Maria Arcila, MD, Zofia Piotrowska, MD, and Joshua Bauml, MD, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC/CC activity titled “New Horizons in EGFR-Mutated NSCLC: Broadening the Impact of Precision Testing in the Context of an Expanding Treatment Landscape.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/CC information, and to apply for credit, please visit us at https://bit.ly/3kH1ygr. CME/MOC/CC credit will be available until January 25, 2022.

1. Therapies for EGFR-Mutated NSCLC
Current Approvals and Indications1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
1. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications.
First-Generation
Reversible EGFR TKIs
Third-Generation
Irreversible EGFR TKI
Third-Generation
Irreversible EGFR TKI
Osimertinib
Osimertinib
EGFR TKI + VEGFR2
Antagonist
Erlotinib + Ramucirumab
Second-Generation
Irreversible EGFR TKIs
Gefitinib Erlotinib
Metastatic
Early Stage
Afatinib Dacomitinib
• 1L for EGFR exon 19
deletions or L858R
mutations
• 1L for EGFR exon 19 deletions or L858R mutations
• Treatment of T790M-positive NSCLC with progression
on or after EGFR TKI therapy
• 1L for EGFR exon 19 deletions or L858R mutations
• Adjuvant therapy after tumor resection in patients with stage IB-IIIA NSCLC
whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations
• 1L for EGFR exon 19
deletions or L858R
mutations
• 1L for EGFR exon 19
deletions or L858R, S768I,
L861Q, and/or G719X
mutations
• 1L for EGFR exon 19
deletions or L858R
mutations

2. Molecular Testing Guidelines for NSCLC
Latest Updates, Best Practices, and Patient-Reported Insights1
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/CWE40
Why Test Lung Cancer Patients for Genomic Alterations?
• Genomic alterations are common in nonsquamous NSCLC (approximately 50%)
• Targeted therapies produce better treatment outcomes (eg, higher response rates, improved quality of life) compared
with chemotherapy as treatment of NSCLC with genomic alterations
• Immunotherapy has low efficacy and a high risk of serious adverse events in patients with NSCLC with molecular
driver alterations
Which Molecular Targets Are Relevant for Testing in NSCLC?
Genotypes with emerging
targeted therapies
q EGFR exon 20 mutations
q HER2 mutations
q KRAS G12C mutations
q MET amplifications
q Many other promising targets with
matched therapies are undergoing
investigation in trials
Genotypes with approved
targeted therapies
q EGFR mutations
q ALK rearrangements
q ROS1 rearrangements
q BRAF V600E mutations
q NTRK fusions
q MET exon 14 skipping mutations
q RET fusions
Molecular alterations to test for in patients
with newly diagnosed stage IV NSCLC
Molecular alterations to test for in patients with resectable stage IB-IIIA NSCLC
• EGFR mutations (exon 19 deletions or exon 21 L858R mutations)
The specific genes covered vary by assay; therefore, it is important to know which
genes/alterations are covered by each assay
Which Molecular Testing Techniques Should Be Used for Detection
of Different Molecular Alterations in NSCLC?1
++: Highest sensitivity +: Lower sensitivity (higher chance of false negative) –: Not useful
Tissue PCR
sequencing
Tissue allele–specific
PCR sequencing
Tissue FISH
Tissue IHC
Tissue NGS
ctDNA PCR
ctDNA NGS
Tissue RNA
EGFR
(Sensitizing
andT790M)
+
++
–
–
++
+
+
+
HER2
Mutation
+
++
–
–
++
+
+
+
MET
Exon 14
Mutation
–
++
–
–
++
+
+
++
BRAF
Mutation
+
++
–
–
++
+
+
+
KRAS
Mutation
+
++
–
–
++
+
+
+
ALK
Rearrangement
–
–
++
++
+
+
+
++
ROS1
Rearrangement
–
–
++
–
+
–
+
++
MET
Amplification
–
–
++
–
+
–
+
+
RET
Rearrangement
–
–
++
–
+
+
+
++
PD-L1 Protein
Expression
–
–
–
++
–
–
–
–
NTRK
Fusion
–
–
++
+
+
–
+
++

3. Molecular Testing Guidelines for NSCLC
Latest Updates, Best Practices, and Patient-Reported Insights1
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/CWE40
• NCCN guidelines recommend plasma-based testing for all patients with advanced-stage,
treatment-naïve lung cancer for whom tissue sampling may be infeasible or insufficient
• Recent studies found that simultaneously adding plasma ctDNA analysis to tissue testing
enhanced the chances of detecting a relevant actionable mutation
• Based on these findings, it is reasonable to consider plasma-based testing for every patient with
advanced-stage, treatment-naïve lung cancer who has a tissue biopsy
• A new tissue biopsy and/or ctDNA plasma test also needs to occur when patients with
genotype-directed NSCLC develop resistance/disease progression while on targeted TKI therapy
75%
more actionable
mutations found
with tissue +
plasma vs
tissue alone
When Should Liquid Biopsies Be Considered for Use?
Use liquid biopsy when
• Biopsy is insufficient
• Biopsy is not feasible
• cfDNA is a more suitable
sample than biopsy
Timing considerations
Benefits
ü Minimally invasive, highly
accessible
ü Multiple sampling easy:
enables real-time monitoring
ü Systemic approach: may
effectively capture tumor
heterogeneity
cfDNA
Plasma Body
Fluids
Screening Diagnosis
Staging and
prognosis
Therapy
selection
Monitoring

4. Molecular Testing Guidelines for NSCLC
Latest Updates, Best Practices, and Patient-Reported Insights1
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/CWE40
a
Patient self-reported data obtained from GO2
Foundation for Lung Cancer's 1-800 help line. Population comprised mostly of US-based patients (approx. 95%) and includes those being treated at
community cancer centers and academic centers.
1. https://www.uptodate.com/contents/personalized-genotype-directed-therapy-for-advanced-non-small-cell-lung-cancer. 2. Provided courtesy of GO2
Foundation for Lung Cancer.
Molecular Testing/Biomarker Testing
I don't know if the cancer was tested
The cancer was not tested
The cancer was tested and I know the results
The cancer was tested and I don't know the results
Total
2018, %
(n)
27.21
(151)
12.25
(68)
48.11
(267)
12.43
(69)
100
(555)
2019, %
(n)
21.22
(222)
10.13
(106)
56.12
(587)
12.52
(131)
21.22
(1,046)
2020 (Q1-Q3), %
(n)
21.75
(122)
10.16
(57)
58.65
(329)
100
(561)
9.45
(53)
Real-World, Patient-Reported Biomarker Data2,a
Why should patients be educated about the
importance of molecular testing and informed
about their results?
Shortcomings exist in current molecular
testing rates as well as patient awareness
about testing and their testing results

5. Addressing Unmet Needs and Improving Outcomes in Early-Stage NSCLC
New Role for Adjuvant EGFR-Targeted Therapy1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
• About 30% of patients with NSCLC present with resectable
disease at diagnosis1-3
• Surgery with curative intent is the primary treatment for these
patients4
• Adjuvant cisplatin-based chemotherapy is recommended for
patients with resectable stage II-IIIA NSCLC and select patients
with stage IB disease5
• Adjuvant impact depends on stage, and there is much room
for improvement6
• Rates of disease recurrence following surgery remain high across
disease stages, regardless of postoperative chemotherapy use7
On December 18, 2020, the FDA approved osimertinib
for adjuvant therapy after tumor resection in patients
with NSCLC whose tumors have EGFR exon 19 deletions
or exon 21 L858R mutations, as detected by an
FDA-approved test
New
Approval
NSCLC 5-Year Overall Survival
Stage I (IB) Stage II Stage III
CALGB
JBR.10
ALPI
IALT
ANITA
LACE
34 57 9
30 7 63
36 60 4
33 65 2
36 60
33 64 3
32 45 23
53 32 15
53 43 4
43 39 18
51 39 10
76 19 5
55 30 15
51 26
61 26 13
23
4
Death (%) with/without chemotherapy
Survival without chemotherapy
Survival due to chemotherapy
Death due to chemotherapy
Localized/early stage
Stage IB Stage II Stage IIIA
Regional/locally advanced

6. Addressing Unmet Needs and Improving Outcomes in Early-Stage NSCLC
New Role for Adjuvant EGFR-Targeted Therapy1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
ADAURA: Phase 3 Double-Blind Studya
DFS According to Investigator Assessment10
Patients with completely resected stageb
IB, II, IIIA NSCLC, with or without adjuvant chemoc
Stage I to IIA Disease Stage IB to IIIA Disease
• EGFR TKIs are standard of care for patients with EGFRmut advanced NSCLC
• Previous studies have suggested there may be a role for EGFR TKIs in the resected setting, but results have been inconclusive8,9
• ADAURA: Based on efficacy and safety data, and the new FDA approval, adjuvant osimertinib represents a big opportunity to improve outcomes in more patients
with early-stage NSCLC10
• ≥18 y (Japan/Taiwan, ≥20 y)
• WHO PS 0/1
• Confirmed primary nonsquamous NSCLC
• Ex19del/L858Rd
• Brain imaging, if not completed
preoperatively
• Complete resection with negative marginse
• Maximum interval between surgery and
randomization: 10 wk without adjuvant
chemo; 26 wk with adjuvant chemo
• At 24 mo, 90% of patients treated with osimertinib (95% CI, 84-93) and 44%
of patients treated with placebo (95% CI, 37-51) were alive and disease free
• HR = 0.17; 99.06% CI, 0.11-0.26; P < .001; 83% reduction in risk of disease
recurrence or death
• In the overall population, 89% of patients treated with osimertinib (95% CI, 85-92)
and 52% of patients treated with placebo (95% CI, 46-58) were alive and disease free
at 24 mo
• HR = 0.20; 99.12% CI, 0.11-0.26; P < .001; 80% reduction in risk of disease
recurrence or death
• Primary endpoints: DFS by investigator assessment in stage II/IIIA patients; designed for superiority under the assumed DFS HR of 0.70
• Secondary endpoints: DFS in the overall population;f
DFS at 2, 3, 4, and 5 years; OS; safety; QoL
Osimertinib
90% DFS
Placebo
44% DFS
Stratified by
• Stage (IB vs II vs IIIA)
• EGFRmut (ex19del
vs L858R)
• Race (Asian
vs non-Asian)
Planned treatment duration: 3 y
Treatment continues until
• Disease recurrence
• Treatment completed
• Discontinuation criteria met
Follow-up
• Until recurrence: wk 12 and 24,
then every 24 wk to 5 y, then yearly
• After recurrence: every 24 wk for
5 y, then yearly
Patients
Osimertinib
80 mg, once daily
Placebo
once daily
Osimertinib
89% DFS
Placebo
52% DFS
1:1 randomization

7. Addressing Unmet Needs and Improving Outcomes in Early-Stage NSCLC
New Role for Adjuvant EGFR-Targeted Therapy1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
a
NCT0251106; ADAURA data cutoff: January 17, 2020. b
AJCC, 7th edition. c
Prior, post, and planned radiotherapy was not allowed. d
Centrally confirmed in tissue. e
Patients received a CT after resection and within 28 days before treatment. f
Stage IB/II/IIIA.
1. Datta D, Lahiri B. Chest. 2003;123:2096-2103. 2. Le Chevalier T. Ann Oncol. 2010;21(suppl 7):vii196-vii198. 3. Cagle PT et al. Arch Pathol Lab Med. 2013;137:1191-1198. 4. Chansky K et al. J Thorac Oncol. 2017;12:1109-1121. 5. Postmus PE et al. Ann Oncol. 2017;28(suppl 4):iv1-iv21.
6. Kris MG et al. J Clin Oncol. 2017;35:2960-2974. 7. Pignon J et al. J Clin Oncol. 2008;26:3552-3559. 8. Wu Y-L et al. J Clin Oncol. 2020;38(suppl 15):9005. 9. Huang Q et al. Chest. 2016;149:1384-1392. 10. Wu Y et al. N Engl J Med. 2020;383:825-835.
Subgroup HR 95% CI
Overall (N = 682)
Stratified log-rank
Unadjusted Cox PH
0.21
0.20
0.16 -0.28
0.14 -0.29
Sex
Male (n = 204)
Female (n = 478)
0.21
0.20
0.11 -0.38
0.12 -0.30
Age
<65 y (n = 380)
≥65 y (n = 302)
0.18
0.24
0.10 -0.28
0.14 -0.38
Smoking status
Smoker (n = 194)
Nonsmoker (n = 488)
0.14
0.23
0.06 -0.27
0.15 -0.34
Race
Asian (n = 434)
Non-Asian (n = 248)
0.22
0.17
0.14 -0.33
0.08 -0.31
Stage
Stage IB (n = 212)
Stage II (n = 236)
Stage IIIA (n = 234)
0.50
0.17
0.12
0.25 -0.96
0.08 -0.31
0.07 -0.20
EGFRmut
Exon 19 deletion (n = 378)
L858R (n = 304)
0.12
0.35
0.07 -0.20
0.21 -0.55
Adjuvant chemo
Yes (n = 378)
No (n = 304)
0.18
0.23
0.11 -0.29
0.13 -0.38
0.01 0.1 1
Favors osimertinib Favors placebo
HR for DFS (95% CI)
Safety profile was consistent with the established safety profile
of osimertinib, with mild EGFR TKI class effects reported
Consistent improvement in DFS was seen regardless of whether
patients received prior adjuvant chemotherapy
0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30 36 42 48 56
Probability
of
DFS
Time, mo
0
0.2
0.4
0.6
0.8
0 6 12 18 24 30 36 42 48
Probability
of
DFS
Time, mo
Osimertinib
Placebo HR = 0.16 (95%CI, 0.10-0.26)
Osimertinib
Placebo HR = 0.23 (95%CI, 0.13-0.40)
Osimertinib (N = 337), N (%) Placebo (N = 343), N (%)
Adverse Event Any Grade Grade 1 Grade 2 Grade 3 Any Grade Grade 1 Grade 2 Grade 3
Diarrhea 156 (46) 116 (34) 32 (19) 8 (2) 68 (20) 54 (16) 13 (4) 1 (<1)
Paronychia 85 (25) 31 (9) 50 (15) 3 (1) 5 (1) 3 (1) 2 (1) 0
Dry skin 79 (23) 75 (22) 3 (1) 1 (<1) 22 (6) 18 (5) 4 (1) 0
Pruritus 65 (19) 49 (15) 16 (5) 0 30 (9) 28 (8) 2 (1) 0
Cough 62 (18) 43 (13) 19 (6) 0 57 (17) 42 (12) 15 (4) 0
Stomatitis 59 (18) 35 (10) 18 (5) 6 (2) 14 (4) 10 (3) 4 (1) 0
Nasopharyngitis 47 (14) 30 (9) 17 (5) 0 35 (10) 25 (7) 10 (3) 0
Upper respiratory infection 45 (13) 24 (7) 19 (6) 2 (1) 35 (10) 19 (6) 16 (5) 0
Decreased appetite 44 (13) 29 (9) 13 (4) 2 (1) 13 (4) 9 (3) 4 (1) 0
Mouth ulceration 39 (12)
37 (11)
32 (9) 7 (2) 0 8 (2) 6 (2) 2 (1) 0
Dermatitis acneiform 29 (9) 8 (2) 0 16 (5) 12 (3) 4 (1) 0
1.0
Adverse Events10
DFS by Investigator ± Adjuvant Chemo10
CNS DFS by Investigator in the Overall Population10
Subgroup Analysis of DFS by Investigator10
Osimertinib DFS benefit was observed across all predefined subgroups Osimertinib was associated with fewer local/regional and distant
relapses, with a lower incidence of metastatic disease in patients with
recurrence, including fewer CNS recurrence events
HR = 0.18 (95% CI, 0.10-0.33; P < .0001)
Adjuvant osimertinib
demonstrated a clinically
meaningful improvement in
CNS DFS compared
with placebo
82%
reduction
in CNS DFS
Adjuvant osimertinib
is the first targeted agent
to show a statistically
significant and clinically
meaningful improvement
in DFS in patients with
stage IB/II/IIIA EGFRmut
NSLC10

8. The Emerging Role of EGFR Exon 20 Insertions in NSCLC
A New Era of Targeted Therapy
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
Impact of Deletions and Insertions on EGFR Activation1,2
Incidence of EGFR Exon 20 Insertions in NSCLC1-3
• EGFR exon 20 insertion mutations represent the third most common EGFR mutation in NSCLC1
• First- and second-generation EGFR TKIs have limited efficacy in patients with NSCLC harboring EGFR exon 20 insertions1
• Advances with EGFR TKIs and bispecific antibodies may establish a new standard of care in NSCLC for patients with EGFR exon 20 insertions1
WT EGFR WT EGFR
Exon 19 Deletion Exon 20 Insertion
Deletions
Insertions
“C-helix
in”
“C-helix
out”
Inactive Active
Active Active
β3
β3
β3
β4
β4
β4
β3
β4
• Insertions: 6%
• S768I: 1%
• T790M (de novo): 5%
EGFR
1.7%
D761-E762
insX
“Classical” EGFR mutations
Exon 19 deletions L858R
Extracellular
domain
Trans-
membrane
domain
Tyrosine kinase
domain
I/II III/IV
Exon
18
Exon
19
Exon
20
Exon
21
Exon
22
Exon
23
Exon 20 insertions
C-helix Loop following C-helix
762
E
763
A
764
Y
765
V
766
M
767
A
768
S
769
V
770
D
771
N
772
P
773
H
774
V
775
C
A763-Y764
insX
Y764-V765
insX
V765-M766
insX
A767-S768
insX
S768-V769
insX
V769-D770
insX
D770
N771
insX
N771-P772
insX
P772-H773
insX
H773-V774
insX
V774-C775
insX
4.6%
0.3%
0.3%
1.4%
0.9%
5.4%
8.3%
22.6%
4.3%
Percentage
of
Total
Exon
20
EGFR
Insertions
(n
=
349)
761
D
24.6%
25.5%
• 4%-10% of all EGFR-mutant NSCLC
- This could be limited by testing type
• First/second-generation EGFR TKIs have
limited activity
- Erlotinib/gefitinib: mPFS, 1.5-2 mo
- Afatinib: mPFS, 2.9 mo
• Worse prognosis than other types
of EGFR-mutant NSCLC
Exon 18
3%
Exon 19
45%
Exon 21
42%
Exon 20
10%

9. The Emerging Role of EGFR Exon 20 Insertions in NSCLC
A New Era of Targeted Therapy
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
Emerging Treatment Strategies for NSCLC With EGFR Exon 20 Insertions1
Amivantamab
Osimertinib Mobocertinib
Tarloxotinib Poziotinib
CLN-081a
EGFR/MET bispecific antibody
Third-generation EGFR TKI EGFR/HER2 exon 20ins TKI
EGFR/HER2/HER4 TKI
Pan-EGFR-mutation TKI
Hypoxia-activated EGFR TKI
C-lobe
Exon 20
insertions
Exon 19
deletions
Gly719
A-loop
Leu858
Leu861
N-lobe
EGFR

10. The Emerging Role of EGFR Exon 20 Insertions in NSCLC
A New Era of Targeted Therapy
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
a
Other name: TAS6417.
1. Remon J et al. Cancer Treat Rev. 2020;90:102105. 2. Vyse S, Huang PH. Signal Transduct Target Ther. 2019;4:5. 3. Le X et al. 2020 American Association for Cancer Research Annual Meeting (AACR 2020). Abstract CT081. 4. Socinski M et al. European Society for Medical Oncology
Congress 2020 (ESMO 2020). Abstract LBA60. 5. Riely G et al. ESMO 2020. Abstract 1261MO. 6. Park K et al. 2020 American Society of Clinical Oncology Annual Meeting (ASCO 2020). Abstract 9512. 7. Piotrowska Z et al. ASCO 2020. Abstract 9513. 8. Piotrowska Z et al. ESMO 2020.
Abstract 1345P. 9. Liu S et al. ESMO 2020. Abstract LBA61. 10. Hamilton EP et al. ASCO 2020. Abstract TPS3665.
Overview of Emerging Targeted Therapies for NSCLC With EGFR Exon 20 Mutations
Drug MOA n ORR mPFS Major Toxicities
Dose
Reduction
Discontinuation
Due to Toxicity
FDA BT
Therapy
Poziotinib3,4
TKI 115 15% 4.2 mo
82% diarrhea; 26% gr 3+
68% rash; 30% gr 3+
78% 12% –
Mobocertinib5
(TAK-788)
TKI 28 43% 7.3 mo
88% diarrhea; 22% gr 3+
25% rash; 1% gr 3+
49% nausea; 4% gr 3+
NR NR
Amivantamab6
(JNJ-372)
EGFR/
MET Ab
39 36%
8.3 mo
(95% CI,
3.0-14.8)
72% rash; 0% gr3
60% infusion reaction
34% paronychia
10% 6%
Osimertinib7
TKI 17 24% 9.6 mo
76% diarrhea; 0% gr 3+
38% rash; 0% gr 3+
10% gr 3+ plts,
10% gr 3+ QTc
NR 1/17 –
CLN-0818
TKI 22
35%
(uncon-
firmed)
NR
60% rash; 0% gr 3+
13% stomatitis, 0% gr 3
9% 0% –
Tarloxotinib9
Hypoxia-
activated
TKI
11 0% –
61% QTc prolonged; 35% gr 3+
43% rash; 4% gr 3+
21% diarrhea; 4% gr 3+
5/23 (22%) 1/23 (4%) –
BDTX-18910
Oral
allosteric
ErbB
inhibitor
Phase 1 study ongoing (NCT04209465)
Targeted
Therapies
for EGFR
Exon 20
Insertions
Other Emerging
Therapies
for EGFR
Exon 20
Insertions