CCO_Biomarkers_Lung_Cancer_ASCO_Slides_2.pptx

Evolving Understanding of Biomarkers of
Response to Immune Checkpoint Inhibition
in NSCLC
Supported by an educational grant from Lilly. For further information
concerning Lilly grant funding, visit www.lillygrantoffice.com.

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Faculty
Edward S. Kim, MD, FACP
Chair, Solid Tumor Oncology and
Investigational Therapeutics
Donald S. Kim Distinguished Chair for
Cancer Research
Levine Cancer Institute
Atrium Health
Charlotte, North Carolina
Leora Horn, MD, MSc, FRCPC
Ingram Associate Professor of Cancer
Research
Director, Thoracic Oncology Research
Program
Assistant Vice Chairman for Faculty
Development
Vanderbilt Ingram Cancer Center
Nashville, Tennessee

Faculty Disclosures
Edward S. Kim, MD, FACP, has disclosed that he has received consulting fees
from AstraZeneca, Boehringer Ingelheim, Lilly, Merck, Roche, and Takeda.
Leora Horn, MD, MSc, FRCPC, has disclosed that she has received consulting
fees from Amgen, AstraZeneca, Bayer, EMD Serono, Genentech, Incyte, Merck,
Pfizer, and Xcovery and funds for research support from Boehringer Ingelheim,
Bristol-Myers Squibb, and Xcovery.

Evolution of Therapy in Lung Cancer
 NSCLC was once considered a single disease, until distinct subtypes, characteristics identified[1-4]
 NSCLC subtype characteristics are clinically relevant for treatment planning from diagnosis[1]
Traditional View
Present View
NSCLC
SCLC
Histologic Breakdown
(eg, SQ, NSQ, large cell,
adenocarcinoma)
Molecular Pathology
(eg, EGFR, ALK, ROS1)
PD-L1 Expression Level[5]
Lung
Cancer
≥ 50%
Tumor Mutational Burden[6]
≥ 10 mut/Mb
< 10 mut/Mb
≥ 1-49%
< 1%
1. Cooper. Pathology. 2011;43:103. 2. Langer. J Clin Oncol. 2010;28:5311. 3. Galon. Immunity. 2013;39:11.
4. Pao. Lancet Oncol. 2011;12:175. 5. Krigsfeld. AACR 2017. Abstr CT143. 6. Hellmann. NEJM. 2018;378:2093. Slide credit: clinicaloptions.com

Increased Clinical Benefit of Immunotherapy Across
PD-L1 Expression Levels in Second-line NSCLC
 OS benefit observed across the PD-L1 spectrum, including < 1% PD-L1 expression[1]
 Enhanced benefit with increasing PD-L1 expression[1-3]
Docetaxel
(n = 343)
Pembrolizumab
(n = 690)
PD-L1 Expression
≥ 50%
1-49%
Overall (PD-L1+ only)
KEYNOTE-010‡[3]
OS HR
< 1%
Docetaxel
(n = 612)
Atezolizumab
(n = 613)
PD-L1 Expression
TC1/2/3 or IC1/2/3†
TC0 and IC0
Overall
TC3 or IC3
TC2/3 or IC2/3
OAK (ITT1225)†[2]
OS HR
1
0.77
0.84
0.80
0.45
0.64
0.2 2
Checkmate 017/057*[1]
(Pooled Analysis)
PD-L1 Expression
Docetaxel
(n = 427)
Nivolumab
(n = 427)
OS HR
≥ 1%
< 1%
Overall
≥ 10%
≥ 50%
≥ 5%
0.25 0.5 1 2
0.67
0.78
0.72
0.47
0.42
0.51
0.1 1 10
Not included
0.53
0.76
0.67
*Unstratified HR. Pooled analysis of 2 trials with NSQ and SQ histologies. NSQ: N = 582; SQ: N = 272. †Unstratified HR for TC0 and IC0. Stratified HR for overall and other
PD-L1 subgroups. Overall, NSQ: 74%; SQ: 26%. NSQ and SQ histologies were pooled. ‡In patients who received pembro 2 mg/kg, NSQ: 70%; SQ: 22%. In patients who
received pembro 10 mg/kg, NSQ: 71%; SQ: 23%. In patients who received docetaxel, NSQ: 70%; SQ: 19%. Pooled analysis of NSQ and SQ histologies.
1. Horn. JCO. 2017;35:3924. 2. Fehrenbacher. JTO. 2018;13:1156. 3. Herbst. Lancet. 2016;387:1540. Slide credit: clinicaloptions.com

TMB and Tumor PD-L1 Expression Identify Distinct and
Independent Populations of NSCLC
29%
71%
CheckMate 227: TMB and Tumor PD-L1 Expression in
All TMB-Evaluable Patients (n = 1004)*
PD-L1 Expression (%)
TMB
(No.
of
Mutations/Mb)
0
20
40
60
80
100
160
120
140
0 20 40 60 80 100
TMB ≥ 10 mut/Mb
(n = 299)
PD-L1 < 1%
PD-L1 ≥ 1%
29%
71%
PD-L1 < 1%
PD-L1 ≥ 1%
TMB < 10 mut/Mb
(n = 380)
CheckMate 227: TMB and Tumor PD-L1 Expression in
NIVO + IPI and CT Arms
*Dots may represent multiple data points, in particular for PD-L1 < 1%. Line is relationship between TMB and PD-L1 expression as described by a linear regression.
Hellmann. AACR 2018. Abstr CT077. Slide credit: clinicaloptions.com

PD-L1 IHC: Expression Heterogeneity and Potential for
Sampling Error
Biopsy Core 1
Biopsy Core 2
18g needle =
800 µm
Slide courtesy of Ben Solomon via Michael Boyer. Slide credit: clinicaloptions.com

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
Paradigm Shift in First-line Therapy for Advanced NSCLC:
Pembro Is Superior to CT in Patients With TPS ≥ 50%
 KEYNOTE-024: open-label, randomized phase III study
Mos
154
151
136
123
121
107
112
88
106
80
89
61
83
55
22
16
5
5
HR: 0.63
(95% CI: 0.47-0.86;
P = .002)
OS
(%)
96
70
52
31
0
0
100
90
80
70
60
50
40
30
20
10
0
33
0 3 6 9 12 15 18 21 24 27 30
Patients
at Risk, n
Pembro
CT
Effective crossover rate from CT to anti–PD-L1 therapy: 62.3% (82 patients crossed over
to pembrolizumab and 12 received anti–PD-L1 therapy outside of crossover).
Data cutoff: July 10, 2017.
Reck. NEJM. 2016;375:1823. Brahmer. WCLC 2017. Abstr OA 17.06.
Pembrolizumab 200 mg IV Q3W
for up to 35 cycles
(n = 154)
Platinum-Doublet CT
(histology based) for 4-6 cycles
(n = 151)
*≥ 50% tumor cell staining using 22C3 companion diagnostic IHC assay.
Chemotherapy-naive,
stage IV NSCLC;
PD-L1 selected (TPS ≥ 50%*);
ECOG PS 0/1;
no actionable EGFR/ALK
mutations; no untreated CNS
mets or active autoimmune
disease requiring treatment
(N = 305)
Stratified by ECOG PS (0 vs 1), histology
(squamous vs nonsquamous), and
enrollment site

Similar Efficacy With First-line Atezolizumab in Patients
With NSCLC and High PD-L1 Expression (TC3 or IC3)
 IMpower110: randomized phase III study
Untreated LA or
metastatic NSCLC of
any histology;
PD-L1 ≥ 1% on TC or IC*;
no sensitizing EGFR or ALK
alterations; ECOG PS 0/1;
no untreated or unstable
CNS mets or pneumonitis
requiring tx
(N = 572)
Atezolizumab 1200 mg Q3W
until PD
(n = 107)
Platinum-Doublet CT
(histology based)
for 4-6 cycles
(n = 98)
HR: 0.59 (95% CI: 0.40-0.89; P = .0106)
Median OS: 20.2 mos
(95% CI: 16.5-NE)
Median OS: 13.1 mos
(95% CI: 7.4-16.5)
Herbst. SITC 2019. Abstr O81.
Data cutoff: September 10, 2018. Median follow-up: 15.7 mos (range: 0-35).
No crossover permitted.
*PD-L1 tumor cell staining on TC or IC using VENTANA SP142 IHC assay.
WT efficacy populations: TC1/2/3 or IC1/2/3, n = 554; TC2/3 or IC2/3,
n = 328; TC3 or IC3, n = 205.
Stratified by sex, ECOG PS, histology,
and tumor PD-L1 status
Mos
OS
(%)
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
2 8 14 20 26 32 38
4 10 16 22 28 34
Patients at Risk, n
Atezolizumab 107 94 85 80 66 61 48 40 34 25 18 16 11 7 6 5 2
Chemotherapy 98 89 75 65 50 40 33 28 19 12 9 7 6 4 3 3 3 1
Atezolizumab
Chemotherapy
Censored

Limited OS Benefit With Atezolizumab in Patients With
NSCLC and Low PD-L1 Expression (TC1/2/3 or IC1/2/3)
HR: 0.83
(95% CI: 0.65-1.07; P = .1481*)
*For descriptive purposes only.
Data cutoff: September 10, 2018. Median follow-up: 13.4 mos (range: 0-35).
Atezolizumab
(n = 277)
Chemotherapy
(n = 277)
Median OS, mos
(95% CI)
17.5
(12.8-23.1)
14.1
(11.0-16.6)
6-mo OS, % 76.2 75.7
12-mo OS, % 57.6 54.3
Herbst. SITC 2019. Abstr O81.
Mos
OS
(%)
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
2 8 14 20 26 32 38
4 10 16 22 28 34
Patients at Risk, n
Atezolizumab 277 252 226 204 170 134 93 74 58 37 22 17 11 7 6 5 2
Chemotherapy 277 254 223 199 153 108 79 63 43 24 10 7 6 4 3 3 3 1

Pembrolizumab Not As Impressive in PD-L1 ≥ 1%: KEYNOTE-042
The PD-L1 ≥ 50% subgroup is the main driver of OS benefit in PD-L1-positive patients
KEYNOTE-042: Pembrolizumab Not
as Impressive in PD-L1 ≥ 1%
 PD-L1 ≥ 50% subgroup is main driver of OS benefit in
PD-L1–positive patients
OS: PD-L1 TPS ≥ 50%
0
20
40
60
80
100
0 6 12 18 24 30 36 42
44.7%
OS
(%)
OS: PD-L1 TPS ≥ 1%
0 6 12 18 24 30 36 42
0
20
40
60
80
100
OS
(%)
39.3%
Events,
n
Median OS, Mos
(95% CI)
Pembrolizumab 371 16.7 (13.9-19.7)
Chemotherapy 199 12.1 (11.3-13.3)
Lopes. ASCO 2018. Abstr LBA4. Mok. Lancet. 2019;393:1819. *Exploratory analysis; no alpha allocated to this comparison.
HR: 0.69
(95% CI: 0.56-0.85; P = .0003)
HR: 0.81
(95% CI: 0.71-0.93; P = .0018)
34.6%
OS: PD-L1 TPS ≥ 1-49%*
HR: 0.92
(95% CI: 0.77-1.11)
Mos
Mos
0
20
40
60
80
100
0 6 12 18 24 30 36 42
OS
(%)
28.0%
26.5%
30.1%
Events,
n
Median OS, Mos
(95% CI)
Pembrolizumab 157 22.0 (15.4-24.9)
Chemotherapy 199 12.2 (10.4-14.2)
Events,
n
Median OS, Mos
(95% CI)
Pembrolizumab 214 13.4 (1.7-18.2)
Chemotherapy 239 12.1 (11.0-14.0)

*Nonsquamous: pem + cis or carbo Q3W for
≤ 4 cycles with optional maintenance (CT: pem;
nivolumab + CT: nivolumab + pem); squamous: gem +
cis or carbo Q3W for ≤ 4 cycles. †1 patient randomized
as < 1% PD-L1 and subsequently determined to have
≥ 1% PD-L1 expression.
CheckMate 227: Nivolumab ± Ipilimumab in NSCLC
 Open-label, multipart, randomized phase III trial
Patients with
stage IV or recurrent
NSCLC, no previous
systemic treatment,
no known sensitizing
EGFR/ALK alterations,
ECOG PS 0/1
(N = 1739)
NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W
(n = 187)
NIVO 360 mg Q3W + Histology-Based CT*
(n = 177)
Histology-Based CT*
(n = 186)
Stratified by histology
(squamous vs nonsquamous)
NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W
(n = 396)
NIVO 240 mg Q2W
(n = 396)
Histology-Based CT*
(n = 397)
Part 1b:
< 1% PD-L1
expression†
(n = 550)
Part 1a:
≥ 1% PD-L1
expression
(n = 1189)
Up to 2 yrs for IO
 Coprimary endpoints: for
nivolumab + ipilimumab vs
CT, PFS in patients with
high TMB (≥ 10 mut/Mb),
OS in patients with ≥ 1%
PD-L1 expression
 Secondary endpoints: PFS,
OS in patients with PD-L1
< 1% receiving nivolumab +
CT vs CT; OS in patients
with PD-L1 ≥ 50% receiving
nivolumab vs CT
Hellmann. NEJM. 2018;378:2093. Hellmann. NEJM. 2019;381:2020. Peters. ESMO 2019. Abstr LBA7128. Slide credit: clinicaloptions.com

NIVO + IPI NIVO CT
Median OS, mos 17.1 15.7 14.9
HR (vs CT)* 0.79
(97.72% CI:
0.65-0.96)
0.88
(95% CI:
0.75-1.04)
OS
CheckMate 227: OS and PFS in Patients With ≥ 1% PD-L1
Expression
NIVO + IPI NIVO CT
Median OS, mos 5.1 4.2 5.6
HR (vs CT)†
(95% CI)
0.82
(0.69-0.97)
0.99
(0.84-1.17)
PFS by BICR
100
80
60
40
20
0
OS
(%)
Mos
0 3 45
6 27
9 30
12 15 36
18 39
21 42
33
24
Patients at Risk, n
NIVO + IPI
NIVO
CT
396
396
397
341
330
358
295
299
306
264
265
250
244
220
218
212
201
190
190
176
166
165
153
141
153
139
126
145
129
112
129
115
93
91
70
57
41
36
22
9
10
6
1
2
1
0
0
0
NIVO + IPI
NIVO
CT
63%
57%
56%
40%
36%
33%
100
80
60
40
20
0
PFS
(%)
Mos
0 3 6 27
9 30
12 15 36
18 39
21 33
24
396
396
397
221
199
253
158
136
130
130
104
63
108
85
44
91
68
32
83
56
23
73
47
17
65
42
12
62
37
12
47
24
8
31
15
2
7
3
1
0
0
0
NIVO + IPI
NIVO
CT
33%
26%
19%
22%
14%
7%
Hellmann. NEJM. 2019;381:2020. Peters. ESMO 2019. Abstr LBA7128.
*HR for NIVO + IPI vs NIVO: 0.90 (95% CI: 0.76-1.07). †HR for NIVO + IPI vs NIVO: 0.83 (95% CI: 0.71-0.97). 35% receiving NIVO + IPI, 44% receiving NIVO,
and 54% receiving CT received subsequent systemic tx; subsequent IO was received by 6%, 8%, and 43%, respectively.

CheckMate 227: 3-Yr OS Update in Patients With NSCLC
and PD-L1 ≥ 1%
Ramalingam. ASCO 2020. Abstr 9500.
Data cutoff: February 28, 2020. Minimum follow-up for OS: 37.7 mos. Among patients who were alive at 3 yrs, 35% receiving NIVO + IPI, 45%
receiving NIVO + chemo, and 76% receiving CT received subsequent systemic therapy; subsequent immunotherapies were received by 13%, 21%,
and 71%, respectively; subsequent chemotherapy was received by 28%, 33%, and 30%, respectively.
Mos
OS
(%)
NIVO + IPI
NIVO
CT
396
396
397
341
330
358
295
299
306
264
265
250
244
220
218
212
201
190
190
176
166
165
153
141
153
139
126
145
129
112
132
119
98
54
4
4
0
0
0
124
112
87
121
108
80
97
83
62
67
45
32
27
21
13
NIVO + IPI
(n = 396)
NIVO
(n = 396)
CT
(n = 397)
Median OS, mos 17.1 15.7 14.9
HR (vs CT)
(95% CI)
0.79
(0.67-0.93)
0.88
(0.77-1.06)
57%
56%
36%
33%
29%
22%
40%
33%
NIVO + IPI
NIVO
CT
63%
100
80
60
40
0
20
0 3 45
6 27
9 30
12 15 36
18 39
21 42
33
24 48 51

CheckMate 227: Efficacy in Patients With NSCLC and
PD-L1 ≥ 50%
 Median DoR with NIVO + IPI, NIVO and CT was 31.8, 17.5, and 5.8 mos, respectively
PFS by BICR
ORR by BICR OS
ORR
(%)
n/N:
36.9
8.8
35.6
2.1
33.3
4.7
32.2
35.4
PR
CR
6 12 18 24 30 36 42
3 9 15 21 27 33 39
OS
(%)
0
0 45
100
80
60
40
20
Mos
54%
67%
61%
PFS
(%)
0
0 39
100
80
60
40
20
Mos
6 12 18 24 30 36
3 9 15 21 27 33
15%
41%
34%
NIVO + IPI
NIVO + IPI
NIVO
NIVO
CT
CT
NIVO + IPI
(n = 205)
NIVO
(n = 214)
CT
(n = 192)
Median OS,
mos (95% CI)
21.2
(15.5-38.2)
18.1
(14.4-22.1)
14.0
(10.0-18.6)
HR (vs CT)
(95% CI)
0.70
(0.55-0.90)
0.79
(0.63-1.01)
NIVO + IPI
(n = 205)
NIVO
(n = 214)
CT
(n = 192)
Median PFS,
mos (95% CI)
6.7
(4.5-11.0)
5.6
(4.2-8.3)
5.6
(4.6-6.6)
HR (vs CT)
(95% CI)
0.62
(0.49-0.79)
0.75
(0.59-0.95)
36%
48%
42%
5%
31%
20%
NIVO + IPI NIVO CT
79/214 68/192
91/205
Hellmann. NEJM. 2019;381:2020. Peters. ESMO 2019. Abstr LBA7128.
0
10
20
30
40
50
44.4

CheckMate 003: 5-Yr OS With Nivolumab
 Phase 1 trial of nivolumab in patients with advanced NSCLC of any histology after
1-5 lines of prior systemic therapy
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8
129 49 27 20 17 16 3 1 0
Yrs
Patients
at Risk, n
OS
(%)
1-yr OS: 42%
2-yr OS: 24%
3-yr OS: 18% 5-yr OS: 16%
n = 3 deaths in Yrs 3-5 due to PD; n = 1 censored for OS prior to 5 yrs (OS: 58.2+ mos).
Brahmer. AACR 2017. Abstr CT077.
Overall (N = 129)
Median OS, Mos
(95% CI)
9.9
(7.8-12.4)

KEYNOTE-189: First-line Pembrolizumab + CT in
Advanced Nonsquamous NSCLC
 Randomized, double-blind, international phase III study
Gandhi. NEJM. 2018;378:2078.
Patients with previously
untreated stage IIB/IV
nonsquamous NSCLC;
any PD-L1 status;
no actionable
EGFR/ALK mutations;
ECOG PS 0/1;
no untreated CNS mets or
pneumonitis requiring tx
(N = 616)
 Primary endpoints: OS, PFS by BICR
 Secondary endpoints: ORR, DoR, safety
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)
*Carboplatin AUC 5 or cisplatin 75 mg/mm2. †500 mg/m2. ‡Up to total of
35 cycles. ‡If verified PD, then crossover to pembrolizumab allowed.
No
PD
No
PD‡
12-mo rate
34.1%
17.3%
PFS
0
20
40
60
80
100
0 3 6 9 12 15 18 21
Mos
PFS
(%)
HR: 0.52
(95% CI: 0.43-0.64; P < .00001)
Median PFS,
Mos
Pembro + CT 8.8
Pbo + CT 4.9
Median OS,
Mos
Pembro + CT NR
Pbo + CT 11.3
12-mo rate
69.2%
49.4%
OS
0
20
40
60
80
100
0 3 6 9 12 15 18 21
OS
(%)
HR: 0.49
(95% CI: 0.38-0.64; P < .001)

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)
Atezolizumab 1200 mg IV Q3W +
Carboplatin/Paclitaxel Q3W +
Bevacizumab 15 mg/kg IV Q3W
(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
Socinski. NEJM. 2018;378:2288.
Maintenance therapy
(no crossover allowed)
 Primary endpoints: PFS, OS
 Secondary endpoints: PFS (IRF), ORR, OS at Yrs 1 and 2, QoL, safety, PK
*Patients with a sensitising EGFR or ALK aberration must have
PD or intolerance with ≥ 1 approved targeted therapies.

+
IMpower150 Trial: OS in ITT WT
 Significant improvement of OS with addition of atezolizumab to bevacizumab + CT
Socinski. NEJM. 2018;378:2288.
Median in BCP group: 14.7 mos
(95% CI: 13.3-16.9)
Median in Atezo + BCP group: 19.2 mos
(95% CI: 17.0-23.8)
Rate of OS, % (95% CI)
Stratified HR: 0.78 (95% CI: 0.64-0.96; P = .02)
At 12 Mos
67.3 (62.4-72.2)
60.6 (55.3-65.9)
At 24 Mos
43.4 (36.9-49.9)
33.7 (27.4-40.0)
Atezo + BCP
BCP
OS
(%)
Mos
100
80
60
40
20
0
33
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
+ ++
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+ ++
++
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++
+ + +
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+ +
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++
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+ +
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+ +
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+
+
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+ +
+
+ +
+
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++
++
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+
+ +
++
++
+
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++
+ +
+
+ +
+ +
+ +++
+ +
+
+
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+
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+
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+ +
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+ +
+
+ +
+
++++ +
+
++
+ +
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
++
+
+
+
+
+
+
+
+
+
+
+
Patients at Risk, n
Atezo + BCP 359 339 328 323 314 310 296 284 273 264 256 235 218 188 167 147 133 119 103 84 66 57 41 34 28 16 9 2 2 2
BCP 337 326 315 308 287 280 268 255 247 233 216 203 196 174 152 129 115 101 87 77 66 56 40 32 29 22 13 6 3 1 1 1 1
+
+
+
+
+
+

 Randomized, multicenter, open-label phase III study
 Coprimary endpoints: PFS (investigator assessed), OS in ITT-WT population
 Secondary endpoints: PFS and OS in ITT and by PD-L1 expression in ITT and ITT-WT populations;
ORR and DoR in ITT-WT population; safety
IMpower130: Atezolizumab ± Carboplatin/
nab-Paclitaxel in Advanced Nonsquamous NSCLC
West. Lancet Oncol. 2019;20:924.
Atezolizumab +
Carboplatin + nab-Paclitaxel
3-wk cycles x 4-6
(n = 483 ITT; 451 ITT-WT)
Patients with CT-naive
stage IV nonsquamous
NSCLC, ECOG PS 0/1,
EGFR mut or ALK+
enrolled if PD on
targeted therapy
(N = 724*;
n = 679 ITT-WT)
Stratified by sex, baseline liver metastases,
tumor PD-L1 expression
*n = 723 included in ITT population. Carboplatin AUC 6 Q3W, nab-paclitaxel 100 mg/m2 QW,
paclitaxel 200 mg/m2 Q3W, atezolizumab 1200 mg Q3W, pemetrexed 500 mg/m2 Q3W. Crossover
to atezolizumab permitted for patients in chemotherapy alone arm enrolled before 6/15/2016,
with confirmed PD status.
Carboplatin + nab-Paclitaxel
3-wk cycles x 4-6
(n = 240 ITT; 228 ITT-WT)
Atezolizumab
until PD
BSC or
Pemetrexed
until PD
OS
OS
(%)
Atezo + CT
CT
18.6
13.9
Median
OS, Mos
451
228
Patients,
n
63.1
55.5
12-Mo
OS, %
HR: 0.79
(95% CI: 0.64-0.98; P = .033)
100
90
80
70
60
50
40
30
20
10
0
33
0 3 6 9 12 15 18 21 27
24 30
Mos After Randomization
39.6
30.0
24-Mo
OS, %
Patients at Risk, n
Atezo + CT
CT
451
228
400
190
351
161
305
136
268
119
194
90
129
58
75
31
40
13
12
3
4
0

Phase III KEYNOTE-407: Carboplatin + Paclitaxel/nab-
Paclitaxel ± Pembrolizumab in Advanced Squamous 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.
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
23
278 256 188 124 17
281 246 175 93 16
62
45
0
0
2
4
Patients at Risk, n
Pembrolizumab + CT
Placebo + CT
OS at Interim Analysis 2 (ITT)
Paz-Ares. NEJM. 2018;379:2040.
HR: 0.64
(95% CI: 0.49-0.85; P = .0008)
Mos
OS
(%)
100
80
60
40
20
0
0 3 6 9 12 15 18 21
15.9 (13.2-NE)
11.3 (9.5-14.8)
Pembrolizumab + CT
Placebo + CT
30.6
42.7
Events,
%
Median OS,
Mos (95% CI)

243
185
221
165
186
127
153
83
92
34
117
56
0
1
79
26
Patients at Risk, n
Pembro + CT
CT
Mos
OS
(%) 100
80
60
40
20
0
0 3 6 9 12 15 18 33
Pooled Analysis of KEYNOTE-021G, 189, and 407: OS in
Patients Without Tumor PD-L1 Expression (TPS < 1%)
Events, n
Median OS,
Mos (95% CI)
Pembrolizumab + CT 112 19.0 (15.2-24.0)
CT 110 11.0 (9.2-13.5)
Data cutoff: KN021G, December 1, 2017; KN189, September 21, 2018; KN407, April 3, 2018.
Paz-Ares. ESMO. 2019. Abstr 4311.
49
16
29
7
13
5
2
4
21 24 27 30
66%
52%
47%
29%
HR: 0.56 (95% CI: 0.43-0.73)

CheckMate 227: 3-Yr OS Update in Patients With NSCLC
and PD-L1 < 1%
Data cutoff: February 28, 2020. Minimum follow-up for OS: 37.7 mos. Among patients who were alive at 3 yrs, 49% receiving NIVO + IPI, 38%
receiving NIVO + chemo, and 78% receiving CT received subsequent systemic therapy; subsequent immunotherapies were received by 12%, 12%,
and 74%, respectively; subsequent chemotherapy was received by 46%, 35%, and 33%, respectively.
Ramalingam. ASCO 2020. Abstr 9500.
OS
(%)
Mos
177 159 139 119 102 88 67 60 0
78
NIVO + CT 0
4
34
39
42
48 25 15
Patients at Risk, n
187 165 142 120 110 100 87 80 0
NIVO + IPI 73 6
16
23
43
59
69 65 62
186 164 135 107 92 74 49 41 0
62
CT 3
9
12
17
27
35 33 29
NIVO + IPI
(n = 187)
NIVO + CT
(n = 177)
CT
(n = 186)
Median OS, mos 17.2 15.2 12.2
HR (vs CT)
(95% CI)
0.64
(0.51-0.81)
0.82
(0.66-1.03)
51%
60%
59%
23%
40%
35%
15%
20%
34%
NIVO + IPI
NIVO + CT
CT
100
80
60
40
0
20
0 3 45
6 27
9 30
12 15 36
18 39
21 42
33
24 48 51

 Primary endpoint: OS
 Secondary endpoints: PFS, ORR, efficacy by tumor PD-L1 expression
Phase III CheckMate 9LA: Nivolumab + Ipilimumab + CT
 Randomized, open-label, phase III study
Reck. ASCO 2020. Abstr 9501.
Data cutoff for interim analysis: October 3, 2019. Minimum follow-up: 8.1 mos for OS; 6.5 mos for all other endpoints.
Data cutoff for updated analysis: March 9, 2020. Minimum follow-up: 12.7 mos for OS and 12.2 mos for all other endpoints.
*PD-L1 assessed by 28-8 IHC assay. †Patients unevaluable for PD-L1 were
stratified to PD-L1 < 1% and capped to 10% of all randomized patients.
‡NSQ: platinum + pemetrexed; SQ: carboplatin + nab-paclitaxel.
Patients with
stage IV or recurrent
NSCLC, no previous
systemic tx, no
sensitizing EGFR/ALK
alterations, ECOG PS 0/1
(N = 719)
NIVO 360 mg Q3W + IPI 1 mg/kg Q6W
+ CT‡ Q3W (2 cycles)
(n = 361)
CT‡ Q3W (4 cycles)
Optional pemetrexed maintenance (NSQ)
(n = 358)
Stratified by PD-L1 expression* (≥ 1% vs < 1%†),
sex, and histology (squamous vs nonsquamous)
Until PD,
unacceptable
toxicity,
or for 2 yrs for
IO
OS
Mos
OS
(%)
20
40
60
80
100
0
0 3 6 9 12 15 18 21 24 27 30
NIVO + IPI + CT
CT
81%
73%
63%
47%
Patients at Risk, n
NIVO + IPI + CT
CT
361
358
326
319
292
260
250
208
227
166
153
116
86
67
33
26
10
11
1
0
0
0
HR: 0.66 (95% CI: 0.55-0.80)
Patients,
n
Median OS,
Mos (95% CI)
NIVO + IPI + CT
CT
361
358
15.6 (13.9-20.0)
10.9 (9.5-12.6)

 Primary endpoint: OS
 Secondary endpoints: PFS, ORR, efficacy by
tumor PD-L1 expression and bTMB, safety
CCTG BR.34: Durvalumab/Tremelimumab ±
Chemotherapy in Stage IV NSCLC
Leighl. ASCO 2020. Abstr 9502. NCT03057106.
*NSQ: platinum + pemetrexed; SQ: platinum + gemcitabine. †NSQ: durvalumab +
pemetrexed; SQ: durvalumab. Crossover not permitted.
 Randomized, open-label phase II study
Patients with stage IV A
(high risk) or IVB metastatic
NSCLC (any histology);
no prior CT for adv disease;
no sensitizing EGFR/ALK
alterations; ECOG PS 0/1;
no untreated brain mets or
prior autoimmune disease
(N = 301)
Durvalumab 1500 mg IV +
Tremelimumab 75 mg IV
Q28D
(n = 150)
Durvalumab 1500 mg IV +
Tremelimumab 75 mg IV +
Platinum-Doublet CT* Q21D
(n = 151)
Stage (IVA vs IVB), histology (squamous vs nonsquamous), and
smoking status (never vs current vs former)
4 cycles
Durvalumab
until PD
Durvalumab ±
Pemetrexed
until PD
Mos
OS
(%)
100
80
60
40
20
0
0 4 8 12 16 20 24 28
Durva/Trem
Durva/Trem + CT
14.1 (10.6-18.3)
16.6 (12.6-19.1)
Median OS,
Mos (90% CI)
Durva/Trem
Durva/Trem
+ CT
150
151
125
129
85
100
63
79
37
44
11
18
3
9
1
2
HR (stratified): 0.88
(95% CI: 0.67-1.16; log-rank P = .46)
Patients at Risk, n

Most Trials Excluded Patients With EGFR+ and ALK+
NSCLC: Decreased Efficacy in Specific Molecular Cohorts
PD-L1 Positive,
n (%)
EGFR Mutant ALK Positive KRAS Mutant
Pre-TKI
(n = 62)
Post-TKI
(n = 63)
Pre-Criz
(n = 19)
Post-Criz
(n = 12)
Pre-TKI
(n = 56)
PD-L1 ≥ 50% 7 (11) 9 (14) 5 (26) 2 (17) 11 (17)
PD-L1 ≥ 5% 10 (16) 18 (29) 9 (47) 3 (25) 20 (31)
P = .053 P = .123
Gainor. Clin Cancer Res. 2016;22:4585.
20.6
4.2
23.3
3.6
Objective
Response
Rate
(%)
Never/
Light Smokers
Heavy Smokers
40
35
30
25
20
15
10
5
0
EGFR Mutant or
ALK Positive
EGFR WT/
ALK Negative
40
35
30
25
20
15
10
5
0
Objective
Response
Rate
(%)

Or Is Carboplatin/Paclitaxel/Bevacizumab/Atezolizumab
a Good Option?
*Prevalence for ALK rearrangement and EGFR mutation out of EGFR/ALK+ only (n = 108).
†Prevalence for ex19del and L858R out of EGFR mutation only (n = 80).
‡Must have PD with or intolerance to ≥ 1 approved targeted therapies.
§n = 6 with both EGFR mutation and ALK rearrangement.
‖Other EGFR mutations include L861Q, G719X, S7681, exon 20 insertion, T790M, and other.
Data cutoff: September 15, 2017.
IMpower150 Populations n (%)
ITT (including EGFR/ALK+) 800 (100)
EGFR/ALK+ only*‡ 108 (14)
ALK rearrangement*§ 34 (31)
EGFR mutation*§ 80 (74)
Exon 19 deletion or L858R†‖ 59 (74)
ITT-WT 692 (87)
Liver metastases 110 (14)
No liver metastases 690 (86)
Median PFS, Mos
ABCP BCP
8.3 6.8
9.7 6.1
8.3 5.9
10.2 6.9
10.2 6.1
8.3 6.8
8.2 5.4
8.3 7.0
0.61
0.2 2.0
1.0
In favor of
BCP
HR
In favor of
ABCP
0.59
0.40
0.64
0.62
0.65
0.41
0.60
Kowanetz. AACR 2018. Slide credit: clinicaloptions.com

MYSTIC: OS Across bTMB Cutoffs With Durvalumab +
Tremelimumab vs Chemotherapy
 ≥ 20 mut/Mb cut-off selected based on observed effect size for durvalumab + tremelimumab and patient
population with benefit
bTMB High bTMB Low
Rizvi. ASCO 2019. Abstr 9016.
HR (95% CI)
2.5
0.5 1.0
0.25
Favors
chemotherapy
Favors durvalumab +
tremelimumab
bTMB
(Mut/Mb) n (%)
≥ 4
≥ 8
≥ 12
≥ 16
≥ 20
487 (93)
400 (76)
290 (55)
208 (40)
134 (26)
0.87 (0.72-1.07)
0.79 (0.63-0.98)
0.65 (0.50-0.84)
0.62 (0.45-0.86)
0.49 (0.32-0.74)
HR (95% CI)
2.5
0.5 1.0
0.25
Favors
chemotherapy
Favors durvalumab +
tremelimumab
bTMB
(Mut/Mb) n (%)
< 4
< 8
< 12
< 16
< 20
36 (7)
123 (24)
233 (45)
315 (60)
389 (74)
2.72 (1.29-5.86)
1.71 (1.15-2.54)
1.49 (1.11-1.99)
1.23 (0.96-1.58)
1.16 (0.93-1.45)

CheckMate 227: Median OS by Subgroup and in All
Randomized Patients
 No consistent correlation between OS with NIVO + IPI vs chemo and by PD-L1 or TMB
alone or in combination
Median OS, Mos
NIVO + IPI CT
HR HR (95% CI)
(n = 583) (n = 583)
Randomized groups Stratified Stratified
PD-L1 status
All randomized (N = 1166) 17.1 13.9 0.73
< 1% (n = 373) 17.2 12.2 0.62
≥ 1% (n = 793) 17.1 14.9 0.79*
Additional exploratory subgroups analyses†‡ Unstratified Unstratified
PD-L1 status
1-49% (n = 396) 15.1 15.1 0.94
≥ 50% (n = 397) 21.2 14.0 0.70
TMB§
(mut/Mb)
Low, < 10 (n = 380) 16.2 12.6 0.75
High, ≥ 10 (n = 299) 23.0 16.4 0.68
0.25 0.5 1 2
NIVO + IPI CT
*97.72% CI. †Subgroup analyses should be interpreted with caution as patients were not stratified by TMB or PD-L1 ≥ or < 50%. ‡Not controlled by randomization.
§Unstratified HR for NIVO + IPI vs CT in TMB-evaluable (n = 679) and nonevaluable (n = 487) patients was 0.74 (95% CI: 0.61-0.88) and 0.74 (95% CI: 0.60-0.92), respectively.
Peters. ESMO 2019. LBA7128. Slide credit: clinicaloptions.com

Risk of Death and Progression in Combined bTMB and
PD-L1 TC Subgroups
Leighl. ASCO 2020. Abstr 9502.
Survival in Patients with PD-L1 TC ≥ 25%,
bTMB < 20 or ≥ 20 mutations/Mb
PFS in Patients with PD-L1 TC ≥ 25%,
bTMB < 20 or ≥ 20 mutations/Mb
bTMB < 20,
PD-L1 < 25%
bTMB < 20,
PD-L1 ≥ 25%
bTMB ≥ 20,
PD-L1 < 25%
bTMB ≥ 20,
PD-L1 ≥ 25%
102
48
42
15
0.65 (0.45-0.92)
0.6 (0.35-1.04)
0.82 (0.45-1.50)
1.22 (0.37-4.01)
.79
bTMB < 20,
PD-L1 < 25%
bTMB < 20,
PD-L1 ≥ 25%
bTMB ≥ 20,
PD-L1 < 25%
bTMB ≥ 20,
PD-L1 ≥ 25%
102
48
42
15
0.93 (0.62-1.40)
0.83 (0.42-1.62)
1.18 (0.59-2.37)
0.74 (0.07-7.63)
.76
Combined bTMB and
PD-L1 TC Groups n HR (90% CI) P Value
bTMB and PD-L1 TC:
Combined bTMB and
PD-L1 TC Groups n HR (90% CI) P Value
bTMB and PD-L1 TC:
DT +
Chemo
Better
DT
Better
0.01 0.1 1 10 100
DT +
Chemo
Better
DT
Better
0.01 0.1 1 10 100

KEYNOTE 189: tTMB Does Not Predict for Clinical
Outcomes After Chemo-IO
Pembro + Pem + Platinum
No association between tTMB and PD-L1
(r = -0.08, two-sided P = .27)
tTMB-Evaluable Population (N = 293)
HR: 0.64 (95% CI: 0.46-0.88)
TMB ≥ 175 mut/exome (n = 134)
HR: 0.64 (95% CI: 0.38-1.07)
TMB ≥ 150 Mut/exome (n = 159)
HR: 0.68 (95% CI: 0.43-1.09)
Garassino. WCLC 2019. Abstr OA04.06.
Placebo + CT
Pembrolizumab + CT
PD-L1 TPS (%)
tTMB
(mut/exome)
Patients at Risk, n
111 93 84 78 70 47 19 4 0
41 36 25 21 15 11 6 1 0
Mos
OS
(%)
0 4 8 12 16 20 24 28 32
100
80
60
40
0
20
Patients at Risk, n
100 83 78 74 67 44 19 4 0
34 30 21 18 13 9 5 0 0
Mos
OS
(%)
0 4 8 12 16 20 24 28 32
100
80
60
40
0
20
1000
300
100
30
1000
0 10 20 30 40 50 60 70 80 90 100
Nonresponder
Responder
Mos
OS
(%)
0 4 8 12 16 20 24 28 32
100
80
60
40
0
20

STK11/LKB1 Genomic Alterations in Nonsquamous
NSCLC
Skoulidis. ASCO 2019. Abstr 102. Skoulidis. Cancer Discov. 2018;8:822.
LKB1
loss
LKB1
mutation LKB1
proficient
65-70%
30%-35%
75.6%
7.2%
10.7%
6.5%
STK11WT; KEAP1WT
STK11MUT; KEAP1WT
STK11MUT; KEAP1MUT
STK11WT; KEAP1MUT
P = .0072
CD8+/mm
2
5000
4000
3000
2000
1000
0
STK11/
LKB1MUT
STK11/
LKB1WT
KL
KMUT; STK11/LKB1WT
mOS, Mos
6.4
16.0
HR for death: 1.99
(95% CI: 1.29-3.06;
log-rank P = .0015)
KL
KRASMUT; STK11/LKB1WT
54
120
25
81
10
46
4
8
1
2
1
2
2
2
0
0
0
1
Mos
 STK11/LKB1 genomic alterations mediate cold tumor immune microenvironment and are a
major driver of primary resistance to PD-1 axis blockade
0 6 12 18 24 30 36 42 48
OS
(%)
100
80
60
40
20
0
IgG
anti-PD-1
Days (Post Randomization)
LKR10
(Stk11/Lkb1 WT)
Tumor
Volume
(mm
3
)
1500
1000
500
0
18
0 4 7 11 14
LKR10KO
(Stk11/Lkb1 KO)
Tumor
Volume
(mm
3
)
600
400
200
0
0 4 7 11 14
Days (Post Randomization)
** *

STK11/LKB1 Genomic Alterations in Nonsquamous
NSCLC: Study Design and Patient Characteristics at BL
 Multicenter, international, retrospective study
 Cohorts
‒ Cohort 1: metastatic nonsquamous NSCLC
treated with first-line pembrolizumab +
carboplatin/pemetrexed with available genomic
profiling, including STK11
‒ Cohort 2: metastatic STK11 and/or KEAP1-
mutant nonsquamous NSCLC treated with
first-line carboplatin/pemetrexed prior to
regulatory approval of pembrolizumab +
carboplatin/pemetrexed
 Alive ≥ 14 days after cycle 1, Day 1
 All nonsynonymous STK11 and KEAP1
mutations and biallelic deletions included
 Sensitizing EGFR mutations and ALK
translocations excluded
Skoulidis. ASCO 2019. Abstr 102.
Characteristic
PCP
(n = 452)
PCP*
(n = 131)
PC
(n = 169)
STK11 status, n
 Mutant
 WT
 NA
117†
335‡
0
117
14 (KEAP1Mut)
0
142
21 (KEAP1Mut)
6 (KEAP1Mut)
ECOG PS, n (%)
 0/1
 2/3
 NA
379 (84)
59 (13)
56 (3)
113 (86)
17 (13)
1 (1)
132 (78)
30 (18)
7 (4)
Brain mets, n (%)
 No
 Yes
 NA
286 (63)
142 (31.5)
24 (5.5)
80 (61)
47 (36)
4 (3)
111 (66)
44 (26)
14 (8)
Histology, n (%)
 LUAD
 NSCLC-NOS
 Other
421 (93)
18 (4)
13 (3)
122 (93)
4 (3)
5 (4)
154 (91)
10 (6)
5 (3)
*Cohort receiving PCP with available KEAP1 data. †26%. ‡74%.

Integration of STK11, KEAP1 Onco-Genotypes Identifies
Nonsq NSCLC Subgroup With Inferior Outcomes With CIT
 STK11MUT and/or KEAP1MUT: PR/CR, 21.5%; SD, 38.5%; PD, 40%
Skoulidis. ASCO 2019. Abstr 102.
OS
Mos
PFS
(%)
OS
(%)
Mos
PFS, Mos
STK11WT and KEAP1WT (n = 73) 8.4
STK11MUT and/or KEAP1MUT (n = 66) 3.6
PFS
OS, Mos
STK11WT and KEAP1WT (n = 74) 20.4
STK11MUT and/or KEAP1MUT (n = 66) 10.6
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
HR: 2.39 (95% CI: 1.58-3.63;
log rank P < .0001)
HR: 2.0 (95% CI: 1.18-3.41;
log rank P = .01)

Log-rank P = .0005
Skoulidis. ASCO 2019. Abstr 102. Slide credit: clinicaloptions.com
PFS OS
Integration of STK11 and KEAP1 Genomic Alterations
With TMB
Mos
PFS
(%)
100
80
60
40
20
0
24
0 6 12 18
STK11WT; KEAP1WT; TMBHIGH
STK11WT; KEAP1WT; TMBLOW
STK11MUT and/or KEAP1MUT; TMBHIGH
STK11MUT and/or KEAP1MUT; TMBLOW
Median
PFS, Mos
12.4
4.5
4.1
3.6
Log-rank P = .03
Mos
OS
(%)
100
80
60
40
20
0
36
0 6 12 18
STK11WT; KEAP1WT; TMBHIGH
STK11WT; KEAP1WT; TMBLOW
STK11MUT and/or KEAP1MUT; TMBHIGH
STK11MUT and/or KEAP1MUT; TMBLOW
Median
OS, Mos
28.9
20.4
10.7
9.1
24 30

MYSTIC: No Clear Predictive Role for STK11mut
*Mutation-evaluable patients.
Rizvi. WCLC 2019. Abstr OA04.07.
Durvalumab vs CT Durvalumab + Tremelimumab vs CT
Mos to Event or Censor
Probability
of
OS
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0
0.2 D STK11mut
CT STK11mut
D STK11wt
CT STK11wt
D + T STK11mut
CT STK11mut
D + T STK11wt
CT STK11wt
STK11wt D (n = 257) CT (n = 268)
mOS, mos 13.3 13.1
(95% CI) (10.0-16.2) (11.6-15.1)
HR vs CT
(95% CI)
0.98
(0.80-1.19)
Probability
of
OS
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0
0.2
Probability
of
OS
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0
0.2
Probability
of
OS
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0
0.2
STK11mut D (n = 55) CT (n = 41)
mOS, mos 10.3 6.7
(95% CI) (6.1-14.8) (4.5-10.0)
HR vs CT
(95% CI)
0.64
(0.41-1.0)
STK11wt D + T (n = 257) CT (n = 268)
mOS, mos 11.3 13.1
(95% CI) (9.7-13.7) (11.6-15.1)
HR vs CT
(95% CI)
1.05
(0.86-1.27)
STK11mut D + T (n = 51) CT (n = 41)
mOS, mos 4.4 6.7
(95% CI) (3.3-9.2) (4.5-10.1)
HR vs CT
(95% CI)
0.76
(0.48-1.21)

N mOS, Mos
(95% CI)
G12C 74 5.2 (4.3-6.9)
G12D 62 5.7 (4.6-7.6)
G12V 54 4.1 (3.1-5.1)
Others 78 4.9 (4.0-6.9)
N mOS, Mos
(95% CI)
G12C 62 3.8 (2.7-6.8)
G12D 58 1.2 (1.2-3.2)
G12V 41 5.7 (2.8-10.8)
Others 57 2.7 (1.6-3.3)
STK11 Mutation Associated With Worse Prognosis in
KRAS-Positive NSCLC
PFS by
First-line
CT + IO
PFS by
2nd-4th line
IO
KRAS G12C or G12V Mutated NSLC by
Concomitant STK11 Status
KRAS-Mutated NSLC by Mutation Subtype
Tamiya. ASCO 2020. Abstr 9589.
1.0
0.8
0.6
0.4
0.2
0
Probability
of
PFS
0 3 6 9 12 15
Mos
1.0
0.8
0.6
0.4
0.2
0
Probability
of
PFS
0 3 6 9 12 15
Mos
G12C vs G12D, P = .02
G12C vs Others, P < .01
G12V vs G12D, P = .01
G12V vs Others, P < .01
1.0
0.8
0.6
0.4
0.2
0
Probability
of
PFS
0 3 6 9 12 15
Mos
N mPFS, Mos
(95% CI)
STK11(-) 117 4.9 (4.1-5.7)
STK11(+) 11 5.5 (0.7-9.5)
HR: 0.80
(95% CI: 0.44-1.64;
P = .50)
1.0
0.8
0.6
0.4
0.2
0
Probability
of
PFS
0 3 6 9 12 15
Mos
N mPFS, Mos
(95% CI)
STK11(-) 89 5.7 (3.3-9.3)
STK11(+) 14 1.8 (1.0-5.8)
HR: 1.97
(95% CI: 1.06-3.41;
P = .02)

Current Paradigm for Immunotherapy in Advanced
NSCLC Without an Actionable Mutation
 For PD-L1 low (1%-49%) or
negative (< 1%), SoC is
combination ICI + CT
 For ≥ 50% PD-L1, choice of
single-agent ICI or ICI + CT
‒ Single-agent ICI approved for
≥ 1% PD-L1 but not broadly
recommended by experts
Lim. Immune Netw. 2020;20:e10. Slide credit: clinicaloptions.com
PD-L1 high
(≥ 50%)
PD-(L)1 inhibitor
or CT +
PD-(L)1 inhibitor
PD-L1 low (1%-49%)
or negative (< 1%)
Squamous
histology
Nonsquamous
histology
CT +
PD-1 inhibitor
CT +
PD-(L)1 inhibitor
 In May 2020, nivolumab/ipilimumab approved for first-line treatment of advanced
NSCLC with ≥ 1% PD-L1, and nivolumab/ipilimumab plus 2 cycles of platinum-
doublet chemotherapy approved for first-line treatment of advanced NSCLC
without EGFR or ALK genomic aberrations

Lack of Efficacy With Immune Checkpoint Inhibition in
EGFR Mutation–Positive NSCLC
 Phase II study of pembrolizumab in patients with PD-L1–positive EGFR-mutated advanced
NSCLC (planned N = 25); stopped for futility at 11 patients
Lisberg. J Thorac Oncol. 2018;13:1138. Slide credit: clinicaloptions.com
Best Response for Target Lesions Subsequent Therapies and Reasons
for Treatment Discontinuation
*AE led to discontinuation.
†Completed tx, under surveillance.
‡Died while on erlotinib
(1 by fatal pneumonitis).
§Report of EGFR mut was in error.
EGFR-WT§
20
10
0
-10
-20
-30
-40
-50
Change
From
Baseline
(%)
*
†
Mos
0 2 4 6 8 10 12
*
*
* ‡
‡
†
Pembrolizumab
No therapy
Erlotinib
Afatinib
Chemotherapy
Clinical trial
PD
Tx ongoing
*Patient with dural thickening on brain MRI deemed to have PD.
†Patient had CR of target lesion but nontarget progression on first scan.
‡Report of EGFR mut was in error.
EGFR-WT‡

Potential Toxicity With Sequential Use of
Immunotherapy Followed by a TKI
 Retrospective review of patient records to identify severe toxicity with ICI and EGFR
TKI, regardless of sequence, in patients with EGFR-mutated NSCLC (N = 126)
‒ In patients treated with osimertinib within 3 mos of ICI, 24% developed a severe irAE;
conversely, no severe irAEs were identified if osimertinib was given before ICI
Schoenfeld. Ann Oncol. 2019;30:839. Slide credit: clinicaloptions.com
Pt
No.
ICI
Days on
ICI
Days Between
ICI and Osi
Days to irAE Onset
After 1st Osi Dose
irAE Hospitalized?
Response to
Steroids?
1 Nivolumab 14 29 24 G3 pneumonitis Y Y
2 Pembrolizumab + CT* 21 23 15 G3 pneumonitis N Y
3 Nivolumab +
ipilimumab
392 22 167 G3 pneumonitis Y Y
4 Pembrolizumab 126 28 14 G3 colitis Y N
5 Pembrolizumab 126 314 15 G3 pneumonitis Y Y
6 Nivolumab 68 39 39 G4 hepatitis Y N
*Carboplatin plus pemetrexed.

Conclusions
 Checkpoint inhibitors have become first-line standard of care as monotherapy or in
combination with chemotherapy for a cohort of lung cancer patients
 PD-L1 can be used to select patients for single-agent pembrolizumab, atezolizumab,
or nivolumab + ipilimumab
 Combination checkpoint inhibitor therapy lacks a good biomarker but is standard of
care in patients with PD-L1 < 50%
 STK11 and KEAP1 genomic alterations are associated with poor clinical outcomes
with chemotherapy and immunotherapy in nonsquamous NSCLC
 Ongoing phase III trials are comparing checkpoint inhibition to chemotherapy or in
combination with chemotherapy in patients in the neoadjuvant setting and may help
us answer some open questions

clinicaloptions.com/oncology
clinicaloptions.com/LungTool
clinicaloptions.com/immuneAETool
Go Online for More CCO
Coverage of Lung Cancer!
Downloadable slidesets and on-demand Webcast from the live Webinar
Downloadable summary resource on key biomarkers for personalizing lung cancer care in 2020
Expert commentaries on challenges in managing lung cancer
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(update coming soon!)

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