Papel de la inmunoterapia en tumores digestivos no colorrectal · 2017-06-27 · –Elevación de...
Transcript of Papel de la inmunoterapia en tumores digestivos no colorrectal · 2017-06-27 · –Elevación de...
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