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Tratamiento en primera línea, ¿Cuando indicar y retirar la inmunoterapia?
Papel del re-tratamiento
Ángel Artal
Servicio de Oncología Médica
Hospital Universitario Miguel Servet
Pre-inmunoterapia
Chansky, JTO 2017Ekman, WCLC 17, MA18.14
5-yr OS
Advanced
Checkpoint inhibitors in NSCLC<br />Key milestones
Anti Pd1/ PDL1 en segunda líneaNivolumab Pembrolizumab Atezolizumab
Ensayo CheckMate 017 CheckMate 057 Keynote 010 POPLAR OAK
Fase III III II/ III II III
N 272 (135/ 137) 582 (292/ 290) 1.033 144 425
Dosis 3 mg/ Kg 3 mg/ Kg 2 mg/ Kg y 10 mg/ Kg 1.200 mg 1.200 mg
Brazo control Docetaxel Docetaxel Docetaxel Docetaxel Docetaxel
Histología Escamoso No escamoso Escamoso y no
escamoso
Escamoso y no
escamoso
Escamoso y no
escamoso
Respuesta objetiva (%) 20 19 18 18 14 15
Duración respuesta (meses) No alcanzada 17,2 No
alcanzada
No
alcanzada
17,2 16,3
Tiempo hasta progresión
(mediana, HR)
3,5
0,62
2,3
0,92 NS
5,0
0,88 NS
5,2
0,79 NS
2,8
0,94 NS
2,7
0,94 NS
Supervivencia global
(mediana, HR frente a
Docetaxel)
9,2
0,62
12,2
0,75
10,4
0,71
12,7
0,61
12,6
0,94
13,8
0,73
Supervivencia 1 año (%) 42 51 43,2 52,3 52 55
2 años (%) 23 29 - - 32 31
3 años (%) 17* - - - 19 -
*: combinado 017 y 057. NS: No significativa
Monoterapia
0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
T im e , m o n th s
OS
, %
P e m b r o 1 5 4 1 3 6 1 2 1 1 1 2 1 0 6 9 6 8 9 8 3 5 2 2 2 5 0
C h e m o 1 5 1 1 2 3 1 0 7 8 8 8 0 7 0 6 1 5 5 3 1 1 6 5 0
N o . a t r is k
Median (95% CI)30.0 mo (18.3 mo–NR)14.2 mo (9.8 mo–19.0 mo)
70.3%
54.8%
aEffective crossover rate from chemotherapy to anti-PD-L1 therapy, 62.3% (82 patients crossed over to pembrolizumab during the study and 12 received anti-PD-L1 therapy outside of crossover). bNominal P value. NR, not reached.Data cutoff: July 10, 2017.
51.5%
34.5%
Events, n HR (95% CI)
Pembrolizumaba 73 0.63
(0.47–0.86)
P = 0.002bChemotherapy 96
Bhramer JR. IASLC Tokio 2017
Keynote 024. PDL1 > 50%. QT vs pembrolizumab. Beneficio SG para pembrolizumab
Nivolumab
Chemotherap
y
Months
PFS
(%
)
2421181512963 27
100
80
60
40
0
20
0
All randomized patients (≥1% PD-L1+)
HR = 1.17 (95% CI: 0.95, 1.43)
HR = 1.15 (95% CI: 0.91, 1.45), P = 0.2511
MonthsO
S (%
)
2421181512963 30
100
80
60
40
0
20
0 27
Nivolumab
Chemotherapy
HR = 1.02 (95% CI: 0.80, 1.30)
All randomized patients (≥1% PD-L1+)
HR = 1.07 (95% CI: 0.86, 1.33)
CI=confidence interval; HR=hazard ratio; mos=months; OS=overall survival; PFS=progression-free survival; PD-L1=programmed death ligand 1..
Nivolumabn = 211
Chemon = 212
Median PFS, mos(95% CI)
4.2(3.0, 5.6)
5.9(5.4, 6.9)
1-year PFS rate, % 23.6 23.2
Nivolumab
n = 211
Chemo
n = 212
Median OS, mos
(95% CI)
14.4
(11.7, 17.4)
13.2
(10.7, 17.1)
1-year OS rate,
%56.3 53.6
No. of patients at risk:
Nivo 211 104 71 49 35 24 6 3 1 0
Chem
o
212 144 74 47 28 21 8 1 0 0
No. of patients at risk:
Nivo 211 186 156 133 118 98 49 14 4 0 0
Chemo 212 186 153 137 112 91 50 15 3 1 0
Socinski M et al. Oral presentation at ESMO 2016
Checkmate 026. PDL1 > 5%. Quimioterapia vs Nivolumab.
fármaco /combinaciones aún no aprobadas por Agencias Regulatorias en esta indicación
Keynote 042. PDL1 > 1%. Fase III Quimioterapia vs pembrolizumab. Pembrolizumab. Beneficio en SG para pembrolizumab
G Lopes. ASCO 2018. Plenary sesion. Abstract LBA4
Beneficio a expensas de casi el 49% de pacientes PDL1 >50%
G Lopes. ASCO 2018. Plenary sesion. Abstract LBA4
Inmuno-Inmunoterapia
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
CheckMate 227 Part 1 Study Designa
Database lock: January 24, 2018; minimum follow-up: 11.2 months
N = 1189
<1% PD-L1expression
N = 550
Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W
n = 396
Histology-based chemotherapyb
n = 397
Nivolumab 240 mg Q2Wn = 396
Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W
n = 187
Histology-based chemotherapyb
n = 186
Nivolumab 360 mg Q3W + histology-based chemotherapyb
n = 177
R
1:1:1
Key Eligibility Criteria• Stage IV or recurrent NSCLC
• No prior systemic therapy
• No known sensitizing
EGFR/ALK alterations
• ECOG PS 0–1
Stratified by SQ vs NSQ
R
1:1:1
7
aNCT02477826 bNSQ: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemotherapy or nivolumab + pemetrexed maintenance following nivolumab + chemotherapy; SQ: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles; cThe TMB co-primary analysis was conducted in the subset of patients randomized to nivolumab + ipilimumab or chemotherapy who had evaluable TMB ≥10 mut/Mb
≥1% PD-L1expression
Nivolumab + ipilimumab n = 396
Chemotherapyb
n = 397
Patients for PD-L1 co-primary analysis
Co-primary endpoints: Nivolumab +
ipilimumab vs chemotherapy
• OS in PD-L1–selected populations
• PFS in TMB-selected populations
Nivolumab + ipilimumab n = 139
Chemotherapyb
n = 160
Patients for TMB co-primary analysisc
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
• Whole exome sequencing in tumor tissue samples from patients with NSCLC and SCLC treated with nivolumab + ipilimumab demonstrates the potential of TMB as an independent biomarker of efficacy, distinct from PD-L11,2
12
1. Hellmann MD, et al. Cancer Cell 2018. doi: https://doi.org/10.1016/j.ccell.2018.03.018. Epub; 2. Hellmann MD, et al. Cancer Cell (in press) 2018.
Preliminary Analyses of TMB in Lung Cancers Treated With Nivolumab + Ipilimumab
SCLC (CheckMate 032; n = 78)
High TMB tertile
Medium TMB tertile
Low TMB
tertile
100
75
50
25
0
0 6 12 18 24 30
PF
S (
%)
Months
PF
S (
%)
NSCLC (CheckMate 012; n = 75)
60 12 18 24 30 36 42 48
0
50
100
Months
TMB > median
TMB ≤ median25
75
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
CheckMate 026. Nivo vs Quimioterapia 1º línea PDL1>5%. No diferencias SG. Pero en
pacientes con alta carga mutacional, nivolumab tiene PFS significativamente menor.
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
TMB Analysis Using FoundationOne CDx™
• 58% of all randomized patients had TMB-evaluable samplesa
TMB-evaluable patients
(n = 1004)
≥10 mut/Mb<10 mut/Mb
44%56%
All randomized patients
(N = 1739)a
TMB-evaluable patients
(n = 1004)
Age, median (range), y 64 (26-89) 64 (29-89)
Female, % 32 33
ECOG PS, %
0
1
≥2
Not reported
34
65
<1
<1
33
67
<1
<1
Smoking status, %
Current/former smoker
Never smoker
Unknown
85
13
1
87
12
1
Histology, %
Squamous
Non-squamous
28
72
29
71
Tumor PD-L1 expression, %
<1%
≥1%
32
68
29
71
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
TMB and Tumor PD-L1 Expression Identify Distinct and Independent Populations of NSCLC
Tumor PD-L1 expression
11aSymbols (dots) in the scatterplot may represent multiple data points, especially for patients with <1% tumor PD-L1 expression. The black line shows the relationship between TMB and PD-L1
expression as described by a linear regression model; bAmong patients in the nivolumab +ipilimumab and chemotherapy arms; TMB ≥10 mut/Mb, n = 299; TMB <10 mut/Mb, n = 380
TMB and tumor PD-L1 expressiona
PD-L1 expression (%)
TM
B (
nu
mb
er
of
mu
tati
on
s/M
b)
0
20
40
60
80
100
160
120
140
0 20 40 60 80 100
TMB ≥10 mut/Mbb
TMB <10 mut/Mbb
<1%
29%≥1%
71%
<1%
29%≥1%
71%
<1%
29%≥1%
71%
<1%
29%≥1%
71%
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Co-primary Endpoint: PFS With Nivolumab + Ipilimumab vs Chemotherapy in Patients With High TMB (≥10 mut/Mb)a
16
Nivo + ipi 139 85 66 55 36 24 11 3 0
Chemo 160 103 51 17 7 6 4 0 0
Nivo + ipi
(n = 139)
Chemo
(n = 160)
Median PFS,b mo 7.2 5.4
HRc
97.5% CI
0.58
0.41, 0.81
P = 0.0002
Months
0
20
40
60
80
100
0 6 12 183 9 15 21 24
PF
S (
%)
Chemotherapy
Nivolumab +ipilimumab
1-y PFS = 43%
1-y PFS = 13%
aPer blinded independent central review (BICR); median (range) of follow-up in the co-primary analysis population was 13.6 mo (0.4, 25.1) for nivo + ipi and 13.2 mo (0.2, 26.0) for chemo;b95% CI: nivo + ipi (5.5, 13.2 mo), chemo (4.4, 5.8 mo); c95% CI: 0.43, 0.77 mo; dThe P-value for the treatment interaction was 0.0018
No. at risk
• In patients with TMB <10 mut/Mb treated with nivo + ipi vs chemo, the HR was 1.07 (95% CI: 0.84, 1.35)d
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
ORR and DOR in Patients With High TMB (≥10 mut/Mb)a
17
0
10
20
30
40
50
Nivo + Ipi Chemo
ORR (TMB ≥10 mut/Mb)b
OR
R (
%)
DOR (TMB ≥10 mut/Mb)
63/139n/N:
Months
100
Chemotherapy
Nivolumab +ipilimumab
Pa
tie
nts
in
re
sp
on
se
(%
)
• Median time to response was 2.7 months with nivolumab + ipilimumab and 1.5 months with chemotherapy
43/160
a Per BICR; bORR in patients with TMB <10 mut/Mb was 24.6% in nivo + ipi arm and 25.9% in chemo arm
45.3
26.9
CR
PR
Nivo + ipi Chemo
≥1-y DOR = 68%
≥1-y DOR = 25%
Nivo + ipi
(n = 63)
Chemo
(n = 43)
Median DOR, mo
(95% CI)
NR
(12.2, NR)
5.4
(4.2, 6.9)
Nivo + ipi 63 56 46 32 22 10 5 0
Chemo 43 32 15 5 2 2 1 0
No. at risk
0
20
40
60
80
0 6 12 183 9 15 21
3.6
41.70.6
26.3
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Nivo + ipi
(n = 95)
Chemo
(n = 104)
Median PFS, moa 9.5 5.6
HR
95% CI
0.55
0.38, 0.80
PFS in Patients With High TMB (≥10 mut/Mb) by Tumor Histology
18
Non-squamous
1-y PFS = 46%
1-y PFS = 17%
Nivo + ipi 95 59 49 41 27 18 8 1 0
104 70 38 15 6 6 4 0 0
Chemotherapy
Nivolumab +ipilimumab
Months
PF
S (
%)
0
20
40
60
80
100
0 6 12 183 9 15 2421
Squamous
44 26 17 14 9 6 3 2 0
56 33 13 2 1 0 0 0 0
Months
1-y PFS = 36%
1-y PFS = 7%
Nivo + ipi
(n = 44)
Chemo
(n = 56)
Median PFS, mob 4.9 4.3
HR
95% CI
0.63
0.39, 1.04
Chemotherapy
Nivolumab +ipilimumab
0
20
40
60
80
100
0 6 12 183 9 15 2421
No. at risk
Chemo
a95% CI: nivo + ipi (5.6 mo, NR), chemo (4.5, 7.0 mo); b95% CI: nivo + ipi (2.7, 13.7 mo), chemo (3.2, 5.6 mo)
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Preliminary Overall Survival With Nivolumab + Ipilimumab vs Chemotherapy in Patients With High TMB (≥10 mut/Mb)
19
Nivo + ipi
(n = 139)
Chemo
(n = 160)
Median OS,b mo 23.0 16.4
HR
95% CI
0.79
0.56, 1.10
Months
OS
(%
)a
aIn the first 1.5 months, 8 deaths occurred in the nivo + ipi arm (4 due to disease progression; 1 patient never treated [respiratory sepsis]; 2 due to AEs unrelated to study drug per investigator [thromboembolism, septic shock]; 1 due to myocarditis related to study drug), and 2 deaths occurred in the chemo arm (1 due to disease progression; 1 due to multiple brain infarctions related to carboplatin); b95% CI: nivo + ipi (16.5 mo, NR), chemo (12.6 mo, NR); cPer investigator
No. at risk
Nivo + ipi 139 120 112 98 90 71 44 16 5
Chemo 160 148 129 104 90 75 45 23 9
0
1
0
0
Chemotherapy
Nivolumab + ipilimumab
1-y OS = 67%
1-y OS = 58%
0
20
40
60
80
100
0 6 12 183 9 15 21 24 27 30
• Database lock: March 15, 2018; minimum follow-up: 14.2 months; 53% of patients were censored
• In the chemotherapy arm, 31.3% received subsequent immunotherapy (38.3% among those with disease progressionc)
Combinaciones con QT
21
Brahmer J
22
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Luis Paz-Ares. ASCO 2018. ORAL
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Atezolizumab 1200 mg IV q3w; carboplatin AUC 6 IV q3w; nab-paclitaxel 100 mg/m2 IV qw; paclitaxel 200 mg/m2 IV q3w. a Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance to treatment with ≥ 1 approved targeted therapies. Testing for EGFR mutation or ALK translocation was not mandatory.
Arm A
Atezolizumab + Carboplatin + Paclitaxel
4 or 6 cycles
Atezolizumab
Arm C (control)
Carboplatin + Nab-Paclitaxel
4 or 6 cycles
Best Supportive Care
Surv
ival
fo
llow
-up
Stage IV squamous NSCLC• Chemotherapy naivea
• ECOG PS 0 or 1 • Any PD-L1 IHC status
Stratification factors:• Sex• PD-L1 IHC expression• Liver metastases
N = 1021
R1:1:1
Arm B
Atezolizumab + Carboplatin + Nab-Paclitaxel
4 or 6 cycles
Atezolizumab
Maintenance therapy
(no crossover permitted)
Until PD per RECIST v1.1 or loss of clinical
benefit
Until PD per RECIST v1.1
Co-primary endpoints
• Investigator-assessed PFS per RECIST v1.1 (ITT)• OS (ITT)
Secondary endpoints
• PFS and OS in PD-L1 subgroups• ORR, DOR; safety
IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in
advanced non- squamous NSCLC.
fármaco /combinaciones aún no aprobadas por Agencias Regulatorias en esta indicación
Robert Jotte, et al. ASCO 2018
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
INV-Assessed PFS in the ITT Population (Arm B vs Arm C)
Data cutoff: January 22, 2018. INV, investigator. a Stratified HR.
Minimum follow-up, 9.8 mo
Median follow-up, 17.1 mo
Time (months)
12.0%
24.7%
12-month PFS
Arm B:
Atezo +
CnP
Arm C:
CnP
Median
PFS
(95% CI),
mo
6.3
(5.7, 7.1)
5.6
(5.5, 5.7)
HRa (95%
CI)
P value
0.71 (0.60, 0.85)
0.0001
Pro
gre
ssio
n-F
ree
Su
rviv
al (
%)
No. at risk
IPW 131, INV-Assessed PFS
fármaco /combinaciones aún no aprobadas por Agencias Regulatorias en esta indicación
Robert Jotte, et al. ASCO 2018
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Data cutoff: January 22, 2018. a Stratified HR.
56.9
%55.6
%
12-month OS
24.1
%
31.9
%
24-month OS
Arm B:
Atezo +
CnP
Arm C:
CnP
Median OS
(95% CI),
mo
14.0
(12.0, 17.0)
13.9
(12.3, 16.4)
HRa (95%
CI)
P value
0.96 (0.78, 1.18)
0.6931
Ove
rall
Surv
ival
(%
)
Time (months)No. at risk
IPW 131, INV-Assessed OS . Datos inmaduros
fármaco /combinaciones aún no aprobadas por Agencias Regulatorias en esta indicación
Robert Jotte, et al. ASCO 2018
Inmuno + QT + Antiangiogénico
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
IMpower150 Study Design
Presented By Mark Socinski at 2018 ASCO Annual Meetingfármaco /combinaciones aún no aprobadas por Agencias Regulatorias en esta indicación
Mark A Socinski, et al. ASCO 2018
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Updated PFS Analysis in the ITT-WT (Arm B vs Arm C)
Mark A Socinski, et al. ASCO 2018
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
OS in the ITT (Arm B vs Arm C)
Presented By Mark Socinski at 2018 ASCO Annual Meetingfármaco /combinaciones aún no aprobadas por Agencias Regulatorias en esta indicación
Mark A Socinski, et al. ASCO 2018
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
Safety
Presented By Mark Socinski at 2018 ASCO Annual Meetingfármaco /combinaciones aún no aprobadas por Agencias Regulatorias en esta indicación
Mark A Socinski, et al. ASCO 2018
CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)
OS in Key Subgroups (Arm B vs Arm C)
Presented By Mark Socinski at 2018 ASCO Annual Meetingfármaco /combinaciones aún no aprobadas por Agencias Regulatorias en esta indicación
Mark A Socinski, et al. ASCO 2018
Duración del tratamiento
➢ Dos años vs Hasta pérdida de beneficio clínico
➢ En segunda línea parece que 1 años es inferior a 2 años
Robert C, Ribas A, Hamid O, et al: Durable complete response following
discontinuation of pembrolizumab in patients with metastatic melanoma.
J Clin Oncol 36:1668-1674, 2018
Resumen➢ Inmunoterapia en primera línea
Actual: MonoterapiaPróximamente: Combinaciones
➢ Integrar marcadores (TMB)
➢ Duración: Basada en ensayos clínicos
➢ Papel del re-tratamiento: EspeculativoTipo de respuesta previa, tiempo hasta la progresión, tipo de progresión, motivo de la interrupción
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