Embed Size (px)
Citation preview
LA ANGIOGÉNESIS COMO FACTOR
CLAVE EN EL TRATAMIENTO DEL
CÁNCER RENAL Teresa Alonso Gordoa
Servicio de Oncología Médica
Hospital Ramón y Cajal
ANGIOGENESIS
METABOLICS
IMMUNOLOGY
EPIGENETIC AND CHROMATIN MODIFIERS
PI3K/AKT/mTOR
METABOLICS
IMMUNOLOGY
EPIGENETIC AND CHROMATIN MODIFIERS
PI3K/AKT/mTOR
ANGIOGENESIS
ANGIOGENIC SWITCH
Molecular and cellular players underlying the angiogenic switch
Pericytes
Cancer-associated fibroblasts
Immune system
TAM
Baeriswyl & Christofori. The angiogenic switch in carcinogenesis. Seminars in Oncology Biology 19 (2009); 329-337
RELEVANCE OF ANGIOGENESIS IN KIDNEY CANCER
Yao X, et al. Clin Cancer Res 2007
H-Differentiated
H-Undifferentiated
Undifferentiated vessels: CD31+/CD34-/SMA- Differentiated immature vessels: CD31+/CD34+/SMA– Differentiated mature vessels CD31+/CD34+/SMA+
RELEVANCE OF ANGIOGENESIS IN KIDNEY CANCER
Hemmerlein B, et al. Virchows Arch, 2001 Qian Ch, et al. Cancer, 2009
VEGF EXPRESSION MICROVESSEL DENSITY NECROSIS/APOPTOSIS
VEGF expression at the rim VEGF expression within the spheroid center
Tumor spheroid develop apoptosis
Within tumor tissue necrosis (*) is located away from microvessels
Comparison of VEGFmRNA expression Pericyte recruitment and MMP expression in endothelia of tumor
and tumor-free tissue.
RELEVANCE OF ANGIOGENESIS IN KIDNEY CANCER
VESSEL CO-OPTION AND REMODELLING
Bauman TM, et al. Neovascularity as a prognostic marker in renal cell carcinoma. Human Pathology (2016) 57; 98–105
THERAPEUTIC TARGETING OF THE HALLMARKS OF CANCER
Hanahan & Weinberg. Hallmarks of cancer; the next generation. Cell 144, March 4 2011; 646-674.
MOLECULAR BIOLOGY INTO THE CLINIC
CCRm
Histología de células claras
Sin tratamiento sistémico previo
Enfermedad medible por RECIST
ECOG 0–1
Adecuada función de órganos
Sunitinib 50 mg/día según el esquema 4/2 oral
(4 semanas on/2 semanas off)
IFN- 3 veces/semana sc
3 MU 1ª semana 6 MU 2ª semana 9 MU a partir de la 3ª semana
(n=750)
(n=375)
(n=375)
Noviembre 2005: datos de corte para el análisis provisional: Primer objetivo SLP alcanzado + SG realizado, mediana no alcanzada Febrero 2006: corrección del protocolo: Corrección del protocolo para permitir a los pacientes el crossover
ALEA
TOR
IZAC
IÓN
Primer objetivo: SLP
RCC study 1034; NCT00083889
Motzer RJ, et al. Sunitinib versus Interferon Alfa in Metastatic Renal cell-Carcinoma. N Engl J Med, January 11, 2007. Vol 356 No.2. 115-24.
Progression Free Suvival
mPFS= 11.0m (S) vs 5.1m (IFN) HR0.42 (95% CI, 0.32 to 0.54; P<0.001)
Motzer RJ, et al. Sunitinib versus Interferon Alfa in Metastatic Renal cell-Carcinoma. N Engl J Med, January 11, 2007. Vol 356 No.2. 115-24.
Varón de 45 años
Consulta tras 3 episodios de hematuria en otro centro
TC Tórax-Abdomen (04/2014): – Extensa masa renal derecha.
– Múltiples nódulos pulmonares bilaterales.
PRONÓSTICO INTERMEDIO MSKCC/IMDC
07/05/2014: Nefrectomía citorreductora
Carcinoma renal de células claras grado 3 Fuhrman.
Crecimiento invasivo infiltrando tejido perirrenal y tejido adiposo en seno renal, sin alcanzar márgenes ni sobrepasar la fascia de Gerota.
Bordes quirúrgicos libres.
Estadio pT3aNxM1
CLINICAL CASE
Alonso Gordoa T, Unpublished
CLINICAL CASE
SUNITINIB 50 mg 4/2
Mayo 2014 Diciembre 2015
RESPUESTA PARCIAL MANTENIDA PULMONAR
SUNITINIB 50 mg 2/1
Alonso Gordoa T, Unpublished
MOLECULAR PRINCIPLES OF VESSEL GROWTH
Mode of action of antiangiogenic therapies
Potente M. et al., Basic and therapeutics aspects of angiogenesis, Cell 146, September 16, 2011.; 873-887.
RESISTANCE AND ESCAPE FROM ANTIANGIOGENICS THERAPY
Bottsford-Miller JN, Coleman RL & Sood AK. J Clin Oncol 2012
VHL-HIF-VEGF AND DIRECTED APPROVED DRUGS
(1) Yang JC, et al. NEJM 2003 (2) Escudier B, et al. AVOREN. JCO 2010 (3) Rini BI, et al. CALGB90206. JCO 2010 (4) Escudier B, et al. NEJM 2007 (5) Motzer RJ, et al. NEJM 2007
SORAFENIB(4)
2005*
SUNITINIB(5)
2006*
BEVACIZUMAB +IFNα(1-3)
2009*
(6) Sternberg C, et al. JCO 2010 (7) Motzer RJ, et al. COMPARZ. NEJM 2013 (8) Rini BI, et al. AXIS. Lancet 2011 (9) Choueiri TK, et al. NEJM 2015 (10) Motzer RJ, et al. Lancet Oncology 2015 (11) Motzer RJ, et al. J Clin Oncol 2013
PAZOPANIB(6,7) AXITINIB(8)
2009* 2011*
LENVATINIB +
EVEROLIMUS(10)
2016*
CABOZANTINIB(9)
2016*
• Fecha de la aprobación por la FDA
Pazopanib : Comercializado por Novartis. Cabozantinib: comercializado por Ipsen. Sorafenib: Comercializado por Bayer. Bevacizumab: Comercializado por Roche. Axitinib; Comercializado por Pfizer
TIVOZANIB(11)
2017*
CLINICAL CASE
Diciembre 2015:
El paciente consulta por empeoramiento de la astenia y melenas.
Analítica (09/12/2015): Hb 6.7; Leucocitos 3680 (N2650; L670); Plaquetas 333000; Creatinina 1.37; LDH 217
TC TAP (20/12/2017)
Alonso Gordoa T, Unpublished
CLINICAL CASE
AXITINIB 5 mg/12h
Alonso Gordoa T, Unpublished
AXITINIB 3 mg/12h
CICLO 10: • Toxicidad: SMP G2, Disfonía G1, Diarrea G2. • Analítica (31/05/2016):
– Hb 14.6; Leucocitos 6600 (N 3830; L1810); Plaquetas 203000 – Creatinina 1.16; LDH 201; perfil hepático normal; perfil férrico normal.
AXIS TRIAL
Rini BI, et al. Lancet 2011 Robert JM, et al. Lancet Oncol 2013
N=723 - mCCR (células claras) - 1 línea previa - Sunitinib - Bevacizumab+IFNα - Temsirolimus - Citoquinas - Excl: Metástasis SNC
1:1
AXITINIB 5mg/12h
SORAFENIB 400mg/12h
Estratificación: - ECOG PS (0 vs 1) - Tratamiento previo
OBJETIVO Iº: - SLP OBJETIVO IIº: - SG - TRO - DR - QoL
N=361
N=362
SLP pre-estimada=5m vs 7m con sig 1-cola=0.025 Eventos=409/650 para potencia 90%
AXIS TRIAL
SLP (477 eventos) = 6.7 m vs 4.7 m (HR 0.665, IC95% 0.54-0.812; p < 0.0001)
Rini BI, et al. Lancet 2011 Robert JM, et al. Lancet Oncol 2013
CLINICAL CASE
AXITINIB 5 mg/12h
Diciembre 2015 Marzo 2017
RESPUESTA PARCIAL MANTENIDA PULMONAR Y PERITONEAL
Alonso Gordoa T, Unpublished
AXITINIB 3 mg/12h
SELECTING PATIENTS ACCORDING TO CLINICAL FACTORS
IMDC favorable/intermediate risk Non-bulky disease
No bone metastases No liver metastases
Bracarda S, et al. Presented at ASCO GU, 2018
MSKCC favorable risk, mOS at 24 months=68,7% (A) vs 45,9%(So)
IMMUNOMODULATORY EFFECT FROM ANGIOGENESIS
Khan K and Kerbel RS. Nature Reviews 2018
Khan K and Kerbel RS. Nature Reviews 2018
IMMUNOMODULATORY EFFECT FROM ANGIOGENESIS
PRIMARY AND ACQUIRED RESISTANCE TO IMMUNOTHERAPY
1. Lack of sufficient or suitable neo-antigens
2. Impaired processing or presentation of tumour antigens
3. Impaired intratumoural immune infiltration
4. Impaired IFNγ signaling 5. Metabolic/inflammatory mediators 6. Immune suppressive cells 7. Alternate immune checkpoints
8. Severe T-cell exhaustion 9. T-cell epigenetic changes
ICI + Targeted therapies
Jenkins RW, et al. Br. J Cancer, 2018
ONGOING AND RECENTLY PRESENTED CLINICAL TRIALS VEGFi + IO
Estudio Diseño Tratamiento Histología Objetivo primario
NCT identificación
WO29637 FASE III
Atezolizumab + Bevacizumab vs Sunitinib
Célula clara +/- sarcomatoide
SLP SG
NCT02420821
JAVELIN Renal 101 Fase III
Avelumab + Axitinib vs sunitinib Componente célula clara
SLP NCT02684006
MK3475-426 Fase III
Pembrolizumab + Axitinib vs sunitinib
Componente célula clara +/- sarcomatoide
SLP SG
NCT02853331
CLEAR Fase III
Lenvatinib + Everolimus vs Lenvatinib + Pembrolizumab vs
Sunitinib
Componente célula clara
SLP NCT02811861
PROTOCOL 2013-0375 Fase I
Nivolumab vs Nivolumab + Ipilimumab vs Nivolumab +
Bevacizumab Nephrectomy
Componente célula clara
Toxicidad NCT02210117
Checkmate 9ER Fase III
Cabozantinib + Nivolumab vs Sunitinib
Componente célula clara
SLP NCT03141177
FIRST LINE Study design Treat line Control arm PFS OS
Sunitinib Phase III (F/I) 1st IFNα 11 vs 5,1 m (HR0,42) 26,4 vs 21,8 m (HR0,82)
Pazopanib Phase III non-inf (F/I)
1st Sunitinib 8,4 vs 9,5 m (HR1,04) 28,4 vs 29,3 m
Nivolumab + Ipilimumab
Phase III (Int/P) 1st Sunitinib 11,6 vs 8,4m (HR0,82) NR vs 26 m (HR0,63)
Cabozantinib Phase II (Int/P) 1st Sunitinib 8,2 vs 5,6 m (HR 0,69) 30,3 vs 21,8m (HR0,80)
Atezolizumab + Bevacizumab
Phase III (F/Int/P) 1st Sunitinib ITT= 9,6 vs 8,3 m (HR0,88)
NR vs NR (HR0,81)
Tivozanib Phase III 1st /after cytokines
Sorafenib 11,9 vs 9,1 m (HR0,797)
29,3 vs 28,8 m (HR1,24)
2nd/3rd LINE Study design Treat line Control arm PFS OS
Everolimus Phase III 2nd – 5th Placebo 4,9 vs 1,8 m (HR 0,33) 14,7 vs 14,3 (HR 0,87)
Axitinib Phase III 2nd Sorafenib 6,7 vs 4,7 m (HR 0,66) 20,1 vs 19,2 (HR0,97)
Nivolumab Phase III 2nd – 3rd Everolimus 4,6 vs 4,3m (HR0,88) 25 vs 19 m (HR0,73)
Cabozantinib Phase III 2nd – 3rd Everolimus 7,4 vs 3,8m (HR0,66) 21,4 vs 16,5m (HR0,66)
Lenvatinib + Everolimus
Phase II 2nd Lenvatinib and Eve 14,6 vs 7,4 vs 5,5 m (HR 0,66 and HR0,40)
25,5 vs 18,4 vs 17,5m (HR0,55 and HR0,74)
CONCLUSIONS
Angiogenesis is a cornerstone in kidney cancer tumorogenesis and antiangiogenic agents have changed the natural history of this tumor. Angiogenesis is also involved in immunomodulation and resistance mechanisms to ICI If we do not cure, we need to improve treatment patient selection to prolong life of our patients.
