cabozantinib, la vuelta al control tumoral como objetivo ... · hospital ramón y cajal . ... o...
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Cabozantinib, la vuelta al control tumoral como objetivo de tratamiento en el
cáncer renal Pablo Gajate Borau
Servicio Oncología Médica
Hospital Ramón y Cajal
HIFα
Pro
Hypoxia
VHL
Inactivated VHL
Transcriptional activation of HIF target genes
Pro MET
AXL
VEGFR
EGFR
PDGFR
Pro
HIFα
Pro
HIFα
HIF accumulation
Endothelial cell
MET and AXL in RCC
Receptor Activation and tumourigenic activities
MET
Loss of VHL expression/VHL mutation and hypoxia lead to upregulation of MET in ccRCC Activation of MET through gene mutations identified in hereditary/sporadic papillary RCC Dysregulation of MET implicated in tumour development, invasion, and angiogenesis
AXL
AXL expression directly activated by HIF-1 and HIF-2 In metastatic ccRCC, inactivation of AXL reverses invasive and metastatic phenotype AXL expression in primary ccRCC tumours correlates with aggressive tumour behaviour and increased risk of
patient mortality Gibney GT, et al. Ann Oncol 2013; Rankin EB, et al. PNAS 2014
Cabozantinib is an oral small molecule inhibitor of multiple tyrosine kinase receptors, including:
• VEGFR-1, 2, 3
• MET
• AXL
CABOZANTINIB
Shen C Semin Cancer Biol 2013; Zhou et al Oncogene 2015
Targeting AXL and MET activation by Cabozantinib overcomes resistance to VEGFR inhibition in preclinical models
Tum
ou
r si
ze (
mm
³)
450
Start Sunitinib/ Saline treatment
400
350
300
250
200
150
100
50
0
wk3
wk4
wk5
wk6
wk7
wk8
wk9
w1
0
w1
1
w1
2
w1
3
w1
4
Start Cabozantinib treatment
Ctrl
Suni
Suni+Cab
Cabozantinib abolished AXL and MET activation
Cabozantinib rescues acquired resistance to Sunitinib in a RCC model
Decrease in cell migration and invasion when targeting MET and AXL
Zhou L, et al. Oncogene 2016
Caso clínico
Varón de 40 años con ANTECEDENTES PERSONALES: • NAMC. • DL en tratamiento dietético. • Fumador de 50 paq/año.
Ingreso Octubre de 2013: • Cuadro constitucional de astenia, anorexia y pérdida de peso (15 kg en 6
meses). • TC t/a/p (Octubre´13): masa renal derecha de 13 cm. Cirugía (22/11/2013): mediante nefrectomía radical derecha
ANATOMÍA PATOLÓGICA: CARCINOMA RENAL DE CÉLULAS CLARAS GRADO 3 DE FURHAM pT3a
Caso clínico
Diciembre 2014: • Recaída ganglionar retroperitoneal IQ: linfadenectomía retroperitoneal
ANATOMÍA PATOLÓGICA: METÁSTASIS DE CARCINOMA RENAL DE CÉLULAS CLARAS
Marzo 2016: • Sospecha recaída ganglionar retroperitoneal
Caso clínico
Marzo´16 Julio´16 Noviembre´16
Mejor respuesta: Enf Estable
SLP: 7 meses
TOXICIDAD:
HTA G2
Diarrea G1
1º LÍNEA: SUNITINIB
Caso clínico
¿Que tratamiento propondríais en este momento?
1. Nivolumab
2. Cabozantinib
3. Lenvatinib-Everolimus
4. Axitinib
5. Everolimus
METEOR phase 3 study: Design
Cabozantinib
60 mg oral OD
Tumour assessment every 8 weeks
(RECIST v1.1)
Treatment until loss of clinical benefit
or intolerable toxicity
Endpoints
Primary
PFS (IR)
Secondary
OS
ORR
SAFETY
Advanced RCC
- Clear-cell component
- ≥1 prior VEGFR therapy
(no limit to prior number of therapies)
- Progression within 6 months of prior
VEGF TKI
- PD-1 checkpoint inhibitors allowed
Stratification factors
Number of previous VEGFR therapies
MSKCC criteria
Everolimus
10 mg oral OD
1:1
Choueiri TK, et al. N Engl J Med 2015
Characteristic Cabozantinib (n=330) Everolimus (n=328)
MSKCC risk category, n (%)
Favourable 150 (45) 150 (46)
Intermediate 139 (42) 135 (41)
Poor 41 (12) 43 (13)
Metastatic site per Independent Review Committee, n (%)
Lung 204 (62) 212 (65)
Liver 88 (27) 103 (31)
Bone 77 (23) 65 (20)
Prior VEGFR tyrosine kinase inhibitors, n (%)
1 235 (71) 229 (70)
≥2 95 (29) 99 (30)
Prior therapies
Sunitinib 210 (64) 205 (62)
Pazopanib 144 (44) 136 (41)
Axitinib 52 (16) 55 (17)
Nivolumab 17 (5) 14 (4) Choueiri TK, et al. N Engl J Med 2015
METEOR phase 3 trial: Safety
Cabozantinib (n=331)
Everolimus (n=322)
Median duration of exposure, months 8.3 4.4
Median average daily dose 43 mg 9 mg
Any dose reduction, n (%) 206 (62) 80 (25)
Discontinued due to adverse event not associated with RCC, n (%)
40 (12) 34 (11)
The most common adverse reactions that led to dose reduction with cabozantinib were diarrhoea, palmar-plantar erythrodysaesthesia syndrome, fatigue and hypertension1,2
The most frequent adverse reactions leading to permanent discontinuation in patients treated with cabozantinib were decreased appetite (2%) and fatigue (1%)1,2
METEOR phase 3 trial: Safety Cabozantinib (n=331) n (%) Everolimus (n=322) n (%)
Adverse event Any grade Grade 3/4 Any grade Grade 3/4
Any AE 322 (97) 195 (59) 293 (91) 131 (41)
Diarrhoea 227 (69) 35 (11) 65 (20) 6 (1.9)
Fatigue 164 (50) 26 (7.9) 114 (35) 14 (4.3)
Nausea 145 (44) 9 (2.7) 56 (17) 1 (0.3)
PPE syndrome 136 (41) 27 (8.2) 14 (4.3) 2 (0.6)
Decreased appetite 129 (39) 8 (2.4) 77 (24) 1 (0.3)
Hypertension 109 (33) 47 (14) 10 (3.1) 6 (1.9)
Weight decreased 79 (24) 5 (1.5) 26 (8.1) 0
Vomiting 75 (23) 3 (0.9) 18 (5.6) 0
Dysgeusia 72 (22) 0 27 (8.4) 0
Stomatitis 67 (20) 7 (2.1) 75 (23) 7 (2.2)
Mucosal inflammation
62 (19) 3 (0.9) 70 (22) 11 (3.4)
Hypothyroidism 61 (18) 0 1 (0.3) 1 (0.3)
Dysphonia 55 (17) 2 (0.6) 2 (0.6) 0
OS by Prior VEGFR TKI Therapy
Subgroup N HR for OS (95% CI)
Prior VEGFR TKIs
1 464 0.65 (0.50–0.85)
≥2 194 0.73 (0.48–1.10)
Treatment duration of first VEGFR TKI
≤6 months 190 0.69 (0.47–1.01)
>6 months 466 0.69 (0.52–0.90)
Time to progression on last prior VEGFR TKI
<3 months 112 0.76 (0.47–1.24)
≥3 months 542 0.68 (0.53–0.88)
Cabozantinib better Everolimus better
0.125 0.25 1 2 4 0.5
Choueiri TK ASCO 2016; Choueiri TK, et al. Lancet Oncol 2016
OS by Prior VEGFR TKI Therapy
Median, mo
Cabozantinib (n=135) 21.4
Everolimus (n=132) 16.5
HR = 0.66 (95% Cl, 0.47-0.93)
Median, mo
Cabozantinib (n=88) 22.0
Everolimus (n=83) 17.5
HR = 0.66 (95% Cl, 0.42-1.04)
Median, mo
Cabozantinib (n=18) NE
Everolimus (n=14) 16.3
HR = 0.56 (95% Cl, 0.21-1.52)
Pro
babili
ty o
f O
S
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30
Sunitinib Only
Time
(months)
Pazopanib Only
Time
(months)
Anti-PD-1/PD-L1
Time
(months)
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30
Cabozantinib Everolimus
Choueiri TK ASCO 2016; Choueiri TK, et al. Lancet Oncol 2016
OS by MET expression level
15% 47% 37%
MET high was based on a cut-off of >50% for tumor tissue stained with an intensity of >2+ by IHC
Powles Kidney Cancer Symposium 2016; Choueiri TK, et al. Lancet Oncol 2016;
Caso clínico
¿Que tratamiento propondríais en este momento?
1. Nivolumab
2. Cabozantinib
3. Lenvatinib-Everolimus
4. Axitinib
5. Everolimus
Caso clínico
2º LÍNEA: CABOZANTINIB
Noviembre´16 Marzo´17
• HTA G2
• Diarrea G1 controla Fortasec
• Anorexia G2
• Pérdida de peso G2 o 11 kg 4 meses
o Endocrino: controlado con suplementos proteico-calóricos
Caso clínico
2º LÍNEA: CABOZANTINIB
Noviembre´16 Marzo´17 Febrero´18
TOXICIDAD:
HTA G2
Diarrea G2
Pérdida de peso G2
Mejor respuesta: Enf Estable
SLP: 17 meses
VARIANTES HISTOLÓGICAS CARCINOMA RENAL
Overall PFS on cabozantinib PFS: papillary vs non-papillary histologies
Papillary Non-papillary
0 10 20 30
Time (months)
0 10 20 30
PFS (months)
Per
cen
t Su
rviv
al
Per
cen
t su
rviv
al
Median 8.6 mo 95% CI 6.1 to 14.7 mo
HR 0.778 Log-rank p=0.6
100
80
60
40
20
0
100
80
60
40
20
0
Censored
Potential Role of Multiple Cabozantinib Targets in Promoting Tumor
Inmmune Supression
Terme et al Cancer Res 2012; Benkhoucha et al PNAS 2010; Paolino et al Nauture 2014
• Cabozantinib es un inhibidor tirosina kinasa contra VEGFR-1, 2, 3, MET y AXL
• El efecto contra MET y AXL ha revertido la resistencia a fármacos antiangiogénicos en modelos preclínicos
• Cabozantinib es el único fármaco que ha demostrado un aumento en tasa de respuesta, supervivencia libre de progresión y supervivencia global en pacientes con carcinoma renal tratados previamente
• Los resultados son consistentes en los diferentes análisis por subgrupos
• Futuro:
– Combinaciones con IO
– Carcinoma renal no células claras
CONCLUSIONES