Lung cancer manegement

1. Immunotherapy Options For Nonmetastatic NSCLC
Supported by an educational grant from Regeneron Pharmaceuticals, Inc.

2. About These Slides
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Slide credit: clinicaloptions.com

3. Faculty
Zofia Piotrowska MD, MHS
Assistant Professor
Harvard Medical School
Attending Physician
Division of Hematology/Oncology
Department of Medicine
Massachusetts General Hospital
Boston, Massachusetts
Zofia Piotrowska, MD, MHS: consultant/advisor/speaker: AstraZeneca, Cullinan
Oncology, C4 Therapeutics, Daiichi-Sankyo, Janssen, Lilly, Takeda; researcher: AbbVie,
AstraZeneca, Blueprint, Cullinan, Daiichi-Sankyo, Janssen, Novartis, Spectrum, Takeda,
Tesaro/GlaxoSmithKline.

4. Slide credit: clinicaloptions.com
Stage III NSCLC: A Heterogeneous Group
Adjuvant
therapy
Incidental N2
(or stage III)
Potentially
resectable N2
(or stage III)
Dedicated
multidisciplinary
assessment
Surgical
multimodality
treatment
Unresectable
N2 (or stage III)
Nonsurgical
multimodality
treatment
T/M Subgroup N0 N1 N2 N3
T1
T1a
T1b
T1c
IA1
IA2
IA3
IIB
IIB
IIB
IIIA
IIIA
IIIA
IIIB
IIIB
IIIB
T2 T2a IB IIB IIIA IIIB
T2b IIA IIB IIIA IIIB
T3 T3 IIB IIIA IIIB IIIC
T4 T4 IIIA IIIA IIIB IIIC
M1
M1a
M1b
IVA
IVA
IVA
IVA
IVA
IVA
IVA
IVA
M1c IVB IVB IVB IVB
Stage mOS, Mo 2-Yr OS, % 5-Yr OS, %
IIIA 41.9 65 41
IIIB 22.0 47 24
IIIC 11.0 30 12
Van Meerbeeck. Eur J Cancer Suppl. 2013;11:150. Detterbeck. Chest. 2017;151:193.
Goldstraw. J Thorac Oncol. 2016;11:39. Eberhardt. Ann Oncol. 2015;26:1573.
OS by
Pathologic
Stage
8th Edition AJCC/UICC Stage Approach to Treatment Decisions for Stage III NSCLC

5. Slide credit: clinicaloptions.com
Unresectable Stage III NSCLC: Evolution of Treatment
In February 2018, FDA approved durvalumab for treatment of
unresectable stage III NSCLC without disease progression following concurrent CRT
5
RT vs
Sequential RT + CT*1
Sequential RT + CT vs
Concurrent CRT2
1. NSCLC Collaborative Group. BMJ. 1995;311:899. 2. Aupérin. JCO. 2010;28:2181. 3. Spigel. JCO. 2022;40:1301.
PACIFIC: Concurrent CRT ±
Immunotherapy3
Median OS, Mo
(95% CI)
47.5 (38.1-52.9)
29.1 (22.1-35.1)
cCRT > durvalumab (n = 476)
cCRT > placebo (n = 237)
5-yr stratified HR: 0.72 (95% CI: 0.59-0.89)
Mo
1.0
0.8
0.6
0.4
0.2
0
01 3 6 9 12151821242730333639424548515457606366697275
83.1%
66.3%
49.7% 42.9%
74.6%
55.3%
36.3% 33.4%
43.6%
Probability
of
OS
56.7%
cCRT (n = 603)
Sequ RT + CT (n = 602)
HR: 0.84
(95% CI: 0.74-0.95; P = .004)
Sequ RT + CT (n = 887)
RT (n = 893)
HR: 0.87 (P = .005)
*Cisplatin-based regimens.
Mo
Mo
OS
(%)
100
90
80
70
60
50
40
30
20
10
0
60
0 6 12 18 24 30 36 42 48 54 60
0 12
100
36 48
80
60
40
20
0
OS
(%)
24
35.6%
23.8%
18.4%15.1%
10.6%
12.8%
18.1%
30.3%

6. Slide credit: clinicaloptions.com
12 24 36 48 60 72 84 96108
0
20
40
60
80
100
P = .60
Stage III-N2 Resectable NSCLC:
Should We Operate or Radiate?
 No universal definition of “resectable” stage III-N2 disease; case-by-case multidisciplinary determination3
– Tend to consider single station, smaller (≤1.5 cm) N2 nodal involvement, better operative risk
 Resection and radical RT, combined with systemic tx, provide benefit in resectable stage III-N2 disease
 Adding surgical resection (trimodality) did not increase PFS, OS compared with CRT alone
 Patient selection (lobectomy, low operative risk) may identify subgroup that may benefit from trimodality tx
INT0139: Induction CRT (45 Gy) +
Resection vs Radical CRT (61 Gy)2 1
INT0139 Subgroup Analysis: Lobectomy
as Trimodality Tx vs Bimodality CRT2
1. Van Meerbeeck. J Natl Cancer Inst. 2007;99:442. 2. Albain. Lancet. 2009;374:379. 3. Patel. Oncologist. 2005;10:335.
EORTC 80941: Induction CRT >
Response > Resection vs RT (60 Gy)1
Patients
Alive
(%)
Mo Mo
Patients
Alive
(%)
Patients
Alive
(%)
HR: 0.87
(95% CI: 0.7-1.10; P = .24)
Surgery
RT
CRT CRT
CRT + surgery
CRT + surgery
0 12 24 36 48 60
0
25
50
75
100
Mo
0 12 24 36 48 60
0
25
50
75
100

7. Slide credit: clinicaloptions.com
Potential for Greater Tumor-Specific T-Cell Expansion
With Neoadjuvant Immunotherapy
Versluis. Nat Med. 2020;26:475.
Surgeon removes tumor Receive IO therapy
Activation of a
few T-cell clones
Fewer, less diverse T-cells
search for tumor cells
Receive IO therapy Surgeon removes tumor
Activation of
many T-cell clones
Increased frequency
and diversity of T-cells
search for tumor cells
Proposed Rationale With Adjuvant Immunotherapy
Proposed Rationale With Neoadjuvant Immunotherapy
1 2 3 4
1 2 3 4

8. Slide credit: clinicaloptions.com
Preoperative Nivolumab: Proof-of-Concept Study
Pathologic response: 45%
RECIST ORR: 10%
Pathologic Regression to Neoadjuvant PD-1
Blockade in Resected Primary Tumors (n = 20)
Neoantigen-Specific T-Cells in PB
Before and After Nivolumab*
Neoantigen-Specific T-Cells in
Tumor and Resected Tissue*
Forde. NEJM. 2018;376:1976.
MPR
(-90%)
Regression
(%)
Regression
(%)
0
-20
-40
-60
-80
-100
PD-L1+
PD-L1-
Unknown
*Colored dots represent 3 T-cell clones identified in PB sample from a patient on
Day 44, as well as in the pretreatment tumor-biopsy and resection specimens.
-28 -14 -3 44
Days Relative to Surgery
Frequency
Among
PB
T-Cells
(%)
0.03
0.02
0.01
0.00
Surgery
(Day 0)
Nivolumab
Tumor
Before
Resection
0.8
0.4
0.2
0.0
Frequency
Among
T-Cells
in
Tumor
and
Resected
Tissue
(%)
0.6
Resection
Tumor
Bed
Resection
Normal
Lung
Resection
Involved
Node
Resection
Uninvolved
Node

9. Smoking
status
RECISTv1.1
LN
status
Histology
Stable disease
Partial response
Complete response
Disease progression
Died
The Next Step:
Preoperative Chemo-
Immunotherapy
MPR: 83%
pCR: 63%
3-Yr PFS: 70%
3-Yr OS: 82%
Provencio. Lancet Oncol. 2020;21:1413. Provencio. JCO. 2022;40:2924.
PFS in Modified ITT Population (n = 46)
Sex
Sex Smoking Status Lymph Nodes
Histology
Pathologic Response
0 6 12 18 24 30 36
RECIST v1.1
N2
N1
N0
Smoker
Former smoker
Adenocarcinoma
Squamous
Other
Follow-up
Not resected
Incomplete pathologic response
Major pathologic response
Complete pathologic response
Female
Male
 Phase II NADIM: neoadjuvant
nivolumab + CT in stage IIIA
resectable NSCLC
Slide credit: clinicaloptions.com

10. Slide credit: clinicaloptions.com
CheckMate 816: Neoadjuvant Nivolumab + Platinum
Chemotherapy for Resectable Stage IB-IIIA NSCLC
 Randomized, open-label phase III trial (data cutoff: September 16, 2020; min f/u: 7.6 mo)
Patients with
newly diagnosed, resectable
stage IB (≥4 cm) to IIIA
NSCLC*; no sensitizing EGFR
mutations or ALK alterations;
ECOG PS 0/1
(N = 358)
Follow-up
Nivolumab 360 mg Q3W +
CT†‡ Q3W
(n = 179)
CT†§ Q3W
(n = 179)
Surgery
(within 6 wk
post tx)
Optional
adjuvant CT
± RT
Stratified by stage (IB/II vs IIIA), PD-L1‖ (≥1% vs <1%), and sex
*By TNM 7th edition. †3 cycles. ‡NSQ: cisplatin/pemetrexed or carboplatin/paclitaxel; SQ: cisplatin/gemcitabine or carboplatin/paclitaxel.
§NSQ: cisplatin/pemetrexed; SQ: cisplatin/vinorelbine, cisplatin/docetaxel, cisplatin/gemcitabine; both: carboplatin/paclitaxel. ‖PD-L1 28-8 pharmDx IHC assay.
Spicer. ASCO 2021. Abstr 8503. Forde. NEJM. 2022;386:1973. Girard. AACR 2022. Abstr CT012.
 Primary endpoints: pCR (by BIPR) and EFS
(by BICR)
 Key secondary endpoints: OS, MPR (by
BIPR), time to death or distant metastasis
 Key exploratory endpoints: ORR (by BICR),
feasibility of surgery, peri- and
postoperative surgery-related AEs
Radiologic restaging

11. Slide credit: clinicaloptions.com
CheckMate 816: pCR by Disease Stage at Baseline
(Coprimary Endpoint)
 Overall pCR rate: 24% with nivolumab + CT vs 2.2% with CT alone (OR: 13.94; 99% CI: 3.49-55.75; P <.001);
improvement evident regardless of radiologic downstaging
 In March 2022, nivolumab was approved by the FDA for adult patients with resectable (tumors ≥4 cm or
node positive) NSCLC in the neoadjuvant setting, in combination with platinum-doublet CT
Spicer. ASCO 2021. Abstr 8503. Forde. NEJM. 2022;386:1973. Nivolumab PI.
50
40
30
20
10
0
pCR
Rate
(%)
IB IIA IIB IIIA
BL Stage
Nivolumab + CT
CT
40
0
23
3
24
9
23
1
n/N 4/10 0/8 7/30 1/32 6/25 2/23 26/113 1/115

12. Slide credit: clinicaloptions.com
CheckMate 816: Nivolumab + Chemotherapy Showed
Benefit in Surgical Outcomes vs Chemotherapy
 Lower pneumonectomy rates were evident with nivolumab + chemotherapy
 Complete resection rates (R0) were similar across treatment arms
Spicer. ASCO 2021. Abstr 8503. Forde. NEJM. 2022;386:1973.
100
80
60
40
20
0
Patients
(%)
All IB/II IIIA
BL Stage
n/N 115/149 82/135 41/55 33/52 74/94 49/83
77
61
74
64
79
59
Lobectomy
n/N 25/149 34/135 9/55 9/52 16/94 25/83
Pneumonectomy
100
80
60
40
20
0
Patients
(%)
All IB/II IIIA
BL Stage
17
25
16 17 17
30
83
11
3 3
78
16
3 4
0
20
40
60
80
100
R0 R1 R2 Rx
Patients
(%)
80
60
40
20
0
100
Complete Resection Rate
Nivolumab + CT CT

13. Slide credit: clinicaloptions.com
CheckMate 816: EFS (Coprimary Endpoint)
Nivolumab + CT
(n = 179)
CT
(n = 179)
Median EFS,* Mo (95% CI) 31.6 (30.2-NR) 20.8 (14.0-26.7)
HR: 0.63 (97.38% CI†: 0.43-0.91; P = .0052‡)
100
80
60
40
20
0
EFS
(%)
Mo From Randomization
42
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Patients at Risk, n
Nivolumab + CT
CT
179
179
151
144
136
126
124
109
118
94
107
83
102
75
87
61
74
52
41
26
34
24
13
13
6
11
3
4
0
0
76%
64%
Nivolumab + CT
CT
45%
63%
+
+
++
+
+
+
+ +
+
+
+
+
+
+ +
+ +
+++
++
+
+
+ +
+
+
+
+
+ +
+
+
++ +
+ +
+
Minimum follow-up: 21 mo. Median follow-up: 29.5 mo.
*Per BICR. †95% CI: 0.45-0.87. ‡Significant boundary for EFS at time of interim analysis: 0.0262.
Girard. AACR 2022. Abstr CT012. Forde. NEJM. 2022;386:1973.

14. Slide credit: clinicaloptions.com
CheckMate 816: EFS (Coprimary Endpoint)
Minimum follow-up: 21 mo. Median follow-up: 29.5 mo.
*Per BICR. †95% CI: 0.45-0.87. ‡Significant boundary for EFS at time of interim analysis: 0.0262.
Nivolumab + CT
(n = 179)
CT
(n = 179)
Median EFS,* Mo (95% CI) 31.6 (30.2-NR) 20.8 (14.0-26.7)
HR: 0.63 (97.38% CI†: 0.43-0.91; P = .0052‡)
100
80
60
40
20
0
EFS
(%)
Mo From Randomization
42
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Patients at Risk, n
Nivolumab + CT
CT
179
179
151
144
136
126
124
109
118
94
107
83
102
75
87
61
74
52
41
26
34
24
13
13
6
11
3
4
0
0
76%
64%
Nivolumab + CT
CT
45%
63%
+
+
++
+
+
+
+ +
+
+
+
+
+
+ +
+ +
+++
++
+
+
+ +
+
+
+
+
+ +
+
+
++ +
+ +
+
Parameter, %
Nivo + CT
(n = 179)
CT
(n = 179)
Compliance 94 85
Resection 83 78
Adjuvant CT 11.9 22
Girard. AACR 2022. Abstr CT012. Forde. NEJM. 2022;386:1973.

15. Slide credit: clinicaloptions.com
*Per BICR.
CheckMate 816: EFS by Subgroup
Girard. AACR 2022. Abstr CT012.
0.125 0.25 0.5 1 2 4
Favors CT
Favors Nivolumab + CT
Median EFS,* Mo
Unstratified HR
Unstratified HR (95% CI)
Nivolumab + CT
(n = 179)
CT
(n = 179)
0.63
0.57
0.70
0.68
0.46
0.78
0.80
0.45
0.61
0.71
0.87
0.54
0.77
0.50
0.68
0.33
0.85
0.41
0.58
0.24
0.86
0.69
0.71
0.31
21
21
18
17
32
NR
21
16
23
14
NR
16
23
20
22
10
18
21
27
20
27
22
21
11
32
NR
30
31
NR
NR
32
NR
NR
30
NR
32
31
NR
32
NR
25
NR
NR
NR
30
NR
NR
NR
Overall (N = 358)
<65 yr (n = 176)
≥65 yr (n = 182)
Male (n = 255)
Female (n = 103)
North America (n = 91)
Europe (n = 66)
Asia (n = 177)
ECOG PS 0 (n = 241)
ECOG PS 1 (n = 117)
Stage IB-II (n = 127)
Stage IIIA (n = 228)
Squamous (n = 182)
Nonsquamous (n = 176)
Current/former smoker (n = 318)
Never smoker (n = 39)
PD-L1 <1% (n = 155)
PD-L1 ≥1% (n = 178)
PD-L1 1%-49% (n = 98)
PD-L1 ≥50% (n = 80)
TMB <12.3 mut/Mb (n = 102)
TMB ≥12.3 mut/Mb (n = 76)
Cisplatin (n = 258)
Carboplatin (n = 72)

16. Slide credit: clinicaloptions.com
CheckMate 816: Interim OS
Girard. AACR 2022. Abstr CT012.
Nivolumab + CT
(n = 179)
CT
(n = 179)
Median OS, mo (95% CI) NR (NR-NR) NR (NR-NR)
HR: 0.57 (97.67% CI*: 0.30-1.07; P = .0079†)
Minimum follow-up: 21 mo. Median follow-up: 29.5 mo.
*95% CI: 0.38-0.87. †Significance boundary for OS at time of interim analysis: 0.033 (not met).
100
80
60
40
20
0
OS
(%)
Mo From Randomization
48
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Patients at Risk, n
Nivolumab + CT
CT
179
179
176
172
166
165
163
161
156
154
148
148
146
133
143
123
122
108
101
80
72
59
48
41
26
24
16
16
0
0
90%
83%
Nivolumab + CT
CT
90%
71%
42 45
7
7
3
2
+
++ +
+
+
+
++
+ +
++
+
+
+ +
+
+ +
+
+
+ +
++
+
+
+ +
+
+
+
++
+
+
++
+++
++
+
+ +
+
+ +
+ +
++
+
+
+ +
+
+
+
+ +
+
+ +
++
++
++
+ +
+ +
++
+
+
+

17. Slide credit: clinicaloptions.com
CheckMate 816: Exploratory EFS by pCR Status
 EFS HR for no pCR with
nivolumab + CT vs CT: 0.84
(95% CI: 0.61-1.17)
Girard. AACR 2022. Abstr CT012.
Nivolumab + CT CT
pCR No pCR pCR No pCR
mEFS, mo
(95% CI)
NR
(30.6-NR)
26.6
(16.6-NR)
NR
(NR-NR)
18.4
(13.9-26.2)
HR
(95% CI)*
0.13 (0.05-0.37) Not computed†
Minimum follow-up: 21 mo. Median follow-up: 29.5 mo.
*EFS HR for pCR vs no pCR in pooled population of nivolumab + CT and CT arms combined: 0.11 (95% CI: 0.04-0.29).
†Due to only 4 patients having a pCR.
100
80
60
40
20
0
EFS
(%)
Mo From Randomization
42
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Patients at Risk, n
Nivo + CT (pCR)
CT (pCR)
Nivo + CT (no pCR)
CT (no pCR)
43
4
136
175
43
4
108
140
41
4
95
122
40
4
84
105
40
4
78
90
40
4
67
79
40
4
62
71
35
4
52
57
32
4
42
48
19
3
22
23
14
2
20
22
6
2
7
11
3
2
3
9
2
1
1
3
0
0
0
0
Nivo + CT (pCR)
CT (pCR)
Nivo + CT (no pCR)
CT (no pCR)
++
+
+
+
+ +
++
+
+
+
+ +
+ +
+
+
+
++
+
+
+
+ +
+
+
+ + + +
+ +
+
+ +
+
+ +
+ +
+
+
+
+
+

18. Slide credit: clinicaloptions.com
Ongoing Phase III Periadjuvant Studies in
Resectable NSCLC
*Stages included differ between trials. †Dosage, timing, duration, and chemotherapy backbones differ between trials. ‡By contrast, CheckMate 816 allowed
optional adjuvant CT ± RT. §Includes stage IIIB patients with N2 disease that is considered resectable. Cross trial comparisons are not intended. ‖June 2022.
IO + Chemotherapy
≥4 cycles†
IO
12-16 cycles†‡
Placebo +
Chemotherapy†
Patients with stage II-III*
resectable NSCLC,
ECOG PS 0-1 Placebo/BSC
Surgery
Surgery
CheckMate 77T1,2 KEYNOTE-6713,4 IMpower0305,6 AEGEAN7,8
IO agent Nivolumab Pembrolizumab Atezolizumab Durvalumab
Primary endpoint(s) EFS EFS, OS EFS pCR, EFS
Accrual status (est. PCD)‖ Recruiting (Dec 2023) Active (Jan 2024) Active (Nov 2024) Recruiting (Apr 2024)
Disease stage (8th TNM ed) II-IIIB§ II-IIIB§ II-IIIB§ IIA-IIIB§
Target N 452 786 453 (actual enrollment) 824
Chemotherapy backbone ≥4 cycles carbo/pac, cis/doc,
carbo/pemetrexed,
cis/pemetrexed, or
carbo/pac
≥4 cycles of cis/
(gem or pemetrexed)
4 cycles of carbo/pemetrexed,
carbo/nab-pac,
cis/pemetrexed, or cis/gem
4 cycles of carbo/pac,
carbo/pemetrexed, cis/gem,
or cis/pemetrexed
1. Cascone. ASCO 2020. TPS 9076. 2. NCT04025879. 3. Tsuboi. ESMO 2020. 1235TiP. 4. NCT03425643.
5. Peters. ESMO 2019. 82TiP. 6. NCT03456063. 7. Heymach. WCLC 2019. P1.18-02. 8. NCT03800134.
Neoadjuvant Adjuvant

19. Slide credit: clinicaloptions.com
 Primary endpoint: DFS
Phase III Adjuvant Immunotherapy Trials
 Primary endpoint: DFS by investigator
(hierarchical design) in PD-L1+ stage II-IIIA
> all stage II-IIIA > ITT (stage IB-IIIA)
19
Adults with stage IB
(T≥4 cm)/II/IIIA NSCLC per
AJCC 7th ed after complete
surgical resection with
provision of tumor tissue for
PD-L1 testing
(N = 1177)
Pembrolizumab
200 mg IV Q3W x 1 yr
Placebo
IV Q3W x 1 yr
PEARLS/KEYNOTE-0914
Chemotherapy not mandatory
Adults with stage IB
(T≥4 cm)/II/IIIA NSCLC
per AJCC 7th ed
after complete
surgical resection
(N = 1280)
Atezolizumab
1200 mg IV Q3W x 16
BSC
x 1 yr
IMpower0101-3
Cisplatin +
pemetrexed,
gemcitabine,
docetaxel, or
vinorelbine
1-4 cycles
Chemotherapy mandatory
Stratified by PD-L1 expression, sex,
stage (IB vs II vs IIIA), and histology
Stratified by disease stage (IB vs II vs IIA), PD-L1 TPS
(<1% vs 1%-49% vs ≥50%), and geographic region
1. Wakelee. ASCO 2021. Abstr 8500. 2. Felip. Lancet. 2021;398:1344.
3. Felip. WCLC 2022. Abstr PL03.09 4. Paz-Ares. ESMO Virtual 2022. Abstr VP3-2022.
Crosstrial comparisons have significant limitations. The information in this section is presented
to generate discussion, not to make direct comparisons between study results.

20. Slide credit: clinicaloptions.com
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Adjuvant IO Trials: DFS in Overall Population (ITT)
20
IMpower0101,2 PEARLS/KEYNOTE-0913
Median DFS,
Mo (95% CI)
NE (36.1-NE)
37.2 (31.6-NE)
Atezo
BSC
Median DFS,
Mo (95% CI)
53.6 (39.2-NR)
42.0 (31.3-NR)
Pembro
Placebo
1. Wakelee. ASCO 2021. Abstr 8500. 2. Felip. Lancet. 2021;398:1344. 3. Paz-Ares. ESMO Virtual 2022. Abstr VP3-2022.
+
+
+
++
+
63.6%
+
+
+
+
+
+
+
57.9%
+
+
+
+
71.4%
+
+
100
80
60
40
20
0
DFS
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Mo
+
+
+
+ +
+ ++
+
+ ++
+
++
+
+
+ +
+
++
+
+
+
+
+
+
+
+
+
+
+
++
+
+ +
+
+
+
+
+
+
+
+
+ +
+ +
+ +
+
+
+
+
++ +
+
+
+
+
+
+ ++ +
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
52.6%
Patients at
Risk, n
++
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Atezo
BSC
507
498
478
467
437
418
418
383
403
365
387
342
367
324
353
309
306
269
257
219
212
173
139
122
97
90
53
46
38
30
19
13
14
10
8
5
4
4
Stratified HR: 0.81 (95% CI: 0.67-0.99; P = .040)
64.3%
73.4%
100
80
60
40
20
0
DFS
(%)
0 6 12 18 24 30 36 42 48 66
Mo
Patients at
Risk, n
Pembro
Placebo
590
587
493
493
434
409
358
326
264
241
185
160
82
72
70
57
28
22
16
18
0
0
54 60
1
1
+
+
+
+
+
+
+ +
++
+
+
+
+
+
+
+
+
+
+ +
+
+
++
+
+
+++
+++ +
++ +
+
+
+
+
+
+
+++
+
+
+
+ +
+ +
+
+
++ +
+
+
+ +
+
+
+ +
+ +
+
++
+
HR: 0.76 (95% CI: 0.63-0.91; P = .0014)

21. Slide credit: clinicaloptions.com
Adjuvant IO Trials: OS in Overall Population (ITT)
21
1. Felip. WCLC 2022. Abstr PL03.09. 2. Paz-Ares. ESMO Virtual 2022. Abstr VP3-2022.
Mo
Patients at Risk, n
Pembro
Placebo
590
587
572
582
548
556
520
524
419
420
318
309
226
213
143
135
83
78
52
44
0
0
23
16
2
1
IMpower0101
Patients
w/Event, %
16.6
18.9
PEARLS/KEYNOTE-0912
Median OS,
Mo (95% CI)
NR
NR
Pembro
Placebo
100
80
60
40
20
0
OS
(%)
0 6 12 18 24 30 36 42 48 72
54 60
HR: 0.87 (95% CI: 0.68-1.15; P = .17)
66
91.7%
91.3%
No formal testing for statistical significance is allowed until
statistical significance is observed for DFS in ITT population
based on prespecified hierarchical testing strategy
439
428
Atezo (n = 507) 127 (25.0) NR
BSC (n = 498) 124 (24.9) NR
Median OS,
Mo (95% CI)
Events,
n (%)
HR: 0.995 (95% CI: 0.78-1.28; P = .9661)
430
417
100
80
60
40
20
0
72
0 3 6 9 1215182124273033363942454851545760636669
507
498
492
484
488
473
478
462
472
452
463
444
450
437
419
405
408
391
393
381
381
371
372
357
328
325
262
253
203
207
144
148
96
101
61
57
30
25
17
14
8
11
4
5
NE
NE
OS
(%)
Patients at Risk, n
Atezo
BSC
Mo

22. Slide credit: clinicaloptions.com
Subgroup
No. Events/
No. Participants
HR (95% CI)
Overall 472/1177 0.79 (0.63-0.91)
Pathologic stage
IB 46/169 0.76 (0.43-1.37)
II 246/667 0.70 (0.55-0.91)
IIIA 178/339 0.92 (0.69-1.24)
Received adjuvant
chemotherapy
No 64/167 1.25 (0.76-2.05)
Yes 408/1010 0.73 (0.60-0.89)
Histology
Nonsquamous 330/761 0.67 (0.54-0.83)
Squamous 142/416 1.04 (0.75-1.45)
PD-L1 TPS
≥50% 117/333 0.82 (0.57-1.18)
1%-49% 160/379 0.67 (0.48-0.92)
<1% 195/465 0.78 (0.58-1.03)
EGFR mutation
No 185/434 0.78 (0.59-1.06)
Yes 40/73 0.44 (0.23-0.84)
Unknown 246/670 0.82 (0.63-1.06)
Subgroup N HR (95% CI)
All patients 882 0.79 (0.64-0.96)
Stage
IIA 295 0.68 (0.46-1.00)
IIB 174 0.88 (0.54-1.42)
IIIA 413 0.81 (0.61-1.06)
Regional lymph node stage (pN)
N0 229 0.88 (0.57-1.35)
N1 348 0.67 (0.47-0.95)
N2 305 0.83 (0.61-1.13)
SP263 PD-L1 status
TC ≥50% 229 0.43 (0.27-0.68)
TC ≥1% 476 0.66 (0.49-0.87)
TC <1% 383 0.97 (0.72-1.31)
EGFR mutation status
Yes 109 0.99 (0.60-1.62)
No 463 0.79 (0.59-1.05)
Unknown 310 0.70 (0.49-1.01)
ALK rearrangement status
Yes 31 1.04 (0.38-2.90)
No 507 0.85 (0.66-1.10)
Unknown 344 0.66 (0.46-0.93)
Adjuvant IO Trials: DFS by Subgroup
22
IMpower010: All Randomized Stage II-IIIA1,2 PEARLS/KEYNOTE-091: Overall Population3
1. Wakelee. ASCO 2021. Abstr 8500. 2. Felip. Lancet. 2021;398:1344. 3. Paz-Ares. ESMO Virtual 2022. Abstr VP3-2022.
0.1 1.0 10.0
Atezolizumab Better
HR
BSC Better
0.2 2 5
Pembrolizumab Better Placebo Better
0.5 1

23. Slide credit: clinicaloptions.com
IMpower010: DFS and OS in Patients With
Resected Stage II-IIIA NSCLC With PD-L1 ≥1%
 FDA approved in October 2021 for adjuvant treatment following resection and adjuvant plt-based CT for adults
with stage II-IIIA NSCLC, PD-L1 TC ≥1%
1. Wakelee. ASCO 2021. Abstr 8500. 2. Felip. Lancet. 2021;398;1344. 3. Felip. WCLC 2022. Abstr PL03.09.
DFS1,2
Patients at Risk, n
Atezo
BSC
Median DFS,
Mo (95% CI)
NE (36.1-NE)
35.3 (29.0-NE)
Atezo
BSC
248
228
235
212
225
186
217
169
206
160
198
151
190
142
181
135
159
117
134
97
111
80
76
59
54
38
31
21
22
14
12
7
8
6
3
4
3
3
54
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Mo
100
80
60
40
20
0
DFS
(%)
+
74.6%
61.0%
48.2%
+ + +
++ ++
+
+
+ +
+
+
+
+
+
+
+
+
++
+
+ +
+ +
+
+
+
+
+
+
+
+
+
++ ++
+
+
+
+
+ +
+
+
+ +
+
++
+
+
+ +
+
+
+
++
++ +
+
+
+
+
+
+
++ +
+
+
+
+
+ +
+
+
+
+
+ ++ +++
+
60.6%
+
+
+
+
+
+ +
+
+
+
+
Stratified HR: 0.66 (95% CI: 0.50-0.88; P = .004)
Atezo (n = 248) 52 (21.0) NR
BSC (n = 228) 64 (28.1) NR
Median OS,
Mo (95% CI)
Events,
n (%)
HR: 0.71 (95% CI: 0.49-1.03)
Patients at Risk, n
Atezo
BSC
248
228
241
220
241
214
237
210
234
205
231
201
225
198
222
192
218
185
210
180
208
172
200
167
195
166
190
158
172
140
140
110
116
95
83
72
56
49
37
27
23
15
12
8
5
7
3
4
NE
NE
72
0 3 6 9 1215182124273033363942454851545760636669
100
80
60
40
20
0
82.1%
76.8%
67.5%
78.9%
OS3
OS
(%)
Mo
Median follow-up: 46 mo
Median follow-up: 32.8 mo (range: 0.1-57.5; IQR: 27.4-38.3).

24. Slide credit: clinicaloptions.com
Adjuvant IO Trials: Summary of Adverse Events
24
AE, %
Atezo
(n = 495)
BSC
(n = 495)
Any grade AE
 TRAE
92.5
67.9
70.9
0
Grade 3/4 AE
 Grade 3/4 TRAE
22.0
10.7
11.5
0
Serious AE
 Treatment-related serious AE
17.8
7.5
8.5
0
Grade 5 AE
 Treatment-related grade 5 AE
1.8*
0.8
0.6†
0
AE leading to atezo dose interruption 28.7 0
AE leading to treatment d/c 18.2 0
Any grade immune-mediated AE
 Grade 3/4 immune-mediated AE
 Immune-mediated AE requiring
systemic corticosteroid use‡
52.1
7.9
12.3
9.5
0.6
0.8
IMpower0101 PEARLS/KEYNOTE-0912
AE, n (%)
Pembro
(n = 580)
Placebo
(n = 581)
Any 556 (95.9) 529 (91.0)
Grade 3-5 AE 198 (34.1) 150 (25.8)
AE leading to death
 Treatment related
11 (1.9)
4 (0.7)§
6 (1.0)
0
Serious AE 142 (24.5) 90 (15.5)
AE leading to treatment d/c 115 (19.8) 34 (5.9)
AE leading to treatment interruption 221 (38.1) 145 (25.0)
§n = 1 each: myocarditis with cardiogenic shock, myocarditis with septic shock,
pneumonia, and sudden death.
1. Felip. WCLC 2022. Abstr PL03.09. 2. Paz-Ares. ESMO Virtual 2022. Abstr VP3-2022.
*n = 1 each related to atezolizumab: ILD, multiple organ dysfunction syndrome, myocarditis, and AML; n = 1 each: pneumothorax, cerebrovascular accident,
arrhythmia, and acute cardiac failure. †Pneumonia, pulmonary embolism, and cardiac tamponade and septic shock in the same patient. ‡Atezolizumab related.

25. Slide credit: clinicaloptions.com
Ongoing or Recent Phase III Adjuvant Studies in
Resected NSCLC
1. NCT02273375. 2. Chaft. ASCO 2018. Abstr TPS8581. 3. NCT02595944. 4. Peters. WCLC 2020. Abstr P03.03. 5. NCT04385368.
6. Spigel. ELCC 2021. Abstr 93TiP. 7. NCT04642469. 8. Sands. Immunotherapy. 2021;13:727. 9. NCT04267848.
Adjuvant Immunotherapy
x 1 yr
Placebo/Observation
x 1 yr
Patients with stage IB-III
resected NSCLC,
ECOG PS 0-1
CCTG BR.311 ANVIL2,3 MERMAID-14,5 MERMAID-26,7 ACCIO*8,9
IO agent
Durvalumab
(sequential)
Nivolumab
(sequential)
Durvalumab
(concurrent)
Durvalumab
(sequential)
Pembrolizumab
(concurrent or sequ)
Primary endpoint(s) DFS DFS, OS DFS (MRD+) DFS (PD-L1 ≥1%) DFS
Accrual status
(est. PCD)†
Active
(Jan 2023)
Active
(Jul 2024)
Active
(Dec 2024)
Active
(Nov 2025)
Recruiting
(Dec 2024)
Disease stage (7th TNM ed) IB-IIA IB-IIIA‡ II-IIIA II-IIIA (MRD+) IB-IIIA
Target N 1415 (actual) 903 332 284 1210
Adjuvant chemotherapy CT permitted CT and/or RT
permitted
SoC CT CT and/or RT
permitted§
1-4 cycles of carbo
or cis + pemetrexed,
pac, or gem
*ALCHEMIS chem-IO. †June 2022. ‡8th TNM ed. §Neoadjuvant therapy also permitted. Crosstrial comparisons are not intended.
Adjuvant
Chemotherapy
(varies by trial)

26. Slide credit: clinicaloptions.com
Neoadjuvant Adjuvant
Complete pathologic
staging
No increased
perioperative risks
due to preop therapy
No risk of surgical
delay
More commonly
used in routine
practice (>95%)
Potential
downstaging
Better antigen
priming?
In vivo test of drug
sensitivity
Can add further
therapy
postoperatively
Better treatment
compliance
How Do We Decide?
Multidisciplinary
and Patient
Discussion

27. Slide credit: clinicaloptions.com
Neoadjuvant Adjuvant
Complete pathologic
staging
No increased
perioperative risks
due to preop therapy
No risk of surgical
delay
More commonly
used in routine
practice (>95%)
Potential
downstaging
Better antigen
priming?
In vivo test of drug
sensitivity
Can add further
therapy
postoperatively
Better treatment
compliance
How Do We Decide?
Multidisciplinary
and Patient
Discussion
Neoadjuvant
Approaches Provide
Rich Research
Opportunities:
• Rapid assessment
of response to
novel therapies
within tumors
and surrounding
tissue, LNs
• Platform for
biomarker
development

28. Go Online for More CCO
Education on Lung Cancer!
Downloadable slidesets from today’s symposium
CME-certified on-demand webcast of today’s symposium (coming soon!)
FAQ commentary from today’s symposium (coming soon!)
Interactive Decision Support Tool individualizing guideline recommendations for
management of immune-related adverse events to each patient
clinicaloptions.com/oncology
clinicaloptions.com/immuneAETool