Dra. Cristina Grávalos

Hospital Universitario 12 de Octubre

Papel de la inmunoterapia

en tumores digestivos no colorrectal

Los cánceres GI suponen 20-25% de todos los cánceres

Mal pronóstico a pesar de terapias actuales: cirugía, RT, QT y terapias antidiana

Necesidad de nuevas estrategias terapéuticas

INMUNOTERAPIA

INMUNOTERAPIA

Alsina M et al. Targ Oncol 2016; 11:469-477

AcMo contra receptor del linfocito T

• Anti-CTLA-4 • Ipilimumab

• Tremelimumab

• Anti-PD1 • Nivolumab

• Pembrolizumab

• Pidilizumab

AcMo contra ligandos

• Anti-PD-L1 • Atezolizumab

• Durvalumab

• Avelumab

• Anti-PD-L2 – AMP-224

CÁNCER ESÓFAGO-GÁSTRICO

• Cáncer de esófago: • Tabaco y alcohol Mutaciones susceptibles de reconocimiento por

sist. Inmunológico

• 44% expresan PD-L1 o PD-L2 y se asocia con mal pronóstico

• Cáncer gástrico • La respuesta inmune puede jugar un papel importante en:

• Tumores positivos para virus Epstein-Barr EBV por estimulación del virus (9%)

• Tumores con inestabilidad de microsatélites (MSI) (22%) por alta carga mutacional

• Tumores estables genómicamente (GS)

• Tumores con inestabilidad de cromosomas (CIN)

• 20-40% expresan PD-L1 o PD-L2 y se asocia con mal pronóstico

CÁNCER DE ESÓFAGO, GEJ

Y GÁSTRICO

Cancer Genome Atlas Network. Nature 2014; 513: 202-9

Resultados: n= 160 pts pretratados 24% eran PD-L1+ (≥ 1%).

Janjigian Y, et al. ASCO 2017; abs 4014

N3 N1 + I3 N3 + I1

N= 59 N= 49 N= 52

RR 12% 24% 8% RR PD-L1 > 1% 19% 40% 23%

RR PD-L1 <1% 12% 22% 0% DORm 7,1 m 7,9 m NA

Esquemas • Nivo 3 mg/kg Q2W (N3) • Nivo 1 mg/kg + Ipi 3 mg/kg Q3W (N1+I3) • Nivo 3 mg/kg + Ipi 1 mg/kg Q3W (N3+I1)

CheckMate 032 Fase I/II de Nivo ± ipilimumab en tumores sólidos avanzados:

cáncer de esófago, GEJ y gástrico

Países occidentales

• AE grado 3-4 relacionadas con el tratamiento: – Diarrea (N3, 2%, N1+I3, 14%, N3+I1, 2%) – Elevación de ALT (N3, 3%; N1+I3, 14%; N3+I1, 4%) – Elevación de AST (N3, 5%; N1+I3, 10%; N3+I1, 2%).

• Conclusiones:

– N ± I consiguen respuestas duraderas y SG larga en pacientes occidentales muy pretratados

– En línea con los resultados de otros estudios en pacientes asiáticos

– Perfil de seguridad coincide con lo ya descrito

CheckMate 032 Fase I/II de Nivo ± ipilimumab en tumores sólidos avanzados:

cáncer de esófago, GEJ y gástrico

Janjigian Y, et al. ASCO 2017; abs 4014

DISEÑO: Fase II de una rama única - Refractario o intolerante a QT basada en fluoropirimidinas, platino y taxanos - Esquema: Nivolumab: 3 mg/kg iv cada 2 semanas, en ciclos de 6 semanas. - Objetivo principal: RR evaluada según RECIST 1.1

RESULTADOS: - N= 65 - - Seguimiento mediano: 10.8 meses

Asia

Kudo et al. Lancet Oncol 2017

Kudo et al. Lancet Oncol 2017

SLP SG

1,5m 10,2 m

Kudo et al. Lancet Oncol 2017

• Tolerancia: – AE Grado 4: 1 (2%) pt de disnea y 1 (2%) pt hiponatremia – AE Grado 3:

• 5 (8%) infección pulmonar • 2 (3%) disminución del apetito • 2 (3%) aumento de creatinina fosfoquinasa en sangre • 2 (3%) deshidratación.

– 2 casos de enfermedad pulmonar intersticial – No muertes relacionadas con el tratamiento

• Conclusión:

– Nivolumab tiene una actividad prometedora con un perfil de seguridad manejable y podría ser un nuevo enfoque terapéutico para pacientes con carcinoma epidermoide refractario

Kudo et al. Lancet Oncol 2017

Nivolumab as Salvage Treatment After Second- or Later-Line for

Adenocarcinoma Advanced Gastric or GEJ:

Double-Blinded, Randomized, Phase 3 Trial

ONO 12 (ATTRACTION-2)

BOR, best overall response; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; IV; intravenous; ORR, objective response

rate; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; R, randomization; RECIST, Response Evaluation Criteria In Solid Tumors; TTR, time to tumor response.

R

2:1

Nivolumab

3 mg/kg IV Q2W

Placebo

Key eligibility criteria:

• Age ≥ 20 years

• Unresectable advanced or

recurrent gastric or

gastroesophageal junction

cancer

• Histologically confirmed

adenocarcinoma

• Prior treatment with ≥ 2

regimens and refractory

to/intolerant of standard

therapy

• ECOG PS of 0 or 1

Primary endpoint:

• OS

Secondary endpoints:

• Efficacy (PFS,

BOR, ORR, TTR,

DOR, DCR)

• Safety

Exploratory endpoint:

• Biomarkers

Stratification based on:

• Country (Japan vs Korea vs Taiwan)

• ECOG PS (0 vs 1)

• Number of organs with metastases (< 2 vs ≥ 2)

• Patients were permitted to continue treatment beyond initial RECIST v1.1–defined disease progression,

as assessed by the investigator, if receiving clinical benefit and tolerating study drug

N=493

Nov 2014-Feb 2016

Asia

RECIST Response and Disease Control

Nivolumab 3 mg/kg

(n = 268)

Placebo

(n = 131)

ORR, n (%)

[95% CI]

P value

30 (11.2%)

[7.7–15.6]

< 0.0001

0

[0–2.8]

—

BOR, n (%)

Complete response

Partial response

Stable disease

Progressive disease

0

30 (11.2)

78 (29.1)

124 (46.3)

0

0

33 (25.2)

79 (60.3)

DCR, n (%)

[95% CI]

P value

108 (40.3%)

[34.4–46.4]

0.0036

33 (25.2)

[18.0–33.5]

—

Median TTR (range),

months 1.61 (1.4–7.0) —

Median DOR, months

[95% CI]

9.53 [6.14–9.82]

—

Maximum Reduction in Tumor Burden From Baseline

Nivolumab Placebo

Ma

xim

um

Re

du

cti

on

Fro

m B

ase

lin

e

in T

arg

et

Les

ion

s (

%)

-100

-80

-60

-40

-20

0

20

40

60

80

100

-100

-80

-60

-40

-20

0

20

40

60

80

100 a

a Patients with a change in tumor burden that exceeds 100%.

a

Patients with Tumor reduction: 37.3% Patients with Tumor reduction: 12.4%

Progression-Free Survival

Time (months)

Pro

bab

ilit

y o

f P

rog

ressio

n-F

ree S

urv

ival

(%)

20 18 16 14 12 10 8 6 4 2 0

0

10

20

30

40

50

60

70

80

90

100

0 0 2 4 8 19 31 46 83 131 330

0 1 1 2 2 4 7 9 17 41 163

Nivolumab

Placebo

At risk:

Nivolumab

Placebo

Hazard ratio, 0.60 (95% CI, 0.49–0.75)

P < 0.0001

Median Progression-Free Survival

1.61 months

1.45 months

Patients,

n

Events,

n

Median PFS

[95% CI], months

12-Month PFS Rate

[95% CI], %

Nivolumab 330 253 1.61 [1.54–2.30] 7.6 [4.2–12.2]

Placebo 163 145 1.45 [1.45–1.54] 1.5 [0.3–4.8]

Overall Survival

Time (months)

Pro

ba

bil

ity o

f S

urv

iva

l (%

)

22 18 16 14 12 10 8 6 4 2 0

0

10

20

30

40

50

60

70

80

90

100

Hazard ratio, 0.63 (95% CI, 0.50–0.78)

P < 0.0001

0 3 5 10 19 39 57 95 142 275 330

0 1 3 3 4 10 16 32 53 121 163

Nivolumab

Placebo

At risk:

20

193

82

Patients,

n

Events,

n

Median OS

[95% CI], months

12-Month OS Rate

[95% CI], %

Nivolumab 330 225 5.32 [4.63–6.41] 26.6 [21.1–32.4]

Placebo 163 141 4.14 [3.42–4.86] 10.9 [6.2–17.0]

Adverse Event Summary

Patients, n (%)

Nivolumab 3 mg/kg

(n = 330)

Placebo

(n = 161)

Any Grade Grade 3/4 Any Grade Grade 3/4

AEs

Any

Serious AEs

AEs leading to discontinuation

AEs leading to dose delay

300 (90.9)

131 (39.7)

23 ( 7.0)

63 (19.1)

137 (41.5)

91 (27.6)

13 ( 3.9)

40 (12.1)

135 (83.9)

75 (46.6)

12 ( 7.5)

27 (16.8)

63 (39.1)

47 (29.2)

9 ( 5.6)

17 (10.6)

AEs leading to death 35 (10.6) 25 (15.5)

TRAEs

Any

Serious TRAEs

TRAEs leading to discontinuation

TRAEs leading to dose delay

141 (42.7)

33 (10.0)

9 ( 2.7)

25 ( 7.6)

34 (10.3)

21 ( 6.4)

4 ( 1.2)

14 ( 4.2)

43 (26.7)

8 ( 5.0)

4 ( 2.5)

2 ( 1.2)

7 (4.3)

4 (2.5)

3 (1.9)

1 (0.6)

TRAEs leading to death 5 (1.5) 2 (1.2) AE, adverse event; TRAE, treatment-related adverse event.

Conclusions

• This phase 3 study demonstrated the efficacy and safety of nivolumab as a third

or later line of treatment in patients with AGC

– Superior OS vs placebo, with long-term survival

– Superior response rates, disease control, and PFS vs placebo

– Nivolumab was well tolerated with a safety profile comparable to the placebo arm

• Biomarker analysis is under investigation

• These results indicate that nivolumab could be a new treatment option for patients

with heavily pretreated AGC and also provide a strong rationale to explore

nivolumab in earlier lines of treatment for gastric cancer

Nivolumab

Placebo

Post-treatment follow-up

• ≥ 18 years old • Stage II/III • Completed pre-operative CRT followed by surgery • Residual pathological disease following complete resection

CheckMate 577: Randomized, Double-Blind, Phase 3 Study of Adjuvant Nivolumab or

Placebo in Patients With Resected Esophageal or GEJ Cancer

N= 760

Primary endpoints: Disease-free survival and Overall survival Secondary endpoints: OS rate at 1,2, and 3 years

En marcha Inicio mayo 2016

• ≥ 18 years old • Inoperable

advanced/metastatic gastric/GEJ cancer

• No prior systemic treatment, including HER2 inhibitors, as primary therapy for advanced or metastatic disease

• Available tumor tissue from ≤ 6 months prior to study treatment

Nivolumab 1 + ipilimumab 3(4 doses), then nivolumab

monotherapy

XELOX or FOLFOX

Post-treatment follow-up

CheckMate 649: Randomized, Multicenter, Open-Label, Phase 3 Study of Nivolumab

Plus Ipilimumab vs Oxaliplatin Plus Fluoropyrimidine in Patients With Previously Untreated Advanced or Metastatic Gastric or GEJ Cancer

N=1266 Primary endpoint: OS in patients with PD-L1+ tumors Secondary endpoints: • OS in all randomized patients • PFS in patients with PD-L1+ tumors and all randomized patients

En marcha Inicio oct 2016

KEYNOTE-012: cohorte de cáncer gástrico

• Pembrolizumab 10 mg/kg cada 2 semanas

• N= 39 con tumores PD-L1 >1% refractarios

• RR 22% (revisión central)

• Disminución del tumor 53%

• DOR: 40 semanas (rango 20-48+)

• SG 11.4 meses

Muro K, et al. Ann Oncol 2014; LBA 15A

Anti-PD1

KEYNOTE-062: Fase III 1ª línea Pembro vs Pembro + QT en cáncer gástrico

Pembrolizumab 200 mg iv D1 21-day cycle

Primary Endpoints: PFS and OS Secondary Endpoints: ORR, DOR, QOL, safety

N= 750 Pembrolizumab 200 mg Q3W + CDDP 80 mg/m2 D1 + 5FU 800 mg/m2/day ic Days 1-5 Q3W. Capecitabine 1000 mg/m2/12h D1-14 Q3W may be substituted for 5-FU

R

KEYNOTE-061: Fase III 2ª línea Pembro vs Paclitaxel en cáncer gástrico

R

Pembrolizumab 200 mg iv D1 21-day cycle, for up to 35 administrations (approximately 2 years)

Paclitaxel 80 mg/m2 IV, Days 1, 8, and 15 of each 28-day cycle.

Primary Endpoints: PFS and OS in PD-L1-positive Central Radiology Review Key secondary endpoints: PFS and OS all , ORR

N= 720

CÁNCER GÁSTRICO

Estudios fase I-II

AcMo Anti-CTLA-4 y PD1/PD-L1

Alsina M et al. Targ Oncol 2016; 11:469-477

HEPATOCARCINOMA

• Antigenicidad tumoral:

– 50-70% de HCC tienen Ags asociados al tumor que reconocen los linfocitos T citotóxicos

• Sin embargo, existen mecanismos de tolerancia a los antígenos tumorales

– Producción de citoquinas inmunosupresoras

– Hiperregulación de checkpoints inmunológicos inhibidores como CTLA-4 y PD-1

HEPATOCARCINOMA

Justificación

• 1º inhibidor de checkpoint evaluado en HCC • Eficacia (n=17)

• 3 pts (17%) RP de 3,6, 9,2 y 15,8 meses y 10 pts (58,8%) EE • SLPm 6,5 m y SG 8,2 m

• Toxicidad (n=20)

• Grado > 3: Elevación de AST (45%) y ALT (25%), elevación BT (10%), neutropenia, rash y diarrea 5%

• Conclusión: es factible administrar un AcMo anti CLTA-4

en HCC con cirrosis hepática y hepatitis C

HEPATOCARCINOMA

Anti-CTLA-4: Tremelimumab

Sangro et al. J Hepatol 2013;59:81-88

• Disease assessment imaging (CT or MRI)

every 6 weeks

Dose

Escalation

0.1–10 mg/kg

n = 48

Dose

Expansion

3 mg/kg

n = 214

HCV Infected HBV Infected Uninfected

Sorafenib

Naive

n = 11

Study Endpoints

Primary

• Safety and tolerability

(escalation)

• ORRa (expansion)

Secondary

• ORRa (escalation)

• Disease control rate

• Time to response

• Duration of response

• Overall survival

Other

• Biomarker assessments

• Viral kinetics on treatment

ORR, objective response rate. a RECIST v1.1.

All Patients (N = 262)

Sorafenib

Experienced

n = 37

Sorafenib

Naive

n = 69

Sorafenib

Experienced

n = 145

5

CheckMate 040

Lancet. 2017 Apr 20. [Epub ahead of print].

SIN INFECCIÓN VIRAL CON INFECCIÓN VIRAL

CAMBIO DESDE LA BASAL EN LA CARGA TUMORAL DE LA LESION DIANA

MEJOR CAMBIO EN LA LESION

DIANA DESDE LA BASAL DURACIÓN DE LA RESPUESTA

HCV Infected

(n = 30)

HBV Infected

(n = 43)

Uninfected

(n = 72)

All Patients

(N = 145)

Median OS (95% CI)a NR NR 16.7 (11.3–NE) 16.7 (13.2–NE)

12-mo OS rate (95% CI) % 67.1 (46.2–81.4) 55.6 (39.6–69.0) 59.7 (47.4–70.0) 59.9 (51.3–67.4)

NR, not reached; NE, not estimable.

Overall Survival Sorafenib-Experienced Patients — Dose-Expansion Phase

Pro

bab

ilit

y o

f s

urv

ival

Months

0.0

0 3 6 9 12 15 18 21 24

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Objective Responsesa

HCV Infected

(n = 28)

HBV Infected

(n = 41)

Uninfected

(n = 57)

Tumor-cell PD-L1 expression ≥ 1%,

n/n (%)b

[95% CI]

3/8 (37.5)

[8.5–75.5]

2/8 (25.0)

[3.2–65.1]

2/9 (22.2)

[2.8–60.0]

Tumor-cell PD-L1 expression < 1%,

n/n (%)b

[95% CI]

3/20 (15.0)

[3.2–37.9]

4/33 (12.1)

[3.4–28.2]

6/48 (12.5)

[4.7–25.2]

a BICR using RECIST v1.1; b Tumor-cell PD-L1 expression not evaluable in 19 patients (HCV, n = 2; HBV, n = 2; uninfected, n =

15).

Tumor-cell PD-L1 Expression and ORR Sorafenib-Experienced Patients — Dose-Expansion Phase

15

• Objective responses occurred irrespective of PD-L1 expression on tumor

cells

HCV Infected

(n = 30)

HBV Infected

(n = 43)

Uninfected

(n = 72)

n (%) Any

Grade

Grade

3/4

Any

Grade

Grade

3/4

Any

Grade

Grade

3/4

Patients with any treatment-related AE 25 (83) 9 (30) 30 (70) 4 (9) 53 (74) 11 (15)

Treatment-related AEs (≥ 5%)a

Fatigue 6 (20) 1 (3) 5 (12) 0 24 (33) 2 (3)

Pruritus 8 (27) 1 (3) 9 (21) 0 10 (14) 0

Rash 6 (20) 0 6 (14) 0 11 (15) 1 (1)

Diarrhea 5 (17) 0 4 (9) 1 (2) 11 (15) 1 (1)

Nausea 3 (10) 0 1 (2) 0 8 (11) 0

Dry mouth 1 (3) 0 2 (5) 0 5 (7) 0

Decreased appetite 2 (7) 1 (3) 3 (7) 0 3 (4) 0

Laboratory treatment-related AEs (≥ 5%)a

ALT increased 2 (7) 1 (3) 2 (5) 0 6 (8) 2 (3)

AST increased 2 (7) 2 (7) 1 (2) 0 5 (7) 2 (3)

Blood bilirubin increasedb 1 (3) 0 0 0 2 (3) 0

Platelet count decreased 2 (7) 2 (7) 6 (14) 2 (5) 0 0

a Reported in ≥ 5% of all patients (N = 145), any grade; b Blood bilirubin increases were < 5% for all patients.

Safety Sorafenib-Experienced Patients — Dose-Expansion Phase

• Overall safety profile of nivolumab was similar to that of other tumor types with no new safety signals

• Most ALT and AST elevations were reversible with established algorithms

Conclusions Sorafenib-Experienced Patients — Dose-Expansion Phase

• In sorafenib-experienced patients with or without chronic viral hepatitis,

nivolumab demonstrated:

– Long-term survival and durable objective responses with extended follow-up

• Safety profiles of nivolumab in patients with or without chronic

viral hepatitis were similar to what has been observed in other

tumor types

– Hepatic safety events, including ALT/AST elevations, were manageable and

reversible

– No new safety signals were observed

18

CA209-459 (CheckMate 459) Randomized, Multi-center Phase III Study of Nivolumab vs Sorafenib

as First-Line Treatment in Advanced Hepatocellular Carcinoma

Start Date: November 2015 Estimated Study Completion Date: June 2019 Study Director: Bristol-Myers Squibb

Nivolumab 30 min IV Q2W

Sorafenib PO BID

Eligibility Criteria

Advanced HCC

Systemic therapy naïve

Locoregional therapy for HCC completed ≥ 4 weeks prior to baseline scan

Child-Pugh Class A

ECOG PS: 0 or 1

• Tumor imaging assessments

• On-treatment safety assessments

• Viral biomarkers (HBV, HCV)

Until unacceptable

toxicity or

disease progression

Objectives

Primary: OS, TTP (BICR; RECIST v1.1.)

Secondary: ORR, PFS, PD-L1 expression/efficacy

R

N=726

CÁNCER DE PÁNCREAS

PDAC es una enfermedad con una resistencia inmunológica destacada, a diferencia de otros tumores en los que la monoterapia con inhibidores del checkpoint tienen actividad destacada. Por lo que la inmunoterapia en cáncer de páncreas requerirá estrategias de combinación

Beatty et al. Educational Book ASCO 2017

• CP estadio IV • EE tras 8-12 ciclos de FOLFIRINOX • N= 92 rand 1:1

– Rama A: Vacuna + IPI (10 mg/kg c/3s x 4 dosis y luego cada 8 s) – Rama B: Continuar QT

• Objetivos – principal: SG – secundarios: SLP, ir-SLP, DOR, RR RECIST, ir-response

criteria, seguridad – exploratorios: identificación de predictores de respuesta y

toxicidad NCT01896869

Patel RK A et al. ASCO 2014, TPS4160

CÁNCER DE PÁNCREAS Fase II rand de FOLFIRINOX seguido de

Ipilimumab + vacuna tumoral pancreática

transfectada GM-CSF alogénica

• Cáncer epidermoide de esófago refractario, – Nivo consigue una RR 17% y SG 10,2 m (fase II)

• En cáncer gástrico refractario, – Nivo vs placebo aumenta RR, SLP y SG (fase III) – Pembrolizumab consigue RR 22% y SG 11,4 m (fase II)

• En hepatocarcinoma, – Nivo consigue RR 20% y SG 16,7 m (fase I/II)

• En cáncer de páncreas, se necesita investigar estrategias de combinación

• Expresión PD-L1: sugiere mayor eficacia pero también

responden los PD-L1 < 1%

• En marcha estudios con otros fármacos y en fase III

COMENTARIOS Inhibidores de immune checkpoint

ESTUDIOS EN MARCHA

CON INMUNOTERAPIA

CÁNCER DE ESÓFAGO EECC con anti-CTLA-4 y PD-1/PD-L1 y

PD-L2

Tanaka T, et al. Exp Opin Biol Ther 2017; 17: 723-733

CÁNCER DE ESÓFAGO

EECC con Adoptive cell transfer

Tanaka T, et al. Exp Opin Biol Ther 2017; 17: 723-733

CÁNCER DE ESÓFAGO

Vacunas tumorales

terapéuticas

Tanaka T, et al. Exp Opin Biol Ther 2017; 17: 723-733

CÁNCER GÁSTRICO

Principales EECC

Alsina M et al. Targ Oncol 2016; 11:469-477