grad 4) 29% 13% Neutropeni (grad 4) 30% 65% Neutropen feber 2% 14% Neutropen sepsis 1% 12% Cytostatika relaterad död 1% 3% Gem-Cis har på de flesta cancercentra ersatt MVAC von der Maase H, Hansen SW, Roberts JT et al. J Clin Oncol. 17:3068-3077, 2000,2005.

Cisplatin fit - 1st line Tripletter och andra kombinationer: inkl taxaner, cis/carbo, ifosfamide, gemcitabine, larotaxel, sunitinib, bevacizumab mm EORTC / US Intergroup study 30987: Paclitaxel, Cisplatin och Gemcitabine vs. Gem-Cis i mer än 600 patienter Bättre ORR Trend till bättre PFS och OS men ej signifikant skillnad Bellmunt et al J.Clin. Oncol. 2012

EAU guidelines 1st line fit First-line treatment for cisplatin-fit patients: Use cisplatin-containing combination chemotherapy with GC, PCG, MVAC, preferably with G-CSF, or HD-MVAC with G-CSF Grade of recommendation A

OS med eller utan visceral metastasering (GC-MVAC studien) Långtidsöverlevnad eller tom bot kan uppnås hos en fraktion av patienter utan visceral metastasering 20% von der Maase H et al J Clin Oncol 2005

Unfit 1st line

Unfit 1st line vad används? Gemcitabine/Carboplatin M-CAVI (Methotrexate, Carboplatin, Vinblastine) Modifierad cisplatin/gemcitabine, split dose cisplatin Gemcitabine ORR upp till 40 % OS upp till 9 mån

Unfit 1st line vad används? Gemcitabine/Carboplatin M-CAVI (Methotrexate, Carboplatin, Vinblastine) Modifierad cisplatin/gemcitabine, split dose cisplatin Gemcitabine ORR upp till 40 % OS upp till 9 mån Mindre effektivt än cis-komb i fit patienter

Unfit 1st line Randomiserad Fas II/III trial, 238 pts Unfit PS 2 and/or GFR < 60 ml/min Gem/Carbo vs M-CAVI De Santis et al J Clin Oncol 2012

Unfit 1st line ORR (%) CR (%) OS month PFS (%) SAT (%) Gem/Carbo 41 3.4 9.3 5.8 9 M-CAVI 30 3.4 8.1 4.2 21

EAU guidelines - 1st line unfit For cisplatin-ineligible (unfit) patients, with PS2 or impaired renal function, as well as those with 0-1 poor Bajorin prognostic factors and impaired renal function, offer carboplatin-containing combination chemotherapy, preferably with gemcitabine/carboplatin (Grade of recommendation B)

2nd line

2nd line Ett stort antal cytotoxiska läkemedel och kombinationer har studerats Ex, pemetrexed, docetaxel, topotecan, bevacizumab, sunitinib, lapatinib

2nd line Ett stort antal cytotoxiska läkemedel och kombinationer har studerats Ex, pemetrexed, docetaxel, topotecan, bevacizumab, sunitinib, lapatinib Bellmunt et al, JCO 2009 Bellmunt et al, Annals of Oncol 2013 OS 6.9 months vs 4.3 mån SD or better > 50 %

EAU guidelines 2nd line Offer vinflunine to patients progressing after platinum-based combination chemotherapy for metastatic disease. Alternatively, offer treatment within a clinical trial setting Grade of recommendation A*

3rd line

3rd line Få patienter aktuella Ingen etablerad terapi - Best supportive care alternativt klinisk prövning i första hand -Taxan?, Taxan komb?, Re-challenge?, Tolerabel TKI?, Pemetrexed?

Behandling av icke urotelscells cancer Generellt sett saknas randomiserade studier och hög grad av evidens Inkludera om möjligt i kliniska prövningar

Behandling av icke urotelscells cancer Generellt sett saknas randomiserade studier och hög grad av evidens Inkludera om möjligt i kliniska prövningar -småcellig: -adenocarcinom: -sarkom: -lymfom: visst stöd för SCLC regimer etablerade terapier med övertygande evidens saknas. GI-scheman kan prövas. enligt sarkom resp lymfomscheman

Kemoterapi idag Immunterapi i morgon? State of the art systemisk behandling idag Immunterapi Introduktion Genomgång av aktuella studiedata 1st line, 2nd + line Biverkningar Biomarkörer Utvecklingslinjer

Immunterapi vid urotelcellscancer?

Immunterapi vid urotelcellscancer? BCG gold standard vid högrisk NMIBC

Mutationsfrekvens hög vid urinblåsecancer Bild med mutationsfrekvens

Checkpoint inhibition by targeting of PD-1 and PD-L1

Checkpoint inhibition by targeting of PD-1 and PD-L1 Rational for effect on Urothelial Bladder Cancer (BC): The high rates of somatic mutations recognized by the host as foreign. increased number of antigens that can be UC may elude immune surveillance and eradication through expression of programmed cell deathligand 1 (PD-L1). Binding of PD-L1 to PD-1 delivers an inhibitory signal, reducing cytokine production and proliferation of T-cells. Anti-PD-L1 and anti-pd1 antibodies inhibit the interaction of PD-L1 with its T-cell receptors PD-1 (and B7.1). This may enable the activation of T cells as well as recruitment of other T cells to attack the tumor.

Atezolizumab (anti-pd-l1 antibody)

Atezolizumab (anti-pd-l1 antibody) Explosionsartad utveckling

Post-platinum anti-pd-l1/anti-pd-1 Immunterapi

Atezolizumab (anti-pd-l1 antibody) 8

Atezolizumab (anti-pd-l1 antibody) Objective Response by PD-L1 Status Loriot Y, et al. ESMO 2016, poster 783P 8

Atezolizumab (anti-pd-l1 antibody) Durable Responses Loriot Y, et al. ESMO 2016, poster 783P 8

Atezolizumab (anti-pd-l1 antibody) Efficacy Overall survival mos 7.9 months entire cohort 8

Atezolizumab (anti-pd-l1 antibody) Baseline Biomarker Associations With Efficacy Loriot Y, et al. ESMO 2016, poster 783P 8

Atezolizumab (anti-pd-l1 antibody) Treatment-related AE s 8

Atezolizumab (anti-pd-l1 antibody) Treatment-related AE s FDA approval May 18 2016 (First-in-class) 8

Nivolumab (anti-pd-1 antibody) 8

Nivolumab (anti-pd-1 antibody) OS data 8

Nivolumab (anti-pd-1 antibody) Response Rate Durable responses 8

Nivolumab (anti-pd-1 antibody) Treatment related AE s in > 5% of patients 8

Nivolumab (anti-pd-1 antibody) Treatment related AE s in > 5% of patients FDA approval Jan 27 2017 8

Pembrolizumab (anti-pd-1 antibody)

Pembrolizumab (anti-pd-1 antibody) OS benefit mos 10.3 months vs 7.4 months

SITH Nov 9-13, 2016

Pembrolizumab (anti-pd-1 antibody) Durable responses

SITH Nov 9-13, 2016

Pembrolizumab (anti-pd-1 antibody) AEs in as-treated population

Pembrolizumab (anti-pd-1 antibody) AEs in as-treated population FDA approved priority review (not yet approved for treatment)

1st line (unfit) anti-pd-l1/anti-pd-1 Immunterapi

Atezolizumab (anti-pd-l1 antibody) IMvigor210 8

Atezolizumab (anti-pd-l1 antibody) Responses across all PD-L1 subgroups ORR: 23% IMvigor210 8

Atezolizumab (anti-pd-l1 antibody) -Favorable OS data -No significant enrichement of efficacy by PD-L1 expression IMvigor210 8

Atezolizumab (anti-pd-l1 antibody) OS Atezo vs standard CHT Adopted from @PeerView ASCO-GU 2017 8

Pembrolizumab (anti-pd-1 antibody) Keynote-052 ongoing 8

Pembrolizumab (anti-pd-1 antibody) Keynote-052 ongoing Adopted from @PeerView ASCO-GU 2017 8

Möjlig standard behandling av avancerad UC i nära framtid

2:a generationens MAbs på väg

Biverkningar vid checkpoint inhibition

Biverkningar vid checkpoint inhibition Adopted from @PeerView ASCO-GU 2017

Hantering av biverkningar vid checkpoint inhibition Adopted from @PeerView ASCO-GU 2017

Pembrolizumab (anti-pd1 antibody) AEs in as-treated population

Atezolizumab (anti-pdl1 antibody)

Biomarkörer vid anti PD-1/PD-L1 behandling?

Biomarkörer vid anti PD-1/PD-L1 behandling? Molekylär subtyp: ytterligare studier behövs (ex conflict Imvigor 210 vs Checkmate 275)

Biomarkörer vid anti PD-1/PD-L1 behandling? Molekylär subtyp: ytterligare studier behövs (ex conflict Imvigor 210 vs Checkmate 275) PD-L1 status: ytterligare studier behövs, (men lågt uttryck bör tv ej utesluta behandlingsförsök)

Biomarkörer vid anti PD-1/PD-L1 behandling? Powles et al In Press Eur Urol 2017

Biomarkörer vid anti PD-1/PD-L1 behandling? Molekylär subtyp: ytterligare studier behövs (ex conflict Imvigor 210 vs Checkmate 275) PD-L1 status: ytterligare studier behövs, (men lågt uttryck bör tv ej utesluta behandlingsförsök) Mutational load: tycks korrelera med effekt, men ytterligare studier behövs

Kemoterapi idag Immunterapi i morgon? State of the art systemisk behandling idag Prognostiska markörer och prediktiva biomarkörer Immunterapi Introduktion Genomgång av aktuella studiedata 1st line, 2nd + line Biverkningar Biomarkörer Utvecklingslinjer

Immunterapi-studier i alla faser av Urinblåsecancer Non-Musc. Invasive Muscle Invasive 1L Mets Cis-Eligible 1L Metastatic Cis-Ineligible 2L Metastatic 3L+ Metastatic

Immunterapi-studier i alla faser av Urinblåsecancer Non-Musc. Invasive Muscle Invasive 1L Mets Cis-Eligible 1L Metastatic Cis-Ineligible 2L Metastatic 3L+ Metastatic Checkpoint inhibitorer, ex Dual-checkpoint inhibition, ex Checkpoint-combo studier, ex Vaccin och virus approacher ex

Immunterapi-studier i alla faser av Urinblåsecancer Non-Musc. Invasive Muscle Invasive 1L Mets Cis-Eligible 1L Metastatic Cis-Ineligible 2L Metastatic 3L+ Metastatic Checkpoint inhibitorer, ex PD-1 PD-L1 Nivolumab Pembrolizumab Atezolizumab Durvalumab Avelumab Dual-checkpoint inhibition, ex anti-ctla4/anti-pd-l1 eller anti-ctla4/anti-pd1) Nivolumab/Ipilimumab Durvalumab/Tremelimumab Checkpoint-combo studier, ex Pembrolizumab -ramucirumab Nivolumab- cabozantinib Atezolizumab-varlilumab Vaccin och virus approacher ex Enadenotucirev

Urval av aktuella Immunterapi Studier Davarpanah et al Curr Op Urol 2017

Global trends in clinical trials for advanced BC

Global trends in clinical trials for advanced BC Immunotherapy, in particular by use of checkpoint inhibitors of PD-1/PD-L1 axis and CTLA4 anti-pd1/antipd-l1 monotherapy trials in all disease stages anti-pd1/antipd-l1 checkpoint combo s anti-pd1/antipd-l1 combos with chemotherapy and radiotherapy anti- PD1/antiPD-L1 combos with varius targeted compounds and oncolytic cirus approaches

Global trends in clinical trials for advanced BC Immunotherapy, in particular by use of checkpoint inhibitors of PD-1/PD-L1 axis and CTLA4 anti-pd1/antipd-l1 monotherapy trials in all disease stages anti-pd1/antipd-l1 checkpoint combo s anti-pd1/antipd-l1 combos with chemotherapy and radiotherapy anti- PD1/antiPD-L1 combos with varius targeted compounds and oncolytic cirus approaches New chemo s or chemo-combinations eribulin nab-paclitaxel vinflunine-gemcitabine vinflunine-cisplatin

Global trends in clinical trials for advanced BC Immunotherapy, in particular by use of checkpoint inhibitors of PD-1/PD-L1 axis and CTLA4 anti-pd1/antipd-l1 monotherapy trials in all disease stages anti-pd1/antipd-l1 checkpoint combo s anti-pd1/antipd-l1 combos with chemotherapy and radiotherapy anti- PD1/antiPD-L1 combos with varius targeted compounds and oncolytic cirus approaches New chemo s or chemo-combinations eribulin nab-paclitaxel vinflunine-gemcitabine vinflunine-cisplatin Combinations of established chemo s and a new compound docetaxel + OGX-427 paclitaxel + pazopanib gemcitabine/cisplatin + sirolimus gemcitabine/carboplatin + panitumumab vinflunine + sorafenib docetaxel + ramucirumab gemcitabine/cisplatin + enzalutamid

Global trends in clinical trials for advanced BC Immunotherapy, in particular by use of checkpoint inhibitors of PD-1/PD-L1 axis and CTLA4 anti-pd1/antipd-l1 monotherapy trials in all disease stages anti-pd1/antipd-l1 checkpoint combo s anti-pd1/antipd-l1 combos with chemotherapy and radiotherapy anti- PD1/antiPD-L1 combos with varius targeted compounds and oncolytic cirus approaches New chemo s or chemo-combinations eribulin nab-paclitaxel vinflunine-gemcitabine vinflunine-cisplatin Combinations of established chemo s and a new compound docetaxel + OGX-427 paclitaxel + pazopanib gemcitabine/cisplatin + sirolimus gemcitabine/carboplatin + panitumumab vinflunine + sorafenib docetaxel + ramucirumab gemcitabine/cisplatin + enzalutamid New nib s and other small molecules for signal transduction inhibition tipifarnib regorafenib palbociclib alisertib ixazomib nintedanib neratinib crizotinib regorafenib and many others

Kemoterapi idag - Immunterapi i morgon?

Kemoterapi idag + Immunterapi i morgon! Men vi är bara i början på en ny era..

Kemoterapi idag + Immunterapi i morgon! Men vi är bara i början på en ny era - Biomarkörer för patientselektion: PDL1, TCGA subtype, mutational load - Sensitivitets och resistensmekanismer för checkpoint inhibition - Systemisk kombinationsbehandling och kombination med strålbehandling - Sekvensbehandlingar

Kemoterapi idag + Immunterapi i morgon! Men vi är bara i början på en ny era - Biomarkörer för patientselektion: PDL1, TCGA subtype, mutational load - Sensitivitets och resistensmekanismer för checkpoint inhibition - Systemisk kombinationsbehandling och kombination med strålbehandling - Sekvensbehandlingar - Behandlingsutvärdering - Toxicitet

Tack för uppmärksamheten!

Potentiella intressekonflikter Forskningsbidrag: Bayer AB, Pierre-Fabre AB, Pfizer AB Föreläsararvode: Pfizer AB, Roche AB, Pierre-Fabre AB, Oncopeptides AB, Bayer AB Advisory Board: Novartis AB, Sanofi-Aventis AB, Roche AB, Bayer AB, Pierre-Fabre AB, MSD AB

Powles study MPDL3280A was well tolerated -Only 5% of patients experienced Grade 3/4 treatment-related AEs -There were no grade 5 treatment-related AEs -Renal toxicity has not been observed in MPDL3280A-treated patients to date

Targeting of PD1 and PDL1 Rational for effect on Urothelial Bladder Cancer (BC): One hallmark of BC molecular biology is the presence of high rates of somatic mutations. These alterations foreign. increased number of antigens that can be recognized by the host as UC may elude immune surveillance and eradication through expression of programmed cell deathligand 1 (PD-L1). Binding of PD-L1 to PD-1 delivers an inhibitory signal, reducing cytokine production and proliferation of T-cells. The anti-pd-l1 antibody MPDL3280A inhibits the interaction of PD-L1 with its T-cell receptors PD-1 (and B7.1). This may enable the activation of T cells as well as recruit other T cells to attack the tumor.

Powles study

Powles study MPDL3280A was well tolerated -Only 5% of patients experienced Grade 3/4 treatment-related AEs -There were no grade 5 treatment-related AEs -Renal toxicity has not been observed in MPDL3280A-treated patients to date

Powles study

Overview of antipd1/antipdl1 studies in Sweden High risk NMIBC : Pembrolizumab(MK-3475) Neoadjuvant/Adjuvant: WO29636 trial: MPDL3280A in high risk MIBC post-cystectomy Met 1st line Maintainence: Met 1st line unfit Nivolumab (rand ph II versus placebo) Avelumab (rand ph III versus placebo) Pembrolizumab (MK-3475) Met 2nd line: Met 3rd line: NCT02256436 Pembrolizumab(MK-3475) GO29294 Atezolizumab Vinflunine + Anti-PDL1 Nivolumab (BMS336958) GO29294 Atezolizumab NCT02256436 Pembrolizumab(MK-3475) Nivolumab (BMS336958)

Kemoterapi idag Immunterapi i morgon? State of the art systemisk behandling idag Prognostiska markörer och prediktiva biomarkörer Immunterapi Introduktion Genomgång av aktuella studiedata 1st line, 2nd + line Biverkningar Biomarkörer Utvecklingslinjer

Prognostiska markörer

Prognostiska markörer 1st line ( Bajorin factors): 1. PS Karnofsky< 80%, 2. förekomst av viscerala metastaser Bajorin et al JCO 1999

Prognostiska markörer 1st line ( Bajorin factors): 1. PS Karnofsky< 80%, 2. förekomst av viscerala metastaser Bajorin et al JCO 1999 2nd line: 1. Hb < 100 2. lever metastaser 3. PS ECOG/WHO PS >0 Bellmunt et al JCO 2010

Biomarkörer - kan gen- och proteinmarkörer utnyttjas? Plimack et al Eur Urol 2015 68, 959-967

Biomarkörer - kan gen- och proteinmarkörer utnyttjas? Groenendijk et al Eur Urol 2016 69, 384-388.

Biomarkörer - utvecklingstrend Urology, In Press Dec 2016 Eur. Urol. In Press 2017