Quimioterapia en Cáncer de Vejiga. Dr. Ovidio Fernández Calvo Complejo Hospitalario Universitario Ourense

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1 Quimioterapia en Cáncer de Vejiga Dr. Ovidio Fernández Calvo Complejo Hospitalario Universitario Ourense

2 Evolution of systemic therapy for urothelial cancer 1 Sternberg CN et al. Cancer 1989;64(12): ; 2 Roth BJ et al. J Clin Oncol 1994;12(11): ; 3 Eli Lilly. SmPC Gemzar 01-Jul-2014 (access: 4 McCaffrey JA et al. J Clin Oncol 1997;15(5): ; 5 Von der Maase H et al. J Clin Oncol 2000;18(17): ; 6 Sternberg CN et al. J Clin Oncol 2001;19(10): ; 7 Meluch AA et al. J Clin Oncol 2001;19(12): ; 8 EMA. EMEA/CHMP/512295/2008; (access: 9 Bellmunt J et al. J Clin Oncol 2009;27(27): ; 10 EMA. EMEA/H/C/000983; 2012 (access: 11 De Santis M et al. J Clin Oncol 2009;27(33): ; 12 Bellmunt J et al. J Clin Oncol 2012;30(10): ; 13 Rosenberg JE et al. Lancet 2016;387(10031): ; 14 Massard C et al. ASCO 2016: abstract #4502 and oral presentation; 15 AstraZeneca. Press Release (access: 16 FDA. Press Release (access: Apolo AB et al. ASCO 2016: abstract #4514 and poster; 18 Galsky MD et al. ESMO 2016: abstract #LBA31_PR; 19 Balar A et al. ESMO 2016: abstract #LBA32_PR

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4 Primera línea fit. Primera línea unfit. Segunda línea.

5 Primera línea fit. Primera línea unfit. Segunda línea.

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

7 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 dd-mvac GC PCG

8 Van der Maase, J Clin Oncol 2000

9 MVAC VS GEMCITABINE-CISPLATIN (GC) 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

10 MVAC VS GEMCITABINE-CISPLATIN (GC) ~10% 5y-OS Von der Maase et al. J Clin Oncol 2005;23:4602 8

11 MVAC vs HD-MVAC (+ G -CSF) DD-MVAC vs M-VAC higher RC ( 21% vs 9%), reduction in toxicity mucositis y myelosupression ( G-CSF) Sternberg CN, et al. Eur J Cancer 2006;42:50-4

12 MVAC vs HD-MVAC (+ G-CSF) Sternberg CN, et al. Eur J Cancer 2006;42:50-4

13 Patients with favorable risk achieve better outcome: in first line Bajorin D. J Clin Oncol 1999

14 Primera línea fit. Primera línea unfit. Segunda línea.

15 Standard Therapy in Advanced Urothelial Cancer tting Regimen Response Rate Median Survival 1 st line Cisplatin Eligible MVAC + G-CSF. 1 Gemcitabine+Cisplatin 2 PGC % months Cisplatin Ineligible Gemcitabine + Carboplatin Atezolizumab Pembrolizumab 36% 24% 29% 7-9 months 15.9 months??

16 Standard Therapy in Advanced Urothelial Cancer tting Regimen Response Rate Median Survival 1 st line Cisplatin Eligible MVAC + G-CSF 1 Gemcitabine+Cisplatin 2 PGC % months Cisplatin Ineligible Gemcitabine + Carboplatin Atezolizumab Pembrolizumab 36% 24% 29% 7-9 months 15.9 months?? Fase 2. Tasa de respuestas.

17 Standard Therapy in Advanced Urothelial Cancer tting Regimen Response Rate Median Survival 1 st line Cisplatin Eligible MVAC + GSF 1 Gemcitabine+Cisplatin 2 PGC % months Cisplatin Ineligible Gemcitabine + Carboplatin Atezolizumab Pembrolizumab 36% 24% 29% 7-9 months 15.9 months??

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

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20 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

21 10m 9m 5m 12m 9,3m 5,5m

22 Primera línea fit. Primera línea unfit. Segunda línea.

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25 Phase III: 2 nd line for urothelial carcinoma N=357 T4bN0M0 or TxN2-3 o M1 Progression after 1 st platinum treatment R A N D O M I Z E Vinflunine (PS 0: 320mg/m², every 3w; PS 0 with previous pelvic irradiation and PS1: 280mg/m² subsequenly scalated to 320 mg/m²) + BSC Primary end point: Overall Survival Best Suportive Care(BSC) 2:1 Joaquim Bellmunt et al. JCO 2009;27:

26 Supervivencia global Fase III: SG población elegible N= 357 Mediana de SG (IC 95%) VFL + BSC (N= 249) 6.9 (5.7-8) BSC (N= 108) 4.3 ( ) HR (IC 95%) 0.78 ( ) p-valor Meses Vinflunina aumenta significativamente la mediana de SG en 2,6 meses respecto al tratamiento de soporte Bellmunt J. JCO 2009

27 Long term survival also occurs with 2nd line therapy Bellmunt J, JCO 2009 Bellmunt J. Ann Oncol 2013

28 Vinflunine in second-line therapy Bellmunt J, JCO 2009 Bellmunt J. Ann Oncol 2013

29 Bellmunt J. Ann Oncol ESMO guidlines

30 MAJA: diseño del estudio Estudio fase II aleatorizado de 2 brazos, abierto, multicéntrico, desarrollado en 21 centros del grupo SOGUG. Garcia-Donas J. et al. Lancet Oncol 2017

31 MAJA: resultados del estudio VFL 6,5 meses; IC 95% (2,0 11,1) MTS 4,2 meses; IC 95% (2,1 6,3) SUPERVIVENCIA LIBRE DE PROGRESIÓN HR = 0,59; IC 95% [0,37 0,96] p-valor = 0,031 Mediana de seguimiento de los pacientes vivos: 27,6 months (21,5-40,5) Garcia-Donas J. et al. Lancet Oncol 2017

32 - Fases Fases 3: Positivo (Keynote 045) y Negativo (IMVigor 211)

33 Early progression is common with PD-1 inhibition Galsky. ESMO 2016

34 No impact in terms of PFS with IO: Atezolizumab-IMvigor 210 Rosenberg. ESMO 2016

35 KEYNOTE-045 Study Design (NCT ) Bajorin ASCO, Jun 2017

36 OS with IO: KEYNOTE-045-Phase III pembrolizumab vs QT Bellmunt J, et al. SITC 2016

37 IMvigor 211: Phase 3 Trial of Atezolizumab vs. Chemotherapy IMvigor 211 n = 931 Locally advanced or muc - PD after 1L chemo - Within 12 months from neo/adjuvant chemo Predominantly UC histology Tumor tissue evaluable for PD-L1 testing a Atezolizumab 1,200 mg IV every 3 wk until loss of clinical benefit Paclitaxel or docetaxel or vinflunine Overall Survival Press Release May 10, 2017: Negative Trial for OS

38 PD-L1 status as a biomarker: more than a simple question..

39 Molecular TCC: A novel approach to select therapy?

40 Basal Tumors: Strong benefit QT Presented By David McConkey at 2017 Genitourinary Cancers Symposium

41 Lerner, ASCO 2017

42 Cáncer vesical es una enfermedad quimiosensible. Es el estándar de tratamiento en primera línea en pacientes fit % pacientes progresores a Inmunoterapia. Es fundamental utilización de biomarcadores.

43 Muchas gracias.

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45 Limitations of immunotherapy HR (95%CI) univariate HR (95%CI) multivariate Still uncertainties about patient selection Contradictory results of biomarkers in the different studies: Several studies after platinum-failure with favourable results for PD-L1 + vs. PD-L1 - Some studies show a benefit for all patients Based on the existing data, the PD-L1 + population seems to represent only ~30 50% of the overall population An inflammatory environment (PD-L1 + TIMC) is associated with a better outcome 1 rather a prognostic than a predictive marker? 1.87 ( ) p=0.04 mos: 12 mo (95%CI 9-16) 3.19 ( ) p= mos: 23 mo (95%CI 12-NR) CI, confidence interval; HR, hazard ratio; mos, median overall survival; muc, metastatic urothelial carcinoma; PD-L1, programmed death-ligand 1; TIMC, tumour infiltrating mononuclear cells. 1 Bellmunt J et al. Ann Oncol 2015;26:

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47 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

48 Long term follow-up of cisplatin combination- chemotherapy of the post-mvac-era Sternberg 2006; von der Maase 2005