LA ANGIOGÉNESIS COMO FACTOR CLAVE EN EL TRATAMIENTO … · Sin tratamiento sistémico previo...

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.

THANK YOU FOR YOUR ATTENTION

talonso@oncologiahrc.com