quimioterapia en cáncer de vejiga · atezolizumab 1,200 mg iv every 3 wk until loss of clinical...
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Quimioterapia en Cáncer de Vejiga
Dr. Ovidio Fernández Calvo
Complejo Hospitalario Universitario Ourense
Evolution of systemic therapy for urothelial cancer
1 – Sternberg CN et al. Cancer 1989;64(12):2448–2458; 2 – Roth BJ et al. J Clin Oncol 1994;12(11):2264–2270; 3 – Eli Lilly. SmPC Gemzar® 01-Jul-2014 (access: www.medicined.org.uk); 4 – McCaffrey JA et al. J Clin Oncol 1997;15(5):1853–1857; 5 – Von der Maase H et al. J Clin Oncol 2000;18(17):3068–3077; 6 – Sternberg CN et al. J Clin Oncol 2001;19(10):2638–2646; 7 – Meluch AA et al. J Clin Oncol 2001;19(12):3018–3024; 8 – EMA. EMEA/CHMP/512295/2008; 24.09.2018 (access: www.ema.europa.eu); 9 – Bellmunt J et al. J Clin Oncol 2009;27(27):4454–4461; 10 – EMA. EMEA/H/C/000983; 2012 (access: www.ema.europa.eu); 11 – De Santis M et al. J Clin Oncol 2009;27(33):5634–5639; 12 – Bellmunt J et al. J Clin Oncol 2012;30(10):1107–1113; 13 – Rosenberg JE et al. Lancet 2016;387(10031):1909–1920; 14 – Massard C et al. ASCO 2016: abstract #4502 and oral presentation; 15 – AstraZeneca. Press Release 17.02.2016 (access: www.astrazeneca.com); 16 – FDA. Press Release 18.05.2016 (access: www.fda.gov); 17 - 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
• Primera línea fit.
• Primera línea unfit.
• Segunda línea.
• Primera línea fit.
• Primera línea unfit.
• Segunda línea.
Setting Regimen Response Rate Median Survival
1st line Cisplatin Eligible
DD-MVAC + G-CSF1 Gemcitabine+Cisplatin2
PGC3 40-50%
12-15 months
Cisplatin Ineligible
Gemcitabine+Carboplatin4-6 36-56% 7-9 months
2nd line Single Agent Chemotherapy ~10% 5-8 months
1Loehrer JCO 1992; 2Von der Maase JCO 2000; 3 Bellmunt et al JCO 2012 4De Santis ASCO 2010; 5Linardou
Urology 2004 6Nogué-Aliguer Cancer 2003; 7Rosenberg et al Lancet 2016
Standard Therapy in Advanced Urothelial Cancer “FIT”
Sudy N OR % OS m Conclusion
Cisplatin MVAC
120 126
12 39
8.2 12.5
>MVAC
GC MVAC
203 202
49 46
14 15.2
Less toxicity for GC
MVAC ddMAVC
129 134
50 65
14.9 15.1
Less toxicity for dd-MVAC
GC PCG
315 312
43 55
12.7 15.8
Randomized trials in first line “FIT”
Van der Maase, J Clin Oncol 2000
Similary ORR ( 49 VS 46%) Similary DFS and OS
Von der Maase et al. J Clin Oncol 2000;17:3068-77 Von der Maase et al. J Clin Oncol 2005;23:4602–8
MVAC VS GEMCITABINE-CISPLATIN (GC)
Von der Maase et al. J Clin Oncol 2005;23:4602–8
~10% 5y-OS
MVAC VS GEMCITABINE-CISPLATIN (GC)
MVAC vs HD-MVAC (+ G -CSF)
Sternberg CN, et al. Eur J Cancer 2006;42:50-4
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
MVAC vs HD-MVAC (+ G-CSF)
Patients with favorable risk achieve better outcome: in first line…
Bajorin D. J Clin Oncol 1999
• Primera línea fit.
• Primera línea unfit.
• Segunda línea.
Standard Therapy in Advanced Urothelial Cancer
tting Regimen Response Rate Median Survival
1st line Cisplatin Eligible
MVAC + G-CSF.1 Gemcitabine+Cisplatin2
PGC3 40-50%
12-15 months
Cisplatin Ineligible
Gemcitabine + Carboplatin
Atezolizumab
Pembrolizumab
36% 24% 29%
7-9 months 15.9 months
??
Standard Therapy in Advanced Urothelial Cancer
tting Regimen Response Rate Median Survival
1st line Cisplatin Eligible
MVAC + G-CSF1 Gemcitabine+Cisplatin2
PGC3 40-50%
12-15 months
Cisplatin Ineligible
Gemcitabine + Carboplatin
Atezolizumab
Pembrolizumab
36% 24% 29%
7-9 months 15.9 months
??
Fase 2. Tasa de respuestas.
Standard Therapy in Advanced Urothelial Cancer
tting Regimen Response Rate Median Survival
1st line Cisplatin Eligible
MVAC + GSF1 Gemcitabine+Cisplatin2
PGC3 40-50%
12-15 months
Cisplatin Ineligible
Gemcitabine + Carboplatin
Atezolizumab
Pembrolizumab
36% 24% 29%
7-9 months 15.9 months
??
M-CAVI vs GC
J Clin Oncol 2012, 30; 191
M-CAVI vs GC
De Santis M, et al. J Clin Oncol 2012;30:191-9
MCaVi: 8.1 months GCa: 9.3 months
HR: 0.94 (0.72 to 1.22, P= 0.64)
10m 9m 5m
12m 9,3m 5,5m
• Primera línea fit.
• Primera línea unfit.
• Segunda línea.
T4bN0M0 or
TxN2-3 o M1
Progression after 1st
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
Best Suportive Care(BSC)
2:1
Primary end point: Overall Survival
Joaquim Bellmunt et al. JCO 2009;27:4454-4461
Phase III: 2nd line for urothelial carcinoma
N=357
Bellmunt J. JCO 2009
Fase III: SG población elegible N= 357
Meses
Sup
ervi
ven
cia
glo
bal
VFL + BSC (N= 249)
BSC (N= 108)
Mediana de SG (IC 95%)
6.9 (5.7 - 8)
4.3 (3.8 – 5.4)
HR (IC 95%) 0.78 (0.61 – 0.99)
p-valor 0.0403
Vinflunina aumenta significativamente la mediana de SG en 2,6 meses respecto al tratamiento de soporte
Bellmunt J, JCO 2009
Bellmunt J. Ann Oncol 2013
Long term survival also occurs with 2nd line therapy
Vinflunine in second-line therapy
Bellmunt J, JCO 2009
Bellmunt J. Ann Oncol 2013
Bellmunt J. Ann Oncol ESMO guidlines
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
VFL 6,5 meses; IC95% (2,0 – 11,1)
MTS 4,2 meses; IC95% (2,1 – 6,3)
HR = 0,59; IC95% [0,37 – 0,96]
p-valor = 0,031
Mediana de seguimiento de los pacientes vivos: 27,6 months (21,5-40,5)
SUPERVIVENCIA LIBRE DE PROGRESIÓN
MAJA: resultados del estudio
Garcia-Donas J. et al. Lancet Oncol 2017
- Fases 2. - 2 Fases 3: Positivo (Keynote 045) y Negativo (IMVigor 211)
Early progression is common with PD-1 inhibition
Galsky . ESMO 2016
No impact in terms of PFS with IO: Atezolizumab-IMvigor 210
Rosenberg . ESMO 2016
KEYNOTE-045 Study Design (NCT02256436)
Bajorin ASCO, Jun 2017
OS with IO:
KEYNOTE-045-Phase III pembrolizumab vs QT
Bellmunt J, et al. SITC 2016
Overall Survival
Atezolizumab 1,200
mg IV every 3 wk
until loss of clinical
benefit
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
testinga
IMvigor 211: Phase 3 Trial of Atezolizumab vs. Chemotherapy
Paclitaxel or
docetaxel or
vinflunine
Press Release May 10, 2017: Negative Trial for OS
PD-L1 status as a biomarker: more than a simple question..
Molecular TCC: A novel approach to select therapy?
Presented By David McConkey at 2017 Genitourinary Cancers Symposium
Basal Tumors: Strong benefit QT
Lerner, ASCO 2017
• Cáncer vesical es una enfermedad quimiosensible.
• Es el estándar de tratamiento en primera línea en pacientes fit.
• 40 – 50 % pacientes progresores a Inmunoterapia.
• Es fundamental utilización de biomarcadores.
Muchas gracias.
Limitations of immunotherapy
• 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 outcome1 – rather a prognostic than a predictive marker?
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;26:812–817.
HR (95%CI) univariate HR (95%CI) multivariate
1.87 (1.02–3.47)
p=0.04
3.19 (1.64–6.22)
p=0.0007
mOS: 23 mo (95%CI 12-NR)
mOS: 12 mo (95%CI 9-16)
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
Long term follow-up of cisplatin combination- chemotherapy of the post-MVAC-era
Sternberg 2006; von der Maase 2005