Inmunoterapia del Melanoma Maligno: Rompiendo Barreras

Alfonso Berrocal

Servicio Oncología Medica

Hospital General de Valencia

McArthur GA, Ribas A. J Clin Oncol 2013

Avances por mejor conocimiento de la biología

Teoría de las tres señales

2003

Mecanismos de escape tumoral

Tumour cells

CD8+ T cell

A. Presentación ineficaz de

antígenos al Sistema

inmune

Treg MDSC

Adaptado de: Vesely MD, et al. Ann Rev Immunol 2011;29:235–271

B. Atracción células

inmunosupresoras

(Tregs, MDSCs, otras)

CD8+ T cell

CD4+ T cell

TGF-β

IL-10

TGF-β

ARG1

iNOS

C. Secreción factores

inmunosupresores

VEGF APC

TGF-β

IDO

IL-10

D. Alteración

Checkpoints

PD-1

P-DL1 PD-1

PD-L1

CTLA-4 TCR

MHC

Respuesta del huésped al tumor

Pacientes en Riesgo

Ipilimumab 4846 1786 612 392 200 170 120 26 15 5 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 108 120

Ipilimumab

CENSURADO

¿De donde partimos?

Mediana de supervivencia meses (95% CI): 9.5 (9.0–10.0)

Tasa SG a 3 años, % (95% CI): 21 (20–22)

Pro

po

rció

n v

ivo

s

Meses

Schadendorf D, et al. Eur J Cancer 2013;49(suppl 2): abstract 24LBA

CTLA4: Respuesta inicial al antígeno

Ipilimumab y T-regs

Necesidades no cubiertas en Melanoma

• Baja tasa de respuestas • Latencia de acción • Duración de la respuesta • Porcentaje de largos

supervivientes

• Tratamiento de segunda línea

CheckMate 066 KeyNote 006

CheckMate 037 KeyNote 002

PD1/PDL1: Regulación de linfocitos T efectores

PD-1 “también” es terapia dirigida

Primera línea

CheckMate 066: Diseño del estudio

1. Robert C, Long GV, Brady B, et al. N Engl J Med 2015;372(4):320-30.

Estudio de fase III, aleatorizado, doble ciego

La TRO resultó casi 3 veces mayor con OPDIVO

que con dacarbacina1

1. Robert C, Long GV, Brady B, et al. N Engl J Med 2015;372(4):320-30.

2. Atkinson V, Ascierto PA, Long GV, et al. Two-Year Survival and Safety Update in Patients With Treatment-Naïve Advanced Melanoma (MEL) Receiving Nivolumab or Dacarbazine

in CheckMate 066. Presented at Society for Melanoma Research (SMR) 2015 International Congress; November 18–21, 2015; San Francisco, California, USA

CheckMate 066: Respuestas

Mediana de tiempo hasta la respuesta de 2,1 meses (intervalo de 1,2–7,6 meses)

CheckMate 066: Tiempo hasta respuesta

1. Robert C, Long GV, Brady B, et al. N Engl J Med 2015;372(4):320-30.

La mediana del tiempo hasta la respuesta de la dacarbacina también fue de 2,1 meses (intervalo: 1,8-3,6)1

CheckMate 066: Supervivencia global

1. Atkinson V, Ascierto PA, Long GV, et al. Two-Year Survival and Safety Update in Patients With Treatment-Naïve Advanced Melanoma (MEL) Receiving Nivolumab or

Dacarbazine in CheckMate 066. Presented at Society for Melanoma Research (SMR) 2015 International Congress; November 18–21, 2015; San Francisco, California, USA

IC: Intervalo de confianza. HR: Hazard ratio; NC: no calculado

Diseño Keynote 006

Antoni Ribas AACR 2015 Abstract CT101

Respuestas Keynote 006

Antoni Ribas AACR 2015 Abstract CT101

Supervivencia Keynote 006

Robert et all. NEJM. April 2015

CA-209-003. Supervivencia a 5 años P

rob

abili

ty o

f Su

rviv

al

Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 6 18 30 42 54 66 78

Database lock Oct 2015

107 64 86 51 49 41 29 0 3 15 43 36 17 12 1

Number of Patients at Risk

All Patients

All Patients (events: 69/107), median and 95% CI: 17.3 (12.5–37.8)

NIVO 3 mg/kg (events: 11/17), median and 95% CI: 20.3 (7.2–NR)

17 11 15 9 8 7 6 1 6 7 6 6 6 0 NIVO 3 mg/kg

OS Rate, % (95% CI)*

Landmark timepoint All Patients (N = 107)

NIVO 3 mg/kg (n = 17)

12-month 63 (53–71) 65 (38–82)

24-month 48 (38–57) 47 (23–68)

36-month 42 (32–51) 41 (19–63)

48-month 35 (26–44) 35 (15–57)

60-month 34 (25–43) 35 (15–57)

Median OS, months (95% CI) 17.3 (12.5–37.8) 20.3 (7.2-NR)

Hodi FS. AACR 2016 Abstract CT001

Segunda línea

Diseño Keynote 002

Antoni Ribas SMR Meeting 2014

Respuestas Keynote 002

Antoni Ribas SMR Meeting 2014

SLP Keynote 002 (Revisión Central)

CheckMate 037: Diseño

†

Estudio de fase III aleatorizado, controlado, abierto

1. Weber J, D’Angelo SP, Minor D et al. Lancet Oncol 2015;16:375-84.

CheckMate 037: Respuestas globales

1. Weber J, D’Angelo SP, Minor D et al. Lancet Oncol 2015;16:375-84.

Gráfica extraída de 1. Weber et al. 2015

Otros farmacos

T-VEC

1. Hawkins LK, et al. Lancet Oncol 2002;3:17–26; 2. Fukuhara H, Todo T. Curr Cancer Drug Targets 2007;7:149–55;

3. Amgen. Imlygic® Summary of Product Characteristics. Section 5.1; 4. Pol JG, et al. Virus Adapt Treat 2012;4:1–21;

5. Melcher A, et al. Mol Ther 2011;19:1008–16; 6. Dranoff G. Oncogene 2003;22:3188–92; 7. Liu BL, et al. Gene Ther 2003;10:292–303;

8. Andtbacka RHI, et al. J Clin Oncol 2015;33:2780–8.

Proposed mechanism of action for T-VEC.

TDA, tumour-derived antigen.

Tumour cells rupture for an oncolytic effect1–4

GM-CSF

Tumour cell lysis TDAs

2

T-VEC replication in tumour tissue1–3

Local effect: virus-induced tumour-cell lysis

T-VEC Tumour

cells

Healthy cells

1

Systemic antitumour immune

response3,5,6

Systemic effect: antitumour immune response

TDAs

CD8+ cytotoxic

T cell

CD4+ helper T cell

Dendritic cell activated by

GM-CSF

3

Death of distant cancer cells5–8

Distant dying tumour cell

4

Objetivo principal: DRR

Andtbacka RHI, et al. J Clin Oncol 2015;33:2780–8.

*CIs for DRR and ORR were calculated using asymptotic normal approximation; †DRR per EAC between treatment arms was evaluated using unadjusted Fisher’s exact test;

‡No α was allocated for this evaluation of statistical significance. CI, confidence interval.

ITT set

GM-CSF

n = 141

T-VEC

n = 295 Difference (95% CI)

DRR, % (95% CI)* 2.1 (0–4.5) 16.3 (12.1–20.5) Unadjusted odds ratio, 8.9

(2.7–29.2); P < 0.001†

ITT set

GM-CSF

n = 141

T-VEC

n = 295 P-value

ORR, % (95% CI)* 5.7 (1.9–9.5) 26.4 (21.4–31.5) P < 0.001‡

CR, % < 1 10.8

PR, % 5.0 15.6

ORR

DRR (primary endpoint)

0

20

50

75

100

SG por estadio de la enfermedad

Andtbacka RHI, et al. J Clin Oncol 2015;33:2780–8.

NE, not evaluable.

Time (months)

Log rank: P = 0.71 (descriptive) HR, 1.07 (95% CI, 0.75–1.52)

Stage IV M1b/c Stage IIIB/C, IV M1a

5 10 15 20 25 30 35 40 45 50 55 60

Time (months)

Log rank: P < 0.001 (descriptive) HR, 0.57 (95% CI, 0.40– 0.80)

Kapla

n–M

eie

r (%

)

163 157 146 129 113 104 93 73 51 23 10 1 0

86 78 65 55 43 35 30 22 17 10 2 0

T-VEC

GM-CSF

Risk set, n

0

T-VEC

Risk set, n

131 112 84 58 46 41 32 22 15 13 6 1 0

GM-CSF 55 46 35 28 20 17 16 14 10 5 3 0 0

T-VEC 41.1 (30.6–NE)

GM-CSF 21.5 (17.4–29.6)

80/163 (49)

57/86 (66)

T-VEC 13.4 (11.4–16.2)

GM-CSF 15.9 (10.2–19.7)

109/131 (83)

44/55 (80)

|

| | | | | | | | |

|

| | | | | | | | |

|

| | | | | |

| | | | | | | | | | | | | | | |

|

| | | | | |

| | | | | | | | | | | | | | | |

|

|

|

| | | | |

| | | | |

| | | | | | | |

| | | | |

|

|

|

| | | | |

| | | | |

| | | | | | | |

| | | | |

| | | |

|

| | |

|

| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |

| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |

|

| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |

| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |

0

20

50

75

100

0 5 10 15 20 25 30 35 40 45 50 55 60

Events/n, % Median (95% CI), months Events/n, % Median (95% CI), months

0

Kapla

n–M

eie

r (%

)

1

T-VEC

Systemic effect

3

Mature dendritic cell

T cell

GM-CSF

TDA MHC TCR

CD80/ CD86

CD28

4 T cell

5

TDA MHC TCR

PD-L1 PD-1

Cancer Immunity

Cycle

Local effect

2

Healthy cells

T-VEC

GM-CSF

TDA

Immature dendritic cell

Tumour cells

TDA

Combinación de T-VEC

Anti CTLA-4

Anti PD-1

¿Que es lo siguiente?

Combinación anti CTLA-4 + anti PD1

Callahan MK et al. ASCO 2013, Abstract 3003.

1. Larkin J, Chiarion-Sileni V, Gonzalez R et al. N Engl J Med 2015; 373:23-34.

CheckMate 067: Diseño

Estudio de fase III, doble ciego y aleatorizado

Ficha técnica de Opdivo y de Yervoy disponible

CheckMate 067 PFS (Intent-to-Treat)

NIVO + IPI (N=314)

NIVO (N=316)

IPI (N=315)

Median PFS, months (95% CI)

11.5 (8.9–16.7)

6.9 (4.3–9.5)

2.9 (2.8–3.4)

HR (99.5% CI) vs. IPI

0.42 (0.31–0.57)*

0.57 (0.43–0.76)*

--

HR (95% CI) vs. NIVO

0.74 (0.60–0.92)**

-- --

*Stratified log-rank P<0.00001 vs. IPI

**Exploratory endpoint

No. at Risk

314 NIVO + IPI 173 151 65 11 1 219 0

316 NIVO 147 124 50 9 1 177 0

315 IPI 77 54 24 4 0 137 0

0 6 9 12 15 18 3 21

NIVO

NIVO + IPI

IPI

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

po

rtio

n a

live

an

d p

rogr

ess

ion

-fre

e

1. Larkin J, Chiarion-Sileni V, Gonzalez R et al. N Engl J Med 2015; 373:23-34.

No. at Risk

IPI – 202 82 44 31 12 1

NIVO 208 108 88 74 31 5 2

NIVO + IPI 210 142 112 96 42 9 2

0 3 6 9 12 15 17

Months

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15 17

No. at Risk

IPI 0 75 40 22 17 9 2

NIVO 80 57 51 43 16 4 0

NIVO + IPI 68 53 44 39 16 1 0

Months

NIVO + IPI NIVO IPI

NIVO + IPI NIVO IPI

CheckMate 067: PFS por PD-L1 (5%)

PD-L1 ≥5%* PD-L1 <5%*

*Per validated PD-L1 immunohistochemical assay based on PD-L1 staining of tumor cells in a section of at least 100 evaluable tumor cells.

Pro

po

rtio

n a

live

an

d p

rogr

ess

ion

-fre

e

Pro

po

rtio

n a

live

an

d p

rogr

ess

ion

-fre

e 1.0

0.8

0.6

0.4

0.2

0.0

mPFS HR

NIVO + IPI 14.0 0.40

NIVO 14.0 0.40

IPI 3.9 --

mPFS HR

NIVO + IPI 11.2 0.42

NIVO 5.3 0.60

IPI 2.8 --

1. Larkin J, Chiarion-Sileni V, Gonzalez R et al. N Engl J Med 2015; 373:23-34.

CheckMate 067: Seguridad

Patients Reporting Event, %

NIVO + IPI (N=313) NIVO (N=313) IPI (N=311)

Any Grade Grade

3–4 Any Grade Grade

3–4 Any Grade

Grade 3–4

Treatment-related adverse event (AE) 95.5 55.0 82.1 16.3 86.2 27.3

Treatment-related AE leading to discontinuation

36.4 29.4 7.7 5.1 14.8 13.2

Treatment-related death* 0 0.3 0.3

*One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest).

• 67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatment-related AEs developed a response

1. Larkin J, Chiarion-Sileni V, Gonzalez R et al. N Engl J Med 2015; 373:23-34.

Ipilimumab + Pembrolizumab KN029

Diseño estudio CA-209-511

Previously Untreated Unresectable Stage III-IV Melanoma

Randomize (N = 346)

1:1 Stratify by • PD-L1 expression • M stage M0,M1a,M1b vs M1c

Arm A (n = 173) nivolumab 3 mg/kg IV + ipilimumab 1 mg/kg IV Every 3 weeks for 4 doses

Arm B (n = 173) nivolumab 1 mg/kg IV + ipilimumab 3 mg/kg IV Every 3 weeks for 4 doses

Nivolumab Flat Dose 480 mg Every 4 weeks

Nivolumab Flat Dose 480 mg Every 4 weeks

Double Blinded Part 1

Treat until progression** or unacceptable toxicity

Open-label Part 2***

6 weeks*

Conclusiones

• La inmunoterapia del melanoma ya es un tratamiento establecido de la enfermedad

• Las posibilidades de combinación y sinergias son muy importantes

• Ademas de haber sido el primer tratamiento en modificar la historia natural su pleno potencial esta aun por llegar