Título ponencia
Inmunoterapia 2018:
Mejora de la Supervivencia en
Cáncer de Pulmón No Microcítico
Antonio Calles
Servicio de Oncología Médica
Hospital General Universitario Gregorio Marañón
Instituto de Investigación Sanitaria HGUGM
Esquema de la charla
IO en CPNM
• Aumento de Supervivencia en 1ª línea
• Aumento de Supervivencia en 2ª línea
• Biomarcadores de eficacia
– PD-L1, TMB
• Eficacia en poblaciones especiales
– EGFR, ALK
• Toxicidad y QoL
• Mensajes para llevar a casa
Cáncer de Pulmón:
Cada avance impacta en supervivencia
0
5
10
15
20
25
30
35
1980s 1990s 2000s 2006 2013 2016 2017
1. Ganz, et al. Cancer 1989; 2. Bunn, et al. Clin Cancer Res 1998; 3. Schiller, et al. N Engl J Med 2002; 4. Scagliotti, et al. J Clin
Oncol 2008; 5. Sandler, et al. N Engl J Med 2006; 6. Paz-Ares, et al. J Clin Oncol 2013; 7. Paz-Ares, et al. Lancet 2017; 8. Reck,
et al N Eng J Med 2016.
BSC:
2–5
months1
Platinum-doublets:
8–10 months3,4
Single-agent platinum:
6–8
months2
Ove
rall
Surv
ival
(m
on
ths)
1-year
Platinum-based era
Cáncer de Pulmón:
Cada avance impacta en supervivencia
0
5
10
15
20
25
30
35
1980s 1990s 2000s 2006 2013 2016 2017
Pemetrexed-maintenance
14 months6
1. Ganz, et al. Cancer 1989; 2. Bunn, et al. Clin Cancer Res 1998; 3. Schiller, et al. N Engl J Med 2002; 4. Scagliotti, et al. J Clin
Oncol 2008; 5. Sandler, et al. N Engl J Med 2006; 6. Paz-Ares, et al. J Clin Oncol 2013; 7. Paz-Ares, et al. Lancet 2017; 8. Reck,
et al N Eng J Med 2016.
BSC:
2–5
months1
Platinum-doublets:
8–10 months3,4
Single-agent platinum:
6–8
months2
Bevacizumab+chemo
>12.3 months5
Ove
rall
Surv
ival
(m
on
ths)
1-year
Platinum-based era Histology era
Cáncer de Pulmón:
Cada avance impacta en supervivencia
0
5
10
15
20
25
30
35
1980s 1990s 2000s 2006 2013 2016 2017
Targeted therapies:
>24 months7
Pemetrexed-maintenance
14 months6
Pembrolizumab TPS≥50%
30 months8
1. Ganz, et al. Cancer 1989; 2. Bunn, et al. Clin Cancer Res 1998; 3. Schiller, et al. N Engl J Med 2002; 4. Scagliotti, et al. J Clin
Oncol 2008; 5. Sandler, et al. N Engl J Med 2006; 6. Paz-Ares, et al. J Clin Oncol 2013; 7. Paz-Ares, et al. Lancet 2017; 8. Reck,
et al N Eng J Med 2016.
BSC:
2–5
months1
Platinum-doublets:
8–10 months3,4
Single-agent platinum:
6–8
months2
Bevacizumab+chemo
>12.3 months5
Ove
rall
Surv
ival
(m
on
ths)
1-year
Platinum-based era Histology era Biomarkers era
Divide and Conquer to Treat Lung Cancer
Jordan et al., Cancer Discov. 2017 Johnson, NEJM. 2016
Lung adenocarcinoma Non-Small Cell Lung Cancer
≥50%%
<50%
PD-L1 TPS ≥50% in NSCLC
Patient Characteristics • Female • Never-smoker • Adenocarcinoma
Patient Characteristics • Male • 90% Smokers • 20% Squamous
30%
Larger population than EGFR + ALK + ROS1 combined
Ongoing phase III studies of anti-PDL1/PD1 therapy in first-line NSCLC
Study name Study description Monotherapy Chemotherapy combination
Anti-CTLA4 combination
Atezolizumab
IMpower110 Atezolizumab monotherapy (squamous and non-squamous) TC1/2/3 or IC1/2/3 (TC or IC ≥1%)
IMpower130 Atezolizumab + platinum doublet chemotherapy (non-squamous)
IMpower131 Atezolizumab + platinum doublet chemotherapy (squamous)
IMpower132 Atezolizumab + platinum doublet chemotherapy (non-squamous)
IMpower150 Atezolizumab + platinum doublet chemotherapy ± bevacizumab (non-squamous)
Pembrolizumab
KEYNOTE-024 Pembrolizumab monotherapy (squamous and non-squamous) TPS ≥50%
KEYNOTE-042 Pembrolizumab monotherapy (squamous and non-squamous) TPS ≥1%
KEYNOTE-407 Pembrolizumab + platinum doublet chemotherapy (squamous)
KEYNOTE-189 Pembrolizumab + platinum doublet chemotherapy (non-squamous)
Nivolumab
CheckMate 026 Nivolumab monotherapy (squamous and non-squamous) TC ≥1% (TC ≥5% as co-primary endpoint)
CheckMate 227 Nivolumab monotherapy or + ipilimumab or + platinum doublet chemotherapy (squamous and non-squamous) PD-L1+ only for monotherapy arm
Durvalumab
MYSTIC Durvalumab monotherapy or + tremelimumab (squamous and non-squamous)
NEPTUNE Durvalumab + tremelimumab (squamous and non-squamous)
Avelumab
JAVELIN Lung 100 Avelumab monotherapy (squamous and non-squamous)
62% crossover
KEYNOTE-024
KEYNOTE-024
ORR
QOL
AE
Novello, et al. Ann Oncol 2016 27(Suppl.5): v1–27
eUpdate Published: 28 June 2017. Authors: ESMO Guidelines Committee
ESMO & Magnitude of Clinical Benefit Scale
NCCN Guidelines
Phase III studies of first-line monotherapy
(KEYNOTE-024 and CheckMate 026)
• Stage IV NSCLC (EGFR WT, ALK-)
• Squamous or non-squamous
• PD-L1 ≥50% by IHC
• No prior chemotherapy
• ECOG PS 0–1
(n=305)
Paclitaxel or pemetrexed or gemcitabine + carboplatin or
cisplatin (4–6 cycles)
1 2 PFS OS, ORR, PFS in patients with any PD-L1 status Endpoints
Pembrolizumab 200mg i.v. q3w
Optional pemetrexed maintenance
PD-L1 TPS ≥50% by IHC Until PD
Crossover to pembrolizumab permitted
R
1 2 OS, ORR, PFS Endpoints PFS in patients with
PFS in ITT population (PD-L1 TC ≥1% by IHC) [co-primary]
•PD-L1 TC ≥5% by IHC [co-primary]
• Stage IV or recurrent NSCLC
• No prior systemic therapy
• PD-L1 TC ≥1% by IHC
• ECOG PS 0–1
(n=541)
Investigator’s choice chemotherapy (Gemcitabine + cisplatin or carboplatin, paclitaxel +
carboplatin, or pemetrexed + cisplatin or carboplatin)
Nivolumab 3mg/kg i.v. q2w
Until PD
Crossover to nivolumab permitted
KEYNOTE-024
CheckMate 026
PD-L1 TC ≥1% by IHC
Reck, et al. N Engl J Med 2016 [Epub ahead of print]
Reck, et al. ESMO 2016 (Abs. LBA8); Socinski, et al. ESMO 2016 (Abs. LBA7)
R
KEYNOTE-024 and CheckMate 026: PFS
Reck, et al. N Engl J Med 2016 [Epub ahead of print]
Reck, et al. ESMO 2016 (Abs. LBA8); Socinski, et al. ESMO 2016 (Abs. LBA7)
KEYNOTE-024 PFS
PD-L1 TPS ≥50%
CheckMate 026 PFS
TC PD-L1 ≥5%
1.0
0.8
0.6
0.4
0.2
0
0
Time (months)
6 3 9 18 15 12
Nivolumab (n=211)
Chemotherapy (n=212)
HR=1.15 (95% Cl 0.91–1.45)
p=0.2511
4.2 5.9
21 24 27
Time (months)
PF
S e
sti
ma
te
1.0
0.8
0.6
0.4
0.2
0
0 27
Pembrolizumab (n=154)
Chemotherapy (n=151)
HR=0.50 (95% Cl 0.37–0.68)
p<0.001
Median follow-up of 11.2 months Median follow-up not reported
6 3 9 18 15 12
6.0 10.3
21 24
Analysis of the Association Between TMB and PD-L1 Expressiona CheckMate 026 TMB Analysis: Nivolumab in First-Line NSCLC
• There was no association between TMB and PD-L1 expression in patients with ≥1% PD-L1 tumor expression
PD-L1 (% Tumor Expression)a
High TMB
75 50
1000
316
100
32
10
0 25 100
TM
B (N
o. o
f M
isse
ns
e M
uta
tio
ns
)
Low/medium TMB
243
aAll patients had ≥1% PD-L1 tumor expression
PFS by Tumor Mutation Burden Subgroup CheckMate 026 TMB Analysis: Nivolumab in First-Line NSCLC
Nivolumab
Chemotherapy 47 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
Nivolumab n = 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 Risk Months
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)
Can we enhance cancer immunotherapy with
combinations?
Adapted from Sharma and Allison. Cell 2015 161(2): 205–14
Targeted therapy
Immune checkpoint therapy
Combinations with
immunotherapy
Chemotherapy
Hypothetical KM curve
Time
Pe
rce
nt
su
rviv
al
Chemo + IO combos
IO + IO combos
Combinations with anti-PD1 and anti-PDL1
therapies in first line advanced NSCLC
Chemotherapy Checkpoint
inhibitor
Nivolumab Durvalumab
20mg/kg
IV q4w
3mg/kg
IV q2w
Pembrolizumab
2mg/kg
IV q3w
Atezolizumab
1200mg
IV q3w
Anti-PD1 Anti-PDL1 Anti-PD1 Anti-PDL1
Chemotherapy
Checkpoint inhibitor Ph1-Ph2
ORR 40-90% Giaccone, et al. ECC 2015 (Abs. 513)
Gadgeel, et al. ASCO 2016 (Abs. 9016)
Rizvi, et al. J Clin Oncol 2016 34(25): 2969–79
First-line immunotherapy plus chemo combination:
pembrolizumab plus chemo (KEYNOTE-021, cohort G)
56.7% 31.7%
KEYNOTE-021 Cohort G
KEYNOTE-021 Cohort G
FDA accelerated
approval KN-189 KEYNOTE-021 Cohort G
KEYNOTE-021 Cohort G
Reck M, et al. IMpower150 PFS analysis. 22
a Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance of treatment
with one or more approved targeted therapies. b Atezolizumab: 1200 mg IV q3w. c Carboplatin: AUC 6 IV q3w. d Paclitaxel: 200 mg/m2 IV q3w. e Bevacizumab: 15 mg/kg IV q3w.
IMpower150 study design
Arm A
Atezolizumabb +
Carboplatinc + Paclitaxeld
4 or 6 cycles
Atezolizumabb
Arm C (control)
Carboplatinc + Paclitaxeld
+ Bevacizumabe
4 or 6 cycles
Bevacizumabe
Su
rviv
al fo
llo
w-u
p
Stage IV or
recurrent metastatic
non-squamous NSCLC
Chemotherapy-naivea
Tumour tissue available
for biomarker testing
Any PD-L1 IHC status
Stratification factors:
• Sex
• PD-L1 IHC expression
• Liver metastases
N = 1202
R
1:1:1
Arm B
Atezolizumabb +
Carboplatinc + Paclitaxeld
+ Bevacizumabe
4 or 6 cycles
Atezolizumabb
+
Bevacizumabe
Maintenance therapy
(no crossover permitted)
Treated with
atezolizumab
until PD by
RECIST v1.1
or loss of
clinical benefit
AND/OR
Treated with
bevacizumab
until PD by
RECIST v1.1
The principal question is to assess whether the addition of atezolizumab to Arm C provides clinical benefit
Reck M, et al. IMpower150 PFS analysis.
INV-assessed PFS in ITT-WT (Arm B vs Arm C)
23
INV, investigator.
Data cutoff: September 15, 2017
6.8 mo (95% CI: 6.0, 7.1)
8.3 mo (95% CI: 7.7, 9.8)
HR, 0.617 (95% CI: 0.517, 0.737)
P < 0.0001 Minimum follow-up: 9.5 mo
Median follow-up: ~15 mo
Arm B: atezo + bev + CP
Arm C: bev + CP
• Teff gene signature is a surrogate for PD-L1 expression and pre-existing immunity
Teff signature was defined by mRNA expression of 3 genes (PDL1, CXCL9, IFNG) and derived from
a broader 9-gene signature from POPLAR1
In the OAK study, the Teff signature was associated with PD-L1 expression assessed by IHC (P = 7.3 x 10-45)
• Teff signature partially overlaps with patients identified as PD-L1 positive by IHC and also identifies
a unique subset of patients within the PD-L1–negative population
Teff Gene Signature and Overlap With PD-L1 IHC in tumor
specimens from study OAK
IC, tumor-infiltrating immune cell; IHC, immunohistochemistry; mRNA, messenger RNA; TC, tumor cell. a Percentages of the overall NSCLC population (N = 753). b TC1/2/3 or IC1/2/3 = TC or IC ≥ 1% PD-L1–expressing cells.
1. Fehrenbacher L, et al. Lancet. 2016.
Kowanetz et al. OAK Teff biomarker. WCLC 2017. 24
Teff Gene
Signature
PDL1
IFNG
CXCL9
Pre-existing
immunity
PD-L1 expression
on TC and IC
Teff Gene Signature vs PD-L1 IHC (SP142)a
36% 14% 20%
Teff
≥ median
TC1/2/3
or IC1/2/3b
N = 753
Reck M, et al. IMpower150 PFS analysis. 25
a ITT, EGFR/ALK mutants, and ITT-WT % prevalence out of ITT (n = 800);
Teff % prevalence out those tested in ITT-WT (n = 658); PD-L1 IHC % prevalence out of ITT-WT (n = 692). b Patients with a sensitising EGFR mutation or ALK translocation must have disease progression
or intolerance of treatment with one or more approved targeted therapies. c Stratified HRs for ITT, ITT-WT and Teff-high WT populations; unstratified HRs for all other subgroups.
Data cutoff: September 15, 2017
PFS in key biomarker populations
0,25
Population n (%)a
ITT (including EGFR/ALK mutant +) 800 (100%)
EGFR/ALK mutant + onlyb 108 (14%)
ITT-WT 692 (87%)
Teff-high (WT) 284 (43%)
Teff-low (WT) 374 (57%)
PD-L1 IHC TC2/3 or IC2/3 (WT) 244 (35%)
PD-L1 IHC TC1/2/3 or IC1/2/3 (WT) 354 (51%)
PD-L1 IHC TC0 and IC0 (WT) 338 (49%)
PD-L1 IHC TC3 or IC3 (WT) 135 (20%)
PD-L1 IHC TC0/1/2 or IC0/1/2 (WT) 557 (80%)
Median PFS, mo
1.0
In favour of Arm C:
bev + CP
Hazard Ratioc
In favour of Arm B:
atezo + bev + CP
0.61
0.59
0.76
0.48
0.50
0.77
0.51
0.62
1.25
0.39
0.68
Arm B Arm C
8.3 6.8
9.7 6.1
8.3 6.8
11.3 6.8
7.3 7.0
11.1 6.8
11.0 6.8
7.1 6.9
12.6 6.8
8.0 6.8
Reck M, et al. IMpower150 PFS analysis. 26
a Including fatal haemorrhagic AEs: Arm C: haemoptysis n = 1, pulmonary haemorrhage n = 2; Arm B haemoptysis n = 3,
pulmonary haemorrhage n = 2, haemorrhage intracranial n = 1; Arm A: haemoptysis n = 1, haemorrhage intracranial n = 1. b Investigator text for AEs encoded using MedDRA v20.1.
Data cutoff: September 15, 2017
Safety summary
Arm A: atezo + CP (n = 400)
Arm B: atezo + bev + CP
(n = 393)
Arm C (control): bev + CP (n = 394)
Median doses received (range), n Atezolizumab Bevacizumab
10 (1-37)
NA
12 (1-38) 10 (1-38)
NA
8 (1-33)
All cause AE, n (%) Grade 3-4 Grade 5
389 (97%) 226 (57%)
10 (3%)
385 (98%) 242 (62%)
23 (6%)
390 (99%) 230 (58%)
21 (5%)
Treatment-related AE, n (%) Grade 3-4 Grade 5a
372 (93%) 170 (43%)
3 (1%)
371 (94%) 219 (56%)
11 (3%)
376 (95%) 188 (48%)
9 (2%)
Serious AE, n (%) Treatment-related serious AE
155 (39%) 77 (19%)
165 (42%) 100 (25%)
134 (34%) 76 (19%)
AEs of special interest, n (%)b
Grade 3-4 Grade 5
184 (46%) 37 (9%) 2 (1%)
199 (51%) 45 (11%)
0
108 (27%) 13 (3%)
0
AE leading to withdrawal from any treatment 56 (14%) 128 (33%) 98 (25%)
AE leading to dose interruption or modification 203 (51%) 235 (60%) 189 (48%)
Future first-line combinations for NSCLC:
immune doublets
Hellmann, et al. ASCO 2016 (Abs. 3001)
43
18
57 54
64
78
92
23
14
28 31
40 44
50
0
20
40
60
80
100 Nivo 3 q2w + ipi 1 q6/12w (pooled)
Nivo 3 q2w
OR
R (
%)
72 52 17 14 44 32 35 26 28 20 18 18 13 12
Overall <1% ≥1% ≥5% ≥10% ≥25% ≥50%
PD-L1 expression
Combinations of anti-PDL1 or anti-PD1 with other
immunotherapies may offer synergistic benefits
Nivolumab plus ipilimumab (CheckMate 012 phase I study)
OS by Tumor PD-L1 Expression CheckMate 012: First-Line Nivolumab ± Ipilimumab in NSCLC
Based on a September 2016 database lock
All treated patients (n = 77) ≥1% PD-L1 (n = 46) ≥50% PD-L1 (n = 13)
1-year OS rate: 76%
100
80
60
40
20
0
OS
(%
)
0 6 12 18 24 30 36 42 48
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48
1-year OS rate: 87%
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48
1-year OS rate: 100%
Nivo 3 Q2W +
ipi 1 Q6/12W
1-year OS rate: 73%
100
80
60
40
20
0
Months
OS
(%
)
0 6 12 18 24 30 36 42 48
100
80
60
40
20
0
Months
0 6 12 18 24 30 36 42 48
1-year OS rate: 69%
100
80
60
40
20
0
Months
0 6 12 18 24 30 36 42 48
1-year OS rate: 83%
All treated patients (n = 52) ≥1% PD-L1 (n = 32) ≥50% PD-L1 (n = 12)
Nivo 3 Q2W
• Data are based on median follow-up durations of 16 months (combination cohorts) and 22 months (monotherapy)
CM-227
TMB high
Nivo 3 Q2W (n = 52)
Nivo 3 Q2W + Ipi 1 Q12W
(n = 38)
Nivo 3 Q2W + Ipi 1 Q6W
(n = 39)
Any grade
Grade 3–4
Any grade
Grade 3–4
Any grade
Grade 3–4
Treatment-related AEs, % 73 19 84 42 74 31
Treatment-related AEs leading to discontinuation, %
12 12 18 8 18 8
Safety Summary CheckMate 012: First-Line Nivolumab ± Ipilimumab in NSCLC
• There were no treatment-related deaths
• After an additional 6 months of follow-up in the Q12W and Q6W combination cohorts, rates of treatment-
related AEs with nivolumab + ipilimumab remained similar to those previously reported1
Based on a September 2016 database lock; includes events reported between first dose and 100 days after the final dose of nivolumab or ipilimumab, whichever was given last 1. Hellmann MD, et al. Lancet Oncol 2016 Dec 5. [Epub ahead of print].
Conclusiones 1ª línea Mejora de la Supervivencia en Cáncer de Pulmón con Inmunoterapia
30 months median OS is a landmark in 1st line NSCLC Sets a new Standard to compare
Monotherapy (no chemo) Better toxicity profile QoL improvement 20% of patients (TPS PD-L1 >50%)
Combination of anti-PD1/PD-L1 with either anti-CTLA4 or chemo
Potential to increase the proportion of pts who benefit from IO Expect more toxicity Financial toxicity
Pending to define which patients need to combine IO with chemo, IO with IO, and who will do well with IO alone anyway (avoid overtreatment)
PD-L1, TMB, others
Esquema de la charla
IO en CPNM
• Aumento de Supervivencia en 1ª línea
• Aumento de Supervivencia en 2ª línea
• Biomarcadores de eficacia
– PD-L1, TMB
• Eficacia en poblaciones especiales
– EGFR, ALK
• Toxicidad y QoL
• Mensajes para llevar a casa
Anti-PD1 and anti-PDL1 therapies in previously
treated advanced NSCLC: trial design
Brahmer, et al. N Engl J Med 2015 373(2): 123–35; Borghaei, et al. N Engl J Med 2015 373(17): 1627–39
Herbst, et al. Lancet 2016 387(10027): 1540–50; Barlesi, et al. ESMO 2016 (Abs.LBA44)
NSCLC Stage IV (2L/3L)
1. Nivolumab SqCC N=272
2. Nivolumab NSq N=582
3. Pembrolizumab >1% N=1024
4. Atezolizumab Any N=1225
5. Avelumab >1% N=792
Docetaxel
Checkpoint inhibitor
R
1:1 13%
17%
26%
Cro
sso
ver
rate
Nivolumab Durvalumab Avelumab
20mg/kg
IV q4w
3mg/kg
IV q2w
10mg/kg
IV q2w
Pembrolizumab
2mg/kg
IV q3w
Atezolizumab
1200mg
IV q3w
Anti-PD1 Anti-PDL1 Anti-PDL1 Anti-PD1 Anti-PDL1
Efficacy summary for anti-PDL1 and anti-PD1
therapies in previously treated NSCLC
*Phase III dose: 2mg/kg q3w and 10mg/kg q3w; §Tumour
proportion score (TPS) is the proportion of viable tumour cells
showing partial or complete membrane PD-L1 expression
Barlesi, et al. ESMO 2016 (Abs. 1215PD)
Herbst, et al. ESMO 2016 (Abs. LBA48)
Barlesi, et al. ESMO 2016 (Abs. LBA44)
CheckMate 0171
ITT population
(n=272)
CheckMate 0571
ITT population
(n=582)
KEYNOTE-0102
ITT population
(n=1033)
OAK3
ITT population
(n=850)
Histology Squamous Non-squamous All comers All comers
PD-L1
selected No No Yes (TPS§ ≥1%) No
ORR, % Nivo 20%
vs doc 9%
Nivo 19%
vs doc 12%
Pembro 2mg/kg
19%
vs doc 10%
Atezo 14%
vs doc 13%
Follow-up Minimum follow-up
24.2 months
Minimum follow-up
24.2 months
Median follow-up
19.2 months
Minimum follow-up
19 months
HR 0.62 HR 0.75 HR 0.73
Nivo Doc Nivo Doc Atezo Doc 0
4
8
12
16
Me
dia
n O
S
(mo
nth
s)
HR 0.72
Pembro
2mg/kg
Doc
13.8
9.6 9.2 6.0
9.5 12.2
10.5 8.6
CheckMate 017 and CheckMate 057:
phase III nivolumab vs docetaxel
*Included pemetrexed, bevacizumab or erlotinib Borghaei, et al. ASCO 2016; Barlesi, et al. ESMO 2016
PD or
toxicity
Nivolumab 3mg/kg i.v. q2w
(n=135)
PD or
toxicity
Docetaxel 75mg/m2 i.v. q3w
(n=137)
CheckMate 017
• Stage IIIB/IV squamous NSCLC
• Known PD-L1 status
• One prior platinum-based therapy
• ECOG PS 0–1
(n=272)
R
PD or
toxicity
Nivolumab 3mg/kg i.v. q2w
(n=292)
PD or
toxicity
Docetaxel 75mg/m2 i.v. q3w
(n=290)
CheckMate 057
• Stage IIIB/IV non-squamous NSCLC
• Known PD-L1 status
• One prior platinum-based therapy
• Prior maintenance therapy allowed*
• Prior TKI allowed
• ECOG PS 0–1
(n=582)
R
1 OS
2 ORR, PFS, efficacy by
tumour PD-L1
expression, safety, QoL
Endpoints
1 OS
2 ORR, PFS, efficacy by
tumour PD-L1
expression, safety, QoL
Endpoints
PD-L1 expression measured on TCs using Dako 28-8 IHC assay
Crossover permitted
Crossover permitted
CheckMate 017 and CheckMate 057: OS
Barlesi, et al. ESMO 2016 (Abs.1215PD)
CheckMate 057 (non-squamous NSCLC) CheckMate 017 (squamous NSCLC)
Nivolumab
(n=135)
Docetaxel
(n=137)
12-month OS rate,
% 42 24
24-month OS rate,
% 23 8
Nivolumab
(n=292)
Docetaxel
(n=290)
12-month OS rate,
% 51 39
24-month OS rate,
% 29 16
1.0
0.8
0.6
0.4
0.2
0
0 6 12 24 18 Time (months)
OS
es
tim
ate
36 30 42
9.2 6.0
Nivolumab (n=135)
Docetaxel (n=137)
HR=0.62 (95% CI 0.47–0.80)
1.0
0.8
0.6
0.4
0.2
0
0 6 12 24 18 Time (months)
OS
es
tim
ate
36 30 42
12.2 9.5
Nivolumab (n=292)
Docetaxel (n=290)
HR=0.75 (95% CI 0.63–0.91)
Minimum follow-up 24.2 months Minimum follow-up 24.2 months
OS by PD-L1 Expression
1. 1. Paz-Ares L et al.; J Clin Oncol 33, 2015 (suppl; abstr LBA109)
Checkmate 057 – Biomarker-Analysis: OS benefit in the ITT
population in PD-L1 expressing tumors
36
KEYNOTE-010: phase II/III pembrolizumab vs docetaxel
(PDL1-selected)
Herbst, et al. Lancet Oncol 2015
• Advanced NSCLC with progression per
RECIST v1.1
• ECOG PS 0–1
• TPS >1%
• At least 1 prior regimen for advanced NSCLC
• No prior treatment with PD-1 checkpoint
inhibitors or docetaxel
(n=1,033) Docetaxel
75mg/m2 i.v. q3w
(n=343)
Pembrolizumab
2mg/kg i.v. q3w
(n=344)
Pembrolizumab
10mg/kg i.v. q3w
(n=346)
R
1 2 OS and PFS ORR, DoR, safety
Endpoints
PD-L1 expression measured on TCs using Dako 22C3 IHC assay
OAK: phase III atezolizumab vs docetaxel
Barlesi, et al. ESMO 2016
• Locally advanced/metastatic NSCLC
• Tumour specimen available (FFPE)
• 1–2 prior lines of chemotherapy including 1 line of platinum chemotherapy
• Any PD-L1 expression status is permitted
• ECOG PS 0–1
(n=1,225)
R
Until PD or loss of clinical benefit
Until PD Docetaxel
75mg/m2 q3w
Atezolizumab 1,200mg q3w
1 2 • OS ITT in Primary Population (PP,
i.e. the first 850 patients enrolled)
• OS TC1/2/3 or IC1/2/3 in PP
ORR, PFS and DoR, (RECIST v1.1),
safety, tolerability
Endpoints
PD-L1 expression was centrally evaluated on TCs and ICs with the VENTANA SP142 IHC assay
Crossover not permitted
OAK: OS in the ITT population
Barlesi, et al. ESMO 2016 (Abs. LBA44)
9.6 13.8
HR=0.73 (95% CI 0.62–0.87)
p=0.0003
Atezolizumab (n=425)
Docetaxel (n=425) 1.0
0.8
0.6
0.4
0.2
0 0
OS
esti
mate
27 6 3 9 18 24 21 15 12 Time (months)
Minimum follow-up 19 months
OAK: OS in the TC1/2/3 or IC1/2/3 population
Barlesi, et al. ESMO 2016 (Abs. LBA44)
1.0
0.8
0.6
0.4
0.2
0
OS
esti
mate
10.3 15.7
Atezolizumab (n=241)
Docetaxel (n=222)
HR=0.74 (95% CI 0.58–0.93)
p=0.0102
0 27 6 3 9 18 24 21 15 12 Time (months)
Minimum follow-up 19 months
OAK: OS in the TC0 and IC0 population
Barlesi, et al. ESMO 2016 (Abs. LBA44)
1.0
0.8
0.6
0.4
0.2
0 0
Time (months)
OS
esti
mate
27 6 3 9 18 24 21 15 12
Atezolizumab (n=180)
Docetaxel (n=199)
HR=0.75 (95% CI 0.59–0.96)
p=0.0205
8.9 12.6
Minimum follow-up 19 months
OAK: OS by histology
Histology information from eCRF
*Unstratified HRs; §P values for descriptive purpose only Barlesi, et al. ESMO 2016 (Abs. LBA44)
OS in squamous OS in non-squamous
0
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
0 6 27 12 24 18 3 9 15 21 Time (months) Time (months)
OS
es
tim
ate
6 27 12 24 18 3 9 15 21
7.7 8.9 11.2 15.6
HR=0.73*
(95% CI 0.54–0.98)
p=0.0383§
Atezolizumab (n=112)
Docetaxel (n=110) HR=0.73*
(95% CI 0.60–0.89)
p=0.0015§
Atezolizumab (n=313)
Docetaxel (n=315)
Minimum follow-up 19 months
OAK: OS by PD-L1 subgroup
*Stratified HR for ITT and TC1/2/3 or IC1/2/3, unstratified for all other subgroups Barlesi, et al. ESMO 2016
0.73
0.75
0.74
0.67
0.41 TC3 or IC3 (16%)
TC2/3 or IC2/3 (31%)
TC1/2/3 or IC1/2/3* (54%)
TC0 and IC0 (45%)
ITT* (n=850)
0.2 2 1
PD-L1 Subgroups
Atezolizumab Docetaxel
Median OS, months
20.5 8.9
16.3 10.8
15.7 10.3
12.6 8.9
13.8 9.6
In favour of docetaxel In favour of atezolizumab
HR
Esquema de la charla
IO en CPNM
• Aumento de Supervivencia en 1ª línea
• Aumento de Supervivencia en 2ª línea
• Biomarcadores de eficacia
– PD-L1, TMB
• Eficacia en poblaciones especiales
– EGFR, ALK
• Toxicidad y QoL
• Mensajes para llevar a casa
• Biomarkers indicative of
hypermutation & neoantigens may
predict response to IO treatment
Examples:
‒ TMB, MSI-high, neoantigens
Tumor Antigens
• Biomarkers that identify tumor
immune system evasion beyond
PD-1/CTLA-4 to inform new IO
targets and rational combinations
Examples:
‒ Tregs, MDSCs, IDO, LAG-3
Tumor Immune
Suppression
• Biomarkers (intra- or peri-tumoral) indicative of an inflamed phenotype may predict response to IO treatment
Examples:
‒ PD-L1, inflammatory signatures
Inflamed Tumor
Microenvironment
• Biomarkers which characterize the
host environment, beyond tumor
microenvironment, may predict
response to IO treatment
Examples:
‒ Microbiome, germline genetics
Host Environment
Tumor
Antigens
Tumor Immune
Suppression
Inflamed
Tumor
IDO = indoleamine-2,3 dioxygenase; LAG-3 = lymphocyte activation gene-3; MDSCs = myeloid-derived suppressor cells; MSI-high = microsatellite instability high; TMB = tumor mutational burden. Adapted from Blank C.U. et al. Science 2016;352:658–660.
Tumor and Immune Biomarkers Being Evaluated to
Predict Better Outcomes to Immuno-Oncology Therapy
Immunotherapy in previously treated patients:
efficacy by PD-L1 status
*TC3 or IC3: ≥50% of TCs or ≥10% of ICs; TC2/3 or IC2/3: ≥5% of TCs or ICs;
TC1/2/3 or IC1/2/3: ≥1% of TCs or ICs; TC0 and IC0: <1% of TCs and ICs
1. Brahmer, et al. N Engl J Med 2015; 2. Borghaei, et al. N Engl J Med 2015
3. Herbst, et al. Lancet 2015; 4. Barlesi, et al. ESMO 2016
CheckMate 017
(phase III)1
2L nivo vs doc (n=272)
CheckMate 057 (phase III)2
2/3L nivo vs doc
(n=582)
KEYNOTE-010 (phase II/III)3
≥2L pembro¶ vs doc
(n=1,033)
OAK (phase III)4
≥2L atezo vs doc (n=850)
Histology Squamous Non-squamous All comers All comers
PD-L1
selected No No Yes (TPS ≥1%) No
Efficacy by
PD-L1
status
PD-L1
assay 28-8 (Dako) on TCs 22C3 (Dako) on TCs
SP142 (Ventana) on ICs and
TCs
0.53
0.76
HR
1–49% (n=591)
≥50% (n=442)
Subgroup
(pooled doses)
doc
HR
pembro
0.1 1 2 0.5 0.2
0.67 ITT (n=1,033)
≥5% (n=81)
<5% (n=144)
≥10% (n=69)
<10% (n=156)
≥1% (n=119)
<1% (n=106)
ITT (n=272)
0.69
0.58
0.53
0.70
0.50
0.70
0.39
0.59
HR Subgroup
doc
HR
nivo
0.1 1 2 0.5 0.2
NQ (n=47)
≥5% (n=181)
<5% (n=274)
≥10% (n=165)
<10% (n=290)
≥1% (n=246)
<1% (n=209)
ITT (n=582)
0.58
0.87
0.43
0.96
0.40
0.96
0.72
HR Subgroup
doc
HR
nivo
0.1 1 2 0.5 0.2
doc atezo
HR
TC1/2/3 or IC1/2/3 (n=463)
TC0 and IC0 (n=379)
TC3 or IC3 (n=137)
TC2/3 or IC2/3 (n=265)
ITT (n=850) 0.73
0.41
0.67
0.74
0.75
HR Subgroup*
<1% not available
study design
2 1 0.1 0.2 0.5
Nivolumab Pembrolizumab Atezolizumab Durvalumab
Detection
antibody 28-81 22C31 SP1423 SP2634
IHC platform Dako1 Dako1 Ventana1 Ventana4
Cell types scored
for NSCLC TC1 TC1 IC and TC1,3 TC1
Cut-offs in
NSCLC
PDL1-selected as
≥5% of TCs
exhibiting
positive
membrane
PD-L1 staining at
any intensity
PDL1-selected as
≥50% (treatment-
naïve) or ≥1%
(previously treated)
of viable TCs
showing partial or
complete
membrane PD-L1
expression*
TC3 or IC3: ≥50% of TCs or
≥10% of ICs
TC2/3 or IC2/3: ≥5% of TCs or
ICs
TC1/2/3 or IC1/2/3: ≥1% of TCs
or ICs
TC0 and IC0: <1% of TCs and
ICs
(proportion of cells stained at
any intensity)
PDL1-selected as
≥25% of TCs with
membrane PD-L1
staining
Estimated PD-L1
prevalence in
NSCLC
Do we have the right assay?
*For the 22C3 assay, the proportion of viable tumour cells showing partial or complete membrane PD-L1 staining is termed the tumour proportion score (TPS)
1. Kerr, et al. J Thorac Oncol 2015; 2. Aggarwal, et al. ESMO 2016 3. Vansteenkiste, et al. ECC 2015; 4. Rebelatto, et al. ASCO 2015; 5. Rizvi, et al. ASCO 2015
37%
68%
16%
TC <5%
TC ≥5%
≥2L1
54%
46%
TC <25%
TC ≥25%
≥2L5
54%
46%
TPS <1%
TPS 1–49%
TPS ≥50%
1L2 ≥2L2
31% 35%
40% 38%
30% 27%
Harmonization Iniciatives:
Blueprint Trial
Adapted from Hirsch, et al. AACR 2016.
• The vast majority (77%, 115 out of 150 patients) of SP142 PD-L1 negative patients were also
PD-L1 negative by the 22C3 assay
50
Overlap of 22C3 and SP142 PD-L1 Negative Populations in OAK BEP
Gadgeel S, et al. 22C3 vs SP142 in OAK
SP142 Assay
Dx–, n Dx+, n
22C3
Assay
Dx–, n 115 103
Dx+, n 35 145
Dx–, no or low PD-L1 expression; Dx+, positive for PD-L1 expression.
N = 103 N = 115 N = 35 22C3
TPS < 1%
SP142 TC0 and IC0
N = 218
N = 150
115 patients
PD-L1–negative by 22C3 and SP142
Double negative
Negative
By 22C3
Negative
By SP142
• OS benefit observed in PD-L1 negative populations as defined by either assay
SP142 assay: TC0 and IC0, PD-L1 expression on <1% TC and IC.
22C3 assay: TPS <1%, PD-L1 expression on <1% TC.
Dx-, no or low PD-L1 expression.
Overall Survival in PD-L1 Negative Subgroups in OAK BEP
Gadgeel S, et al. 22C3 vs SP142 in OAK
OS HR
(95% CI)
SP142 Dx-
(N = 150)
0.55
(0.37, 0.80)
22C3 Dx-
(N = 218)
0.61
(0.45, 0.84)
+ Censored
Atezolizumab
Docetaxel
SP142 TC0 and IC0
Months
+ Censored
Atezolizumab
Docetaxel
22C3 TPS < 1%
Ove
rall
Su
rviv
al (%
)
Months
Ove
rall
Su
rviv
al (%
)
Gandara DR, et al. bTMB in POPLAR & OAK
Increasing Atezolizumab benefit with higher bTMB cut-points
in OAK
BEP, biomarker-evaluable population; ITT, intention-to-treat.
Progression-Free Survival – OAK Overall Survival – OAK
• Enrichment of PFS benefit was observed in the bTMB ≥16 subgroup,
while OS was consistent between the bTMB ≥16 subgroup and the BEP
Gandara DR, et al. bTMB in POPLAR & OAK
LIMITED Overlap between bTMB ≥16 and PD-L1 expressiona
(OAK BEP)
a PD-L1 expression was evaluated by immunohistochemistry (IHC) using the VENTANA SP142 assay;
TC3 or IC3, ≥50% of TC or ≥10% of IC express PD-L1.
BEP, biomarker-evaluable population; IC, tumor-infiltrating immune cell; TC, tumor cell.
• Non-significant overlap between the
bTMB ≥16 and TC3 or IC3 subgroups
(Fisher exact test, P = 0.62)
– 19.2% of tumors with bTMB ≥16
were also TC3 or IC3
– 29.1% of tumors with TC3 or IC3
also had bTMB ≥16
PFS HR (95% CI) OS HR (95% CI)
bTMB ≥16 0.64 (0.46, 0.91) 0.64 (0.44, 0.93)
TC3 or IC3 0.62 (0.41, 0.93) 0.44 (0.27, 0.71)
bTMB ≥16 and
TC3 or IC3 0.38 (0.17, 0.85) 0.23 (0.09, 0.58)
Gut microbes shape response to
cancer immunotherapy
Blank CU et al. Science 2016; 352:658
Esquema de la charla
IO en CPNM
• Aumento de Supervivencia en 1ª línea
• Aumento de Supervivencia en 2ª línea
• Biomarcadores de eficacia
– PD-L1, TMB
• Eficacia en poblaciones especiales
– EGFR, ALK
• Toxicidad y QoL
• Mensajes para llevar a casa
JAMA Oncol. 2018;4(2):210-216.
Anti-PD1/PD-L1 efficacy in EGFR mutant NSCLC
Garassino et al. Lancet Oncol 2018
Cohort 1: EGFR+/ALK+ NSCLC with at least
25%, or less than 25%, of tumour cells with
PD-L1 expression
Anti-PD1/PD-L1 efficacy in EGFR mutant NSCLC
Reck M, et al. IMpower150 PFS analysis.
a ITT, EGFR/ALK mutants, and ITT-WT % prevalence out of ITT (n = 800);
Teff % prevalence out those tested in ITT-WT (n = 658); PD-L1 IHC % prevalence out of ITT-WT (n = 692). b Patients with a sensitising EGFR mutation or ALK translocation must have disease progression
or intolerance of treatment with one or more approved targeted therapies. c Stratified HRs for ITT, ITT-WT and Teff-high WT populations; unstratified HRs for all other subgroups.
Data cutoff: September 15, 2017
IMpower150: PFS in key biomarker populations
0,25
Population n (%)a
ITT (including EGFR/ALK mutant +) 800 (100%)
EGFR/ALK mutant + onlyb 108 (14%)
ITT-WT 692 (87%)
Teff-high (WT) 284 (43%)
Teff-low (WT) 374 (57%)
PD-L1 IHC TC2/3 or IC2/3 (WT) 244 (35%)
PD-L1 IHC TC1/2/3 or IC1/2/3 (WT) 354 (51%)
PD-L1 IHC TC0 and IC0 (WT) 338 (49%)
PD-L1 IHC TC3 or IC3 (WT) 135 (20%)
PD-L1 IHC TC0/1/2 or IC0/1/2 (WT) 557 (80%)
Median PFS, mo
1.0
In favour of Arm C:
bev + CP
Hazard Ratioc
In favour of Arm B:
atezo + bev + CP
0.61
0.59
0.76
0.48
0.50
0.77
0.51
0.62
1.25
0.39
0.68
Arm B Arm C
8.3 6.8
9.7 6.1
8.3 6.8
11.3 6.8
7.3 7.0
11.1 6.8
11.0 6.8
7.1 6.9
12.6 6.8
8.0 6.8
JAMA Oncol. 2018;4(2):210-216.
Anti-PD1/PD-L1 efficacy in KRAS mutant NSCLC
Best overall response to immunotherapy
(RECIST1.1) in co-mutation defined KRAS-
mutant LUAC subsets
P=0.0028, Fisher’s exact test
WCLC 2017 Presentation Number: 6343
Similar results in independent MSKCC cohort
Hellmann MD, Rizvi H, Rudin CM (unpublished)
ORR: 59% (KP) vs 0% (KL)
Impact of major co-mutations on the immune contexture and
response of KRAS-mutant lung adenocarcinoma to
immunotherapy
K
C
KL KP
KRAS
KRAS
TP53
STK11
ATM
KEAP1
Anti-PD1/PD-L1 efficacy in KRAS mutant NSCLC
Esquema de la charla
IO en CPNM
• Aumento de Supervivencia en 1ª línea
• Aumento de Supervivencia en 2ª línea
• Biomarcadores de eficacia
– PD-L1, TMB
• Eficacia en poblaciones especiales
– EGFR, ALK
• Toxicidad y QoL
• Mensajes para llevar a casa
Toxicidad inmunomediada de la inmunoterapia
Postow; N Engl J Med 2018
KN-024
KN-010 OAK
Safety of anti-PDL1 and anti-PD1
compare to chemotherapy
0
20
40
60
80
100
Pa
tie
nts
, %
Safety summary for anti-PDL1 and anti-PD1
therapies in previously treated NSCLC
NR, not reported Brahmer, et al. N Engl J Med 2015 373(2): 123–35; Borghaei, et al. N Engl J Med 2015 373(17): 1627–39
Herbst, et al. Lancet 2016 387(10027): 1540–50; Herbst, et al. ESMO 2016 (Abs. LBA48); Barlesi, et al. ESMO 2016 (Abs. LBA44)
Nivolumab
Docetaxel
CheckMate 017 CheckMate 057 KEYNOTE-010 OAK
Nivolumab
Docetaxel
Pembrolizumab
Docetaxel
Atezolizumab
Docetaxel
Selected immune-
mediated AEs
(immunotherapy arm)
CheckMate 017
n = 131
CheckMate 057
n = 287
KEYNOTE-010
(2mg/kg arm)
n = 339
OAK
n = 609
All
Grade
Grade
3–4
All
Grade
Grade
3–4
All
Grade
Grade
3–4
All
Grade
Grade
3–4
Pneumonitis 5% 1% 3% 1% 4% 2% 1% 1%
Hypothyroidism 4% 0% 7% 0% 9% 0% NR NR
Hyperthyroidism NR NR 1% 0% 7% 2% NR NR
Hepatitis NR NR NR NR 1% 0% <1% <1%
Colitis 1% 1% 1% <1% 1% <1% <1% 0%
Treatment-related AEs Grade 1–2 Grade 3–4 Immunotherapy
Docetaxel
CHEST 2017 152, 271-281DOI: (10.1016/j.chest.2017.04.177)
Higher incidence of pneumonitis with PD-1 inhibitors compared with PD-L1 inhibitors in NSCLC
Anti-PD-1 Anti-PD-L1 P
Incidence 3.6% 1.3% 0.001
Grade 3-4 1.1% 0.4% 0.02
Anti-PD-1
Anti-PD-L1
La Inmunoterapia con ICI antiPD1-PDL1 aumenta la Supervivencia Global en enfermedad metastásica, independientemente de la línea de
tratamiento.
• Muchos estudios pendientes (redundancia), muchos con resultados a lo largo del 2018, que definirán el mejor esquema (monoterapia, combinación), orden de tratamiento y selección de pacientes óptimo.
• Se pueden identificar pacientes con beneficios extraordinarios a la inmunoterapia:
• TPS PD-L1 >50% (1ª línea > beneficio que en 2L y sucesivas)
• IC3 or TC 3 PD-L1
• High-TMB
• Y subgrupos que no se benefician de monoterapia con anti-PD1/PDL1:
• Low-TMB
• EGFR mutados (diferente biología) - ¿combinaciones con IO?
• Objetivo: Aumentar el número de pacientes que se beneficien de la inmunoterapia (transformar “cold tumors” en “hot tumors”)
• A la espera del impacto de la Inmunoterapia en SG en enfermedad localmente avanzada y en etapa adyuvante. Estudios en marcha.
Take Home Messages Mejora de la Supervivencia en Cáncer de Pulmón con Inmunoterapia
The next pillar of lung cancer therapy
Cancer therapy
Su
rgery
Ch
em
oth
era
py
Rad
ioth
era
py
Ta
rgete
d
thera
py
Imm
un
oth
era
py
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