inmunoterapia en primera línea de cancer de pulmón no ......ph3 rct. un oncólogo ante el cáncer...
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Antonio CallesServicio de Oncología Médica
Unidad de Tumores Torácicos y Unidad de Fases 1
Hospital General Universitario Gregorio Marañón
Instituto Investigación Sanitaria HGUGM
Universidad Complutense de Madrid
Madrid, España
Inmunoterapia en primera línea de cancer de pulmón
no microcítico: ¿sola o en combinación?
Conflicts of interest
Honorary/consulting fees:
AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli
Lilly and Company, Novartis, Merck Sharp & Dohme, Bristol-Myers
Squibb, AbbVie.
Año 2018: La inmunoterapia conquista la 1ª línea a la
quimioterapia en cáncer de pulmón
11
Ph3 RCT
Un oncólogo ante el cáncer de pulmón en el año 2018
Inmunoterapia en 1L de CPNM Avanzado
Y tras AACR18, ASCO18, WCLC18 y ESMO18 ¿qué?
• Cambio de paradigma: La quimioterapia ya no es el el componentefundamental…
• ….la inmunoterapia es el componente fundamental del tratamiento de primera línea del CPNM Avanzado
• Se van a beneficiar más pacientes de recibir tratamiento con IO en 1L (30%-50% no reciben tratamiento tras progresión a 1L)
• Beneficio de la IO parece superior cuanto antes se utilice (1L > 2L)
• Monoterapias: Menos tóxicas que la quimioterapia
• Combos: Similares en toxicidad a la quimioterapia, >irAEs
Inmunoterapia en 1L de CPNM Avanzado
Agenda
Inmunoterapia sola
Inmunoterapia + quimioterapia
Inmunoterapia + Inmunoterapia
Inmunoterapia sola
1L NSCLC: Phase 3 Trials With I-O Monotherapy
KEYNOTE-0241 /
KEYNOTE-0422 Checkmate 0263 MYSTIC4,5
Study ArmsPembrolizumab 200 mg q3w Nivolumab 3 mg/kg q2w
Durvalumab 20 mg/kg q4w
Durvalumab 20 mg/kg q4w
+ tremelimumab 1 mg/kg q4w
Pt-based chemo Pt-based chemo Pt-based chemo
N 305 / 1274 541 675
PD-L1 Cutoff ≥50% / ≥1% ≥5%* ≥25%
PD-L1 Assay Dako 22C3 Dako 28-8 Ventana SP263
Primary
Endpoint(s)PFS / OS PFS PFS, OS
Key Findings
• PFS benefit demonstrated with
pembrolizumab in patients with
PD-L1 ≥50%
• OS benefit demonstrated with
pembrolizumab in patients with
PD-L1 ≥1%
PFS benefit not demonstrated with
nivolumab in patients with PD-L1
≥5%
PFS and OS benefit not
demonstrated with durvalumab
monotherapy† in patients with PD-L1
≥25%
Cross-study comparisons are not intended. *For primary analysis. Patients with ≥1% PD-L1 expression were eligible. †Not yet formally tested.1. Reck M et al. N Engl J Med. 2016;375(19):1823-1833. 2. Lopes G et al. Oral presentation at ASCO 2018. 105. 3. Carbone DP et al. N Engl J Med. 2017;376(25):2415-2426. 4. Peters S et al. Poster presentation at ELCC 2016. 191TiP. 5. AstraZeneca [press release]. July 27, 2017.
MSD AZAZBMS
62% crossover
KEYNOTE-024
KEYNOTE-024: More frequent TRAEs with chemotherapy
Phase III CheckMate 026 Study Design: Nivolumab vs Chemotherapy in First-lineNSCLC
Carbone et al: NEJM 2017
PrimaryEndpoint:PFSin patients with>5%PD-L1
60% crossover
PFS by Tumor Mutation Burden SubgroupCheckMate 026 TMB Analysis (WES): Nivolumab vs Chemotherapy in
First-Line NSCLC
Nivolumab
Chemotherapy47 30 26 21 16 12 4 1
60 42 22 15 9 7 4 1
111 54 30 15 9 7 2 1 1
94 65 37 23 15 12 5 0 0
Nivolumabn = 47 n = 60
9.7(5.1, NR)
5.8(4.2, 8.5)
Chemotherapy
Median PFS, months(95% CI)
High TMB
PF
S (
%)
3 6 9 12 15 18 21
No. at RiskMonths
100
90
80
70
60
50
40
30
20
10
0
0
Nivolumab
Chemotherapy
0 3 6 9 12
Months
15 18 21 24
Nivolumab
Chemotherapy
100
90
80
70
60
50
40
30
20
10
0
n = 111 n = 94
4.1(2.8, 5.4)
6.9(5.5, 8.6)
HR = 1.82 (95% CI: 1.30, 2.55)
Nivolumab Chemotherapy
(95% CI)Median PFS, months
Low/medium TMB
HR = 0.62 (95% CI: 0.38, 1.00)
Carbone DP et al. N Engl J Med. 2017
OS by Tumor Mutation Burden SubgroupCheckMate 026 TMB Analysis: Nivolumab in First-Line NSCLC
n = 111 n = 94
12.7(9.9, 16.1)
13.2(9.5, 15.2)
HR = 0.99 (95% CI: 0.71, 1.40)
Nivolumab Chemotherapy
(95% CI)Median OS, months
Low/medium TMB
55% received nivolumab as crossover and/or post-study treatment
1-y OS rate = 54% vs 53%
0 3 6 9 12
Months
15 18 21 24
100
90
80
70
60
50
40
30
20
10
0
111 99 82 69 59 47 28 11 3
94 87 71 60 50 38 21 6 2
27
Nivolumab
Chemotherapy
0
1
n = 47 n = 60
18.3(11.4, NR)
18.8(11.3, NR)
HR = 1.10 (95% CI: 0.64, 1.88)
Nivolumab Chemotherapy
(95% CI)Median OS, months
68% received nivolumab as crossover and/or post-study treatment
High TMB
0 3 6 9 12
Months
15 18 21 24
No. at Risk
Nivolumab
Chemotherapy
OS
(%
)
100
90
80
70
60
50
40
30
20
10
0Nivolumab
Chemotherapy
47 41 35 33 30 24 13 4 0
60 56 48 45 36 34 19 9 1
1-y OS rate = 64% vs 60%
KN-024, KN-042 y CM 026: Datos dispares en OS de la monoterapia
KEYNOTE-042 OSPD-L1 TPS ≥1%
No crossover
PLENARY SESSION
Checkmate 026 and KEYNOTE-042: Differences in Study Design and Patient Characteristics
• Checkmate 0261,2
• 60.4% in the chemotherapy arm had subsequent nivolumab therapy—crossover allowed
• 43.6% in the nivolumab arm had subsequent systemic therapy
• 32% of patients in the nivolumab arm and 47% of patients in the chemotherapy arm had ≥50% PD-L1 expression
• Primary analysis population included patients with PD-L1 ≥5%
• Lower response rate in nivolumab arm (26%) compared to chemotherapy arm (33%)
• KEYNOTE-0421,3
• 19.8% in the chemotherapyarm had subsequent immunotherapy (3% in pembrolizumab arm)
• 37% in the pembrolizumabarm had subsequent chemotherapy (31.6% in chemotherapy arm)
• 47% of patients in both arms had ≥50% PD-L1 expression
• Primary analysis population included patients with PD-L1 ≥1%
• Response rate similar overall to chemotherapy (27%)
1. Gandhi L. Discussant section at ASCO 2018. LBA4. 2. Carbone DP et al. N Engl J Med. 2017;376(25):2415-2426 [supplemental appendix]. 3. Lopes G et al. Oral presentation at ASCO 2018. LBA4.
KEYNOTE-042 OS by PD-L1
1. Se puede llegar a deducir que el beneficio en OS es derivado fundamentalmente del
subgrupo PD-L1 TPS >50%
2. Amplio sobrecruzamiento en las curvas de supervivencia en el subgrupo de PD-L1
TPS 1-49%, indica probablemente la existencia de 2 poblaciones (¿TMBhigh?)
47% 53%
Combinaciones con Inmunoterapia
• Histología no-escamosa
• Histología escamosa
• Combinaciones con anti-CTLA4
Phase 3 Trials of I-O + Chemotherapy in 1L NSCLC
KEYNOTE-189
Pembro + CT1
IMpower150
(Arms B & C)
Atezo + CT2
IMpower132
Atezo + CT3
IMpower130
Atezo + CT6
KEYNOTE-407
Pembro + CT4
IMpower131
(Arms B & C)
Atezo + CT5
Histology Nonsquamous Nonsquamous Nonsquamous Nonsquamous Squamous Squamous
N 616 800 578 679 559 683
PD-L1
StatusAll comers All comers All comers All comers All comers All comers
Primary
Endpoint(s)PFS, OS PFS, OS PFS, OS PFS, OS PFS, OS PFS, OS
Study Arms Pembro
pem
cis/carb
Pem
cis/carb
Atezo
bev
carb
pac
(Arm B)
Bev
carb
pac
(Arm C)
Atezo
carb/cis
pem
Carb/cis
pem
Atezo
carb
nab-pac
Carb
nab-pac
Pembro
carb
pac/
nab-pac
Carb
pac/
nab-pac
Atezo
carb
nab-pac
(Arm B)
Carb
nab-pac
(Arm C)
Cross-trial comparisons are not intended. *Nonsquamous: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemotherapy or nivo lumab + pemetrexed maintenance following nivolumab + chemotherapy; squamous: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles.1. Gandhi L et al. N Engl J Med. 2018;378(22):2078-2092. 2. Socinski MA et al. N Engl J Med 2018;378(24):2288-2301. 3. Papadimitrakopoulou VA et al. Oral presentation at WCLC 2018. OA05.07. 4. Paz-ares L, et al. N Engl J Med. 2018; doi: 10.1056/NEJMoa1810865. 5. Jotte et al. Oral presentation at ASCO 2018. LBA9000. 6. Capuzzo et al. ESMO 2018.
MSD MSDRoche Roche RocheRoche
Combinaciones con Inmunoterapia
• Histología no-escamosa
• Histología escamosa
• Combinaciones con anti-CTLA4
50%
crossover
Gandhi et al., NEJM 2018
Beneficio independiente de la expresión de PD-L1
KN189
¿Necesitan quimioterapia los pacientes con PD-L1 >50%?
KN189
KN024
¿Necesitan quimioterapia los pacientes con PD-L1 >50%?
Adverse Events
5.2% vs 0.5% acute renal injury
Reck IM150 ESMO-IO 2017Socinski IM150 ASCO 2018
Atezolizumab + Taxane-based 1L Chemo in NSCLC
IMpower130
PFS OS
Cross over to immunotherapy 135 (59.2%)
HR: 0.64
(95% CI: 0.54, 0.77)
P < 0.0001
HR: 0.79
(95% CI: 0.64, 0.98)
P = 0.033
Clear improvement of ORR, PFS and OS adding atezolizumab
Control arm: 20% Pemetrexed switch maintenance
Cappuzzo ESMO 2018
Atezolizumab + Taxane-based 1L Chemo in NSCLC
PFS (ITT-WT)
*Arm B vs. C
Pro
gres
sio
n-F
ree
Surv
ival
(%)
HRa, 0.59(95% CI: 0.50, 0.70)
P < 0.0001b
Median follow-up: ~20 mo
Cappuzzo, ESMO 2018; Socinski ASCO 2018
P(
)
%
F
S
HR: 0.64(95% CI: 0.54, 0.77)
P < 0.0001
Median follow-up: ~19 mo
Median: 7.0 mo
(95% CI: 6.2, 7.3)
Median: 5.5 mo
(95% CI: 4.4, 5.9)
Median, 8.3 mo(95% CI: 7.7, 9.8)
Median, 6.8 mo(95% CI: 6.0, 7.1)
IMpower 130Nab-Pacli.Carbo +/- atezo
IMpower 150Pacli.Carbo.Bev. +/- atezo*
Atezolizumab + Taxane-based 1L Chemo in NSCLC
Ove
rall
Surv
ival
(%)
OS (ITT-WT)
HRa, 0.78(95% CI: 0.64, 0.96)
P = 0.0164
OS
(%)
HR 0.79(95% CI 0.64–0.98)
P=0.033
Median, 18.6 mo(95% CI 16.0–21.2)
Median, 13.9 mo(95% CI 12.0–18.7)
Median, 19.2 mo(95% CI: 17.0, 23.8)
Median, 14.7 mo(95% CI: 13.3, 16.9)
IMpower 130Nab-Pacli.Carbo +/- atezo
IMpower 150Pacli.Carbo.Bev. +/- atezo*
Cappuzzo, ESMO 2018; Socinski ASCO 2018*Arm B vs C
What is the role of bevacizumab?
Atezolizumab + Taxane-based 1L Chemo in NSCLC
Atezolizumab + Taxane-based 1L Chemo in NSCLC
Impower 132 study design
•
a Atezolizumab: 1200 mg IV q3w; Carboplatin: AUC 6 mg/mL/min IV q3w; Cisplatin: 75 mg/m2 IV q3w;
Pemetrexed: 500 mg/m2 IV q3w. NCT02657434. Data cutoff: May 22, 2018
Maintenance therapy
Arm PPa
Carboplatin or cisplatin
+ pemetrexed
4 or 6 cycles
Pemetrexeda
Su
rviv
alfo
llo
w-u
p
Chemotherapy-naive
patients with Stage IV
non-squamous NSCLC
without EGFR or ALK
genetic alteration
Stratification factors:
• Sex
• Smoking status
• ECOG PS
• Chemotherapy regimen
N = 578
R
1:1
Atezolizumaba
+
pemetrexeda Maintenance
Treatment
until PD by
RECIST v1.1
or loss of
clinical benefit
Induction therapy
Arm APPa
Atezolizumab
+ carboplatin or cisplatin
+ pemetrexed
4 or 6 cycles
Barlesi, ESMO 2018
5.2 mo(95% CI: 4.3, 5.6)
7.6 mo(95% CI: 6.6, 8.5)
HR, 0.60(95% CI: 0.49, 0.72)
P < 0.0001
Minimum follow-up: 11.7 mo
Median follow-up: 14.8 mo
13.6 mo(95% CI: 11.4, 15.5)
18.1 mo(95% CI: 13.0, NE)
HR, 0.81(95% CI: 0.64, 1.03)
P = 0.0797
Minimum follow-up: 11.7 mo
Median follow-up: 14.8 mo
Clear improvement of PFS and OS adding atezolizumab
PFS OS
IMpower 132 - OSPemetrexed Platin +/- Atezo
Barlesi, ESMO 2018
Capuzzo, ESMO 2018
IMpower 130 - OSNab-Pac Platin +/- Atezo
* VEGFRexpression
Sandler NEJM 2006, Tagliamonte Curr Opin Immun 2016, Koinis JTO 2016
* ** *
Liver = immunesuppressive microenvironment
Whithout Bevacizumabno benefit in the liver mets
subgroup
Combinaciones con Inmunoterapia
• Histología no-escamosa
• Histología escamosa
• Combinaciones con anti-CTLA4
Phase 3 Trials of I-O + Chemotherapy in 1L NSCLC
KEYNOTE-189
Pembro + CT1
IMpower150
(Arms B & C)
Atezo + CT2
IMpower132
Atezo + CT3
IMpower130
Atezo + CT6
KEYNOTE-407
Pembro + CT4
IMpower131
(Arms B & C)
Atezo + CT5
Histology Nonsquamous Nonsquamous Nonsquamous Nonsquamous Squamous Squamous
N 616 800 578 679 559 683
PD-L1
StatusAll comers All comers All comers All comers All comers All comers
Primary
Endpoint(s)PFS, OS PFS, OS PFS, OS PFS, OS PFS, OS PFS, OS
Study Arms Pembro
pem
cis/carb
Pem
cis/carb
Atezo
bev
carb
pac
(Arm B)
Bev
carb
pac
(Arm C)
Atezo
carb/cis
pem
Carb/cis
pem
Atezo
carb
nab-pac
Carb
nab-pac
Pembro
carb
pac/
nab-pac
Carb
pac/
nab-pac
Atezo
carb
nab-pac
(Arm B)
Carb
nab-pac
(Arm C)
Cross-trial comparisons are not intended. *Nonsquamous: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemotherapy or nivo lumab + pemetrexed maintenance following nivolumab + chemotherapy; squamous: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles.1. Gandhi L et al. N Engl J Med. 2018;378(22):2078-2092. 2. Socinski MA et al. N Engl J Med 2018;378(24):2288-2301. 3. Papadimitrakopoulou VA et al. Oral presentation at WCLC 2018. OA05.07. 4. Paz-ares L, et al. N Engl J Med. 2018; doi: 10.1056/NEJMoa1810865. 5. Jotte et al. Oral presentation at ASCO 2018. LBA9000. 6. Capuzzo et al. ESMO 2018.
MSD MSDRoche Roche RocheRoche
Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting
Beneficio independiente de la expresión de PD-L1
KN407
Jotte IM131 ASCO 2018
First interim OS in the ITT population
42% in control arm received immunotherapy
Jotte IM131 ASCO 2018
No escamosoEscamoso
Terapias dirigidas (EGFR, ALK, ROS1, BRAF…)
Quimioterapia: Pemetrexed, mantenimiento
Antiangiogénicos: Bevacizumab, nintedanib
Inmunoterapia
Inmunoterapia
2L: Nivolumab (Pembrolizumab, Atezolizumab)
New SoC
KN-407
Carcinoma escamoso de pulmón avanzado: Necesidad médica no cubierta
IMPOWER 1501 400 400 0.62 [0.52;0.74]
TrialNo. patients
Immuno Control
HR [95% CI]
Immuno vs. control
IMPOWER 132 292 286 0.60 [0.49;0.72]
KEYNOTE 189 410 206 0.52 [0.43;0.64]
IMPOWER 130 451 228 0.64 [0.54;0.77]
Total 1553 1120 0.60 [0.54;0.65]
p<0.0001
0.2Heterogeneity : p=0.42, I²=0%
1 paclitaxel + carboplatin + bevacizumab + atezolizumab versus paclitaxel + carboplatin + bevacizumab
1.0 2.0
Immuno better | Control better
CT + Immuno - PFS
Besse and Pignon ESMO 2018
IMPOWER 1501 400 400 0.78 [0.64;0.96]
TrialNo. patients
Immuno Control
HR [95% CI]
Immuno vs. control
IMPOWER 1502 402 400 0.88 [0.72;1.08]
IMPOWER 132 292 286 0.81 [0.64;1.03]
KEYNOTE 189 410 206 0.49 [0.38;0.64]
IMPOWER 130 451 228 0.79 [0.64;0.98]
Total 1955 1520 0.76 [0.69;0.83]
p<0.0001
0.2
% of cross over
37.1%
41.3%
59.2%
31.7%
Heterogeneity : p=0.007, I²=71%1 paclitaxel + carboplatin + bevacizumab + atezolizumab versus paclitaxel + carboplatin + bevacizumab
2 paclitaxel + carboplatin + atezolizumab versus paclitaxel + carboplatin + bevacizumab
1.0 2.0
Immuno better | Control better
CT + Immuno - OS
Besse and Pignon ESMO 2018
IMPOWER 1501 191 205 0.77 [0.61;0.99]
TrialNo. patients
Immuno Control
HR [95% CI]
Immuno vs. control
IMPOWER 132 88 75 0.45 [0.31;0.64]
KEYNOTE 189 127 63 0.75 [0.53;1.05]
IMPOWER 130 235 121 0.72 [0.56;0.91]
Total 641 464 0.69 [0.60;0.80]
p<0.0001
Heterogeneity : p=0.10, I²=52%0.2 1.0 2.0
Immuno better | Control better
1 paclitaxel + carboplatin + bevacizumab + atezolizumab versus paclitaxel + carboplatin + bevacizumab
PD-L1 NEGATIVE - PFS
Besse and Pignon ESMO 2018
IMPOWER 1501 191 205 0.82 [0.62;1.08]
TrialNo. patients
Immuno Control
HR [95% CI]
Immuno vs. control
KEYNOTE 189 127 63 0.59 [0.38;0.92]
IMPOWER 130 235 121 0.81 [0.61;1.08]
Total 553 389 0.77 [0.64;0.92]
p=0.005
0.2
% of cross over
41.3%
59.2%
31.7%
Heterogeneity : p=0.42, I²=0%
1 paclitaxel + carboplatin + bevacizumab + atezolizumab versus paclitaxel + carboplatin + bevacizumab
1.0 2.0
Immuno better | Control better
PD-L1 NEGATIVE - OS
Besse and Pignon ESMO 2018
TrialNo. patients
Immuno ControlHR [95% CI]
Immuno vs. control
Chemotherapy
± immuno
320 205
0.39 [0.25;0.60]
0.46 [0.22;0.96]
0.36 [0.25;0.52]
0.51 [0.34;0.85]
0.42 [0.33;0.52]
0.64 [0.57;0.72]
p<0.0001
0.2
1 paclitaxel + carboplatin + bevacizumab + atezolizumab versus paclitaxel + carboplatin + bevacizumab
IMPOWER 1501
IMPOWER132
KEYNOTE 189
IMPOWER130
Subtotal
Chemotherapy
vs. immuno
KEYNOTE 042
KEYNOTE 024
CheckMate 026
Subtotal
Total 861 782
Heterogeneity : p<0.0001, I²=82%
Interaction : p<0.0001
75
25
132
88
73
20
70
42
299
154
88
300
151
126
0.81 [0.67;0.99]
0.50 [0.37;0.68]
1.07 [0.77;1.49]
541 577 0.76 [0.66;0.88]
1.0 2.0
Immuno better | Control better
PD-L1 ≥ 50% - PFS
Besse and Pignon ESMO 2018
TrialNo. patients
Immuno Control
HR [95% CI]
Immuno vs. control
295 185
0.70 [0.43;1.13]
0.42 [0.26;0.68]
0.84 [0.51;1.39]
0.62 [0.47;0.82]
762
0.2
% of
cross over
IMPOWER 1501
KEYNOTE 189
IMPOWER130
75
132
88
73
70
42
31.7%
41.3%
59.2%
300
151
126
Low
43.7%
60.0%
0.69 [0.56;0.85]
0.63 [0.47;0.86]
0.90 [0.63;1.29]
541 577 0.71 [0.61;0.82]
0.69 [0.60;0.79]
p<0.0001
1.0 2.0
Immuno better | Control better
PD-L1 ≥ 50% - OS
Chemotherapy
± immuno
Subtotal
KEYNOTE 042 299
Chemotherapy KEYNOTE 024 154
vs. immuno CheckMate 026 88
Subtotal
Total 836
Heterogeneity : p=0.21, I²=31%
Interaction : p=0.43
1 paclitaxel + carboplatin + bevacizumab + atezolizumab versus paclitaxel + carboplatin + bevacizumab
Besse and Pignon ESMO 2018
Anti-drug Antibodies (ADAs)% of ADAs
Maximum rate reported
13 2.1 3.2 4.1 4.5
48
26
10080604020
0
Circulating ADAs may
▪ Neutralize drugs
▪ Enhance drug clearance
▪ Different sensitivity of assays and cut-off explain discrepancies
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s009lbl.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s035lbl.pdf
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761034s012lbl.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125527s000lbl.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s067lbl.pdf
Maio M, Lancet Oncol 2017; Kverneland, Oncoimmunology 2018; Agrawal, J Clin Pharmacol. 2016; Tolcher CCR 2017, Shimizu Invest New Drugs 2016,
Besse ESMO 2018
Ipilimumab in melanoma
Kverneland, Oncoimmunology 2018
Serum level of ADAsN=31
26% positive for ADA
The FDA and EMA have previously reported frequencies of 5% and <2% respectively.
Besse ESMO 2018
Category No. Entered Hazard Ratio HR [95% CI]
0.80 [0.70;0.91]
(a) ITTITT 1225
(b) TC-IC subgroups
TC3-IC3 174TC1/2/3-IC1/2/3 684TC0-IC0 531
0.45 [0.30;0.67]0.77 [0.64;0.93]0.84 [0.69;1.02]
(c) ADA subgroups
ADA+ADA-
118442
0.89 [0.61;1.30]0.68 [0.55;0.84]
0.2 1.0 5.0Atezolizumab better| Docetaxelbetter
OAK – exploratory analysis
ADAs testedin 560 pts118 (21%)
Positive at 4 weeks
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761034s012lbl.pdf
Besse ESMO 2018
Combinaciones con Inmunoterapia
• Histología no-escamosa
• Histología escamosa
• Combinaciones con anti-CTLA4
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
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
In patients withTMB <10mut/Mb on nivo + ipi vs chemo, the
HRwas1.07 (95%CI: 0.84, 1.35)d
Hellman et al: AACR 2018: NEJM
CM-227: Co-primary Endpoint PFS With Nivolumab + Ipilimumab vs
Chemotherapy in Patients With High TMB (≥10 mut/Mb)a
Results by Histology
Exploratory analysisa95% CI: nivo + chemo (4.3, 9.1 mo), nivo + ipi (2.7, NR mo), chemo (4.0, 6.8 mo); b95% CI: nivo + chemo (4.2, 6.9 mo), nivo + ipi (1.6, 5.4 mo), chemo (3.9, 6.2 mo)
Nivolumab +
chemotherapy
Nivo +
chemo
(n = 54)
Nivo + ipi(n = 52)
Chemo
(n = 59)
Median PFS,b mo 4.7 3.1 4.7
HR (vs chemo)(95% CI)
0.87 (0.57, 1.33)
1.17(0.76, 1.81)
Nivolumab + ipilimumab
1-y PFS = 18%1-y PFS = 18%
Months
Chemotherapy1-y PFS = 16%
TMB <10 mut/Mb and <1% Tumor PD-L1 ExpressionTMB ≥10 mut/Mb and <1% Tumor PD-L1 Expression
Nivolumab +
chemotherap
y
Months
1-y PFS = 45%
1-y PFS = 27%
Nivo +
chemo
(n = 43)
Nivo + ipi(n = 38)
Chemo
(n = 48)
Median PFS,a mo 6.2 7.7 5.3
HR (vs chemo)(95% CI)
0.56(0.35, 0.91)
0.48 (0.27, 0.85)
Nivo + chemo
No. at risk
Nivo + ipi 38 20 16 15 10 8 4 1
43 36 21 14 9 5 2 0
48 30 16 4 1 1 1 0Chemo
0
20
40
60
80
100
0 6 12 183 9 15 21
Chemotherapy
1-y PFS = 8%
PF
S (
%)
No. at risk
Nivo + ipi 52 22 12 7 5 3 1 0
59 39 16 6 6 3 1 0Chemo
Nivo + chemo 54 38 19 13 6 3 0 0
Nivolumab + ipilimumab
0
20
40
60
80
100
0 6 12 183 9 15 21
CheckMate 227: Progression-free survival by tumor mutation
burden and PD-L1 expression
Borghaei H, et al. ASCO2018.Abstract9001.
Platinum Chemotherapy is just as effectiveas Nivo+Ipi or Nivo+Chemo in <1% + TMB<10
patient population
• MYSTIC
1st Line TMB high TMB low Other Charact.
PDL1 Neg
Chemo
Chemo-IO / IO-IO
Chemo
Chemo-IO
?
PDL1 ≥1%
Chemo
Chemo-IO / IO-IO
Chemo
Chemo-IO
?
PDL1 ≥ 50%
IO
Chemo-IO / IO-IO
IO
Chemo-IO
Agressive
Disease ?
IO in First Line NSCLC
In 2019!!
La inmunoterapia es el estándar de tratamiento en primera línea de cáncer de pulmón no microcítico
avanzado/metastásico
• Monoterapia: Menos tóxica vs QT; reservada para PD-L1 ≥50%
• ¿Cuándo asociar quimioterapia?
• PD-L1 sea desconocido o <50% (otros?, Biología agresiva?)
• ¿Son todas las QT intercambiables? De momento, faltan datos
• ¿Cuándo asociar anti-CTLA4?
• TMB alto (≥10 mut/Mb) – Perfil toxicidades diferentes a la QT
• Familiarizarse con irAEs (Guías ESMO, NCCN/ASCO)
• Mejoría en parámetros de calidad de vida, control sintomático y funcional y retraso en el tiempo del deterioro clínico del paciente.
Take Home MessagesInmunoterapia en primera línea de Cáncer de Pulmón
Inmunoterapia en primera línea de cancer de pulmón
no microcítico: ¿sola o en combinación?
antonio.calles@live.com
Gracias por vuestra
atención!
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