Ruolo dei checkpoint inhibitors nelle neoplasie polmonari:
le evidenze scientifiche e l’inserimento
dei checkpoint inhibitors nell’algoritmo decisionale del NSCLC
GRUPPO C
Coordinatore: Diego Signorelli
Alessandro Inno
IRCCS Ospedale Sacro Cuore Don Calabria Negrar, Verona
Immune Checkpoint Inhibitors for NSCLC:
2
ndline and beyond
Nivolumab Pembrolizumab Atezolizumab Study
Phase
CheckMate-017[1]
III
CheckMate-057 [2]
III
KEYNOTE-010 [3]
II/III
OAK [4]
III
n 135 vs 137 292 vs 290 345 vs 346 vs 343 425 vs 425+
Histology SQ (100%)
Non-SQ (100%)
SQ (21%) Non-SQ (79%)
SQ (26%) Non-SQ (74%)
PD-L1 All comers All comers TPS≥1% All comers
IHC test target
28-8 Dako TC
28-8 Dako TC
22C3 Dako TC
SP 142 Ventana TC and IC
Schedule 3 mg/kg
Q 14d
3 mg/kg Q 14d
2 mg/kg, 10 mg/kg Q 21d
1200 mg Q 21d Control Arm Docetaxel 75 mg/m2
Q 21d
Docetaxel 75 mg/m2 Q 21d
Docetaxel 75 mg/m2 Q 21d
Docetaxel 75 mg/m2 Q 21d
Line 100% 2nd 88% 2nd
11% 3rd
69% 2nd 20% 3rd
75% 2nd 25% 3rd
mOS 9.2 vs 6.0
HR 0.59, p<0.001
12.2 vs 9.4 HR 0.73, p=0.002
10.4 vs 12.7 vs 8.5 HR 0.71, p=0.0008*
13.8 vs 9.6 HR 0.73, p=0.0003 1-yr survival 42% vs 24% 51% vs 39% 43.2% vs 52.3% vs 34.6% 55% vs 41%
mPFS 3.5 vs 2.8
HR 0.62, p<0.001
2.3 vs 4.2 3.9 vs 4.0 vs 4.0 2.8 vs 4.0
RR 20% vs 9% 19% vs 12% 18% vs 18% vs 9% 14% vs 13%
TRAEs ≥ G3 7% vs 55% 10% vs 54% 13% vs 16% vs 35% 15% vs 43%
*pembrolizumab 2 mg/kg vs docetaxel; +primary analysis population
2nd line Checkpoint inhibitors for NSCLC: summary of evidence
1) Brahmer J, et al. N Engl J Med 2015;373(2):123-35. 2) Borghaei H, et al. N Engl J Med 2015;373(17):1627-39. 3) Herbst RS, et al. Lancet 2016;387(10027):1540-50.
4) Rittmeyer A, et al. Lancet 2017;389(10066):255-265.
2nd line Checkpoint inhibitors for NSCLC:
a consistent benefit in OS
Vokes EE et al. Ann Oncol 2018;29(4):959-965.
Herbst RS, et al. Lancet 2016;387(10027):1540-50.
Rittmeyer A, et al. Lancet 2017;389(10066):255-265.
2nd line Checkpoint inhibitors for NSCLC: PD-L1 expression
Checkmate 017[1]
Checkmate 057[2]
1) Brahmer J, et al. N Engl J Med 2015;373(2):123-35. 2) Borghaei H, et al. N Engl J Med 2015;373(17):1627-39. 3) Herbst RS, et al. Lancet 2016;387(10027):1540-50.
4) Rittmeyer A, et al. Lancet 2017;389(10066):255-265.
KEYNOTE 001[3]
OAK[4]
How long to treat?
• Continuous vs fixed duration
• Treatment beyond progression
CheckMate 153: continuous vs 1-year fixed duration nivolumab
Spigel DR, et al. Ann Oncol 2017;28(Suppl5): Abstract 1297O.
CheckMate 153: continuous vs 1-year fixed duration nivolumab
Spigel DR, et al. Ann Oncol 2017;28(Suppl5): Abstract 1297O.
PFS from randomization
Response status PFS HR (95% CI) CR/PR 0.45 (0.24-0.85)
SD 0.44 (0.17-1.09)
OS from randomization
OAK:
OS post-PD in the atezolizumab arm by post-PD treatment
Gandara R, et al. ASCO 2017. Abstract #9001
Immune Checkpoint Inhibitors:
1
stline
KEYNOTE-024: study design
Reck M, et al. N Engl J Med 2016;375(19):1823-1833.
KEYNOTE-024: PFS and RR
Reck M, et al. N Engl J Med 2016;375(19):1823-1833.
KEYNOTE-024: Updated OS results (median follow-up 19.1 months)
Kaplan-Meier Estimate of OS: <br />Updated Analysis
Presented By Julie Brahmer at 2017 ASCO Annual Meeting
NSCLC avanzato: algoritmo decisionale in Italia nel 2018
Non-Squamous NSCLC Squamous NSCLC
EGFR/ALK/ROS1+
TKIs
EGFR/ALK/ROS1- PDL1 <50%
Platinum doublet +/-Bevacizumab Maintenance
EGFR/ALK/
ROS1- PDL1 ≥50%
PDL1 ≥50% PDL1<50%
Platinum doublet
Pembrolizumab
Platinum doublet +/-Bevacizumab Maintenance
Platinum doublet Nivolumab/Atezolizumab
Pembrolizumab if PDL1>1%
1st line
Docetaxel +/- nintedanib
2nd
line Nivolumab/Atezolizumab
Pembrolizumab if PDL1>1% Docetaxel
The (next) future:
• 1st-line ICI for PDL1 <50%?
• Biomarkers (TMB)
• Combinations
• ICI + Chemo
• ICI + Chemo + anti-VEGF
• ICI + ICI
KEYNOTE-042: study design
Presented By Gilberto Lopes at 2018 ASCO Annual Meeting
KEYNOTE-042: OS
Lopes G, ASCO 2018.
OS TPS ≥ 50%
OS TPS ≥ 20%
OS TPS ≥ 1%
KEYNOTE-042: OS
Presented By Gilberto Lopes at 2018 ASCO Annual Meeting
KEYNOTE-189 & KEYNOTE-407: study designs
KEYNOTE-189
Primary Endpoints:
- PSF
- OS
KEYNOTE-407
Gandhi L, et al. N Engl J Med 2018;378(22):2078-2092.
Paz-Ares LG, et al. ASCO 2018
KEYNOTE-189 & KEYNOTE-407: OS data
Gandhi L, et al. N Engl J Med 2018;378(22):2078-2092.
Paz-Ares LG, et al. ASCO 2018
KEYNOTE-189
KEYNOTE-407
Jotte R, ASCO 2018
IMpower131
IMpower131: Atezolizumab+CnP vs CnP in SQ-NSCLC
Jotte R, et al. ASCO 2018
IMpower150: study design
Socinski MA, et al. N Engl J Med 2018;378(24):2288-2301.
IMpower150: OS in ITT-WT and Key subgroups
Socinski MA, et al. N Engl J Med 2018;378(24):2288-2301.
CheckMate 227
Hellmann MD, et al. N Engl J Med 2018;378(22):2093-2104.
Co-primary End Points for Nivolumab plus Ipilimumab vs. Chemotherapy:
• Progression-free survival in populations selected on the basis of TMB
• Overall survival in populations selected on the basis of PD-L1 expression
CheckMate 227: PFS in patients with high TMB
Hellmann MD, et al. N Engl J Med 2018;378(22):2093-2104.
PFS: Nivolumab + Chemotherapy and Nivolumab + Ipilimumab <br />By TMB
Presented By Hossein Borghaei at 2018 ASCO Annual Meeting
CheckMate 227: exploratory analysis in PDL1 <1%
1st line Checkpoint inhibitors for NSCLC: summary of evidence
Immune Checkpoint Inhibitors:
Stage III
PACIFIC trial: study design
Antonia SJ, et al. N Engl J Med 2017;377(20):1919-1929.
PACIFIC trial: PFS by BIRC
Antonia SJ, et al. N Engl J Med 2017;377(20):1919-1929.
PACIFIC trial: safety
Antonia SJ, et al. N Engl J Med 2017;377(20):1919-1929.
Aknowledgments
