IO en NSCLC

IO in NSCLC
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia

http://bit.ly/2v8zXA3
Tipo Mundo Estados Unidos Colombia
Incidencia Mortalidad Incidencia Mortalidad Incidencia Mortalidad
Todo 201 100.7 362.2 86.3 182.3 84.7
Mama 47.8 13.6 90.3 12.4 48.3 13.1
Próstata 30.7 7.7 72.0 8.2 49.8 11.9
Pulmón 22.4(3) 18.0(1) 33.1(3) 18.9(1) 10.5(6) 9.2(4)
Colo-recto 19.5 9.0 25.6 8.0 16.9 8.2
Cérvix 13.3 7.3 6.2 2.1 14.9 7.4
Estómago 11.1 7.7 4,2 1.7 12.8 9.9
Hígado 9.5 8.7 6.9 4.7 3.5 3.4
Endometrio 8.7 1.8 21.4 3.1 8.1 1.7
Ovario 6.6 4.2 8.1 4.0 7.5 4.5
Esófago 6.3 5.6 2.4 2.8 1.3 1.2
Tiroides 6.6 0.4 11.8 0.3 9.1 0.7
Páncreas 4.9 4.5 8.2 6.6 4.1 4.0
Leucemia 5.4 3.3 11.1 3.2 6.2 4.1
Incidencia y mortalidad por cáncer en el Mundo, Estados
Unidos y Colombia
GLOBOCAN - 2020
/100.000 habitantes-año

Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01
Lung Cancer Molecular Consortium Analysis in
Lung Adenocarcinomas
No Mutation
Detected KRAS
22%
EGFR
17%
EML4-AKL
7%
BRAF 2%
PIK3CA 2%
HER2
MET AMP
MEK1
NRAS
AKT1

Metastatic NSCLC fit
for cancer therapy
Actionable
mutations?
EGFR ALK ROS1
Afatinib
Osimertinib
etc
Alectinib
Crizotinib
Crizotinib
Yes
PD-L1
≥50%
PD-L1
≤50%
Not an IO
candidate
No

Chemotherapy in
2nd-line NSCLC
Stage IV

Study Treatment Arms
Median OS
(mos) 1-Year Survival
TAX 317[a]
Docetaxel (N = 103) 7.0 37.0%
Best supportive care (N = 100) 4.6 12.0%
Hanna et al. 2004[b]
Pemetrexed (N = 283) 8.3 29.7%
Docetaxel (N = 288) 7.9 29.7%
INTEREST[c]
Gefitinib (N = 723) 7.6 32.0%
Docetaxel (N = 710) 8.0 34.0%
TITAN[d]
Erlotinib (N = 203) 5.3 26.0%
Chemotherapy (N = 221: 116
docetaxel, 105 pemetrexed)
5.5 24.0%
Second-Line Therapy: Options & Outcomes
a. Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.
b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.
c. Kim ES, et al. Lancet. 2008;372:1809-1818.
d. Ciuleanu T, et al. Lancet Oncol. 2012;13:300-308.

Second-Line Therapy: Options & Outcomes
a. Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.
b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.

Immunotherapy in
2nd-line NSCLC
Stage IV

Tumor Cell
Cytotoxic T8
Lymphocyte
PD-L1
PD-1
- - -
Tumor Cell
Cytotoxic T8
Lymphocyte
- - -
Tumor Cell
Cytotoxic T8
Lymphocyte
+ + +
Pembrolizumab
Nivolumab
And many others…

Efficacy of Nivolumab Monotherapy in Pts With Previously
Treated Advanced NSCLC
Gettinger SN, et al. J Clin Oncol. 2015;33:2004-2012.
Nonsquamous
Squamous
0 6 12 18 24 30 36 42
Mos Since Treatment Initiation
Time to and duration of response until
discontinuation of therapy
Ongoing response
Time to response
Duration of response after discontinuation of
therapy
1 yr: 42%
2 yrs: 24%
3 yrs: 18%
48 54 60 66
24 30 36 42
0 6 12 18
100
80
60
40
20
0
OS
(%)
Died/Treated
99/129
Median, Mos
9.9
95% CI
7.8-12.4
1 yr: 56%
2 yrs: 42%
3 yrs: 27%
48 54 60 66
24 30 36 42
0 6 12 18
100
80
60
40
20
0
OS
(%)
Died/
Treated
26/33
23/37
50/59
Median,
Mos
9.2
14.9
9.2
95% CI
5.3-11.1
7.3-30.3
5.2-12.4
Squamous
Nonsquamous
120 140 160
80 100
0 20 40 60
Wks Since Treatment Initiation
120
80
40
0
-40
-100
Change
in
Target
Lesion
From
Baseline
(%)
mg/kg
1
3
10
100
60
20
-20
-80
-60

Survival
Time
Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341.
Survival Pattern with Chemotherapy and Immune checkpoint
blockade
Immune checkpoint
Chemotherapy

Key Trials
• Nivolumab
• CheckMate 017
• CheckMate 057
• Pembrolizumab
• KEYNOTE-010
• Atezolizumab
• POPLAR (Phase II)
• OAK

Inclusion
Stage IIIB or IV squamous-cell NSCLC
who had disease recurrence after one
prior platinum-containing regimen
18 years of age or older
ECOG performance-status score of 0 or 1
Tumor-tissue specimen for biomarker
analyses.
Treated, stable brain metastases were eligible.
Prior maintenance therapy, including an
epidermal growth factor receptor tyrosine
kinase inhibitor, was allowed.
Exclusion
Key exclusion criteria were
autoimmune disease,
Symptomatic interstitial lung
disease, Systemic
immunosuppression,
Prior therapy with T-cell
costimulation or checkpoint-
targeted agents, or
Prior docetaxel therapy.
Patients who had received more
than one prior systemic therapy
for metastatic disease were
excluded
R
(1:1)
272 pts
Nivolumab
Docetaxel
End-point: OS
CheckMate 017
Brahmer J, NEJM, 2015

CheckMate 017
Brahmer J, NEJM, 2015

Inclusion
Stage IIIB or IV or recurrent
nonsquamous NSCLC disease recurrence
or progression during or after one prior
platinum-based doublet.
Patients with known EGFR mutation
or ALK translocation were allowed to
have received or be receiving an
additional line of tyrosine kinase
inhibitor therapy, and a continuation of
or switch to maintenance therapy with
pemetrexed, bevacizumab, or erlotinib
was allowed in all patients.
18 years of age or older
ECOG performance-status score of 0 or 1
Exclusion
Exclusion criteria were
autoimmune disease,
symptomatic interstitial
lung disease, systemic
immunosuppression, prior
treatment with immune-
stimulatory antitumor
agents including
checkpoint-targeted
agents, and prior use of
docetaxel
R
(1:1)
292 pts
Nivolumab
Docetaxel
End-point: OS
CheckMate 057
Borghaei H, NEJM, 2015

CheckMate 057
Borghaei H, NEJM, 2015

Pembrolizumab in NSCLC (KEYNOTE-001 Cohort): OS by PD-
L1 Expression
Pts at Risk, n
119 92 56 22 5 4 3 0
161 119 58 15 6 4 0 0
76 55 33 8 0 0 0 0
100
80
60
40
20
0
0 4 8 12 16 20 24 28
OS
(%)
Mos
PS 1-49%
PS < 1%
PS ≥ 50%
PS
Median OS,
Mos (95% CI)
≥ 50% NR (13.7-NR)
1-49% 8.8 (6.8-12.4)
< 1% 8.8 (5.5-12.0)
Garon EB, et al. N Engl J Med. 2015;372:2018-2028. Garon EB, et al. AACR 2015. Abstract CT04.

Inclusion
Advanced NSCLC
Confirmed PD after ≥1 line of
chemotherapy
No active brain metastases
ECOG PS 0-1
PD-LS TPS ≥1%
No serious autoimmune disease
No ILD or pneumonitis requiring
systemic steroids
R
(1:1:1)
1034 pts
Pembro 10/kg
Docetaxel
End-point: OS and PFS
KEYNOTE-010
Herbst RS, The Lancet, 2016
Pembro 2/kg

KEYNOTE-010
Herbst RS, The Lancet, 2016 (update 2019).

Herbst RS, et al. Lancet. 2015;387:1540-1550.
KEYNOTE-010: PD-L1 Expression Correlates With Improved
OS in Advanced NSCLC
100
80
60
40
20
0
5
0 10 15 20 25
OS
(%)
Mos
Pembrolizumab 2 mg/kg: 43%
Docetaxel: 35%
PD-L1 TPS ≥ 1%
12 mos
100
80
60
40
20
0
5
0 10 15 20 25
OS
(%)
Mos
Docetaxel: 38%
12 mos
PD-L1 TPS ≥ 50%
HR: 0.71 (95% CI: 0.58-0.88)
HR: 0.61 (95% CI: 0.49-0.75)
HR: 0.54 (95% CI: 0.38-0.77)
HR: 0.50 (95% CI: 0.36-0.70)

Inclusion
Squamous or non-squamous non-
small-cell lung cancer.
Patients had received one to two
previous cytotoxic chemotherapy
regimens (one or more platinum
based combination therapies) for
stage IIIB or IV non-small-cell lung
cancer.
EGFR/ALK+ had to have received TKIs
Treated asymptomatic supratentorial brain
metastasis were allowed
18 years or older,
Measurable disease per RECIST
ECOG PS 0/1
Exclusion
Patients with a history of
autoimmune disease and
those who had received
previous treatments with
docetaxel, CD137 agonists,
anti-CTLA4, or therapies
targeting the PD-L1 and PD-1
pathway were excluded.
R
(1:1)
850 pts
Atezolizumab
Docetaxel
End-point: Coprimary endpoints were overall survival in
the intention-to-treat (ITT) and PD-L1-expression
population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour
cells or tumour-infiltrating immune cells)
OAK
Rittmeyer A, The Lancet, 2017

OAK
Rittmeyer A, The Lancet, 2017

LT OS & Impact of Early Response/Disease Control With Nivolumab in 2L+ NSCLC
Table 1. Studies included in the pooled analyses
Study Histology Phase Treatment
Patients,
N
Dose
Current follow-up
median (range),
monthsb
CheckMate 0034,6
NCT00730639
Squamous/
non-squamous
1 Nivolumab 129
1, 3, or 10 mg/kg
Q2W
9.2 (0.5−106.9)c
CheckMate 0637
NCT01721759
Squamous 2 Nivolumab 117 3 mg/kg Q2W 8.0 (0−62.2)c
CheckMate 0178
NCT01642004
Squamous
3
(Randomized)
Nivolumab
Docetaxel
135
137
3 mg/kg Q2Wa
75 mg/m2 Q3Wa
9.2 (0.3−62.1)d
6.0 (0.4−60.0)d
CheckMate 0579
NCT01673867
Non-squamous
3
(Randomized)
Nivolumab
Docetaxel
292
290
3 mg/kg Q2Wa
75 mg/m2 Q3Wa
12.2 (0.2−62.7)d
9.3 (0−61.4)d
30
aAfter the readout of the primary endpoint of CheckMate 017 and 057, nivolumab-treated patients were allowed to transition to nivolumab 480 mg Q4W. Eligible patients in docetaxel arms no longer
deriving benefit could cross over to nivolumab 3 mg/kg Q2W or 480 mg Q4W. In CheckMate 017 and 057, 7 and 15 patients, respectively, received nivolumab 480 mg Q4W; bDatabase lock was
May 11, 2018 for CheckMate 003, and May 18, 2018 for CheckMate 063, 017, and 057; cMedian follow-up time is based on all patients treated with nivolumab; dMedian follow-up time is based on all
patients randomized.
Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks.

Figure 1. OS in all nivolumab-treated patients from
CheckMate 003/ 063/ 017/ 057a
31
Nivolumab
(N = 664)
Median OS
(95% CI), mo
10.3
(9.2, 11.9)
6 18 24 36 42 54 60 72 78 90 96 102
Months
12 30 48 66 84 108
62
664 430 299 164 104 92 28 16 13 2 1 0
214 123 82 16 4 1
46%
26%
17% 14%
100
0
40
60
80
20
0
OS
(%)
No. at risk
Nivolumab
aMedian duration of response in all patients with a CR/PR (n = 122) was 19.1 months (95% CI, 14.7−29.9).
CI, confidence interval.

Figure 2. OS with nivolumab vs docetaxel in CheckMate 017/ 057a
32
Nivolumab
(n = 427)
Docetaxel
(n = 427)
Median OS
(95% CI), mo
11.1
(9.2, 13.1)
8.1
(7.2, 9.2)
427 264 145 84 45 34 19
57 26 11 1 0
100
0
40
60
80
20
34%
14%
8%
5%
14%
17%
48%
27%
427 280 205 150 84 70 55
113 64 37 9 0
Nivolumab
Docetaxel
No. at risk
Nivolumab
Docetaxel
Months
0 6 18 24 30 42 48 60
12 36 54 66
OS
(%)
aIn the nivolumab and docetaxel arms, 4.0% (17/427) and 10.1% (43/427) of patients, respectively, received subsequent immunotherapy (includes 23 patients who crossed over from the
docetaxel arm to the nivolumab arm); 5 of 19 patients (26.3%) originally randomized to docetaxel and still alive at database lock received immunotherapy as subsequent therapy.

33
163 73
105 52 38 27 15
18 12 9 5 0
PD-L1 expression < 1%
100
0
40
60
80
20
Months
153 50
95 31 20 13 9
10 6 3 1 0
OS
(%)
0 12
6 18 24 30 42
36 48 54 60 66
34%
13%
7%
4%
9%
12%
45%
24%
Nivolumab
Docetaxel
No. at risk
Nivolumab
Docetaxel
PD-L1 expression ≥ 1%
Months
Nivolumab
Docetaxel
OS
(%)
100
0
40
60
80
20
0 12
6 18 24 30 42
36 48 54 60 66
34%
15%
10%
21%
4%
20%
54%
32%
185 99
123 76 58 42 36
38 33 20 4 0
179 61
112 36 27 23 10
17 8 5 0 0
No. at risk
Nivolumab
Docetaxel
Figure 3. OS with nivolumab vs docetaxel by tumor
PD-L1 expression in CheckMate 017/ 057a
Nivolumab
(n = 185)
Docetaxel
(n = 179)
Median OS
(95% CI), mo
13.4
(10.0, 17.7)
8.5
(7.0, 9.3)
Nivolumab
(n = 163)
Docetaxel
(n = 153)
Median OS
(95% CI), mo
9.7
(7.6 13.3)
7.8
(6.7, 10.5)
aIn all randomized patients from CheckMate 017 and 057 with evaluable PD-L1 expression.

34
18%
SD
CR/PR
PD
62%
38%
26%
35%
7%
22%
12%
8%
Months from 6-month landmark analysis
SD
CR/PR
PD
58%
81%
63% 61%
35%
24%
40%
13%
8%
70 57
65 52 44 42 37
39 24 7 0 0
66 38
53 29 23 18 13
15 10 2 0 0
144 55
87 32 17 10 5
10 3 0 0 0
CR/PR
(n = 34)
SD
(n = 102)
PD
(n = 128)
Median OS
(95% CI), mo
17.1
(11.1, 28.7)
8.0
(6.6, 10.4)
4.8
(3.4, 5.9)
HR vs PD (95% CI)
0.43
(0.29, 0.65)
0.80
(0.61, 1.04)
–
Figure 4. Landmark analysis of OS by response category status at
6 months in CheckMate 017/ 057a
CR/PR
(n = 70)
SD
(n = 66)
PD
(n = 144)
Median OS
(95% CI), mo
NR
(25.6, NR)
16.1
(10.2, 23.5)
9.1
(6.2, 11.4)
HR vs PD (95% CI)
0.18
(0.12, 0.27)
0.52
(0.37, 0.71)
–
Nivolumab Docetaxel
aIn all randomized patients from CheckMate 017 and 057 studies alive at the 6-month landmark; 65.6% and 61.8% in the nivolumab and docetaxel treatment arms, respectively, were included.
NR, not reached
Months from 6-month landmark analysis
34 21
30 15 13 10 7
9 4 0 0 0
102 35
63 24 17 11 4
7 2 0 0 0
128 28
52 18 15 13 8
10 5 1 0 0
OS
(%)
100
0
40
60
80
20
0 12
6 18 24 30 42
36 48 54 60 66
OS
(%)
0
40
60
80
20
0 12
6 18 24 30 42
36 48 54 60 66
No. at risk
CR/PR
SD
PD
No. at risk
CR/PR
SD
PD
100
58%
19%
4%
12%
2%
5%

Figure 5. OS from time of response with nivolumab vs docetaxel
in CheckMate 017/ 057a
35
Nivolumab
(n = 83)
Docetaxel
(n = 48)
Median OS post response
(95% CI), mo
NR
(26.4, NR)
16.5
(11.8, 22.1)
Median DOR
(95% CI), mo
23.8
(11.4, 36.1)
5.6
(4.4, 7.0)
OS
post
response
(%)
Months
65%
33%
23%
12%
54%
57%
87%
65%
Nivolumab
Docetaxel
83 78 71 62 47 46 36
53 40 17 2
48 45 31 22 15 11 6
16 10 3 0
0
0
No. at risk
Nivolumab
Docetaxel
100
0 6 18 24 30 42 48 60
0
40
60
80
20
12 36 54 66
aOS was calculated from the time of response (CR/PR) for each responder.

Survival
Time
Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341.
Conclusión
Nivolumab
Chemotherapy

NSCLC as
one
disease
Squamous
34%
Other
11%
Adenoca
55%
Non-Small-Cell Lung Cancer: Not One Disease, but Many!
Slide credit: clinicaloptions.com
Li. JCO. 2013;31:1039. Tsao. J Thorac Oncol. 2016;11:613.
Then Histology-Based Subtyping Now
Adenocarcinoma
KRAS
25%
ALK
7%
EGFR
Sensitizing
17%
No Known
Oncogenic Driver
Detected
31%
EGFR Other 4%
MET 3%
> 1 Mutation 3%
HER2 2%
ROS1 2%
BRAF 2%
RET 2%
NTRK < 1%
PIK3CA 1%
MEK1 < 1%

Supervivencia a los 12 meses
50%
79%
90%
Quimioterapia
ROS1
Crizotinib
mEGFR/ALK
Terapia Dirigida

CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer
Treatment
Ribas. NEJM. 2012;366:2517.
Anti–PD-1:
Nivolumab
Pembrolizumab
Anti–PD-L1:
Atezolizumab
Avelumab
Durvalumab
Anti–CTLA-4:
Ipilimumab
Priming Phase (Lymph Node) Effector Phase (Peripheral Tissue)
T-Cell Migration

Key Trials
• PD-L1 ≥50% (Squamous/non-Sq)
• KEYNOTE-024
• KEYNOTE-598
• IO-IO (Squamous/non-Sq)
• CheckMate 227
• CheckMate 9La
• Squamous-NSCLC
• KEYNOTE-407
• Non-Squamous-NSCLC
• Chemotherapy + IO
• KEYNOTE-189
• KEYNOTE-042
• IMpower150

KEYNOTE-024: First-line Pembrolizumab for
Advanced NSCLC
 Primary endpoint: PFS by BICR
 Secondary endpoints: ORR, OS, and safety
Patients with untreated stage IV
NSCLC; ECOG PS 0/1;
no actionable EGFR/ALK mutations;
PD-L1 TPS ≥ 50%*;
no untreated CNS mets or active
autoimmune disease requiring tx
(N = 305)
Pembrolizumab 200 mg IV Q3W
for up to 35 cycles
(n = 154)
Plt-doublet CT
(histology based) for 4-6 cycles
(n = 151)
Until PD or
unacceptable toxicity
Stratified by ECOG PS (0 vs 1), histology
(squamous vs nonsquamous), and enrollment
region
Until PD
(crossover to
pembrolizumab allowed)
*≥ 50% tumor cell staining using 22C3 companion diagnostic IHC assay.
 Open-label, randomized phase III study
Reck. NEJM. 2016;375:1823. Reck. J Clin Oncol. 2019;37:537.

KEYNOTE-024: PFS Pembrolizumab
(n = 154)
Chemotherapy
(n = 151)
Median PFS,
mos (95% CI)
10.3
(6.7-NR)
6.0
(4.2-6.2)
6-mo PFS, % 62 50
12-mo PFS, % 48 15
Reck. ESMO 2016. Abstr LBA8_PR. Reck. NEJM. 2016;375:1823. Slide credit: clinicaloptions.com
HR: 0.50
(95% CI: 0.37-0.68; P < .001)
Mos
PFS
(%)
Patients at Risk, n
Pembrolizumab
CT
154
151
104
99
89
70
44
18
22
9
3
1
1
0
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18

KEYNOTE-024: OS (Updated)
Reck. J Clin Oncol. 2019;37:537.
Mos
154
151
136
123
121
107
112
88
106
80
89
61
83
55
22
16
5
5
Pembrolizumab
(n = 154)
Chemotherapy
(n = 151)
Median OS, mos
(95% CI)
30.0
(18.3-NR)
14.2
(9.8-19.0)
12-mo OS, % 70.3 54.8
24-mo OS, % 51.5 34.5
HR: 0.63 (95% CI: 0.47-0.86; P = .002)
Patients at Risk, n
Pembrolizumab
CT
OS
(%)
96
70
52
31
0
0
100
80
60
70
60
50
40
30
20
10
0
33
0 3 6 9 12 15 18 21 24 27 30

Patients with untreated
stage IV NSCLC
ECOG PS 0/1;
no actionable EGFR/ALK
mutations
PD-L1 TPS ≥ 50%
R
(1:1)
568 pts
Ipilimumab +
Pembrolizumab
Pembrolizumab
End-point: OS and PFS
KEYNOTE-598
Boyer M, JCO, 2021

KEYNOTE-598
Boyer M, JCO, 2021

KEYNOTE-407: Carboplatin + Paclitaxel/nab-Paclitaxel ±
Pembrolizumab in NSCLC
 Randomized, double-blind phase III trial
 Primary endpoint: PFS by RECIST v1.1 (BICR), OS
 Secondary endpoints: ORR and DoR by RECIST v1.1 (BICR), safety
Paz-Ares. NEJM. 2018;379:2040. Slide credit: clinicaloptions.com
Pembrolizumab + Carboplatin +
Paclitaxel or nab-Paclitaxel
3-wk cycles x 4
(n = 278)
Patients with untreated stage IV
squamous NSCLC, ECOG PS 0/1,
available tumor biopsy for PD-L1
assessment, no brain mets, and
no pneumonitis requiring
systemic steroids
(N = 559)
Stratified by PD-L1 TPS (< 1% vs ≥ 1%), taxane (paclitaxel
vs nab-paclitaxel), region (east Asia vs other)
Carboplatin AUC 6 Q3W, nab-paclitaxel 100 mg/m2 QW, paclitaxel 200 mg/m2 Q3W, pembrolizumab 200 mg Q3W.
*Upon confirmation of PD and safety criteria by BICR, optional crossover could occur during combination or monotherapy.
Placebo + Carboplatin +
Paclitaxel or nab-Paclitaxel
3-wk cycles x 4
(n = 281)
Pembrolizumab
up to 31 cycles
Placebo
up to 31 cycles
Pembrolizumab
up to 35 cycles
Crossover
allowed*
PD

KEYNOTE-407: OS (ITT)
Mos
Patients
at Risk, n
Pembro + CT
CT
OS
(%) Median OS,
Mos (95% CI)
15.9 (13.2-NE)
11.3 (9.5-14.8)
100
80
60
40
20
0
0 3 6 9 12 15 18 21
Pembro + CT
CT
HR: 0.64
(95% CI: 0.49-0.85; P < .001 )
278
281
256
246
188
175
124
93
62
45
17
16
2
4
0
0

KEYNOTE-407: OS by Subgroup
Subgroup
Overall
Age
Sex
ECOG PS
Region of enrollment
PD-L1 tumor proportion score
Choice of taxane
0.64 (0.49-0.85)
0.52 (0.34-0.80)
0.74 (0.51-1.07)
0.69 (0.51-0.94)
0.42 (0.22-0.81)
0.54 (0.29-0.98)
0.66 (0.48-0.90)
0.44 (0.22-0.89)
0.69 (0.51-0.93)
0.61 (0.38-0.98)
0.65 (0.45-0.92)
0.57 (0.36-0.90)
0.64 (0.37-1.10)
0.67 (0.48-0.93)
0.59 (0.36-0.98)
HR (95% CI)
CT Better
Pembro + CT Better
0.1 0.5 1.0
< 65 yrs
≥ 65 yrs
Male
Female
0
1
East Asia
Rest of world
< 1%
≥ 1%
1% to 49%
≥ 50%
Paclitaxel
nab-Paclitaxel
Deaths/Patients, n/N
205/559
88/254
117/305
167/455
38/104
48/163
157/396
34/106
171/453
73/194
129/353
76/207
53/146
140/336
65/223

KEYNOTE-407: PFS (ITT)
Mos
PFS
(%) Median PFS,
Mos (95% CI)
6.4 (6.2-8.3)
4.8 (4.3-5.7)
100
80
60
40
20
0
0 3 6 9 12 15 18 21
Pembro + CT
CT
278
281
223
190
142
90
57
26
23
12
5
4
0
0
0
0
HR: 0.56
(95% CI: 0.45-0.70; P < .001 )
Patients
at Risk, n
Pembro + CT
CT

Inmunoterapia más
quimioterapia en PD-L1 <50%

KEYNOTE-189: First-line Pembrolizumab + CT vs Placebo
+ CT in Stage IV Nonsquamous NSCLC
 Randomized, double-blind, international phase III study
Patients with previously
untreated stage IV
nonsquamous NSCLC;
ECOG PS 0/1; any PD-L1 status;
no actionable
EGFR/ALK mutations;
no symptomatic CNS mets or
pneumonitis requiring tx
(N = 616)
Pembrolizumab 200 mg Q3W +
Plt*/pemetrexed† Q3W
(n = 410)
Placebo Q3W +
Plt*/pemetrexed† Q3W
(n = 206)
4 cycles
Pembrolizumab‡ +
Pemetrexed†
Q3W
Placebo‡ +
Pemetrexed†
Q3W
Stratified by PD-L1 TPS (≥ 1% vs < 1%), platinum agent (carboplatin vs cisplatin),
smoking history (never vs former/current)
Until PD or
unacceptable
toxicity;
crossover from
placebo allowed
*Carboplatin AUC 5 or cisplatin 75 mg/mm2.†500 mg/m2. ‡Up to total of 35 cycles.
Gandhi. NEJM. 2018;378:2078.
 Primary endpoints: OS, PFS by BICR
 Secondary endpoints: ORR, DoR, safety
No PD
No PD

KEYNOTE-189: Frequency of PD-L1 TPS Categories
Gandhi. NEJM. 2018;378:2078.
Pembrolizumab + plt/pemetrexed
Placebo + plt/pemetrexed
50
45
40
35
30
25
20
15
10
5
0
Frequency
(%)
< 1% 1% to 49% ≥ 50% Not Evaluable
31.0% 30.6% 31.2%
28.2%
32.2%
34.0%
5.6%
7.3%

KEYNOTE-189: Survival by PD-L1 Tumor Proportion
Score
TPS < 1% TPS ≥ 50%
TPS 1% to 49%
0
20
40
60
80
100
0 3 6 9 12 15 18 21
Mos
OS
(%)
127
63
113
54
104
45
79
32
42
21
20
6
6
1
0
0
HR: 0.59
(95% CI: 0.38-0.92)
Pembro + CT
Pbo + CT
Patients at
Risk, n
Pembro + CT
Pbo + CT
128
58
119
54
107
47
84
32
52
17
21
5
5
2
0
0
HR: 0.55
(95% CI: 0.34-0.90)
Pembro + CT
Pbo + CT
132
70
122
64
114
50
96
35
56
19
25
13
6
4
0
0
HR: 0.42
(95% CI: 0.26-0.68)
Pembro + CT
Pbo + CT
0
20
40
60
80
100
0 3 6 9 12 15 18 21
0
20
40
60
80
100
0 3 6 9 12 15 18 21
Mos Mos
Gandhi. NEJM. 2018;378:2078.
61.7%
52.2%
71.5%
50.9%
73.0%
48.1%
Pembro + CT Placebo + CT
Events, % 38.6 55.6
mOS, mos
(95% CI)
15.2
(12.3-NE)
12.0
(7.0-NE)
Events, % 28.9 48.3
mOS, mos
(95% CI)
NR
(NE-NE)
12.9
(8.7-NE)
Events, % 25.8 51.4
mOS, mos
(95% CI)
NR
(NE-NE)
10.0
(7.5-NE)

KEYNOTE-189: OS in Patients With PD-L1 Tumor
Proportion Score ≥ 50%
Gandhi. NEJM. 2018;378:2078.
Pembrolizumab + CT
(n = 127)
Placebo + CT
(n = 63)
Events, % 25.8 51.4
Median OS,
mos (95% CI)
NR
(NE-NE)
10.0
(7.5-NE)
TPS ≥ 50%
132
70
122
64
114
50
96
35
56
19
25
13
6
4
0
0
HR: 0.42
(95% CI: 0.26-0.68)
Pembro + CT
Pbo + CT
0
20
40
60
80
100
0 3 6 9 12 15 18 21
Mos
73.0%
48.1%
Patients at Risk, n
Pembro + CT
Pbo + CT
OS
(%)

IMpower150: Addition of Atezolizumab to Carbo/Pac +
Bevacizumab in Advanced NSCLC
 Randomized phase III study
Patients with stage IV or
recurrent, chemotherapy-
naive nonsquamous NSCLC
(PD on or intolerance to
targeted agents allowed);
available tumor tissue
(N = 1202)
Atezolizumab 1200 mg IV Q3W +
Carboplatin/Paclitaxel
(n = 510)
Carboplatin/Paclitaxel Q3W +
Bevacizumab 15 mg/kg IV Q3W
(n = 336; control arm)
(n = 356)
Atezolizumab
until PD or loss of
benefit and/or
bevacizumab
until PD
Atezolizumab
Bevacizumab
Atezolizumab +
Bevacizumab
Stratified by sex, PD-L1 expression, liver mets
4-6 cycles
Reck. ESMO I-O Congress 2017. Abstr LBA1_PR. Kowanetz. AACR 2018. Abstr CT076. Socinski. NEJM. 2018;378:2288. Slide credit: clinicaloptions.com
Maintenance therapy
(no crossover allowed)
 Primary endpoints: PFS, OS
 Secondary endpoints: PFS (IRF), ORR, OS at Yrs 1 and 2, QoL, safety, PK

Reck. ESMO I-O Congress 2017. Abstr LBA1_PR. Kowanetz. AACR 2018. Abstr CT076. Socinski. NEJM. 2018;378:2288.

IMpower150: Addition of Atezolizumab to Carbo/Pac +
Bevacizumab in Advanced NSCLC
 Randomized phase III study
Patients with stage IV or
recurrent, chemotherapy-
naive nonsquamous NSCLC
(PD on or intolerance to
targeted agents allowed);
available tumor tissue
(N = 1202)
(n = 336; control arm)
(n = 356)
Atezolizumab
until PD or loss of
benefit and/or
bevacizumab
until PD
Bevacizumab
Atezolizumab +
Bevacizumab
Stratified by sex, PD-L1 expression, liver mets
4-6 cycles
Reck. ESMO I-O Congress 2017. Abstr LBA1_PR. Kowanetz. AACR 2018. Abstr CT076. Socinski. NEJM. 2018;378:2288. Slide credit: clinicaloptions.com
Maintenance therapy
(no crossover allowed)
 Primary endpoints: PFS, OS
 Secondary endpoints: PFS (IRF), ORR, OS at Yrs 1 and 2, QoL, safety, PK

IMpower150: Updated PFS in ITT WT Population*
(Coprimary Endpoint)
Socinski. ASCO 2018. Abstr 9002. Slide credit: clinicaloptions.com
Data cutoff: January 22, 2018. *ITT WT: patients without
EGFR or ALK alterations; 87% of randomized patients.
Atezolizumab +
Carbo/Pac + Bev
(n = 359)
Carbo/Pac + Bev
(n = 337)
Median PFS, mos
(95% CI)
8.3
(7.7-9.8)
6.8
(6.0-7.1)
6-mo PFS, % 66 56
12-mo PFS, % 38 20
18-mo PFS, % 27 8
HR: 0.59 (95% CI: 0.50-0.70; P < .0001)
Median follow-up: ~ 20 mos
Patients at Risk, n
PFS
(%)
Mos
100
90
80
70
60
50
40
30
20
10
0
34
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
Atezolizumab +
Carbo/Pac + Bev
Carbo/Pac + Bev
359
337
336
323
315
294
301
263
293
244
267
215
234
180
213
148
190
127
168
103
154
89
146
78
125
61
112
50
85
35
80
29
69
21
68
18
53
14
50
13
37
6
33
6
24
5
20
5
12
1
11
1
6 3 1 1 1
+
+
+
++ +
+
+
+
+
+
+ +
+ +
++
+
+ +
+
+
+
+
+
+
++++
+ +
+ +
+
+
+
+
++
+ +
+ +
+
+
+
+ +
++
+
+
+
+ + +
+ +
+ + +
+ +
++
+
+
+
+
+ +
+
+
+ +++
+
+
+
+
+
+
+
+
+
+
+

IMpower150: Landmark OS in ITT Population (Including
Patients With EGFR and ALK Aberrations)
 Clinically meaningful OS benefit with atezolizumab + bevacizumab + chemotherapy vs bevacizumab
+ chemotherapy was observed in all patients
HR: 0.76
(95% CI: 0.63-0.93)
Median follow-up: ~ 20 mos
100
90
80
70
60
50
40
30
20
10
0
OS
(%)
Mos
34
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
Atezolizumab +
Carbo/Pac + Bev
(n = 400)
Carbo/Pac
+ Bev
(n = 400)
Median OS, mos
(95% CI)
19.8
(17.4-24.2)
14.9
(13.4-17.1)
12-mo OS, % 68 61
18-mo OS, % 54 42
24-mo OS, % 45 36

IMpower150: OS by Subgroup
Favors
Atezolizumab + Carbo/Pac + Bev
Favors
Carbo/Pac + Bev
*For prevalence, ITT WT (n = 696) used for PD-L1,
liver metastases groups; ITT (n = 800) for rest.
Median OS, Mos
25.2
20.3
17.1
13.2
19.8
19.8
NE
19.2
15.0
16.4
14.1
9.1
16.7
14.9
17.5
14.7
Subgroup
PD-L1 high (TC3 or IC3) WT
PD-L1 low (TC1/2 or IC1/2) WT
PD-L1 negative (TC0 and IC0) WT
Liver metastases WT
No liver metastases WT
ITT (including EGFR/ALK+)
EGFR/ALK+ only
ITT WT
n (%)*
136 (20)
226 (32)
339 (49)
94 (14)
602 (86)
800 (100)
104 (13)
696 (87)
0.2 1.0 2.0
HR
HR
0.70
0.80
0.82
0.54
0.83
0.76
0.54
0.78
ABCP BCP

Inclusion
Squamous or nonsquamous stage
IV or recurrent NSCLC
PD-L1≥1%
ECOG 0/1
None of the patients had received
previous systemic anticancer
therapy for advanced or
metastatic disease.
Exclusion
EGFR mutations or
known ALK translocations
sensitive to targeted therapy,
Autoimmune disease,
Untreated or symptomatic central
nervous system metastases.
R
(1:1)
1166 pts
Nivolumab +
Ipilimumab
Platinum doublet
chemotherapy
End-point: OS
CheckMate 227 (PD-L1 ≥1% cohort)
Hellman MD, NEJM, 2019

CheckMate 227 (PD-L1 ≥1% cohort)
Hellman MD, NEJM, 2019

Inclusion
Treatment-naive, histologically
confirmed stage IV or
recurrent NSCLC,
ECOG PS 0–1.
R
(1:1)
1150 pts
Nivolumab +
Ipilimumab
Platinum doublet
chemotherapy x4
cycles
End-point: OS
CheckMate 9LA
Paz-Ares L, Lancet Oncol, 2021
+2 cycles of platinum
doublet chemotherapy

CheckMate 9LA
Paz-Ares L, Lancet Oncol, 2021

Conclusiones
74
mNSCLC – candidato a tratamiento
Mutación accionable Terapia blanco-dirigida
PD-L1 ≥ 50% Considerar pembrolizumab
PD-L1 <50% - Alta carga tumoral Quimio + IO o IO+IO
Sí
Sí
Sí
Sí
No
No
mEGFR
Lux-Lung 3/6
FLAURA
RELAY
ALK+
ALEX
PROFILE1014
KEYNOTE-24
No-escamosos
IMpower150
KEYNOTE-189
Escamosos
KEYNOTE-407
Arte

Supervivencia a los 12 meses
50%
73%
79%
90%
Quimioterapia
Inmunoterapia
+/- quimioterapia
ROS1
Crizotinib
mEGFR/ALK
Terapia Dirigida

mNSCLC fit for
therapy
Mutaciones
accionables
PD-L1 ≥50% Otros
Escamo.
IO-IO
CT + IO
Pembro + CT6
Nivo + Ipi + CT4
Nivo + Ipi5
No
Ecamo.
IO-IO
CT + IO
Pembro + CT2
Atezo (+Bev) + CT3
Nivo + Ipi + CT4
Nivo + Ipi5
Pembro1
Terapia dirigida
Atezo (+Bev) + CT3
cuando la terapia
dirigida ya no
funciona
1. KN-024
2. KN-189
3. IMpower150
4. CM-9LA
5. CM-227
6. KN-407
IO’s crowded space in mNSCLC 1L
20% 20%
20%
60%
40%
Spanglish Oncology

IO en NSCLC

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