Aprile
2011
Targeted therapies and immunotherapy
Piano Generale di Emergenza
Presidio Ospedaliero di Livorno
Federico Cappuzzo
Viale Alfieri 36
Istituto Toscano Tumori
Ospedale Civile
Livorno-Italy
D.Lgs del 9 aprile 2008 n. 81 – Titolo I – Sezione VI
Gestione delle emergenze
Istituto Toscano Tumori –Livorno, Italy
Studies of EGFR TKIs versus chemotherapy as
first-line therapy in EGFRmut+ NSCLC
Study
IPASS *
First SIGNAL *
WJTOG 3405
NEJ 002
OPTIMAL
EURTAC
ENSURE
LUX Lung 3
LUX Lung 6
#
Treatment
RR %
PFS
OS
mPFS
HR
(mos)
P-value
mOS (mos)
HR
P-value
97
Gefitinib
71.2
9.5
0.48
21.6
1.00
111
CBDCA + TXL
47.3
6.3
<0.0001
21.9
0.99
159
Gefitinib
84.6
8.0
0.54
27.2
1.04
150
CDDP+ GEM
37.5
6.3
0.008
25.6
NR
88
Gefitinib
62.1
9.2
0.48
36.0
1.18
89
CDDP + TXT
32.2
6.3
<0.001
39.0
NR
114
Gefitinib
73.7
10.4
0.36
27.7
0.89
114
CBDCA + TXL
30.7
5.5
<0.001
26.6
0.48
82
Erlotinib
83.0
13.1
0.16
22.6
1.06
72
CBDCA + GEM
36.0
4.6
<0.0001
28.8
0.68
84
Erlotinib
54.5
9.4
0.34
19.3
1.04
82
Platinum Doublet
10.5
5.2
<0.0001
19.5
0.87
110
Erlotinib
68.2
11.1
0.43
NR
NR
107
CDDP + GEM
39.3
5.7
<0.0001
NR
NR
230
Afatinib
56.0
11.1
0.58
16.6
1.12
115
CDDP + PEM
23.0
6.9
0.0004
14.8
0.60
242
Afatinib
66.9
11.0
0.28
22.1
0.95
CDDP + GEM
23.0
5.6
<0.0001
22.2
0.76
122
* Shown data are restricted to
EGFRmut + population
Istituto Toscano Tumori – Livorno, Italy
Quesiti clinici con gli EGFR-TKIs
• Posso determinare lo stato mutazionale con
un test sul sangue?
• Qual è il miglior inibitore?
• Il tipo di mutazione di EGFR è importante?
• Cosa fare alla progressione?
• Posso potenziare l’efficacia?
Istituto Toscano Tumori –Livorno, Italy
Detection of plasma EGFR mutations
Detection of EGFR mutations by UD-NGS
EGFR status
Baseline
Progression
Mutated
31 (72%)
11 (76%)
Wild type
12 (28%)
4 (24%)
Total
43 (100%)
15 (100%)
Sensitivity: 72%
Specificity: 100%
Detection of EGFR mutations by cobas® test
EGFR status
Baseline
Progression
Mutated
30 (70%)
11 (73%)
Wild type
13 (30%)
4 (27%)
Total
43 (100%)
15 (100%)
Sensitivity: 71%
Specificity: 100%
Marchetti, et al. WCLC 2015
Istituto Toscano Tumori – Livorno, Italy
Gefitinib versus erlotinib as second line treatment
in unselected NSCLC: Phase III trial
Erlotinib
150 mg/die
• Stage III-IV
Adenocarcinoma
• Evaluable disease
• 2° line & after
• Age >20 years
• No interstitial lung disease
R
Gefitinib
250 mg/die
Stratification factors:
Gender, PS, Stage, Smoking history, Mutation status,Institution, Prior regimen
Non-Inferiority trial
Katakami N, et al. ASCO 2014
Istituto Toscano Tumori –Livorno, Italy
Gefitinib versus Erlotinib: PFS according to EGFR status
Treatment
mPFS (mos)
Erlotinib
10.09
Gefitinib
8.90
Treatment
mPFS (mos)
Erlotinib
2.10
Gefitinib
2.07
p value
0.532
p value
0.221
Treatment
mPFS (mos)
Erlotinib
2.53
Gefitinib
2.27
p value
0.878
Katakami N, et al. ASCO 2014
Istituto Toscano Tumori –Livorno, Italy
Erlotinib versus gefitinib in patients with EGFR
mutations: CTONG0901 study
• Advanced NSCLC
• EGFR Mut+
(exon 19 or 21)
• ECOG PS 0–2
(n=256)
Erlotinib
150mg/day
Until PD or
unacceptable
toxicity
Gefitinib
250mg/day
Until PD or
unacceptable
toxicity
R
Primary end-point: mPFS
Yang, et al. WCLC 2015
Istituto Toscano Tumori –Livorno, Italy
CTONG0901: efficacy and toxicity
PFS and OS (any line)
Gefitinib
10.4
10.4 12.4
13.0
HR=0.81; p=0.108
mPFS
Erlotinib
PFS
20.1
mOS
22.9
HR=0.84; p=0.250
0
5
10
15
20
Time (months)
25
OS
Treatment-emergent AEs >10% in either arm
AE, %
Rash
Cough
Diarrhoea
Hand and foot syndrome
Nail changes
Anorexia
Gefitinib
n=128
All grade Grade ≥3
63
0
30
0
19
0
13
0
13
0
12
0
Erlotinib
n=128
All grade Grade ≥3
70
2
23
0
17
0
6
0
19
0
5
0
Yang, et al. WCLC 2015
Istituto Toscano Tumori –Livorno, Italy
CTONG0901: PFS and OS by mutation type
Subgroup
HR (95% Cl)
P
PFS
EGFR exon 19
EGFR exon 21
0.79 (0.56–1.13)
0.84 (0.55–1.26)
1.092
0.388
OS
EGFR exon 19
EGFR exon 21
0.83 (0.56–1.22)
0.86 (0.55–1.34)
0.345
0.497
0.1
0.2
0.5
Erlotinib
1
2
5
10
Gefitinib
Yang, et al. WCLC 2015
Istituto Toscano Tumori –Livorno, Italy
Dacomitinib versus erlotinib in EGFRex19 mut+: PFS
and OS (N=78)
PFS
OS
Suresh S. Ramalingam et al, WCLC 2015
Istituto Toscano Tumori – Livorno, Italy
Afatinib versus chemotherapy: OS by EGFR
mutation type
Exon 19
Exon 21
Yang J C-H, et al. Lancet Oncol 2015
Istituto Toscano Tumori – Livorno, Italy
Indirect comparison of toxicities reported with
gefitinib or erlotinib or afatinib
*Shown data include all patients treated with gefitinib
Data are reported as percentage of AEs of any grade and, in parenthesis, of grade 3
Landi L , Expert Opin Pharmacother 2014
Istituto Toscano Tumori – Livorno, Italy
Erlotinib versus erlotinib+bevacizumab as first-line
therapy in EGFRmut+ NSCLC: phase IIR study
Chemotherapy-naive
stage IIIB-IV or
postoperative recurrence
Non-squamous NSCLC
Activating EGFR
mutations
•Exon 19 deletion
•Exon 21 L858R
Age ≥ 20 years
PS 0-1
No brain metastasis
Erlotinib 150mg/day +
Bevacizumab 15 mg/kg q3w
(N=77)
1:1R
PD
2-yr treatment period
Erlotinib 150 mg/day
(N=75)
PD
Primary end-point: PFS
Secondary End points: OS, ORR, QoL, symptoms improvement FACT-L scale and safety
Seto T, et al. Lancet Oncol 2014
Istituto Toscano Tumori – Livorno, Italy
Erlotinib versus erlotinib+bevacizumab as first-line
therapy in EGFRmut+ NSCLC: PFS
Seto T, et al. Lancet Oncol 2014
Istituto Toscano Tumori – Livorno, Italy
Erlotinib+bevacizumab as first-line therapy in
EGFRmut+ NSCLC: the BELIEF phase II study
Chemotherapy-naive
stage IIIB-IV or
postoperative recurrence
Non-squamous NSCLC
Activating EGFR mutations
•Exon 19 deletion
•Exon 21 L858R
•Brain metastases allowed
Erlotinib 150mg/day +
Bevacizumab 15 mg/kg q3w
PD
Primary end-point: PFS
Stahel, et al. ECC 2015
Istituto Toscano Tumori – Livorno, Italy
ETOP 2-11 BELIEF: Best % change from baseline in
the sum of tumor diameters for targeted lesions
N=97
CR
PR
SD
PD
NE
All
7 (6.4)
76 (69.7)
18 (16.5)
3 (2.8)
5 (4.6)
T790M +
3 (8.1)
23 (62.2)
9 (24.3)
0 (0.0)
2 (5.4)
T790M 4 (5.6)
53 (73.6)
9 (12.5)
3 (4.2)
3 (4.2)
Response duration (Median, 95%CI):
All : 14.8 m (12.0-NE); T790M+ : NE (14.7-NE); T790M- : 12.0 m (8.2-23.3)
Stahel, et al. ECC 2015
Istituto Toscano Tumori – Livorno, Italy
BELIEF: PFS by T790M mutation
Events/N Median PFS (95%CI) 12m PFS (95%CI)
All
57/109
13.8 m (10.3-21.3) 56.7% (46.0-66.0)
T790M+
15/37
16.0 m (13.1-NE)
72.4% (53.4-84.7)
T790M-
42/72
10.5 m (9.2-16.2)
49.4% (36.6-61.0)
Stahel, et al. ECC 2015
Istituto Toscano Tumori – Livorno, Italy
BELIEF: data on context with other studies
Stahel, et al. ECC 2015
Istituto Toscano Tumori – Livorno, Italy
Rociletinib and AZD9291 in patients EGFRT790M+
AZD9291
Janne PA, NEJM 2015
RR:61%
Rociletinib
Sequist L, ASCO 2015
RR:53%
Istituto Toscano Tumori – Livorno, Italy
PFS with rociletinib or AZD9291 in patients
EGFRT790M+
Rociletinib
AZD9291
Sequist L, et al. ASCO 2015
Goss G. et al, ECC 2015
Istituto Toscano Tumori – Livorno, Italy
Rociletinib and AZD9291 in patients EGFRT790M-
Rociletinib
AZD9291
RR:21%
Istituto Toscano Tumori – Livorno, Italy
PFS with AZD9291 according to EGFR T790M status
9.6 mos
2.8 mos
PFS with rociletinib: 5.6 months in EGFRT790M-
Janne PA, et al. NEJM 2015
Istituto Toscano Tumori – Livorno, Italy
AZD9291 is distributed to mouse brain to a
greater extent than gefitinib, afatinib or
Rociletinib
Ballard P, et al. WCLC 2015
Istituto Toscano Tumori – Livorno, Italy
(11C) AZD9291is distributed to cynomolgus
monkey brain
Ballard P, et al. WCLC 2015
Istituto Toscano Tumori – Livorno, Italy
Treatment-related AEs occurring in patients
receiving Rociletinib or AZD9291
AZD9291
Rociletinib
Sequist L, et al. NEJM 2015
Janne PA, et al. NEJM 2015
Istituto Toscano Tumori – Livorno, Italy
Different mechanisms and different options
Molecular event
Therapy option
AZD9291
EGFR Del19+ and EGFR T790M+ and EGFR C797S+
Resistant to ALL EGFR-TKIs
EGFR L858R+ and EGFR T790M+ and EGFR C797S+
Partially sensitive to cetuximab
EGFR del 19+ or L858R+ and EGFR T790M- and EGFR C797S+
Sensitive to gefitinib/afatinib
Rociletinib
EGFR Del19+ or L858R+ and EGFR T790M+ and EGFR L718Q+ or L844V+
Potentially sensitive to AZD9291
EGFR del 19+ or L858R+ and EGFR T790M- and EGFR L718Q+ or L844V+
Sensitive to gefitinib/afatinib
Ercan D et al. Clin Cancer Res 2015
Thress KS et al. Nature Med 2015
Piotrowska Z et al. Cancer Discov 2015
Eberlein CA et al. Cancer res 2015
Istituto Toscano Tumori –Livorno, Italy
Take home messages sugli EGFR-TKIs
• La biopsia liquida è un’alternativa che può essere utilizzata nella
pratica clinica quando il tessuto tumorale non è disponibile o al
momento della progressione
• Gefitinib, erlotinib e afatinib hanno simile efficacia e lievi differenze
in termini di effetti collaterali
• Non vi sono dati che dimostrano un diverso effetto o superiorità di
un inibitore rispetto ad un altro in relazione al tipo di mutazione di
EGFR
• L’associazione erlotinib-bevacizumab promettente ma ad oggi NON
raccomandata nella pratica clinica
• Rociletinib e AZD9291 differiscono:
–
–
–
–
Profilo di efficacia
Tossicità
Capacità di penetrazione a livello del SNC
Meccanismi di resistenza acquisita
Istituto Toscano Tumori – Livorno, Italy
Quesiti clinici con gli inibitori di ALK
• Cosa fare in presenza di metastasi cerebrali?
• Bisogna ripetere la biopsia del tumore alla
progressione a crizotinib?
• Qual’ è oggi la migliore sequenza di
trattamento?
• Vi sono differenze in tossicità?
• Quali nuove prospettive?
Istituto Toscano Tumori –Livorno, Italy
ALK inhibitors: CNS activity
Agents
Brain RR
Reference
N
%
Crizotinib
22 *
18 %
Costa, J Clin Oncol 2015
Alectinib
9
55 %
Gadgeel, Lancet Oncol 2015
Alectinib
34
58.8 %
Barlesi, ECC 2015
Alectinib
16
75 %
Shaw, WCLC 2015
Ceritinib
33
39.4 %
Mok, #8059 ASCO2015
Ceritinib
17 *
58.8 %
Felip, #8060 ASCO2015
PF06463922
14 **
36 %
Shaw, #8018 ASCO2015
AP26113
15 **
53 %
Camidge, #8062 ASCO 2015
*ALKi naïve pts, **including ALKi naïve pts (10-16%)
Istituto Toscano Tumori –Livorno, Italy
Alectinib: activity by prior radiation
Waterfall plot of patients with measurable CNS disease
70
60
Prior CNS Radiation
Yes (n=34)
No (n=16)
Sum of longest diameter,
max. decrease from baseline (%)
50
40
30
20
10
0
–10
–20
–30
–40
–50
–60
–70
–80
–90
–100
Patients
•
•
In the overall population, only 17% of patients had CNS PD
Progression in the CNS occurred in 8% of patients without CNS disease at baseline
Gadgeel, et al. WCLC 2015
Istituto Toscano Tumori – Livorno, Italy
ALK tyrosine kinase mutations and sensitivity
to new anti-ALK agents
Pall Curr Opin 2015
Istituto Toscano Tumori – Livorno, Italy
ALK inhibitors at crizotinib failure
Selection of second-line next generation ALK inhibitors based on ALK
mutation status
1L
2L
None
Crizotinib
PD
Bx
F1174
I1171
G1202R
Alectinib or ceritinib or
brigatinib or lorlatinib
Alectinib, brigatinib or
lorlatinib
Ceritinib or lorlatinib
Lorlatinib
Istituto Toscano Tumori –Livorno, Italy
Lorlatinib is a potent and selective, CNS
penetrant ALK/ROS1 TKI
ALK WT NIH3T3 IC50 (nM)
ALK L1196M NIH3T3 IC50
(nM)
ROS1-CD74 IC50 (nM)
MDR BA/AB
CSF or free brain:
free plasma (rodent)
Log D
Crizotinib
PF-06463922
80
1.5
843
21
11
0.24
45
1.5
–
0.23–0.33
2.0
2.3
PF-06463922 Is Active Against All Known
ALK and ROS1 Resistance Mutations
PF 06463922 activity
PF-06463922
Crizotinib
Zou HY, et al. Proc Natl Acad Sci U S A 2015;112:3493
Zou HY, et al. AACR-NCI 2013, poster A277
Istituto Toscano Tumori – Livorno, Italy
Lorlatinib phase I: response by prior TKI
R:ROS1 translocated
Bauer, et al. WCLC 2015
Istituto Toscano Tumori – Livorno, Italy
ALK inhibitors in the crizotinib-failure setting:
most common AEs
Alectinib (NP28673) (n=138)
100
Brigatinib (n=137)*
90
80
Ceritinib ATU (n=208)
81
80
Ceritinib (ASCEND-2) (n=140)
Percentage
70
60
52
50
42
40
40
36
36
29
30
20
20
30
17
15
10
1 1
20
15
5 6
0 1
0
Diarrhoea
(all grades)
Diarrhoea
(grade ≥3/
severe)
Nausea
(all grades)
5 6
Nausea
(grade ≥3/
severe)
NR
Constipation
(all grades)
0 0 NR 2
Constipation
(grade ≥3/
severe)
NR
Fatigue
(all grades)
0
6
4
NR
Fatigue
(grade ≥3/
severe)
Brigatinib: pulmonary events
• Observed in 13/137 (9%) of patients* who received treatment with brigatinib
• Incidence was numerically lower with lower starting doses
Barlesi, et al. ECC 2015; Gettinger, et al. WCLC
*All ALK+ NSCLC patients
Cortot, et al. ECC 2015; Mok, et al. ASCO 2015
Istituto Toscano Tumori – Livorno, Italy
Take home messages sugli inibitori di
ALK
• Al momento crizotinib è l’agente anti-ALK da utilizzare in prima battuta
• Alectinib, brigatinib e ceritinib hanno mostrato efficacia nei pazienti in
progressione a crizotinib.
• Alectinib, ceritinib e brigatinib hanno mostrato efficacia nei pazienti con
metastasi cerebrali
• La migliore sequenza di trattamento non è definita: identificare il
meccanismo di resistenza può aiutare nel decidere la sequenza da
utilizzare
• Il profilo di tossicità di alectinib, ceritinib e brigatinib è differente
• Lorlatinib sembra essere efficace in presenza di tutte le mutazioni
secondarie a crizotinib inclusa la G1202R
• Lorlatinib sembra essere efficace nei pazienti ROS1 traslocati resistenti a
crizotinib
Istituto Toscano Tumori – Livorno, Italy
Quesiti clinici sui checkpoint inhibitors
• Nivolumab è standard terapeutico in seconda
linea?
– In tutti i pazienti?
– Solo negli squamosi?
• Qual è il ruolo predittivo dell’espressione di
PDL1?
– Vi sono pazienti che possiamo escludere?
Istituto Toscano Tumori –Livorno, Italy
CheckMate 017 (NCT01642004) - Study Design
• Stage IIIb/IV SQ NSCLC
• ECOG PS 0–1
• Pre-treatment (archival or fresh)
tumor samples required for PD-L1
analysis
N = 272
Randomize 1:1
• 1 prior platinum doublet-based
chemotherapy
Nivolumab
3 mg/kg IV Q2W
until PD or
unacceptable toxicity
n = 135
Docetaxel
75 mg/m2 IV Q3W
until PD or
unacceptable toxicity
n = 137
• Primary Endpoint:
– OS
• Additional Endpoints:
̶ Investigator-assessed ORR
̶ Investigator-assessed PFS
̶ Correlation between PD-L1
expression and efficacy
̶ Safety
̶ Quality of life (LCSS)
Patients stratified by region
and prior paclitaxel use
• One pre-planned interim analysis for OS
• At time of DBL (December 15, 2014), 199 deaths were reported (86% of deaths required for final analysis)
• The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03
LCSS = Lung cancer symptom scale
Brahmer J, et al. NEJM 2015
Istituto Toscano Tumori – Livorno, Italy
Checkmate 017: updated overall survival
Reckamp, et al. WCLC 2015
Istituto Toscano Tumori – Livorno, Italy
• Stage IIIB/IV non-SQ NSCLC
• Pre-treatment (archival or recent) tumor
samples required for PD-L1
• ECOG PS 0–1
• Failed 1 prior platinum doublet
• Prior maintenance therapy alloweda
• Prior TKI therapy allowed for known
ALK translocation or EGFR mutation
N = 582
Randomize 1:1
CheckMate 057 (NCT01673867) Study Design
Nivolumab
3 mg/kg IV Q2W
until PD or
unacceptable toxicity
n = 292
Docetaxel
75 mg/m2 IV Q3W
until PD or
unacceptable toxicity
n = 290
• Primary Endpoint
– OS
• Additional Endpoints
– ORRb
– PFSb
– Safety
– Efficacy by tumor PD-L1 expression
– Quality of life (LCSS)
Patients stratified by prior maintenance therapy
and line of therapy (second- vs third-line)
• PD-L1 expression measured using the Dako/BMS automated IHC assay14,15
– Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity,
precision, and robustness
a
Maintenance therapy included pemetrexed, bevacizumab, or erlotinib (not considered a separate line of therapy); b Per RECIST v1.1 criteria as determined by the investigator.
Paz-Ares L, et al. ASCO 2015
Istituto Toscano Tumori – Livorno, Italy
Overall Survival
100
Nivolumab
(n = 292)
Docetaxel
(n = 290)
12.2
9.4
90
80
mOS, mo
70
HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015
OS (%)
60
1-yr OS rate = 51%
50
40
1-yr OS rate = 39%
30
Nivolumab
20
10
Docetaxel
0
0
3
6
9
12
15
18
21
24
27
Time (months)
Number of Patients at Risk
Nivolumab
292
232
194
169
146
123
62
32
9
0
Docetaxel
290
244
194
150
111
88
34
10
5
0
Symbols represent censored observations.
Paz-Ares L, et al. ASCO 2015
Istituto Toscano Tumori – Livorno, Italy
OS by PD-L1 Expression
1% PD-L1 Expression level
5% PD-L1 Expression level
mOS (mo)
10% PD-L1 Expression level
mOS (mo)
Nivolumab Docetaxel
mOS (mo)
Nivolumab
Docetaxel
Nivolumab Docetaxel
100
PD-L1 ≥1%
9.3
7.2
PD-L1 ≥5%
10
6.4
PD-L1 ≥10%
11
7.1
PD-L1 <1%
8.7
5.9
PD-L1 <5%
8.5
6.1
PD-L1 <10%
8.2
6.1
90
80
70
OS (%)
60
50
40
30
20
10
0
0
3
6
9
12
15
Time (months)
18
21
24
0
3
6
9
12
15
18
21
Time (months)
Nivolumab PD-L1+
Nivolumab PD-L1–
Docetaxel PD-L1+
Docetaxel PD-L1–
24
0
3
6
9
12
15
18
21
24
Time (months)
Brahmer J, et al. NEJM 2015
Istituto Toscano Tumori – Livorno, Italy
OS by PD-L1 Expression
≥1% PD-L1 expression level
≥5% PD-L1 expression level
100
mOS (mo)
90
Nivo
17.2
80
Doc
9.0
70
90
80
OS (%)
70
100
mOS
(mo)
18.2
Niv
o
Doc
80
50
50
50
40
40
30
30
20
20
30
20
10
60
8.1
10
HR (95% CI) = 0.59 (0.43, 0.82)
10
HR (95% CI) = 0.43 (0.30, 0.63)
0
0
0
3
6
9
12
15
18
21
24
27
0
3
6
9
12
15
18
21
24
27
<1% PD-L1 expression level
70
Nivo
Doc
40
<5% PD-L1 expression level
10.4
60
10.1
50
20
10
6
9
12
15
18
Time (months)
Symbols represent censored observations.
21
24
27
12
15
18
21
24
mOS (mo)
70
9.7
60
Nivo
9.9
10.1
50
Doc
10.3
Doc
40
40
30
30
20
20
27
mOS (mo)
10
HR (95% CI) = 1.01 (0.77, 1.34)
HR (95% CI) = 1.00 (0.76, 1.31)
0
0
0
3
9
<10% PD-L1 expression level
90
Nivo
10
HR (95% CI) = 0.90 (0.66, 1.24)
0
6
80
70
Nivo
Doc
30
3
Time (months)
80
mOS (mo)
50
0
100
90
80
60
HR (95% CI) = 0.40 (0.26, 0.59)
Time (months)
100
90
8.0
0
Time (months)
100
Doc
70
60
Nivo
Doc
Nivo
mOS
(mo)
19.4
90
60
40
OS (%)
≥10% PD-L1 expression level
100
0
3
6
9
12
15
Time (months)
18
21
24
27
0
3
6
9
12
15
18
21
24
27
Time (months)
Paz-Ares L, et al. ASCO 2015
Istituto Toscano Tumori – Livorno, Italy
Checkpoint inhibitors in NSCLC: Data in 2nd/3rd line
POPLAR
PhII allcomer 2/3L atezo
vs. doc
(n=287)
HR 0.73
p=0.040
HR 0.94
CheckMate 017
PhIII 2L Sq nivo vs. doc
CheckMate 057
PhIII 2/3L NSq nivo vs. doc
KEYNOTE-001
PhIb (inc. NSCLC) pembro
(n=272)
(n=582)
(n=394 for previously treated)
HR 0.59 / 0.62
HR 0.63
p=0.00025 / p=0.0004 p=0.0008
HR 0.73
p=0.0015
HR 0.92
p=0.3932
15.0
Time (months)
12.6
12.2
9.7
10.0
10mg/kg*
q2w and q3w
11.3
9.4
9.2
6.0
5.0
0.0
Atezo
OS
Doc
OS
2.7
3.0
Atezo
PFS
Doc
PFS
3.5
Nivo
OS
Doc
OS
Nivo
PFS
4.2
2.8
Doc
PFS
3.0
2.3
Nivo
OS
Doc
OS
Nivo
PFS
Doc
PFS
Pembro
OS
Pembro
PFS
ORR, %
Atezo 15% vs doc 15%
Nivo 20% vs doc 9%
Nivo 19% vs doc 12%
Pembro 18%
Notes
G3–4 treatment-related
AEs: 12 vs 40%
G3–4 treatment-related
AEs: 8 vs 56%
Reduction from baseline in
lung cancer symptoms with
nivolumab
G3–4 treatment-related
AEs: 10 vs 54%
Low incidence of
immune-related AEs
Refs.
Spira, et al. ASCO 2015
Vansteenkiste, et al. ECC 2015
Paz-Ares, et al. ASCO 2015
Horn, et al. ECC 2015
Garon, et al. AACR 2015
Soria, et al. ECC 2015
Spigel, et al. ASCO 2015
Reckamp, et al. WCLC 2015
Gralla, et al. WCLC 2015
*Phase III dose: 2mg/kg q3w and 10mg/kgReck,
q3w et al. ECC 2015
Istituto Toscano Tumori – Livorno, Italy
Checkpoint inhibitors: efficacy by PD-L1 expression
POPLAR
PhII all comer 2/3L atezo vs.
doc (n=287)
HR 0.77
Improved
p=0.1071
Time (months)
15
HR 0.98
survivalp=0.8606
with
atezolizumab correlated
with increasing PD-L1 expression
11.4
Subgroup
HR
TC3 or IC3
Efficacy
by PD-L1
5
status
0.49
9.5
10
CheckMate 017
PhIII 2L Sq nivo vs. doc
(n=272)
HR 0.59
CheckMate 057
PhIII 2/3L NSq nivo vs. doc
(n=582)
HR 0.62
Benefit
from nivolumab
was
p=0.00025
p=0.0004
independent from PD-L1
expression in squamous NSCLC
Subgroup
HR
≥1% cut-off
0.69
9.2
<1% cut-off
0.58
TC2/3 or IC2/3
0.54
≥5% cut-off
0.53
TC1/2/3 or IC1/2/3
0.59
<5% cut-off6
0.70
TC0 and IC0
3.41.04
2.8
≥10% cut-off
0.50
3.5
2.8
0.70
<10% cut-off
Not quantifiable
0
Atezo
OS
ITT
Doc
OS
0.73
Doc
PFS
Atezo
PFS
0.2
1
HR
atezo
2
doc
PD-L1
assay
SP142 (Ventana)
on ICs and TCs
Refs.
Spira, et al. ASCO 2015
Vansteenkiste, et al. ECC 2015
Nivo
OS
Doc
ITT
OS
0.39
Nivo
PFS
Doc
0.63
PFS
0.1
1
2
HR
nivo
HR 0.73
HR 0.92
PD-L1
expression is predictive
p=0.0015
p=0.3932 of
nivolumab benefit in
non-squamous NSCLC
12.2
Subgroup
HR
PD-L1 proportion score ≥50%
showed greatest benefit from
pembrolizumab
≥1% cut-off
Median OS (months)
9.3
PD-L1 cut-off
≥50%: 15.5
PD-L1 cut-off 1-49%: 7.8
PD-L1 cut-off <1%: 8.6
0.59
9.4
<1% cut-off
0.90
≥5% cut-off
0.43
<5% cut-off
1.01
4.2
≥10% cut-off
<10% cut-off
Nivo
OS
ITT Doc
OS
0.40
2.3
3
1.00
Nivo
PFS
0.1
doc
Doc
0.73
PFS
1
HR
nivo
Pem
OS
Pem
PFS
2
doc
28-8 (Dako) on TCs
Spigel, et al. ASCO 2015
Reckamp, et al. WCLC 2015
Gralla, et al. WCLC 2015
KEYNOTE-001
PhIb (inc. NSCLC) pembro
(n=394 for previously treated)
Paz-Ares, et al. ASCO 2015
Horn, et al. ECC 2015
22C3 (Dako) on TCs
Garon, et al. AACR 2015
Soria, et al. ECC 2015
Istituto Toscano Tumori – Livorno, Italy
Take home messages sui checkpoint
inhibtors
• Nivolumab è lo standard terapeutico di seconda linea nei
pazienti con NSCLC senza driver (EGFR, ALK e ROS1 negativi)
indipendentemente dall’istologia
• Confronti indiretti suggeriscono che pembrolizumab e
atezolizumab hanno un’efficacia simile a nivolumab
• PDL1 è un predittore debole di sensibilità a nivolumab
• Al momento i dati sono insufficienti per escludere qualsiasi
paziente pretrattato con chemioterapia da un trattamento
con checkpoint inhibitors
Istituto Toscano Tumori – Livorno, Italy