Optimizando la combinación de inhibidores

de “check-points”

Almudena García Castaño

Servicio de Oncología Médica

HUM Valdecilla. Santander

Formigal, 20 de Junio de 2019

¿Checkpoint?

Berlín, 1-10-05

Manipulación checkpoints→ Activación sistema inmune frente al cáncer

Karagiannis SN, et al. Frontiers in Immunology 2019

Frontiers in Oncology 2015

Bloqueo

CTLA-4

Pooled analysis of long-term survival data from phase II

and phase III trials of ipilimumab in metastatic or locally

advanced, unresectable melanoma

Schadenforf D, et al. J Clin Oncol 2015

1861 pacientes fases II y III

2985 pacientes de programa acceso expandido

Frontiers in Oncology 2015

Bloqueo

PD1

ACCR 2019. 5-Year Survival and Other Long-Term Outcomes From the KEYNOTE-

006 Study of Pembrolizumab for Ipilimumab-Naive Advanced Melanoma

Robert C et al

Algunas cuestiones…

Combinar… ¿Por qué?

En el pasado…

Para mejorar la calidad de vida

Y ya!!

Ahora…

Para mejorar la calidad de vida (también)

Para aumentar la supervivencia

¿Y curar?

Combinar… ¿Para qué?

51%

21%

Akkinson V, et al. JAMA 2018. Checkmate 066

DS Chen et al. Immunity 39, 1-10 (2013)

αPD1

Daniel Chen, Inmunity 2013

Something + inhibidor PD-1

Nature Reviews | Cancer

CD28CD80 or CD86

CD40LCD40

CTLA4CD80 or CD86

ICOSB7RP1

OX40L OX40

CD137CD137L

?PDL1 or PDL2

Antigen-presenting cell T cell

PD1PDL1 or PDL2

?B7-H3

BTLAHVEM

KIR

MHC class I or II TCR

LAG3

CD27CD70

TIM3GAL9

A2aR

Adenosine

+

–

–

–

–

–

–

–

+

+

?B7-H4

+

+

+

Signal 1

Cytokines(TGFα, IL-1,IL-6, IL-10,IL-12, IL-18)

+

Peptide

–

–

CD4 + helper T cells

T cells that are characterized

by the expression of CD4. They

recognize antigenic peptides

presented by MHC class II

molecules. This type of T cell

produces a vast range of

cytokines that mediate

inflammatory and effector

immune responses. They also

facilitate the activation of CD8+

T cells and B cells for antibody

production.

the expression of which determines the TReg

cell line-

age34,35, and TReg

cells therefore express CTLA4 consti-

tutively. Although the mechanism by which CTLA4

enhances the immunosuppressive function of TReg

cells is not known, TReg

cell-specific CTLA4 knockout

or blockade significantly inhibits their ability to regu-

late both autoimmunity and antitumour immunity30,31.

Thus, in considering the mechanism of action for

CTLA4 blockade, both enhancement of effector CD4+

T cell activity and inhibition of TReg

cell-dependent

immunosuppression are probably important factors.

Clinical application of CTLA4-blocking antibodies —

the long road from mice to FDA approval. Initially,

the general strategy of blocking CTLA4 was ques-

tioned because there is no tumour specificity to the

expression of the CTLA4 ligands (other than for some

myeloid and lymphoid tumours) and because the dra-

matic lethal autoimmune and hyperimmune pheno-

type of Ctla4-knockout mice predicted a high degree of

immune toxicity associated with blockade of this recep-

tor. However, Allison and colleagues36 used preclinical

models to demonstrate that a therapeutic window was

indeed achieved when CTLA4 was partially blocked with

antibodies. The initial studies demonstrated significant

antitumour responses without overt immune toxicities

when mice bearing partially immunogenic tumours were

treated with CTLA4 antibodies as single agents. Poorly

immunogenic tumours did not respond to anti-CTLA4 as

a single agent but did respond when anti-CTLA4 was

combined with a granulocyte–macrophage colony-

stimulating factor (GM-CSF)-transduced cellular

Figure 1 | Multiple co-stimulatory and inhibitory

Depicted are

response to antigen (which is mediated by peptide–

major histocompatibility complex (MHC) molecule

(TCR)). These responses can occur at the initiation of

are dendritic cells) or in peripheral tissues or tumours

(where effector responses are regulated). In general,

interactions unless they first recognize their cognate

antigen through the TCR. Many of the ligands bind to

multiple receptors, some of which deliver co-stimulatory

signals and others deliver inhibitory signals. In general,

pairs of co-stimulatory–inhibitory receptors that bind the

same ligand or ligands — such as CD28 and cytotoxic

T-lymphocyte-associated antigen 4 (CTLA4) — display

distinct kinetics of expression with the co-stimulatory

activation. One important family of membrane-bound

ligands that bind both co-stimulatory and inhibitory

and their known ligands belong to the immunoglobulin

superfamily. Many of the receptors for more recently

Tumour necrosis factor (TNF) family members that bind

to cognate TNF receptor family molecules represent a

second family of regulatory ligand–receptor pairs. These

receptors predominantly deliver co-stimulatory signals

when engaged by their cognate ligands. Another major

comes from soluble cytokines in the microenviron-

bidirectional. In some cases, this occurs when ligands

themselves signal to the APC. In other cases, activated

cognate receptors on APCs. A2aR, adenosine A2a

lymphocyte attenuator; GAL9, galectin 9; HVEM,

herpesvirus entry mediator; ICOS, inducible T cell

co-stimulator; IL, interleukin; KIR, killer cell immunoglobulin-

like receptor; LAG3, lymphocyte activation gene 3;

PD1, programmed cell death protein 1; PDL, PD1 ligand;

TGFβ, transforming growth factor-β; TIM3, T cell

membrane protein 3.

REVIEWS

254 | APRI L 2012 | VOLUM E 12 www.nature.com/reviews/cancer

REVIEWS

© 2012 Macmillan Publishers Limited. All rights reserved

Combinar… ¿Con quién?

DS Chen et al. Immunity 39, 1-10 (2013)

αPD1

Daniel Chen, Inmunity 2013

Something + inhibidor PD-1

Combinar… ¿Con quién?

Pardoll DM, et al. Nat Rev Cancer 2012

Censored

100

90

80

70

60

50

40

30

20

10

0

Su

rviv

al (%

)

Months

2 Yr OS 88%

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Nivo 1 mg/kg + IPI 3 mg/kg (n=17)

1 Yr OS 94%

2 Yr OS 79%1 Yr OS 85%

2 Yr OS 50%1 Yr OS 57%

Nivo 0.3 mg/kg + IPI 3 mg/kg (n=14)

Nivo 3 mg/kg + IPI 1 mg/kg (n=16)

Nivo 3 mg/kg + IPI 3 mg/kg (n=6)

Concurrent Cohorts 1–3 (n=53)

Nivolumab plus Ipilimumab in advanced melanomaWolchok JD, et al. N Engl J Med 2013

Sznol M, et al. ASCO 2014

Abstrat 9533. Sznol M, et al. ASCO 2019

• Mediana seguimiento 43 meses

• Supervivencia global 4.5 años → 57%

Efficacy and safety results from a phase III trial of nivolumab alone or combinedwith ipilimumab versus ipilimumab alone in treatment-naïve patients with

advanced melanoma. CHECKMATE 067Larkin J, et al. N Eng J Med 2015

Estratificación

• Estadio

• Status BRAF (32% pacientes)

• PD-L1*(positivo vs. negativo)

• Objetivos primarios SLP, SG (Nivo + Ipi vs Ipi o Nivo vs Ipi)

• Objetivos secundarios

• Respuestas (Nivo + Ipi o Nivo vs Ipi),

• SG, SLP y respuestas (Nivo + Ipi vs Nivo)

• Eficacia según expresión PD-L1, calidad vida

• Objetivos exploratorios

• Duración respuesta, seguridad

*PD-L1 positivo (expresión ≥ 5%)

Melanoma irresecable

Estadios III, IV

1ª línea

ECOG 0-1N= 945

Nivolumab 1 mg/kg

+

Ipilimumab 3 mg/kg

Cada 3 semanas

R

Nivolumab 3 mg/kg

+

Placebo

Cada 2 semanas

Ipilimumab 3 mg/kg (4 dosis)

+

Placebo

Cada 3 semanas

Nivo 3 mg/kg

Cada 2 semanas

4 dosis

Hasta toxicidad

o progresión

Resultados

Nivolumab

+

Ipilimumab

N= 314

Nivolumab

N= 316

Ipilimumab

N= 315

Respuestas (%)

Globales

Completas

Parciales

58

21

37

45

18

27

19.0

5

14

Enfermedad estable (%) 12 10 22

Progresión (%) 24 38 51

Mediana duración respuesta

(meses) 95% CI 50.1 (44-NR) NR (45.7-NR) 14.4 (8.3-NR)

Supervivencia global

Hodi FS, et al. Lancet Oncol 2018

NIVO+IPI (n = 314)

NIVO(n = 316)

IPI (n = 315)

Mediana SG meses (95% CI)

NR(38.2, NR)

36.9(28.3, NR)

19.9 (16.8, 24.6)

53%

46%

30%

Pacientes con eventosadversos (%)

Hodi FS, et al. ESMO 2018

NIVO + IPI

(n=313)

NIVO

(n=313)

IPI

(n=311)

Cualquiergrado

Grados3–4

Cualquier

grado

Grados

3–4

Cualquiergrado

Grados3–4

Eventos adversos (EA)

relacionados tratamiento (%)95.8 59.1 86.3 22.4 86.2 27.7

EA relacionados tratamiento

conducen a cese del mismo (%)40.3 30.4 12.5 8.0 15.1 13.5

Muertes relacionadas con

tratamiento (%)2 (0.6) 1 (0.3) 1 (0.3)

¿Y qué toxicidad cabe esperar?

• No muertes adicionales por toxicidad se comunicaron desde el anterior análisis

– Cardiomegalia y necrosis hepática NIVO+IPI (>100 días después último tratamiento), neutropenia NIVO (n = 1) y perforación colónica IPI (n = 1)

…Y esta es la única combinación de

inmuno-checkpoints aprobada a día de hoy

DS Chen et al. Immunity 39, 1-10 (2013)

αPD1

Daniel Chen, Inmunity 2013

Something + inhibidor PD-1

ESMO 2017

68 pacientes

Progresión anti-PD-1

Nivolumab + Relatlimab

Beneficio clínico 55% si LAG3>1%

Toxicidad grados 3-4 10%

0 5 10 15 20 25 30 35 40 45 50

*

**

**

*

LAG-3

≥ 1%

LAG-3

< 1%

LAG-3

unknown

Ongoing Clinical Follow-Up

96

Weeksd

aResponse-evaluable patients; all progressed during prior anti–PD-1/PD-L1 therapy. bCensored on last visit. cOne response was unconfirmed. dEvaluations are planned for every 8 weeks.

34% of patients (21/61a) had not progressed at data cutoff

• LAG-3 ≥ 1%: 55% (18/33a)

• LAG-3 < 1%: 5.0% (1/20a)

• LAG-3 unknown: 25% (2/8a)

*

Ongoing progression-free survivalb

Time to progression or death

*Patients with an objective responsec

Inhibidores LAG-3

Relatlimab

Combinar… ¿Con quién?

DS Chen et al. Immunity 39, 1-10 (2013)

αPD1

Daniel Chen, Inmunity 2013

Something + inhibidor PD-1

Nature Reviews | Cancer

CD28CD80 or CD86

CD40LCD40

CTLA4CD80 or CD86

ICOSB7RP1

OX40L OX40

CD137CD137L

?PDL1 or PDL2

Antigen-presenting cell T cell

PD1PDL1 or PDL2

?B7-H3

BTLAHVEM

KIR

MHC class I or II TCR

LAG3

CD27CD70

TIM3GAL9

A2aR

Adenosine

+

–

–

–

–

–

–

–

+

+

?B7-H4

+

+

+

Signal 1

Cytokines(TGFα, IL-1,IL-6, IL-10,IL-12, IL-18)

+

Peptide

–

–

CD4 + helper T cells

T cells that are characterized

by the expression of CD4. They

recognize antigenic peptides

presented by MHC class II

molecules. This type of T cell

produces a vast range of

cytokines that mediate

inflammatory and effector

immune responses. They also

facilitate the activation of CD8+

T cells and B cells for antibody

production.

the expression of which determines the TReg

cell line-

age34,35, and TReg

cells therefore express CTLA4 consti-

tutively. Although the mechanism by which CTLA4

enhances the immunosuppressive function of TReg

cells is not known, TReg

cell-specific CTLA4 knockout

or blockade significantly inhibits their ability to regu-

late both autoimmunity and antitumour immunity30,31.

Thus, in considering the mechanism of action for

CTLA4 blockade, both enhancement of effector CD4+

T cell activity and inhibition of TReg

cell-dependent

immunosuppression are probably important factors.

Clinical application of CTLA4-blocking antibodies —

the long road from mice to FDA approval. Initially,

the general strategy of blocking CTLA4 was ques-

tioned because there is no tumour specificity to the

expression of the CTLA4 ligands (other than for some

myeloid and lymphoid tumours) and because the dra-

matic lethal autoimmune and hyperimmune pheno-

type of Ctla4-knockout mice predicted a high degree of

immune toxicity associated with blockade of this recep-

tor. However, Allison and colleagues36 used preclinical

models to demonstrate that a therapeutic window was

indeed achieved when CTLA4 was partially blocked with

antibodies. The initial studies demonstrated significant

antitumour responses without overt immune toxicities

when mice bearing partially immunogenic tumours were

treated with CTLA4 antibodies as single agents. Poorly

immunogenic tumours did not respond to anti-CTLA4 as

a single agent but did respond when anti-CTLA4 was

combined with a granulocyte–macrophage colony-

stimulating factor (GM-CSF)-transduced cellular

Figure 1 | Multiple co-stimulatory and inhibitory

Depicted are

response to antigen (which is mediated by peptide–

major histocompatibility complex (MHC) molecule

(TCR)). These responses can occur at the initiation of

are dendritic cells) or in peripheral tissues or tumours

(where effector responses are regulated). In general,

interactions unless they first recognize their cognate

antigen through the TCR. Many of the ligands bind to

multiple receptors, some of which deliver co-stimulatory

signals and others deliver inhibitory signals. In general,

pairs of co-stimulatory–inhibitory receptors that bind the

same ligand or ligands — such as CD28 and cytotoxic

T-lymphocyte-associated antigen 4 (CTLA4) — display

distinct kinetics of expression with the co-stimulatory

activation. One important family of membrane-bound

ligands that bind both co-stimulatory and inhibitory

and their known ligands belong to the immunoglobulin

superfamily. Many of the receptors for more recently

Tumour necrosis factor (TNF) family members that bind

to cognate TNF receptor family molecules represent a

second family of regulatory ligand–receptor pairs. These

receptors predominantly deliver co-stimulatory signals

when engaged by their cognate ligands. Another major

comes from soluble cytokines in the microenviron-

bidirectional. In some cases, this occurs when ligands

themselves signal to the APC. In other cases, activated

cognate receptors on APCs. A2aR, adenosine A2a

lymphocyte attenuator; GAL9, galectin 9; HVEM,

herpesvirus entry mediator; ICOS, inducible T cell

co-stimulator; IL, interleukin; KIR, killer cell immunoglobulin-

like receptor; LAG3, lymphocyte activation gene 3;

PD1, programmed cell death protein 1; PDL, PD1 ligand;

TGFβ, transforming growth factor-β; TIM3, T cell

membrane protein 3.

REVIEWS

254 | APRI L 2012 | VOLUM E 12 www.nature.com/reviews/cancer

REVIEWS

© 2012 Macmillan Publishers Limited. All rights reserved

Terapia dirigida

Combinar… ¿Con quién?

BRAF/MEK inhibitors as immunomodulating agents

Bases favorecen combinación inmunoterapia e inhibidores BRAF

The anti–PD-1 antibody spartalizumab (S) in

combination with dabrafenib (D) and trametinib (T) in

previously untreated patients (pts) with advanced BRAF

V600–mutant melanoma: Updated efficacy and safety

from parts 1 and 2 of COMBI-i.

Abstrat 9531. Dummer R.

ASCO 2019

• 36 pacientes

• Tasa respuestas→ 75%

• Respuestas completas→ 33%

• SLP 1 año → 65.3%

• SG 1 año → 85.9%

• Toxicidad grado ≥ 3→ 75%

KEYNOTE 022

Toxicidad grado ≥ 3→ 67%

DS Chen et al. Immunity 39, 1-10 (2013)

αPD1

Daniel Chen, Inmunity 2013

Something + inhibidor PD-1

Nature Reviews | Cancer

CD28CD80 or CD86

CD40LCD40

CTLA4CD80 or CD86

ICOSB7RP1

OX40L OX40

CD137CD137L

?PDL1 or PDL2

Antigen-presenting cell T cell

PD1PDL1 or PDL2

?B7-H3

BTLAHVEM

KIR

MHC class I or II TCR

LAG3

CD27CD70

TIM3GAL9

A2aR

Adenosine

+

–

–

–

–

–

–

–

+

+

?B7-H4

+

+

+

Signal 1

Cytokines(TGFα, IL-1,IL-6, IL-10,IL-12, IL-18)

+

Peptide

–

–

CD4 + helper T cells

T cells that are characterized

by the expression of CD4. They

recognize antigenic peptides

presented by MHC class II

molecules. This type of T cell

produces a vast range of

cytokines that mediate

inflammatory and effector

immune responses. They also

facilitate the activation of CD8+

T cells and B cells for antibody

production.

the expression of which determines the TReg

cell line-

age34,35, and TReg

cells therefore express CTLA4 consti-

tutively. Although the mechanism by which CTLA4

enhances the immunosuppressive function of TReg

cells is not known, TReg

cell-specific CTLA4 knockout

or blockade significantly inhibits their ability to regu-

late both autoimmunity and antitumour immunity30,31.

Thus, in considering the mechanism of action for

CTLA4 blockade, both enhancement of effector CD4+

T cell activity and inhibition of TReg

cell-dependent

immunosuppression are probably important factors.

Clinical application of CTLA4-blocking antibodies —

the long road from mice to FDA approval. Initially,

the general strategy of blocking CTLA4 was ques-

tioned because there is no tumour specificity to the

expression of the CTLA4 ligands (other than for some

myeloid and lymphoid tumours) and because the dra-

matic lethal autoimmune and hyperimmune pheno-

type of Ctla4-knockout mice predicted a high degree of

immune toxicity associated with blockade of this recep-

tor. However, Allison and colleagues36 used preclinical

models to demonstrate that a therapeutic window was

indeed achieved when CTLA4 was partially blocked with

antibodies. The initial studies demonstrated significant

antitumour responses without overt immune toxicities

when mice bearing partially immunogenic tumours were

treated with CTLA4 antibodies as single agents. Poorly

immunogenic tumours did not respond to anti-CTLA4 as

a single agent but did respond when anti-CTLA4 was

combined with a granulocyte–macrophage colony-

stimulating factor (GM-CSF)-transduced cellular

Figure 1 | Multiple co-stimulatory and inhibitory

Depicted are

response to antigen (which is mediated by peptide–

major histocompatibility complex (MHC) molecule

(TCR)). These responses can occur at the initiation of

are dendritic cells) or in peripheral tissues or tumours

(where effector responses are regulated). In general,

interactions unless they first recognize their cognate

antigen through the TCR. Many of the ligands bind to

multiple receptors, some of which deliver co-stimulatory

signals and others deliver inhibitory signals. In general,

pairs of co-stimulatory–inhibitory receptors that bind the

same ligand or ligands — such as CD28 and cytotoxic

T-lymphocyte-associated antigen 4 (CTLA4) — display

distinct kinetics of expression with the co-stimulatory

activation. One important family of membrane-bound

ligands that bind both co-stimulatory and inhibitory

and their known ligands belong to the immunoglobulin

superfamily. Many of the receptors for more recently

Tumour necrosis factor (TNF) family members that bind

to cognate TNF receptor family molecules represent a

second family of regulatory ligand–receptor pairs. These

receptors predominantly deliver co-stimulatory signals

when engaged by their cognate ligands. Another major

comes from soluble cytokines in the microenviron-

bidirectional. In some cases, this occurs when ligands

themselves signal to the APC. In other cases, activated

cognate receptors on APCs. A2aR, adenosine A2a

lymphocyte attenuator; GAL9, galectin 9; HVEM,

herpesvirus entry mediator; ICOS, inducible T cell

co-stimulator; IL, interleukin; KIR, killer cell immunoglobulin-

like receptor; LAG3, lymphocyte activation gene 3;

PD1, programmed cell death protein 1; PDL, PD1 ligand;

TGFβ, transforming growth factor-β; TIM3, T cell

membrane protein 3.

REVIEWS

254 | APRI L 2012 | VOLUM E 12 www.nature.com/reviews/cancer

REVIEWS

© 2012 Macmillan Publishers Limited. All rights reserved

Terapia dirigida

Combinar… ¿Con quién?

“Otras” terapias

1:1

Pembrolizumab 200mg iv cada 3 s

T-VEC Intralesional

Pembrolizumab 200mg iv cada 3 s

T-VEC placebo Intralesional

Objetivos primarios: SLP y SGR

• MASTERKEY-265

• N= 660

• Estadios IIIC irresecables o IV

• 1ª línea

• Inhibidores BRAF permitidos

Fase Ib (Ribas A, et al. Cell 2017) T-VEC + pembrolizumab N=21

Respuestas (%) (95% CI) 71 (48-89)

Respuesta completa 33

Respuesta parcial 29

Enfermedad estable 14

Progresión 24

Beneficio clínico (%) 85

DS Chen et al. Immunity 39, 1-10 (2013)

αPD1

Daniel Chen, Inmunity 2013

Something + inhibidor PD-1

Inhibidores IDO

Epacadostat

Overall Survival

CI, confidence interval; E, epacadostat; HR, hazard ratio; NR, not reached; OS, overall survival; P, pembrolizumab.

Georgina V. Long 12

100

90

80

70

60

50

40

30

20

10

0

Ove

rall S

urv

iva

l (%

)

0 2 4 6 8 10 12 14 16 18

Time, months

354

352

340

342

322

323

290

304

274

285

263

263

183

186

96

115

42

43

5

2

E + P

Placebo + P

Number at risk

74.4% 74.1%

84.1% 87.2%

E + P

Placebo + P

HR (95% CI): 1.13 (0.86–1.49)

P = 0.807

Events,

n (%)

Median OS, months

(95% CI)

E + P 106 (29.9) NR (NR, NR)

Placebo + P 98 (27.8) NR (NR, NR)

Combinar… ¿Con quién?

Y más o menos…

hasta aquí puedo leer…

En realidad lo que me habéis pedido…

¿Cómo podemos optimizar la combinación de

inhibidores de “check-points”?

Aunque lo que me hubiera gustado que me preguntarais…

¿Cómo podemos optimizar el look de

boda de Pilar Rubio?

En realidad lo que me habéis pedido…

¿Cómo podemos optimizar la combinación de

inhibidores de “check-points”?

Es decir…

“Conseguir que la combinación de inmuno check-points

dé los mejores resultados posibles”

Lo que yo os propongo…

Optimizar la combinación de checkpoints requiere contestar a 3 preguntas

1. ¿Quién?

Aquí está una de las claves…

Diferentes poblaciones de pacientes

Características clínicas

Cinética de crecimiento

Niveles de LDH

Metástasis cerebrales

Mutación de BRAF

Variable presencia de

neoantígenos

Diferentes mecanismos de

resistencia

Desconocidos

Poblaciones

poco/nada

representadas en

ensayos clínicos

Melanoma mucosas

Enfermedades

autoinmunes

Pacientes con melanoma

avanzado irresecable/metastásico

▪ Desde un punto de vista clínico…

Niveles elevados LDH

Frontiers in Oncology 2015

Metástasis cerebrales

Tropismo cerebral

• 20-30% al diagnóstico

• 50% a lo largo de la enfermedad

• 70% series autopsias

Mal pronóstico→ Mediana SG 4 meses

Nivolumab + Ipilimumab

eficacia significativa M1 asintomáticas no tratadas

Poblaciones de

peor pronóstico

Melanoma

mucosas/uveal

Melanomas especial

mal pronóstico

Anti-PD1 poco eficaz

¿Combinaciones

mejor aquí?

Time (Months)

PF

S (

%)

100

90

80

70

60

50

40

30

20

0

10

3 6 9 12 15 18 21 24 270 30

60%

50%47%35%

23%17%

71%

56% 54%

Time (Months)

PF

S (

%)

100

90

80

70

60

50

40

30

20

0

10

3 6 9 12 15 18 21 24 270

34%29%

28%

15%

7% 6%

47%

38% 35%

LDH ≤ LSN LDH > LSNNIVO + IPI (n = 269)

NIVO(n = 316)

IPI(n = 230)

Median PFS, months (95% CI)

NR (11.7, NR)

11.3(7.7, 20.2)

4.1(3.1, 5.1)

HR (95% CI)NIVO+IPI over NIVO or IPI

–0.7

(0.6, 0.9)0.4

(0.3, 0.5)

NIVO+IPI (n = 138)

NIVO(n = 191)

IPI(n = 126)

Median PFS, months (95% CI)

5.2(2.9, 9.6)

2.7(2.6, 3.2)

2.6(2.6, 2.8)

HR (95% CI) NIVO+IPI over NIVO or IPI

–0.8

(0.6, 1.0)0.5

(0.4, 0.6)

Time (Months)

PF

S (

%)

100

90

80

70

60

50

40

30

20

0

10

3 6 279 12 15 18 21 240

10%

17%

10%

20%

18%

29%

NIVO+IPI(n = 43)

NIVO(n = 58)

IPI(n = 31)

Median PFS, months (95% CI)

2.6 (1.7, 2.9) 2.1 (1.9, 2.6)2.3 (1.7,

2.6)

HR (95% CI) NIVO+IPI over NIVO or IPI

– 0.7 (0.5, 1.1)0.5 (0.3,

0.9)

LDH > 2 LSN

Larkin J, et al. SMR 2016

OR

R,a

% (

95%

CI)

100

90

80

70

60

50

40

30

20

0

10

LDH ≤ ULN LDH > ULN LDH > 2x ULN

NIVO+IPI NIVO IPI

65%

51%

23%

45%

31%

10%

33%

17%

n 269 316 230 138 191 126 43 58 31

Efficacy of Nivolumab Plus Ipilimumab Combination in Patients With Advanced Melanoma and

Elevated Serum Lactate Dehydrogenase:

a Pooled Analysis (CheckMate 066, 067 y 069)

• Criterios exclusión→ Pacientes sintomáticos, esteroides > 10 días, RT holocraneal, tratamiento previo inhibidores checkpoint, enfermedadleptomeníngea

Nivolumab1 mg/kg/3s

4 dosis

+

Ipilimumab

3 mg/kg/3s4 dosis

Nivolumab

3 mg/kg

Cada 2 semanas

Hasta progresión o toxicidad

(máximo 24 meses)

Inducción MantenimientoCohorte A

• ≥ 1 lesión medible no irradiada

(0.5-3 cm)

• Tratamiento local previo (3

semanas)

• Tratamiento previo BRAFi/MEKi

permitido

• ECOG 0-1

• Asintomáticos

CkeckMate 204. Margolin K, et al. N Engl J Med 2018

▪ Respuestas en más de la mitad de los pacientes, rápidas y duraderas

▪ Concordancia respuestas intracraneales y extracraneales

▪ Previene progresión durante más de 6 meses en 61% pacientes

Hussein Tawbi at 2019 ASCO Annual Meeting

CheckMate 204 Study Design with Cohort B

Presented By Hussein Tawbi at 2019 ASCO Annual Meeting

▪ 22% Respuestas

▪ 11% Respuestas completas

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

15129630

Number of patients at risk

IPI --0002836

NIVO+IPI --0211121935

NIVO 01722294086

NIVONIVO+IPIIPI

IPI 04235279135269

Number of patients at risk

NIVO+IPI 1957126183235326

NIVO 62490231303384665

CutáneoNIVO+IPI(n = 326)

NIVO (n = 665)

IPI(n = 269)

Median, months(95% CI)

11.7 (8.9, 16.7)

6.2 (5.1, 7.5)

3.9 (2.9, 4.4)

HR (95% CI) vs IPI

0.49 (0.40, 0.61)

0.73 (0.61, 0.87) ‒

P value vs IPIb < 0.0001 0.04 ‒

Median follow-up, months (range)

11.7 (0.1-18.8)c

10.0 (0.3-62.5)

11.7 (0.3-18.7)c

NIVONIVO+IPIIPI

MucosaNIVO+IPI(n = 35)

NIVO (n = 86)

IPI(n = 36)

Median, months(95% CI)

5.9(2.8, NR)

3.0(2.2, 5.4)

2.7(2.6, 2.8)

HR (95% CI) vs IPI

0.42 (0.23, 0.75)

0.61 (0.39, 0.96)

‒

P value vs IPIa 0.003 0.12 ‒

Median follow-up, months (range)

8.1(0.5-16.9)

6.2(0.5-17.4)

8.6(1.9-17.1)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1815129630

Pro

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ility

of

Pro

gre

ssio

n-f

ree

Su

rviv

al

Months

Pro

bab

ility

of

Pro

gre

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n-f

ree

Su

rviv

al

Months

1. Adaptado de Larkin J, et al. Presented at SMR 2015

2. Adaptado de D’Angelo SP, et al. J Clin Oncol 2017

Melanoma de mucosas

• Análisis conjunto 1653 pacientes melanoma metastático, (157 melanoma mucosas, 10% del total)

– Fase 1: CA209-003 and CA209-038, Fase 2: CA209-069 y Fase 3: CA209-037, CA209-066 y CA209-067

• Objetivo primario→ Supervivencia global 12 meses

• Objetivos secundarios→ Supervivencia libre progresión, respuestas, seguridad

Nivolumab 1 mg/kg/ 3s

4 dosis

+

Ipilimumab 3 mg/kg/ 3s4 dosis

Nivolumab 3 mg/kg

Cada 2 semanas

Hasta progresión, toxicidad o retirada

consentimiento

Inducción Mantenimiento

• Melanoma uveal avanzado

• No subsidiario tratamiento radical

• 1ª línea tratamiento

• N= 52 pacientes

▪ Desde un punto de vista mecanístico…

Dammeijer F, et al. Cytokine & Growth Factor Reviews 2017

Estos pacientes “tienen suficiente” con un anti-PD1

Dammeijer F, et al. Cytokine & Growth Factor Reviews 2017

Pero estos no…

Y estos tampoco

Mecanismos de resistencia primaria

1. Ausencia expresión neoantígenos

2. No maduración células dendríticas

3. No generación o reclutamiento de

linfocitos T específicos

4. Población células inmunes supresoras

Y tenemos que aprender a identificarlos y conocer mecanismos de resistencia…

Dammeijer F, et al. Cytokine & Growth Factor Reviews 2017

Mecanismos de resistencia

secundaria

5. Regulación al alza de moléculas

co-inhibitorias

6. Pérdida expresión neoantígenos

…Para optimizar los tratamientos de combinación

Lo que yo os propongo…

Optimizar la combinación de checkpoints requiere contestar a 3 preguntas

1. ¿Quién?

2. ¿Cuándo?

¿Más vale prevenir o curar?

Anti-PD1

+

Something

Pro

gre

sió

n

Anti-PD1

Pro

gre

sió

n

Ipilimumab

Anti-PD1

+

Something

Something

Lo que yo os propongo

Optimizar la combinación de checkpoints requiere contestar a 3 preguntas

1. ¿Quién?

2. ¿Cuándo?

3. Y de nuevo… ¿con quién?

DS Chen et al. Immunity 39, 1-10 (2013)

αPD1

Daniel Chen, Inmunity 2013

Nuevas combinaciones

Something + inhibidor PD-1

Something + otros inmunocheckpoint (TIM3 y LAG3)

Terapia dirigida + inmunocheckpoint

Otros

Anti-CD73

Agonistas TLR-9

Anti-OX40

Agonistas GIRT

Agonistas CD40

Agonistas CD137

Otras formas de inmunoterapia

Vacunas

TILs, CAR TC

Lo que yo os propongo…

Optimizar la combinación de checkpoints requiere contestar a 3 preguntas

1. ¿Quién?

2. ¿Cuándo?

3. Y de nuevo… ¿con quién?

Y un aspecto no desdeñable…

¿Podemos disminuir la toxicidad?

Estadios III o

IV no

resecables

No tratados

(N = 360)

Estratificación

• Expresión

PD-L1 ≥5% vs

<5%

• Estadio M

AJCC

NIVO flat dose

480 mg/4s

NIVO flat dose

480 mg/4s

6 semanas

6 semanas

Hasta

toxicidad

inaceptable

o progresión

1:1

NIVO 1 mg/kg IV +

IPI 3 mg/kg IV/ 3s

4 dosis

NIVO 3 mg/kg IV +

IPI 1 mg/kg IV/ 3s

4 dosis

ESMO 2018. LBA47: Initial Results From a Phase 3b/4 Study Evaluating Two Dosing

Regimens of Nivolumab in Combination With Ipilimumab in Patients With Advanced

Melanoma (CheckMate 511)

C. Lebbé

Toxicidad ≥

10% pacientes

NIVO3+IPI1 (n = 180) NIVO1+IPI3 (n = 178)

Any Grade Grade 3–4 Any Grade Grade 3–4

Cualquiera, % 85.6 33.3 93.8 48.3

Diarrea 26.1 2.8 30.9 6.2

Astenia 24.4 0.6 21.9 0.6

Prurito 23.9 0.6 26.4 0

Rash 17.2 0 26.4 0.6

Hipotiroidismo 13.9 0 20.2 0

Náusea 12.2 0 18.5 2.8

Hipertiroidismo 10.6 0 17.4 1.7

Anorexia 10.6 0 10.7 1.7

Vitiligo 10.6 0 6.2 0

GOT elevada 8.9 1.7 18.0 4.5

GPT elevada 7.8 0.6 15.2 2.8

Pirexia 7.8 0 19.7 1.1

Boca seca 6.1 0.6 11.8 0.6

Perc

en

tag

e o

f P

FS

Meses

SG

(%

)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 24 2721

0168 180

0164 178

157

151

146

143

140

136

132

128

106

1043928

1

0

88.2%

(NIVO3+IPI1)

88.0%

(NIVO1+IPI3) 81.0%

(NIVO1+IPI3)

79.7%

(NIVO3+IPI1)

NIVO3+IPI1

NIVO1+IPI3

Resultados Pembro + Ipi 50 mg/6s

N= 51

Pembro + Ipi 100 mg/12s

N= 51

Respuestas (%) 55 61

Respuesta completa (%) 16 25

Respuesta parcial (%) 39 35

Enfermedad estable (%) 20 16

Progresión (%) 16 10

Tiempo a respuesta,

mediana, meses, rango

1.4 (1.3-8.3) 1.5 (1.3- 10.9)

Duración respuesta,

mediana, meses

NR NR

Respuestas ongoing (%) 71 87

ASCO 2019. Standard-Dose Pembrolizumab plus Alternate-Dose Ipilimumab in Advanced

Melanoma: Initial Analysis of KEYNOTE 029 Cohort 1c. C. Long GV

IMPemBRA- study Design

Y por si hay algún gerente (o preocupado por las “perras”…)

• Y porque más es más…

• Las combinaciones son más caras…

• Ahorrar no sólo es guardar, sino también saber gastar…

2019 ASCO – ICI biomarkers

Presented By Leslie Fecher at 2019 ASCO Annual Meeting

“A cada uno lo que necesita”

The Checkpoint Band

“La medicina de precisión es una medicina de justicia”

Dr. García Girón

“Al César, lo que es de César, y a Dios, lo que es de Dios”

Mateo 22:21

Gracias por vuestra atención