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Dra. Margarita Majem
Hospital de la Santa Creu i Sant Pau, Barcelona
Cambio de paradigma del tratamiento de la primera línea del cáncer de pulmón no microcítico metastásico sin
mutaciones driver
INDICE
- INTRODUCCIÓN
- PD-L1> 50%
- CUALQUIER PD-L1
- CA ESCAMOSO
- CA NO ESCAMOSO
- SITUACIONES ESPECIALES
Stage IV NSCLC (no targetable alterations)
PS 0-1 PS 2 PS 3-4
1st
line
PD-L1 < 50%
PD-L1≥ 50%SCC and non-SCC
Pembrolizumab(I,A)(*)
non-SCC
Platinum+Pemetrexed (II,A)Taxol+CBDCA+Bevacizumab (I,A)
Paclitaxel+CBDCA+Bev+Atezolizumab# (I,A)Platinum+Pemetrexed+Pembrolizumab(I,A)
Platinum+Pemetrexed+Atezolizumab#(I,b)
Platinum based-CT (I,A)Platinum+Taxane+Pembrolizumab#
(I,A)Platinum+Taxane+Atezolizumab#(I,
B)
SCC
Single agentCT (I,B)
Carboplatin-based CT (II,A)
BSC (II,B)
(*) combination of immunotherapy + CT may be considered#
• IO MONOTERAPIA
• IO-IO
MONOTHERAPY IN NSCLC PHASE III TRIALS
PFSNivolumab
CT (histology dependent)
PFS PD-L1 ≥5%
1L All histologies NSCLCPD-L1 ≥5% N=541
Checkmate 026
PFS OSDurvalumab
CT (histology dependent)
PFS
OS1L All histologies NSCLCAll comers N=1850
MYSTIC
PFS OSPEM + Platin doublet
Platin/Pem or Platin/GemOS1L All histologies NSCLC
PD-L1 ≥1% N=305IMPower110
Results
PFS OS
Treatment scheme
Pembrolizumab
Platin doubletPFS
Primary endpointsSample
1L All histologies NSCLCPD-L1 ≥50% N=305Keynote 024
PFS OSPembrolizumab
Carbo/pacl or Carbo/PemOS1L All histologies NSCLC
PD-L1 ≥1% N=1274Keynote 042
PFS OSNivolumab
CT (histology dependet)
OS PD-L1>1%1L All histologies NSCLC
All comers N=1739Checkmate 227
Part1
OS
MONOTHERAPY IN NSCLC PHASE III TRIALS
PFSNivolumab
CT (histology dependent)
PFS PD-L1 ≥5%
1L All histologies NSCLCPD-L1 ≥5% N=541
Checkmate 026
PFS OSDurvalumab
CT (histology dependent)
PFS
OS1L All histologies NSCLCAll comers N=1850
MYSTIC
PFS OSPEM + Platin doublet
Platin/Pem or Platin/GemOS1L All histologies NSCLC
PD-L1 ≥1% N=305IMPower110
Results
PFS OS
Treatment scheme
Pembrolizumab
Platin doubletPFS
Primary endpointsSample
1L All histologies NSCLCPD-L1 ≥50% N=305Keynote 024
PFS OSPembrolizumab
Carbo/pacl or Carbo/PemOS1L All histologies NSCLC
PD-L1 ≥1% N=1274Keynote 042
PFS OSNivolumab
CT (histology dependet)
OS PD-L1>1%1L All histologies NSCLC
All comers N=1739Checkmate 227
Part1
OS
PD-L1 ≥ 50%
5-Year Long-Term OS from KEYNOTE 001
Garon et al., ASCO 2019 (LBA 9015)
Reck ESMO 2019
Mok AACR 2019
OS in TC3 or IC3 WT
Spigel ESMO 2019PD-L1 expression (VENTANA SP142 IHC assay) ≥ 1% on TC or IC.
Maintenance therapy
(no crossover permitted)
Arm B
Nsq:
cisplatin/carboplatin +
pemetrexedd
Sq:
cisplatin/carboplatin +
gemcitabinee
4 or 6 cycles
Nsq:
pemetrexed
Sq: best
supportive
care
Su
rviv
al
foll
ow
-up
CPNM
PD-L1 +
R
1:1
Arm A
Atezolizumab
1200 mg q3w
Atezolizumab
1200 mg q3w
PD or
loss of
clinical
benefit
PD
IMpower 110
CM-026
Carbone DP, et al. New Engl J Med 2017;376:2415–26.
Rizvi N, et al. Annals of Oncol. 2018;29:suppl_10(abstr LBA6)
MYSTIC TRIAL
Rizvi N, et al. Annals of Oncol. 2018;29:suppl_10(abstr LBA6)
N = 1189
NIVO + (low-dose) IPIb
n = 396
Chemoc
n = 397
NIVOd
n = 396
R1:1:1
CPNM EGFR ALK WT
PD-L1expression≥
1%
Independent co-primary endpoints: NIVO + IPI vs chemo
• PFS in high TMB (≥10 mut/Mb) populationf
• OS in PD-L1 ≥ 1% populationg
NIVO + IPI(n = 396)
NIVO(n = 396)
Chemo(n = 397)
Median OS, mo 17.1 15.7 14.9
HR (vs chemo)a
CI0.79
0.65–0.96b0.88
0.75–1.04c
OS PD-L1 Expression ≥ 1%
NIVO + IPI
Chemo
NIVO
100
0
40
60
80
20
OS
(%
)
Months0 3 6 9 12 15 18 21 24 27 30 36 3933 42 45
56%
63%
57% 33%
40%
36%
OS PD-L1 Expression ≥ 50%
6 12 18 24 30 36 423 9 15 21 27 33 39
OS
(%
)
00 45
100
80
60
40
20
Months
54%
67%
61%
NIVO + IPI
NIVO
Chemo
NIVO + IPI(n = 205)
NIVO(n = 214)
Chemo(n = 192)
Median OS, mo95% CI
21.2 15.5–38.2
18.114.4–22.1
14.0 10.0–18.6
HR (vs chemo)95% CI
0.700.55–0.90
0.790.63–1.01
36%
48%
42 %
Peters ESMO 2019
CM-227
IO – QTCa no escamosoCa escamoso
Bracci et al., Cell Death and Differentiation 2016
IO – QTCa no escamoso
Bracci et al., Cell Death and Differentiation 2016
Median (95% CI)
24 (8.5–NR)
9.3(6.2–14.9)
Gentzler RD, et al. ASCO 2018
Overall Survival
Crossover~ 73%
Gentzler RD, et al. ASCO 2018
Median (95% CI)
NR (24.5–NR)
21.1 (14.9–NR)
N=616
Gandhi KN-189 AACR 18. Reck IMpower150. ESMO 2017. Papadimitrakopoulou. WCLC 2018. West AACR 2019
KEYNOTE-189: superioridad de Pembro+QT
independientemente de la expresión de PD-L1
Gadgeel et al. ASCO 2019, Abst 9013
Impower 130: Atezolizumab + QT superior en no escamoso
Cappuzzo et al. ESMO 2018West H, et al. Lancet Oncol 2019
Impower 130: Atezolizumab + QT superior en no escamoso en SLP
(SG ?)
Vassiliki A. Papadimitrakopoulou WCLC 2018
IMpower 150: QT+Atezolizumab+ Bev es superior
independientemente de la expresión de PD-L1
Socinski ASCO 2018
IO – QTCa escamoso
Bracci et al., Cell Death and Differentiation 2016
N=559
Paz-Ares ESMO 2019 abstr LBA82Cappuzzo WCLC 2019 abstr OA14.02
Paz-Ares ESMO 2019
KeyNote 407
Cappuzzo WCLC 2019
Impower 131
Treatment until disease
progression, unacceptable toxicity, OR
for 2 years for NIVO + IPI
NIVO 360 mg Q3W +
IPI 1 mg/kg Q6W +
Chemoc Q3W
(2 cyclesd)
Chemoc Q3W
(4 cycles)
Post-Induction
NIVO 360 mg Q3W +
IPI 1 mg/kg Q6W
Optional
Pemetrexed
maintenance
(NSQ histology)
R
1:1
Key Eligibility Criteria
• Stage IV NSCLC
• No prior systemic therapy
• No sensitizing EGFR
mutations or known ALK
alterations
• ECOG PS 0–1
Stratified by PD-L1b(< 1% vs ≥ 1%),
sex, and histology (SQ vs NSQ)
Crossover to immunotherapy from the chemotherapy arm was not permitted per study protocol.
Peters Ann Oncol 2019
PD-L1> 50%
Study
PD-L1
Prevalence
Arms
KN-024(>50%)
30%P vs CT
KN-042>50%46%
P vs CT
IMp-110TC3/IC3
38%A vs CT
MYSTIC>50% (expl)
D vs QT
CM-227>50%54%
N vs QT
CM-227>50%54%
N+I vs CT
MYSTIC> 50% (expl)
D+T VS CT
KN-189(>50%) ≈33%
IO+CT vs CT
IMp-150TC3/IC3
17%IO+CT+Bev vs
CT+Bev
IMp-132TC3/IC3
14%IO+CT vs CT
IMp-130TC3/IC3
19%IO+CT vs CT
RR 45% 39% 38% - 36.9% 44.4% - 61.4% 69% 72% -
mPFS10.3 vs
6mHR 0.5
7.1 vs 6.4m
HR 0.81
8.1 vs 5m
HR 0.63
4.7 vs 5.4m
5.6 vs 5.6mHR 0.75
6.7 vs 5.6 m
HR 0.62
3.9 vs 5.4m
HR 1.0
11.1 vs 4.8m
HR 0.36
12.6 vs 6.8m
HR 0.39
10.8 vs 6.5mHR 0.46
6.4 vs 4.6m
HR 0.51
mOS26.3 vs 14.2m
HR 0.65
20 vs 12.2m
HR 0.70
20.2 vs 13.1m
HR 0.59
18.3 vs 12.7m
HR 0.76
18.1 14m
HR 0.79
21.2 vs 14m
HR 0.70
15.2 vs 12.7mHR 0.77
NR vs 10.1m
HR 0.59
25.2 vs 15m
HR 0.70 (NS)
23.6 vs 14.1m
HR 0.56
17.3 vs 16.9m
HR 0.84 (NS)
MCBSScore
5 - - - - 5 3 - 3
Reck M, et al. NEJM 2016; Reck M, et al WCLC 2019; Mok T, et al. ELCC 2019; Spigel D et al. ESMO 2019; Rizvi N, et al. ASCO 2019;Peters S, et al. ESMO 2019; OA14.01; Gadgeel S.M, ASCO 2019; Socinski MA et al. NEJM 2018; Socinski MA et al, ASCO 2018;PapadimitrakopoulouV.A.,WCLC 2018; Cappuzzo et al ESMO 2018; West H, et al. Lancet Oncol 2019PlanchardD, Updated ESMOGuidelines, Ann Oncol Sept 2019
IO vs CT (All histologies)
IO+CT vs CT (Non-Squamous)
IO+IO (All histologies)
Cortesía Dra G-Campelo
PD-L1> 50%
StudyPD-L1PrevalenceArms
KN-024(>50%)
30%P vs CT
KN-042>50%46%
P vs CT
IMp-110TC3/IC3
38%A vs CT
MYSTIC>50% (expl)
D VS QT
CM-227>50%54%
N vs CT
CM-227>50%54%
N+I vs CT
MYSTIC> 50% (expl)
D+T VS CT
KN-189(>50%) ≈33%
IO+CT vs CT
IMp-150TC3/IC3
17%IO+CT+Bev vs
CT+Bev
IMp-132TC3/IC3
14%IO+CT vs CT
IMp-130TC3/IC3
19%IO+CT vs CT
TRAEs Gr 3/4 26.6% 18% 12.9% 14.6% 19% 33% 22.1% 67% 60% 54% 73%
% Discontin. 7.1% 9% 6.3% 5.4% 7.4% 12% 13.2% 20% (pembro) 34% (any) 15% (atezo) 26.4% (any)
IO vs CT (All histologies)
IO+CT vs CT (Non-Squamous)
IO+IO (All histologies)
Reck M, et al. NEJM 2016; Reck M, et al WCLC 2019; Mok T, et al. ELCC 2019; Spigel D et al. ESMO 2019; Rizvi N, et al. ASCO 2019;Peters S, et al. ESMO 2019; OA14.01; Gadgeel S.M, ASCO 2019; Socinski MA et al. NEJM 2018; Socinski MA et al, ASCO 2018;PapadimitrakopoulouV.A.,WCLC 2018; Cappuzzo et al ESMO 2018
Cortesía Dra G-Campelo
KEYNOTE-1891
(N=607)IMpower1502,3
(N=787)IMpower1324
(N=578)
Pembro+ pem + cis/carb
Pem + cis/carb
Atezo + bev + carb +
pac
Bev + carb +
pac
Atezocarb/cis
pem
Carb/cispem
99.8* 99.0* 94.4 95.4 92 87
67.2* 65.8* 58.5 50 57 42
27.7 14.9 32.63 24.93 24 18
6.7 5.9 2.8 2.3 4 3
KEYNOTE-4075
(N=558)IMpower1316
(N=668)
Pembro + carb + pac/
nab-pac
Carb + pac/ nab-pac
Atezo + carb + nab-
pac
Carb + nabpac
98.2* 97.9* 95 91
69.8* 68.2* 68 57
23.4 11.8 29 17
8.3 6.4 1 1
All TRAEs (%)
Grade 3–5 TRAEs
(%)
Discontinuation
Rate (%) (any
treatment)
Led to death (%)
Nonsquamous Squamous
EA5163/S1709/INSI
GNA
PD-L1 1- 49%
Study
Arms
KN-042P vs CT
CM-227N+I vs CT
KN-189IO+CT vs CT
IMp-150IO+CT+Bev vs CT+Bev
IMp-132IO+CT vs CT
IMp-130IO+CT vs CT
RR - - 49.2 vs 20.7% 58 vs 41% 38 vs 38% -
mPFS - -9.2 vs 4.9m
HR 0.518.3 vs 6.6m
HR 0.566.2 vs 5.7
HR 0.88.3 vs 6mHR 0.61
mOS13.4 vs 12.1mHR 0.9
15.1 vs 15.1m
HR 0.94
21 vs 12m
HR 0.62
20.3 vs 16.4mHR 0.8
-23.7 vs 15.9m
HR 0.70
MCBSScore
- 4 3 - 3
; Mok T, et al. ELCC 2019; Spigel D et al. ESMO 2019; Rizvi N, et al. ASCO 2019; Peters S, et al. ESMO 2019; OA14.01; Gadgeel S.M,ASCO 2019; Socinski MA et al. NEJM 2018; Socinski MA et al, ASCO 2018; PapadimitrakopoulouV.A.,WCLC 2018; Cappuzzo et alESMO 2018; PlanchardD, Updated ESMO Guidelines, Ann Oncol Sept 2019
IO vs CT (All histologies)
IO+CT vs CT (Non-Squamous)
IO+IO (All histologies)
PD-L1<1%
Study
Arms
CM-227N+I vs CT
KN-189IO+CT vs CT
IMp-150IO+CT+Bev vs CT+Bev
IMp-132IO+CT vs CT
IMp-130IO+CT vs CT
RR 27.3 vs 23% 32.3 vs 14.3% 51 vs 36% 44 vs 27% -
mPFS5.1 vs 4.7m
HR 0.736.2 vs 5.1m
HR 0.647.1 vs 6.9m
HR 0.778.5 vs 4.9m
HR 0.456.2 vs 4.7m
HR 0.72
mOS17.2 vs 12.2m
HR 0.62
17 vs 10m
HR 0.52
17.1 vs 14.1m
HR 0.82
15.2 vs 12m
HR 0.81
MCBSScore
- 4 3 - 3
IO+CT vs CT (Non-Squamous)
IO+IO (All
histologies)
Peters S, et al. ESMO 2019; OA14.01; Gadgeel S.M, ASCO 2019; Socinski MA et al. NEJM 2018; Socinski MA et al,ASCO 2018; PapadimitrakopoulouV.A.,WCLC 2018; Cappuzzo et al ESMO 2018; PlanchardD, Updated ESMOGuidelines, Ann Oncol Sept 2019
Pembrolizumab Plus Chemotherapy For Advanced NSCLC Without Tumor PD-L1 Expression: Pooled Analysis of KN021G, KN189 and KN407
1Fox Chase Cancer Center, Philadelphia, PA, USA; 2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 3Hospital Universitario 12 de Octubre, Madrid, Spain; 4Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; 5Montefiore Einstein Center for Cancer Care, New York City, NY, USA; 6The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 8Mid North Coast Cancer Institute, Port Macquarie Base Hospital, Port Macquarie, NSW, Australia; 9Kansai Medical University Hospital, Osaka, Japan; 10Jilin Cancer Hospital, Changchun, China; 11Merck & Co., Inc., Kenilworth, NJ, USA; 12Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
Hossein Borghaei,1 Corey Langer,2 Luis Paz-Ares,3 Delvys Rodríguez-Abreu,4 Balazs Halmos,5
Vassiliki A. Papadimitrakopoulou,6 Marina C. Garassino,7 Baerin Houghton,8 Takayasu Kurata,9
Ying Cheng,10 Jianxin Lin,11 M. Catherine Pietanza,11 Bilal Piperdi,11 Shirish Gadgeel12
0 3 6 9 12 15 18 21 24 27 30 33
0
10
20
30
40
50
60
70
80
90
100
Time, months
OS
, %
No. at risk
Pembrolizumab +chemotherapy
Chemotherapy alone
221243 186 153 117 92 79 49 29 13 2 0
165185 127 83 56 34 26 16 7 5 4 1
66%
47%
52%
29%
Events, n HR (95% CI)
Pembrolizumab + CT
112 0.56(0.43‒0.73)
CT 110
Median (95% CI) OS
19.0 (15.2‒24.0) mo
11.0 (9.2‒13.5) mo
Hossein Borghaei WCLC 2019
• IO monotherapy in previously untreated NSCLC PD-L1 ≥50% is a winner: efficacy, safety, and QoL positive data
compared to conventional chemotherapy (KN-024, KN-042, IMpower110)
• It´s also true today: IO+CT can be considered a new standard of care for previously untreated advanced NSCLC,
independently of PD-L1 status
• PD-L1 testing is still valid and mandatory when enough tumor material… from the beginning
• For those PD-L1 ≥50% IO monotherapy and IO+QT are valid treatment options, so far I would consider a
personalize decision…but today a regulatory decision
• Not direct prospective comparison available IO vs IO+CT
• After IO monotherapy, still you have opportunities for platinum doublets
• Not so clear for me the role of IO+IO
• Toxicity issues, patient preference… must be taken into account
✓ PD-L1✓ TMB✓ SKT-11/KEAP1✓ TIL > 10%✓ dNLR/LIPI
CLINICAL FACTORS