This document discusses recent updates in lung cancer. It begins by noting that lung cancer is the leading cause of cancer death in the US and is often diagnosed at an advanced stage. Screening with low-dose CT scans can detect lung cancer earlier and has been shown to decrease lung cancer mortality by 20% compared to chest x-rays. The National Lung Screening Trial established low-dose CT screening as an effective screening method for those at high risk. Biomarker testing is important to identify driver mutations and guide targeted therapy options, though barriers like tissue availability and turnaround time exist. Osimertinib has demonstrated superior progression-free survival compared to earlier EGFR TKIs for patients with EGFR-mut

1. RECENT UPDATES IN
LUING CANCER
DR.R.RAJKUMAR D.M
CONSULTANT MEDICAL ONCOLOGIST
VELAMMAL MEDICAL COLLEGE HOSPITALS

2. LUNG CANCER FACTS
• Lung Cancer is the #1 cancer killer in the US
Cancer statistics, 2018, Volume: 68

3. LUNG CANCER FACTS
• Most patients diagnosed with advanced disease
Cancer statistics, 2018, Volume: 68
Stage at diagnosis

4. LUNG CANCER FACTS
• Lung cancer is curable when diagnosed early
Journal of Thoracic Oncology 2017 12: 1109-1121

5. LUNG CANCER SCREENING
• What is screening?
• A test done to detect a cancer before symptoms develop
• Symptoms of lung cancer typically do not appear until the disease is
advanced
• Why hasn’t lung cancer screening been routine?
• Until recently, there hasn’t been an effective test
• Lung cancer screening with CXR showed no benefit
• No change in lung cancer deaths

6. NATIONAL LUNG SCREENING TRIAL
• Large clinical trial 2002-2007
• Over 50,000 patients at risk for lung cancer
• 55-74 years old
• Current or former smokers
• Randomized to annual low-dose CT scan to CXR
New England Journal of Medicine August 4th, 2011

7. NATIONAL LUNG SCREENING TRIAL
• People who got low-dose CT scans had a 20% decreased risk of
dying from lung cancer
• 320 people need to be screened to prevent 1 lung cancer death
• 1339 for breast cancer
• More cancers detected at an early stage
• First time that lung cancer screening has been shown to decrease
lung cancer deaths!
• Results announced in 2010
New England Journal of Medicine August 4th, 2011

8. WHO SHOULD GET SCREENED?
• Age 55-80
• Current or former smoker
• >30 pack year smoking history
• Packs per day X years smoked
• 1 pack per day for 30 years or 2 packs per day for 15 years
• No symptoms of lung cancer
• New or changing cough
• Coughing up blood
• New or increasing shortness of breath

9. NSCLC as
one
disease
Squamous
34%
Other
11%
Adenoca
55%
Non-Small-Cell Lung Cancer: Not One
Disease, but Many!
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%

11. EVOLUTION OF THERAPY IN LUNG CANCER
• Heterogeneous disease
Traditional View
Present View
NSCLC
SCLC
Histologic Breakdown
(eg, SQ, NSQ, large cell,
adenocarcinoma)
Molecular Pathology
(eg, EGFR, ALK, ROS1) PD-L1 Expression Level
Lung
Cancer ≥50%
≥1%-49%
<1%

12. Fig. 1
Lung Cancer 2021 154161-175DOI: (10.1016/j.lungcan.2021.02.026)

13. Fig. 3
Lung Cancer 2021 154161-175DOI: (10.1016/j.lungcan.2021.02.026)
Copyright © 2021 The Authors and

14. BIOPSY: ESTABLISH DIAGNOSIS, DETERMINE
HISTOLOGIC SUBTYPE, BIOMARKER TESTING
• Histologic subtyping:
squamous or nonsquamous?[1]
• For biomarker testing:
• Primary tumors and metastatic lesions
equally suitable[2]
• Bone biopsy suboptimal due to
decalcification and degradation of DNA[2]
• Liquid biopsies (cell-free DNA in plasma) are
another option[3]
• Testing for PD-L1 expression
indicated in all NSCLC[4]
• Testing for EGFR, ALK, ROS1, BRAF
V600E, NTRK, RET, and METex14
indicated in all nonsquamous
NSCLC[4]
• Broad NGS testing encouraged to detect a
wider range of mutations using least amount
of tissue[4,5]
• For squamous NSCLC, consider testing in
young, never or light smokers, or if biopsy
specimen is small or of mixed histology[2]
• Completion of testing within 10-14 working
days of biopsy recommended[4,6]
• TAT for PD-L1 much shorter than for NGS
• Wait for results of NGS results
before acting on PD-L1 testing
results!

15. COMPARISON OF ALTERNATIVE MOLECULAR
TESTING APPROACHES
Single Gene Testing Multigene Testing (eg, by NGS)
Advantages  Potentially routine in practice
 Potential for local implementation,
rapid turnaround
 Higher sensitivity with PCR
platforms
 Minimizes use of tumor tissue
 Facilitates testing of multiple biomarkers, including
emerging biomarkers for clinical trial enrollment
 Just need to know to test vs which biomarkers to test
for
 Generally less costly than sequential testing
Limitations  Tumor tissue samples often
inadequate for multiple necessary
tests
 May lead to repeat biopsy
 Multiple platforms available using different
methodology that affect types of alterations detected
 Analysis of complex biomarker reports
 Preauthorization requirements
 May not be easily accessible in community practice
.

16. LIQUID BIOPSY
• What is liquid biopsy?
• Blood sample containing cell-free DNA
from multiple sources, including DNA
shed from tumor
• When do we use liquid biopsy?
• Molecular testing is needed but amount
of available biopsy tissue is inadequate or
unknown, or tissue biopsy not possible
• Resistance to TKIs
• Advantages
• Minimally invasive
• May overcome tumor heterogenicity
• Limitations
• Sensitivity: 70%-80%; specificity: near 100%
• Negative result is noninformative

17. APRIL 2020 TREATMENT PARADIGM FOR
MOLECULAR BIOMARKER–POSITIVE ADVANCED
NSCLC
ALK positive
Progression
EGFR mutation positive
Advanced NSCLC (molecular
biomarker positive)
ROS1 positive
Crizotinib, ceritinib,
or entrectinib
Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker
Osimertinib
EGFR T790M
mutation negative or
previous osimertinib
Alectinib, brigatinib,
ceritinib, or
lorlatinib dependent
on previous therapy
Alectinib (preferred),
brigatinib, ceritinib, or
crizotinib
Osimertinib (preferred)
erlotinib, afatinib, gefitinib, or
dacomitinib*
EGFR T790M
mutation positive
BRAF V600E
positive
Dabrafenib/
trametinib†
First
line
Second
line
and
beyond
*Afatinib, dacomitinib, erlotinib, gefitinib, osimertinib approved for EGFR exon19del, exon 21 L858R; afatinib for EGFR G719X, S768I, L861Q.
†Or as second line after CT.
Entrectinib or
larotrectinib
NTRK positive

18. WHY DOES UPFRONT TESTING MATTER?
 Only 48% of patients with advanced NSCLC
and a driver mutation received NCCN-
recommended targeted therapy1
‒ Alterations included EGFR, ALK, ROS1, BRAF,
MET, RET, ERBB2
 Patients with driver mutations who received
targeted therapy had an improved OS (18.6
vs 11.4 mo; P <.001)1
 Always give the best treatment
upfront
‒ ~30% of patients will NOT go on to receive
second-line treatment2
.
Patients with NSCLC1
(N = 1260)
First-line Therapy Received by Driver Mutation2
%
of
First-line
Therapies
Other
Therapy
52%
NCCN-
Recommended
Targeted
Therapy
48%
100
80
60
40
20
0
Other
Anti–PD-1
EGFR or ALK TKI
Nonplatinum regimen
Platinum regimen
Gene
ALK
(n = 98)
EGFR
(n = 535)
ROS1
(n = 27)
Other
(n = 2092)

19. BARRIERS TO UNIVERSAL BIOMARKER TESTING
 Not enough tissue in small
biopsies—up to 25% lack
sufficient tumor
 TAT not fast enough—
recommended <14 calendar/
10 working days from biopsy
 Poor communication—lack of
reflex testing, differing sites for
biopsy and treatment
 Who pays?
Oncology Team Members
Biomarker
Testing
Tissue
Acquisition
Turnaround
Time
Payment/
Reimbursement
Communication

20. EGFR MUTATIONAL EPIDEMIOLOGY
 Found in ~ 20% to 30% of
patients with NSCLC globally
 More common in never-
smokers, adenocarcinomas,
females, Asians
 Predominantly located in
EGFR exons 18-21
 The specific EGFR mutation
identified is important:
sensitive mutations, primary
resistance mutations, and
de novo and acquired
resistance mutations
EGFR Kinase Domain Mutations
Ligand Binding Transmembrane Tyrosine Kinase Autophosphorylation
N
N
K754R S768I*
L861Q*
A871G
L833V/
H835L/
L838V
E884K
L858R
~ 41%
Ins761 (EAFQ)/
Ins770 (ASV)/
Ins771 (G)/
Ins774 (NPH)
~ 3%
G719S*
~ 5%
E709A/
E709G
C
C
Y891
Y920
Y992
Y1045
Y1068
Y1086
Y1148
Y1173
T790M
~ 3%
EXON 18 19 20 21 22 23 24
del 747-752
and others
~ 48%
*Noncanonical EGFR mutations.

21. EGFR MUTATIONS IN NSCLC
 Exon 19 deletions and L858R mutation in exon 21
‒ ~80% of all EGFR mutations
‒ Clinically relevant as patients respond to
EGFR tyrosine kinase inhibitors
 Uncommon or atypical EGFR mutations
‒ G719X, L861Q, S7681
 EGFR exon 20 insertion mutations
‒ Inherently resistant to approved TKI
‒ Platinum-based chemotherapy remains
the recommended first-line therapy
Exon 18
~4%
Other exons
~3%
Exon 21
~41% Exon 19
~45%
Exon 20
~6%
Exon 19
mutations
- Del 19 (44.8%)
- Ins 19 (0.6%)
Exon 21
mutations
- L858R (39.8%)
- L861Q (0.9%)
Frequency of EGFR mutations

22. Parameter Erlotinib Gefitinib Afatinib Dacomitinib Osimertinib
Generation First First Second Second Third
EGFR mutations
approved for in
first-line setting
Ex19del,
Ex21 L858R
Ex19del,
Ex21 L858R
Ex18 G719X,*
Ex19del,
Ex20 S768I,*
Ex21 L858R,
Ex21 L861Q*
Ex19del,
Ex21 L858R
Ex19del,
Ex21 L858R†
EGFR binding Reversible Reversible Irreversible Irreversible Irreversible
Half life, hr 36 48 37 59-85 48
Food effect
(take on empty stomach)
Increase F from
~60% to ~100%
No change Decrease AUC
by 39%
No change No change
CNS penetration,
AUC ratio
0.03X
CSF/plasma
0.01X CSF/serum 0.02X CSF/plasma CNS activity reported 2X
brain/plasma
EGFR TKIs: Properties
*Uncommon nonresistant EGFR mutations.
†Also approved for resistant mutation T790M in second-line setting and a preferred option for EGFR G719X, S768I, L861Q per NCCN guidelines.

23. FLAURA: PFS BY CNS METASTASES AT BASELINE
 CNS progression occurred in 17 patients (6%) with osimertinib vs 42 (15%) with 1st-generation EGFR TKI
Median PFS,
Mo (95% CI)
Osimertinib (n = 53) 15.2 (12.1-21.4)
1st-Generation EGFR
TKI (n = 63)
9.6 (7.0-12.4)
HR: 0.47
(95% CI: 0.30-0.74; P <.001)
Soria. NEJM. 2018;378:113.
Patients at
Risk, n
Osimertinib
1st-Generation
EGFR TKI
53
63
51
57
40
40
37
33
22
13
9
6
4
2
0
0
32
24
1
1
Mo
Patients at Risk,
n
Osimertinib
1st-Generation
EGFR TKI
226
214
211
182
193
157
173
119
117
65
62
31
22
8
0
0
146
83
3
1
Mo
Median PFS,
Mo (95% CI)
Osimertinib (n = 226) 19.1 (15.2-23.5)
1st-Generation EGFR
TKI (n = 214)
10.9 (9.6-12.3)
HR: 0.46
(95% CI: 0.36-0.59; P <.001)
Probability
of
PFS
Probability
of
PFS
With CNS Metastases at BL (n = 116) Without CNS Metastases at BL (n = 440)
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27
Slide credit: clinicaloptions.com

24. SUMMARY OF FIRST-LINE TREATMENT APPROACHES
FOR PATIENTS WITH EGFR MUTATION–POSITIVE NSCLC
First-line: Treatment Arms PFS, Mo (HR) AE Grade ≥3, %
Erlotinib + bevacizumab
vs erlotinib2 16.0 vs 9.7 (0.54) 91 vs 53
Erlotinib + ramucirumab
vs erlotinib + placebo3 19.4 vs 12.3 (0.59) 72 vs 54
Erlotinib + bevacizumab
vs erlotinib4 16.9 vs 13.3 (0.61) 88 vs 46
Gefitinib + carboplatin/
pemetrexed vs gefitinib5 20.9 vs 11.2 (0.49) NR vs NR
Gefitinib + carboplatin/
pemetrexed vs gefitinib6 16.0 vs 8.0 (0.51) 75 vs 49.4
Afatinib vs gefitinib7 11.0 vs 10.9 (0.73) 57 vs 52
Dacomitinib vs gefitinib8 14.7 vs 9.2 (0.59) 63 vs 41
Osimertinib vs gefitinib
or erlotinib9 18.9 vs 10.2 (0.46) 34 vs 45
First-line Treatment Approach
Erlotinib + antiangiogenics
Gefitinib + carboplatin/pemetrexed
2nd-gen EGFR inhibitors
Osimertinib
Time
TOXICITY

25. ATYPICAL OR UNCOMMON EGFR MUTATIONS
3 most common point mutations:
G719X, S768I, L861Q (approved
drug: afatinib)
Exon 20 insertions: ~9% of EGFR mutations
10%-15% of EGFR-mutant NSCLC, diverse alterations, and can occur in all exons
Patients with EGFR-mutant NSCLC
Ex20ins
9.1%
Complex
atypical
9.1%
Atypical
12.6%
Ex19del
32.7%
L858R
23.0%
Classical
+T790M
11.1%
N = 11619
Classical mutations (67%)
Atypical mutations (31%)
Classical + T790m + atypical (2%)
Classical +
T790M +
atypical
2.2%
T790M
0.3%

26. TREATMENT OPTIONS FOR PATIENTS
WITH EGFR EXON 20 INSERTIONS

27. REAL-WORLD OUTCOMES IN PATIENTS WITH
EGFR EXON 20 INSERTION+ ADVANCED NSCLC
 Retrospective comparative analysis of real-world
outcomes in patients with EGFR ex20ins+
advanced NSCLC (n = 181) vs those with common
EGFR mutations (L858R or ex19del; n = 2833)
‒ Flatiron Health Database (January 2011 to
May 2020)
 75% increased risk of death with EGFR ex20ins
vs common EGFR mutations (primary endpoint)
‒ 5-yr OS: 8% vs 19%
 Secondary endpoints:
‒ 93% increased risk of progression or death
‒ 60% increased risk of shorter time to next therapy
Prognostic Value of EGFR Ex20ins vs EGFR
L858R or Ex19del: Real-World OS (N = 3014)
Patients at Risk, n
Common EGFR
EGFR ex20ins
77%
53%
36%
25%
19%
57%
33%
23%
13% 8%
0 6 12 18 24 30 36 42 48 54 60
2833
181
2245
120
1728
77
1313
53
943
30
675
22
494
16
354
11
262
6
198
5
139
3
0
25
50
75
100
Mo
Patients
(%)
Common
EGFR Mut
EGFR
Ex20ins
25.5 16.2
Median rwOS, mo
Adjusted HR: 1.75
(95% CI: 1.5-2.1; P <.0001)

28. RESISTANCE MORE CHALLENGING WITH NEWER
EGFR TKIS
*Overlap of reported resistance mechanism may occur. †n = 2 with de novo T790M mutations at BL; 1 acquired C797S at progression.
Secondary EGFR mutations†:
C797X: 7%; L718Q+C797S: 1%;
L718Q + ex20ins: 1%; S768I: 1%
HER2 amplification: 2%
HER2 mutation: 1%
MET amplification: 15%
mTOR AKT p53
BIM BCL2
PIK3CA
ERK
BRAF mutations (V600E): 3%
SPTBN1 ALK
SPTBN1-ALK: 1%
Survival
Apoptosis Proliferation
PIK3CA mutations: 7%
Candidate Acquired Resistance Mechanisms With Osimertinib*3
MEK
RAS
RAF
KRAS mutations
(G12D/C, A146T): 3%
Cell cycle gene alterations
CCND amp: 3%
CCNE1 amp: 2%
CDK4/6 amp: 5%
MET
MET
MET
MET
EGFR
EGFR
HER2
HER2
HER2
HER2
M
G2
G1
S
Small cell + MET 1%
T790M is the dominant
mechanism of resistance to
1st- and 2nd-gen EGFR TKIs‡
T790M
60%
HER2 8%
Unknown 18%
HER2 +
T790M
4%
MET amplification 3%
Small cell 1%
Small cell + T790M
2%
MET + T790M
3%
No dominant and more heterogeneous mechanisms of
resistance to 3rd-gen EGFR TKI osimertinib
Acquired Resistance Mechanisms
With Early-Gen EGFR TKIs1
‡In

29. 2022 Treatment Paradigm for Molecular Biomarker–
Positive Advanced NSCLC
Advanced NSCLC
(molecular biomarker positive)
*Osimertinib also approved as second-line therapy for EGFR T790M–positive disease after an earlier-generation EGFR TKI. †Afatinib, dacomitinib, erlotinib (alone or in
combination with ramucirumab), gefitinib, and osimertinib approved for EGFR exon19del, exon 21 L858R; erlotinib, gefitinib, and dacomitinib also options for EGFR G719X,
S768I, L861Q. ‡Or as second-line after CT. ^Crizotinib also an option for METex14 skipping mutation.
ALK
Progression
EGFR ROS1
Crizotinib
or
entrectinib
Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker (ie, chemotherapy ± immunotherapy)
Alectinib,
brigatinib, ceritinib, or lorlatinib
dependent on previous therapy
Alectinib, brigatinib,
or lorlatinib
(preferred); ceritinib,
or crizotinib‡
Osimertinib
(preferred)*,
erlotinib, afatinib,
gefitinib, or
dacomitinib†
BRAF V600E
Dabrafenib/
trametinib†
First
line
Second
line
and
beyond
Entrectinib
or
larotrectinib
NTRK
Selpercatinib
or
pralsetinib
RET
Capmatinib
or
Tepotinib^
METex14
skipping
KRAS G12C
Sotorasib
Classical
(del19 or
L858R)
Uncommon
ex20ins Uncommon
(S768I, L861Q,
G719X)
Amivantamab
or
mobocertinib
Afatinib or osimertinib
(preferred)†

30. IMMUNOTHERAPY
FOR ADVANCED NSCLC

31. Molecular and PD-L1 Testing Should Be Done at Initial
Diagnosis of Advanced NSCLC to Guide 1L Tx Decisions
Initial Diagnosis of Advanced NSCLC
Targetable
Alteration
PRESENT
No Targetable
Alteration
Matched Targeted
Therapy
PD-L1 Low (1%-49%)
or Negative (<1%)
PD-L1 High
(≥50%)
Molecular Testing and PD-L1 IHC

32. Test Approach Malignancies Clinical Outcome Association
PD-L1
Immunohistochemistry-based assessment of
the proportion of PD-L1–positive tumor cells,
immune cells, or both
Multiple tumor types Positive PD-L1 tumor status
Tumor-infiltrating
lymphocyte
Immunohistochemistry-based assessment of T-cells at
invasive tumor margin or tumor parenchyma
Melanoma; multiple
tumor types
Increased CD8+ tumor–infiltrating
lymphocyte density
T-cell receptor clonality
Involves next-generation sequencing of
T-cell receptor β chain
Melanoma
Restricted, clonal T-cell receptor
β chain
Mutational burden
Whole or targeted exome sequencing to assess
nonsynonymous somatic mutations
Melanoma, NSCLC,
bladder cancer
High mutational count
Neoantigen burden
Predicted neoantigens derived from
whole-exome sequencing data
Melanoma, NSCLC High neoantigen count
Immune gene signatures
Assessment of gene expression from the tumor
microenvironment using an automated platform
Melanoma Interferon γ or T-cell inflamed profile
Multiplex
immunohistochemistry
Direct assessment of multiple protein markers on tumor
cells and immune cells, including spatial relationships
Multiple tumor types
Physical interaction with PD-1–positive
and PD-L1–positive cells;
others likely to be determined
Gibney. Lancet Oncol. 2016:17:e542.
Currently Available Biomarker Tests

33. What Is Tumor Mutation Burden and
Is It Associated With Enhanced Clinical Benefit?

34. Mutational Burden in Various Tumor Types
Pilocytic
astrocytoma
ALL
Medulloblastoma
AML
Kidney
chromophobe
Thyroid
CLL
Neuroblastoma
Glioblastoma
Pancreas
Breast
Gliona
low
grade
Lymphoma
B-cell
Myeloma
Prostate
Ovary
Kidney
papillary
Kidney
clear
cell
Liver
Uterus
Stomach
Head
and
neck
Cervix
Colorectum
Esophagus
Melanoma
Lung
squamous
Lung
adenocarcinoma
Bladder
1000
100
10
1.0
0.001
0.01
0.1
Somatic
Mutation
Prevalence
(Number
Mutations
per
Megabase)
Lung
small
cell
Alexandrov. Nature. 2013;500:415.
Lung cancers are associated with particularly high tumor mutation burden*
*Analyzed using an algorithm developed to extract mutational signatures from catalogues of somatic mutations in 7042 primary cancers.

35. High Tumor Mutation Burden May Influence
Immune-Mediated Antitumor Response
Tumor cells with
high TMB…[1,2]
…may have high
neoantigen load…[1,2]
…which can lead to
increased immune and
antitumor response[2-5]
1. Schumacher. Science. 2015;348:69. 2. Kim. Ann Oncol. 2016;27:1492. 3. Liontos. Ann Transl Med.
2016;4:264. 4. Sharma. Science. 2015;348:56. 5. Giannakis. Cell Rep. 2016;15:857.
The hypothesis that high TMB increases the
immunogenicity of tumors makes them a rational
target for treatment with I-O therapies[1,2]

36. 2022 Paradigm for Immunotherapy in
Advanced NSCLC Without an Actionable Mutation
 ICI monotherapy: pembrolizumab,*
atezolizumab, cemiplimab
 ICI + chemotherapy
‒ Pembrolizumab/carboplatin or
cisplatin/pemetrexed (Nsq)
‒ Atezolizumab/carboplatin/paclitaxel/
bevacizumab (Nsq)
‒ Atezolizumab/carboplatin/nab-paclitaxel (Nsq)
‒ Pembrolizumab/carboplatin/taxane (Sq)
‒ Nivolumab/ipilimumab + 2 cycles of CT (Sq/Nsq)
 ICI combination: nivolumab/ipilimumab
NCCN. Clinical practice guidelines in oncology: NSCLC. v.3.2022. nccn.org.
Advanced NSCLC w/o
Actionable Mutation
PD-1/PD-L1i
PD-1/PD-L1i +
Chemotherapy
PD-1i + CTLA-4i +
Chemotherapy
PD-1i + CTLA-4i
PD-1/PD-L1i +
Chemotherapy
PD-1i + CTLA-4i +
Chemotherapy
PD-1i + CTLA-4i
PD-1/PD-L1i +
Chemotherapy
PD-1i + CTLA-4i +
Chemotherapy
PD-1i + CTLA-4i†
PD-L1 1%-49%*
PD-L1 ≥50% PD-L1 <1%
*Single-agent pembrolizumab also approved for ≥1% PD-L1 but not broadly recommended by experts; guideline-recommended
for PD-L1 1-49% if poor PS or contraindications to combining w/CT. †Not an FDA approved indication, but guideline recommended.
Current first-line treatment paradigm
based on PD-L1 expression in TC and/or IC
Updated

37. CheckMate-026: Nivolumab vs Chemotherapy in
First-line Therapy for Advanced NSCLC With PD-L1 ≥ 1%
 Primary endpoint: PFS (≥ 5% PD-L1+) by BICR
 Secondary endpoints: PFS (≥ 1% PD-L1+), ORR, OS, and safety
Patients with stage IV NSCLC and ECOG
PS 0/1, no previous systemic therapy for
advanced disease, brain metastases
permitted if adequately treated, no
actionable EGFR/ALK mutations,
and PD-L1 ≥ 1%*
(N = 541)
Nivolumab
3 mg/kg IV Q2W
(n = 271)
Chemotherapy IV Q3W
(histology dependent) for up to 6 cycles
(n = 270)
Stratified by PD-L1 expression
(< 5% vs ≥ 5%), histology (squamous
vs nonsquamous)
Carbone. NEJM. 2017;376:2415.
Until PD or unacceptable
toxicity
Until PD (crossover to
nivolumab allowed)
*≥ 1% tumor cell staining using 28-8 antibody IHC assay by centralized laboratory.

38. CheckMate-026: Nivolumab vs Chemotherapy in
First-line Therapy for Advanced NSCLC With PD-L1 ≥ 1%
 Primary endpoint: PFS (≥ 5% PD-L1+) by BICR
 Secondary endpoints: PFS (≥ 1% PD-L1+), ORR, OS, and safety
Patients with stage IV NSCLC and ECOG
PS 0/1, no previous systemic therapy for
advanced disease, brain metastases
permitted if adequately treated, no
actionable EGFR/ALK mutations,
and PD-L1 ≥ 1%*
(N = 541)
Nivolumab
3 mg/kg IV Q2W
(n = 271)
Chemotherapy IV Q3W
(histology dependent) for up to 6 cycles
(n = 270)
Stratified by PD-L1 expression
(< 5% vs ≥ 5%), histology (squamous
vs nonsquamous)
Carbone. NEJM. 2017;376:2415.
Until PD or unacceptable
toxicity
Until PD (crossover to
nivolumab allowed)
*≥ 1% tumor cell staining using 28-8 antibody IHC assay by centralized laboratory.

39. Peters. AACR 2017. Abstr CT082. Carbone. NEJM. 2017:376:2415.
High TMB Nivolumab Arm
CheckMate 026: PFS With Nivolumab vs Chemo by
TMB and PD-L1 Expression
 DiscordantoutcomesinTMB high/PD-L1highvsTMB high/PD-L1 low
100
80
60
40
20
0
PFS
(%)
0 3 6 9 12 15 18 21
Mos
Nivolumab
(n = 47)
9.7
(5.1-NR)
Chemotherapy
(n = 60)
5.8
(4.2-8.5)
Median PFS, mos
(95% CI)
HR: 0.62 (95% CI: 0.38-1.00)
Nivolumab
Chemotherapy
100
80
60
40
20
0
PFS
(%)
0 3 6 9 12 15 18 21
Mos
24
High TMB,
PD-L1 1% to 49%
High TMB,
PD-L1 ≥ 50%
Low/medium TMB,
PD-L1 1% to 49%
Low/medium TMB,
PD-L1 ≥ 50%

40.  Responses enriched in patients whose
tumors had both high TMB and high PD-L1
expression
1L, 2L mUC (IMvigor210, IMvigor211)
n = 86 n = 26 n = 44
TMB-H
IC2/3
2L NSCLC (OAK)
n = 45 n = 16 n = 24
TMB-H
IC2/3 or TC2/3
PD-L1 Status TMB*
ORR, % (n/N)
2L NSCLC
1L,* 2L
mUC
IC0/1 or
IC/TC0/1
TMB-L
< 16 mut/Mb
9
(9/95)
12
(29/244)
IC2/3 or
IC/TC2/3
TMB-L
< 16 mut/Mb
20
(9/45)
27
(23/86)
IC0/1 or
IC/TC0/1
TMB-H
≥ 16 mut/Mb
8
(2/24)
25
(11/44)
IC2/3 or
IC/TC2/3
TMB-H
≥ 16 mut/Mb
38
(6/16)
50
(13/26)
Legrand. ASCO 2018. Abstr 12000.
*Cisplatin ineligible.
Tissue TMB ≥ 16 mut/Mb Identifies a Patient Population
Distinct From PD-L1 IHC

41. POSITIVE FIRST-LINE ADVANCED NSCLC
IMMUNOTHERAPY TRIALS: AN EVER-GROWING LIST
4
Trial Comparison Selection ORR, % PFS HR OS HR
KEYNOTE-0241-3 Pembro vs plt-doublet CT PD-L1 ≥50% 46.1 vs 31.1 0.50 0.62
IMpower1104,5 Atezo vs plt-doublet CT PD-L1 ≥50% (TC) or 10% (IC) 38.3 vs 28.6 0.63 0.59
EMPOWER-Lung 16 Cemiplimab vs plt-doublet CT PD-L1 ≥50% 39.2 vs 20.4 0.54 0.57
KEYNOTE-0427,8 Pembro vs plt-doublet CT PD-L1 ≥1% 27.3 vs 26.7 1.05 0.80
KEYNOTE-1899,10 Pembro or placebo + carbo/pem PD-L1 unselected; nonsquamous 48.3 vs 19.9 0.49 0.56
IMpower13011 Atezo + carbo/nab-pac vs CT alone PD-L1 unselected; nonsquamous 49.2 vs 31.9 0.64 0.79
IMpower15012,13 Atezo + carbo/pac + bev vs CT + bev PD-L1 unselected; nonsquamous 63.5 vs 48.0 0.62 0.80
KEYNOTE-40714-16 Pembro or placebo + carbo/pac or nab-pac PD-L1 unselected; squamous 62.6 vs 38.8 0.59 0.71
EMPOWER-Lung 317 Cemiplimab or placebo + plt-doublet CT PD-L1 unselected 43.3 vs 22.7 0.56 0.71
CheckMate 22718-20 Nivo + ipi vs plt-doublet CT
TMB high (≥10 mut/Mb) 45.3 vs 26.9 0.58 NR
PD-L1 ≥1% 36.4 vs 30.0 0.81 0.76
PD-L1 <1% 27.3 vs 23.1 0.74 0.64
CheckMate 9LA21,22 Nivo + ipi + plt-doublet CT vs plt-doublet CT PD-L1 unselected 38.0 vs 25.4 0.67 0.72
1.