AVANCES EN EL TRATAMIENTO DE PRIMERA LINEA EN EL CANCER DE VEJIGA AVANZADO

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1 AVANCES EN EL TRATAMIENTO DE PRIMERA LINEA EN EL CANCER DE VEJIGA AVANZADO Montse Domènech Althaia, Xarxa Assistencial i Universitària Manresa

2 Urothelial Cancer Therapeutics FDA approved drugs for bladder cancer Non-muscle invasive Advanced Cisplatin Vinflunine 2009 (EMA) Valrubicin Atezolizumab BCG Nivolimumab Durvalumab 2017 Avelumab

3 Previous Standard Therapy in Advanced Urothelial Cancer Setting Regimen 1st line Cisplatin MVAC1 Eligible Gemcitabine+Cisplatin2 PGC3 Cisplatin Gemcitabine+Carboplatin4-6 Ineligible 2nd line 1Loehrer Single Agent Chemotherapy Response Rate 40-50% Median Survival months 36-56% 7-9 months ~10% 5-8 months JCO 1992; 2Von der Maase JCO 2000; 3 Bellmunt et al JCO De Santis ASCO 2010; 5Linardou Urology Nogué-Aliguer Cancer 2003; 7Rosenberg et al Lancet 2016

4 Advanced TCC Case 59 y male Initially diagnosed with Non-muscle invasive bladder TCC in 2013 Multiple TURBTs, BCG October /2015: TCC EST IV multiple BONE and retroperitoneal LYMPH NODE metastasis FG 65 mlx PS1 Hb 13, LDH normal

5 PRACTICE CHANGIN randomized trials in first line FIT Sudy N OR % OS m Conclusion Cisplatin MVAC >MVAC GC MVAC Less toxicity for GC MVAC ddmavc Less toxicity for ddmvac GC PCG

6 MVAC vs Cisplatin N= 269 Significant improvement in ORR ( 39 VS 12%) Significant increase in SPF ( 10 vs 4 m) Significant improvement OS ( 13 vs 8m)

7 MVAC vs Cis/Gem CG : Similar disease outcomes and favorable toxocity profile. First line standard Similary ORR ( 49 VS 46%) Similary DFS and OS Von der Maase et al. J Clin Oncol 2000;17: Von der Maase et al. J Clin Oncol 2005;23:4602 8

8 MVAC vs Cis/Gem OVERALL SURVIVAL ~10% 5y-OS Von der Maase et al. J Clin Oncol 2005;23:4602 8

9 DD-MVAC vs MVAC DD-MVAC vs M-VAC higher RC ( 21% vs 9%), reduction in toxicity mucositis y myelosupression ( G-CSF)

10 Add Taxane?? Gem/Cis vs Gem/Cis/Taxol Bellmunt et al. J Clin Oncol 2012;30(10):

11 Standard Therapy in Advanced Urothelial Cancer FIT Setting Regimen 1st line Cisplatin MVAC1 Eligible Gemcitabine+Cisplatin2 PGC3 Cisplatin Gemcitabine+Carboplatin4-6 Ineligible 2nd line 1Loehrer Single Agent Chemotherapy Response Rate 40-50% Median Survival months 36-56% 7-9 months ~10% 5-8 months JCO 1992; 2Von der Maase JCO 2000; 3 Bellmunt et al JCO De Santis ASCO 2010; 5Linardou Urology Nogué-Aliguer Cancer 2003; 7Rosenberg et al Lancet 2016

12 IMMUNOTHERAPY in FIRST LINE atezolizumab IMvigor130 (NCT ) 1L platinum base chemotherapy, locally advanced/metastatic ECOG PS 2 R N=1200 Platinum based chemo + atezolizumab Cisplatin + gemcitabine or carboplatin + gemcitabine Co-primary endpoints: PFS and OS DANUBE (NCT ) Durvalumab + tremelimumab 1L unresectable stage IV Eligible / ineligible for cisplatin-based CT R Durvalumab N=1004 Primary endpoint: OS Cisplatin + gemcitabine or carboplatin + gemcitabine Pembrolizumab + cisplatin/gemcitabine or Pembrolizumab + carboplatin/gemcitabine KEYNOTE-361 (NCT ) 1L unresectable or metastatic ECOG PS 2 R Pembrolizumab N=990 Co-primary endpoints: PFS and OS Cisplatin + gemcitabine or carboplatin + gemcitabine

13 Advanced TCC Case 59 y male Initially diagnosed with Non-muscle invasive bladder TCC in 2013 Multiple TURBTs, BCG (Jan-Feb 2014) October /2015: TCC EST IV multiple BONE and retroperitoneal LYMPH NODE metastasis FG 40 mlx PS1 Hb 13, LDH normal

14 DEFINITION OF CISPLATIN UNFIT PATIENTS Eligibility Criteria (at least one of them) WHO or ECOG PS 2 or Karnofsky PS 60-70% Creatinine clearance (measured or calculated) < 60 ml/min CTCAE v4 grade > 2 audiometric hearing loss CTCAE v4 grade > 2 peripheral neuropathy NYHA Class III heart failure Galsky MD, et al. Lancet Oncol 2011;12(3):211-4 Galsky MD, et al. J Clin Oncol 2011:29(17):2432-8

15 Studies 1st line unfit with carboplatin OS 8-10M ORR 20-40%

16 M-CAVI vs GC J Clin Oncol 2012, 30; 191

17 M-CAVI vs GC Follow up 4,5 y J Clin Oncol 2012, 30; 191

18 M-CAVI vs GC MCaVi: 8.1 months GCa: 9.3 months HR: 0.94 (0.72 to 1.22, P= 0.64) De Santis M, et al. J Clin Oncol 2012;30:191-9

19 M-CAVI vs GC 10m 9m 5m 12m 9,3m 5,5m J Clin Oncol 2012, 30; 191

20 Cisplatin Gem Unfit /2 w Cisplatin 35 mgr/m2 d 1,15 /28d Cr CL < 60 ml/min Gemcitabine 2500 mgr/m2 d 1,15/28d R.Morales Eur J Cancer 48, 2012

21 Vinflunine 1ª Line UNFIT VINFLUNINE/GEM vs VINFLUNINE/CARBO Ac Cr < 60 mlx De Santis, Ann Oncol 2016

22 VINFLUNINE/GEM vs VINFLUNINE/CARBO VG n=34 VC n=35 GC ( n=119 ) De santis) Median OS m Median PFSm ,8 ORR % Sev Toxicity 38% Neutrop 68% Neutrop De Santis, Annals Oncol 2016

23 Studies 1st line unfit free platin OS 8-10M ORR 20-40%

24 Meta-Analysis Gem -Taxane vs Gem-Ca o N= 1032p 27 trials o OS 13.2m ( GT) vs 10m (GCa) p=0.79 o Toxicity 3-4 > Anemia and Trombocytopenia GCa > Neurophaty GT Nechi et al Clinical Genitourinary Cancer Feb 2017

25 WHAT S NEW IN LAST YEAR S IN BLADDER CANCER METASTATIC UNFIT?? Atezolizumab and Pembrolizumab

26 IMvigor 210: Phase 2 Atezolizumab in Metastatic UC1 IMvigor210: Inoperable locally advanced or metastatic urothelial carcinoma Predominantly UC histology Tumor tissue evaluable for PD-L1 testing* Cohort 1 (N = 119): 1st-line cisplatin ineligible Cohort 2: Platinum-treated muc Cohort 1: Specific inclusion criteria No prior treatment for muc (>12 months since perioperative chemotherapy) ECOG PS 0 2 Cisplatin ineligibility1 based on at least one of the following: Atezolizumab 1,200 mg IV q3w until RECIST v1.1 progression Atezolizumab 1,200 mg IV q3w until loss of clinical benefit Primary endpoint Confirmed ORR: RECIST v1.1 (per central IRF) Key secondary endpoints DOR, PFS, OS, safety Renal impairment: GFR <60 and >30 ml/min Grade 2 hearing loss or peripheral neuropathy ECOG PS 2 1. Rosenberg JE et al. Lancet. 2016;387:

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28 Efficacy of Atezolizumab by PD-L1 Subgroups: Cisplatin ineligible cohort IC2/3 All Patient IC1/2/3 s (n = 32) (n = 80) 28% IC1 IC0 (N = 119) (n = 48) (n = 39) 25% 24% 23% 21% (14-47) (16-36) (16-32) (12-37) (9-36) CR 6% 6% 7% 6% 8% PR 22% 19% 17% 17% 13% ORRa (95% CI) Patients in this analysis had a median of follow-up duration of 14.4 mo (range, mo) Confirmed complete responses were observed in all PD-L1 subgroups

29 Overall survival 100 Subgroup Overall survival (%) 80 Median OS (95% Cl) All (N=119) 15.9 months (10.4, NE) IC0/1 (n=87) 19.1 months (9.8, NE) IC2/3 (n=32) 12.3 months (6.0, NE) month OS (95% CI): 57% (48, 66) Poor OS (<6m) : Two risk factors Liver Metastasi Time (months) With a median follow-up of 17.2 months, the event rate was 49.6% Bellmunt et al. ESMO 2016

30 First-Line Therapy for Cisplatin-Ineligible muc1 Gemcitabine and Carboplatin mos, mo Gem/Carbo (n = 119) 9.3 M-CAVI (n = 119) Survival, % OS, % 37% 37% 57% 57% Time, Years ORR: 36% CR rate: 4% mos, mo (95% CI) All (N = 119) 15.9 (10.4-NE) IC0/1 (n = 87) 19.1 (9.8-NE) IC2/3 (n = 32) 12.3 (6.0-NE) Atezolizumab Time, Months Time, Months mos: 9.3 mo mos: 15.9 mo 5-year OS: ~0 5-year OS:? ORR: 23% CR rate: 9%

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34 Standard Therapy in Advanced Urothelial Cancer tting Regimen 1st line Cisplatin MVAC1 Eligible Gemcitabine+Cisplatin2 PGC3 Cisplatin Gemcitabine+Carboplatin Ineligible Atezolizumab Pembrolizumab Response Rate 40-50% 36% 24% 29% Median Survival months 7-9 months 15.9 months??

35 Responses to chemotherapy after immune therapy???

36 Tratamiento secuencial en carcinoma urotelial metastasico (CUM): Valoración de la eficacia de la quimioterapia post immune checkpoint inhibitors (ICI). Hospital Althaia y V.Hebron A B Front-line IO 1L Chemo Second-line Chemo IO-based therapy Third-line Chemo

37 Tratamiento secuencial en carcinoma urotelial metastasico (CUM): Valoración de la eficacia de la quimioterapia post immune checkpoint inhibitors (ICI). Hospital Althaia i V.Hebron

38 Targeted therapies first line??

39 Comprehensive molecular characterization of urothelial bladder carcinoma Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507: :

40 TARGETED THERAPIES first line

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42 Predicting benefit treatment?

43 Slide 18 ATM, FANCC RB1

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45 mrna expression subtypes in MIBC Subtype Molecular characteristics Histology Clinical characteristics Luminal papillary 44% FGFR3 activation More CDKN2A deletions Papillary Low risk Chemosensitive Inhibitors FGFR Luminal infiltrated High lymphocytic infiltrate Inmune marker expresion Highest p53 like and EMT signature Infiltrated Inmunotherapy Luminal Higest Uroplakins Basal/squ amous Stem cell markers histology squamous Strongest immune expresion (T cell markers) Neuronal Differentiation neuronal Loss p53 and RB1 Chemoresistant Target treatment Squamous Chemosensitive +++ immunotherapy Chemotherapy

46 BASAL TUMORS: STRONG BENEFIT QT Slide 21 Presented By David McConkey at 2017 Genitourinary Cancers Symposium

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48 Lerner, ASCO 2017

49 CONCLUSION Combinacions con CDDP tto standard 1ªL FIT Anti PD-1/PD-L1 tratamiento standard para subgrupo de pacientes 1ª L Unfit Resultados EC terapias dirigidas 1ª línea Factores predicitivos QT/ ICP

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