cabozantinib, la vuelta al control tumoral como objetivo ... · hospital ramón y cajal . ... o...

Cabozantinib, la vuelta al control tumoral como objetivo de tratamiento en el

cáncer renal Pablo Gajate Borau

Servicio Oncología Médica

Hospital Ramón y Cajal

Angiogénesis en cáncer renal

Martinez-Sáez Crit Rev Oncol Hematol. 2017; Motzer JCO 2006

Riazalhosseini Nat Rev Nephrol. 2016

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


Mecanismo de resistencia

Zhou L, et al. Oncogene 2016

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 study: PFS & ORR

Choueiri TK, et al. Lancet Oncol 2016

METEOR phase 3 study: Overall Survival

Choueiri TK, et al. Lancet Oncol 2016

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

ESMO GUIDELINES

Escudier et al Ann Oncol. 2016

EAU Guideline Recommendations for Metastatic Clear Cell RCC

Powles et al Eur Urol. 2017.

Overall Survival by MSKCC risk group

Choueiri TK ASCO 2016; Choueiri TK, et al. Lancet Oncol 2016

PFS & Overall Survival by Metastatic Site

Escudier et al J Clin Oncol 2018

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


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


HR = 0.66 (95% Cl, 0.42-1.04)

Median, mo

Cabozantinib (n=18) NE


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


OS by Baseline Plasma Biomarker Levels

Powles T, et al. ESMO 2017;

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

CABOZANTINIB

Otros escenarios más allá del METEOR

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

Choueiri et al J Clin Oncol 2017

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

Muchas Gracias

cabozantinib, la vuelta al control tumoral como objetivo ... · hospital ramón y cajal . ... o...

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