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Advanced EGFRMutation-Positive NSCLCExpert Insights into the Top Questions Regarding Optimal Strategies for Tailoring Therapy and Improving Patient Outcomes
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1) Review the molecular pathology of advanced lung cancer and examine its relevance for clinical practice.
2) Appraise the safety and efficacy of first-line therapies for advanced NSCLC, including chemotherapy, first- and second-generation EGFR TKIs.
Learning Objectives
3) Evaluate treatment approaches used to overcome EGFR resistance in advanced NSCLC, including the safety and efficacy of second- and third-line therapies.
4) Differentiate recommended molecular testing and role for ctDNA in detecting EGFR mutations, including T790M.
Learning Objectives (cont.)
Lung CancerOverview
Lung CancerIncidence and Mortality
Bender E. Nature. 2014; Gridelli C, et al. Nat Rev Dis Primers. 2015; Hirsch FR, et al. Lancet. 2016.
• 1.8 million people are diagnosed and 1.6 million die annually• 5-year survival varies from 4% to 17% (17.8% in the US)
Lung CancerClassification
Lung Cancer
Small-Cell Lung Cancer 15%
Non-Small Cell Lung Cancer85%
Squamous 30%
Non-squamous70%
Large-Cell Carcinoma (10%)• Large-cell Neuroendocrine
Carcinoma
Adenocarcinoma (90%)• Mixed subtypes• Lepidic (non-mucinous or
mucinous)• Acinar• Papillary• Micropapillary• Solid
Gridelli C, et al. Nat Rev Dis Primers. 2015.
What is the clinical relevance of lung cancer molecular pathology, genomic alterations, and aberrant molecular
signaling pathways?
Lung AdenocarcinomaMutation Frequencies
Hirsch FR, et al. Lancet. 2016.
EGFR-sensitizing, 17%
ALK, 7%
EGFR other, 4%
MET, 3%
>1 mutation, 3%
HER2, 2%
ROS1, 2%
BRAF, 2%RET, 2%
NTRK1, 1%
PIK3CA, 1%MEK1, 1%
Unknown oncogenic driver detected, 31%
KRAS, 25%
Lung AdenocarcinomaWorldwide Incidence of EGFR Mutations
Tan DS, et al. J Clin Oncol. 2016.
Scaltriti M, Baselga J. Clin Cancer Res. 2006.
EGFR PathwayModel for Targeted Therapy
Costa DB. Transl Lung Cancer Res. 2016.
EGFR GeneMutation Frequencies
exon 20 insertion13%
G719X6%
L881Q3%
S768I3% EGFR rearrangement
0.3%exon 19
insertion0.2%
exon 18-25 duplication (KDD)
0.2%
Exon 19 deletion
44%
L858R31%
Sheikine Y, et al. Clin Lung Cancer. 2016; *NCCN Guidelines Version 5.2017.
EGFR Mutation TestingSummary of GuidelinesWhy test? • To select patients who are likely to benefit from EGFR TKIs
Which tumors to test? • Any tumor with adenocarcinoma component or NSCLC NOS
When to test?
• At diagnosis: TNM stage IV disease (consider TNM stage I-III disease)• At recurrence/progression: TNM stage I-III disease, not previously
tested; and prior to changing therapy, to determine mechanism of acquired resistance
What to test?
• Primary tumors or metastatic lesions o T790M testing: if tissue biopsy is not feasible, plasma biopsy
should be considered* • Formalin-fixed, paraffin-embedded; or fresh, frozen or alcohol-fixed
specimens (decalcifying solutions should be avoided)• Cytologic specimens are acceptable
How fast should test results be available?
• Test results should be made available within 10 business days of receiving the specimen in the laboratory
How to test?
• Must be able to detect mutations in specimens with >50% cancer cell content
• Testing assay should be able to detect all individual mutations that have been reported with a frequency of >1% of EGFR-mutated adenocarcinomas
• IHC, FISH, and CISH are not recommended
Rocco G, et al. Int J Biochem Cell Biol. 2016; NCCN Guidelines Version 5.2017.
Afatinib, erlotinib, gefitinib
Osimertinib for T790M+
Chemotherapy
First-line
Second-line
Third-line
EGFRm+ NSCLCCurrent Treatment Algorithm
EGFRm+ NSCLCFirst-Line Therapy
Capelletto E, et al. Future Oncol. 2014.
First-Line TherapyTherapeutic Plateau of Chemotherapy
Study RegimenPatients
(n)ORR (%)
Median OS(95% CI); months
1 Year Survival(95% CI); %
ECOG 1594
Cis/pacli 135 mg/m2 288 21 7.8 (7.0-8.9) 31 (26-36)
Cis/gem 288 22 8.1 (7.2-9.4) 36 (31-42)
Cis/doce 289 17 7.4 (6.6-8.8) 31 (26-36)
Carbo/pacli 225 mg/m2 290 17 8.1 (7.0-9.5) 34 (29-40)
ILCP
Cis/vnr 201 30 9.5 (8.3-11.0) 37 (NR)
Cis/gem 205 30 9.8 (8.6-11.2) 37 (NR)
Carbo/pacli 225 mg/m2 201 32 10.0 (9.0-12.5) 43 (NR)
TAX 326
Cis/vnr 404 25 10.1 (9.0-11.3) 41 (35-46)
Cis/doce 408 32 11.3 (10.1-12.4) 46 (42-51)
Carbo/doce 406 24 9.4 (8.7-10.6) 38 (33-43)
Cis = Cisplatin; Pacli= Paclitaxel; Gem = Gemcitabine; Doce = Docetaxel; vnr = venrelibine
Sebastian M, et al. Eur Respir Rev. 2014.
EGFRm+ NSCLCEGFR TKIs vs Chemotherapy Trials
Trial Treatment Mutations PFS ORR (%)
NEJ002n=114
Gefitinibvs Carbo/Pac
EGFRm (absence of T790M)
10.8 months vs 5.4 months P<.001
74 vs 31P<.001
WJTOG3405n=51
Gefitinibvs Cis/Doc
Del19 & L8585R8.4 months vs 5.3
months P<.0001
62 vs 32P<.0001
IPASSn=132
Gefitinibvs Carbo/Pac
No EGFR status required
9.5 months vs 6.3 months P<.001
71 vs 47P<.001
EURTACn=86
Erlotinibvs standard chemo
Del19 or L858R9.7 months vs 5.2
months P<.0001
58 vs 15P value not reported
OPTIMALn=82
Erlotinibvs standard chemo
Del19 or L868R13.1 months vs 4.6
monthsP<.0001
83 vs 36P<.0001
Carbo = Carboplatin; Pac = Paclitaxel; Doc = Docetaxel
EGFRm+ NSCLC (cont.)EGFR TKIs vs Chemotherapy Trials
Sebastian M, et al. Eur Respir Rev. 2014.
Trial Treatment Mutations PFS ORR (%)
ENSUREn=110
Erlotinib vs Cis/Gem Del19 or L868R
11 months vs 5.6 months†P<.0001
63 vs 34†P=.0001
11 months vs 5.5 monthsP<.0001
LUX-LUNG 3n=230
Afatinib vs Cis/Pem EGFR mutation
positive
11.1 months vs 6.9 months†P=.001
56 vs 23†P=.001
11.1 months vs 6.7 monthsP=.001
69 vs 44P=.001
LUX-LUNG 6n=242
Afatinib vs Cis/GemEGFR mutation
positive
11 months vs 5.6 months†P<.0001
67 vs 23†P<.0001
13.7 months vs 5.6 monthsP<.0001
74 vs 31P value not
reported
Cis = Cisplatin; Gem = Gemcitabine; Pem = Pemetrexed† Independently assessed
Lee CK, et al. J Clin Oncol. 2015.
EGFR TKIs vs ChemotherapyOutcomes by Mutation Type
Lee CK, et al. J Clin Oncol. 2015.
EGFR TKIs vs ChemotherapyOutcomes by Smoking Status
Lee CK, et al. J Clin Oncol. 2015.
EGFR TKIs vs ChemotherapyOutcomes by Sex
Lee CK, et al. J Clin Oncol. 2015.
EGFR TKIs vs ChemotherapyOutcomes by Ethnicity
Lee CK, et al. J Clin Oncol. 2015.
EGFR TKIs vs ChemotherapyOutcomes by Age
Lee CK, et al. J Clin Oncol. 2015.
EGFR TKIs vs ChemotherapyOutcomes by Tumor Histology
Lee CK, et al. J Clin Oncol. 2015.
EGFR TKIs vs ChemotherapyOutcomes by ECOG PS
In patients with advanced NSCLC and EGFR sensitizing mutations (exon 19
deletions or exon 21 L858R substitution mutations as detected by an FDA-
approved test), is it better to use first- or second-generation EGFR TKIs?
Park K, et al. Lancet Oncol. 2016.
LUX-Lung 7 Phase IIb Trial Afatinib vs Gefitinib
Randomization
1:1
Afatinib 40 mg once daily(n=160)
Gefitinib 250 mg once daily(n=159)
• Stage IIIB/IV adenocarcinoma of the lung • EGFR mutation (Del19 and/or L858R) in the tumor tissue* • No prior treatment for advanced/metastatic disease• ECOG PS 0/1
Primary endpoints: PFS (independent review), TTF, OS
Secondary endpoints: ORR, time to and duration of response, duration of disease control, tumor shrinkage, HRQoL, safety
*Stratified by mutation type (Del19 vs L858R)and presence of brain metastases (yes vs no)
Treatment beyond progression allowed if deemed beneficial by investigator
.
LUX-Lung 7 Phase IIb Trial PFS by Independent Review
Afatinib N=160
GefitinibN=159
Median PFS (months) 11 10.9
HR (95%CI) P-value
0.73 (0.57–0.95) .0165
*P=.0176; †P=.0184
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27 30 33 36 39 42
27%*
18%†
15%8%
160 142 112 94 67 47 34 27 21 13 6 3 1 0159 132 106 83 52 22 14 9 7 5 3 3 1 1
00
Esti
mat
ed
PFS
pro
bab
ility
Time (months)AfatinibGefitinib
Park K, et al. Lancet Oncol. 2016.
LUX-Lung 7 Phase IIb Trial ORR and DCR
Efficacy ParameterAfatinib (n=160)
Gefitinib (n=159)
P
ORR 70% 56%.0083
(OR=1.87)
DCR 91% 87%.24
(OR=1.55)
ORR Exon 19 (n=186) 73% 66%
ORR Exon 21 L858R (n=133)
66% 42%
DCR=disease control rate; OR=odds ratio; ORR=overall response rate
Park K, et al. Lancet Oncol. 2016.
AE category Gr 1-2 Gr 3 Gr 4 Gr 1-2 Gr 3 Gr 4
Diarrhea 78% 12% 1% 60% 1%
Rash/acne 79% 9% 78% 3%
Stomatitis 60% 4% 24%
Paronychia 54% 2% 16% 1%
Fatigue 15% 6% 14%
Nausea 15% 1% 14%
Vomiting 11% 3% 1%
AST/ALT increased 10% 16% 8% 1%
ILD 0% 1% 1% 1%
Afatinib Gefitinib
Drug-related AE leading to dose reduction: afatinib 39% doses reduced to 30 mg daily, 13% reduced to 20 mg
LUX-Lung 7 Phase IIb Trial Select Drug-Related AEs
Park K, et al. Lancet Oncol. 2016.
AE=Adverse Event; Gr=Grade
Paz-Ares L, et al. Ann Oncol. 2017
LUX-Lung 7 Phase IIb Trial OS Update
• Median overall survival: 27.9 months (afatinib) vs 24.5 months (gefitinib); no statistical significance
− Reduction in the risk of death for patients treated with afatinib: 14%
Group 1 = G719, L861, G709, S768, R776 Group 2 = de novo T790M Group 3 = exon 20 ins
LUX-Lung 2, 3, 6 Uncommon EGFR Mutations
Yang JC, et al. Lancet Oncol. 2015.
Max
imu
m d
ecr
eas
e f
rom
bas
elin
e (
%)
-100
-80
-60
-40
-20
0
20
40
60
80
100
120 Group 1Group 2Group 3
Patient index sorted by maximum % decrease in descending order
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70
0
10
25
35
40
30
20
15
5
Pro
gressio
n-fre
e Su
rvival(m
on
ths)
Tan DS, et al. J Thorac Oncol. 2016.
EGFR TKIsLate Phase First-Line Therapy Trials
Trial Experimental Control Phase SelectionPrimary End
Point
LUX Lung-7 (NCT01466660) Afatinib Gefitinib IIB L858R, exon 19 del PFS
ARCHER 1050 (NCT01774721) Dacomitinib Gefitinib III L858R, exon 19 del PFS
RELAY (NCT02411448)Ramucirumab
+ erlotinib Erlotinib IIIL858R, exon 19 del
T790M excludedPFS
NEJ026 (UMIN000017069)Bevacizumab
+ erlotinib Erlotinib III L858R, exon 19 del PFS
BEVERLY (NCT02633189)Bevacizumab
+ erlotinib Erlotinib IIIL858R, exon 19 del,
other rare sensitizing mutation
PFS
SWOG 1403 (NCT02438722)Afatinib + cetuximab Afatinib II/III L858R, exon 19 del PFS/OS
FLAURA (NCT02296125) OsimertinibGefitinib, erlotinib
III L858R, exon 19 delPFS
(crossoverallowed)
SOLAR (NCT02588261) ASP8273Gefitinib, erlotinib
IIIL858R, exon 19 del
T790M +/- PFS
EGFRm+ NSCLCOptimal First-Line Therapy
Tan DS, et al. J Thorac Oncol. 2016.
• Any of the approved EGFR TKIs, including gefitinib, erlotinib, and afatinib.
− The choice of agent should be based on factors such as PS and access to therapies.
• For patients whose treatment is initiated with chemotherapy up front, due consideration should be given to transitioning them to an EGFR TKI.
EGFRm+ NSCLC
EGFR TKI Resistance
EGFR TKI ResistanceIASLC Definitions
Tan DS, et al. J Thorac Oncol. 2016.
EGFR TKI Resistance Clinical and Molecular Definition
Primary
Secondary
• Stable disease as best response after EGFR TKI monotherapy
• Partial response or stable disease for more than 6 mowith an enlarging extracranial target lesion(s)
• Documented resistance mechanism (eg, T790M mutation, MET amplification, or other emerging mechanism relevant to the TKI)
To avoid re-treatment effect of disease flare1. Patients can have minimal or no washout to
EGFR TKI, especially in absence of grade 2 or higher toxicity
2. Patients should be receiving an EGFR TKI as the last line of therapy
EGFR TKI ResistanceCommon Mechanisms
Tan DS, et al. J Thorac Oncol. 2016.
Mechanism Gene Alterations Prevalence Detection Method
EGFR-dominant EGFR SNV: T790M 41-63% LNA-PCR/sequencing assay
SNV: D761Y, T854A, L747S
<5% PCR-RFLP
Amplification 8% FISH
Bypass signaling tracts
PIK3CA SNV 5% SNaPshot
BRAF SNV 1% SNaPshot
MET Amplification 5% FISH
HER2 Amplification 12-13% FISH
AXL Increased expression 20% IHC
HGF Increased expression 61% IHC
PTEN Loss 10% IHC
Phenotypicalterations
RB1 lossTransformation to small cell lung cancer
14%Histological examination and confirmed by expression of neuroendocrine markers
- Transition to EMT 16-20%ICH stain of vimentin and e-cadherin
What are the treatment options for patients with metastatic EGFR T790M
mutation-positive NSCLC, as detected by an FDA-approved test, who have
progressed on or after EGFR TKI therapy?
EGFRm+ NSCLC
Third-Generation EGFR TKIs
• Selective for resistant/mutant forms of EGFR over wild-type (~200 times greater potency)
– Also inhibits HER2, HER3, HER4
– FDA accelerated approval in 2015
• Treatment of metastatic EGFR T790M mutation-positive NSCLC
• FDA approved test for T790M: cobas® Mutation Test v2
• After progression on or after EGFR TKI therapy
• Dose: 80 mg once daily
Cross D, et al. Cancer Discov. 2014; Osimertinib FDA Prescribing Information.
Osimertinib (AZD9291)Irreversible EGFR TKI
20 mg 40 mg 80 mg 160 mg 240 mg
Be
st P
erc
en
tage
Ch
ange
fro
m B
ase
line
in
Targ
et-L
esio
n S
ize
50
4030
20
100
-10
-20
-30
-40-50
-60
70
-80
-90-100
D*D*
DD
D
D
DDDD
DD
D DDD DDD
D D D
D DDD D D
DDDDD
DResponse rate = 61%
Jänne PA, et al. N Engl J Med. 2015.
OsimertinibEGFR T790M-Positive Patients
Osimertinib AURA Phase I Trial
N=63
Cut off - 4 January 2016; Population: safety analysis set; Investigator assessed; Progression events that do not occur within 14 weeks of the last evaluable assessment (of first dose) are censored.*PFS is the time from date of first dosing until the date of objective disease progression or death
Median PFS*, months (95% CI) 9.7 (8.3, 13.6)
Remaining alive and progression-free, % (95% CI)12 months18 months24 months
41 (29, 53)29 (18, 41)17 (8, 30)
0.00.10.20.30.40.50.60.70.80.91.0
Pro
bab
ility
of
PFS
1Number of patients at risk:
Osimertinib 80 mgMonth
0 3 6 9 12 15 18
63 55 48 36 25 20
21 24 27
15 9 5
Yang JC, et al. ELCC. 2016.
Osimertinib AURA Pooled Phase II Trial
Yang JC, et al. ELCC. 2016.
AURA pooled Phase II data cut off - 1 November 2015; Population: full analysis set; Assessment: BICRProgression events that do not occur within 14 weeks of the last evaluable assessment (of first dose) are censored; Tick marks on the Kaplan-Meier plot denote censored observations*PFS is the time from date of first dosing until the date of objective disease progression or death
Median PFS*, months (95% CI) 11 (9.6, 12.4)
Remaining alive and progression-free, % (95% CI)12 months18 months24 months
48 (42, 53)NCNC
0.00.10.20.30.40.50.60.70.80.91.0
Pro
bab
ility
of
PFS
Number of patients at risk:
Osimertinib 80 mg Month
0 3 6 9 12 15 18
441 332 271 205 161 38
21 24 27
0
N = 411
AURA Pooled Phase II Trial Causally-Related AEs
Yang JC, et al. ELCC. 2016.
Causally-related AEs occurring in ≥15% of patients overall, n (%)
AURA pooled Phase II (80 mg) N=411*
Grade 1 Grade 2 Grade ≥3 Any Grade
Rash (grouped terms) 146 (36) 18 (4) 3 (<1) 167 (41)
Diarrhea 138 (34) 17 (4) 2 (<1) 157 (38)
Dry skin (grouped terms) 116 (28) 9 (2) 0 125 (30)
Paronychia (grouped terms) 88 (21) 30 (7) 0 118 (29)
Select AEs
ILD (grouped terms)† 4 (1) 0 8 (2) 12 (3)
Hyperglycaemia 0 1 (<1) 0 1 (<1)
QT prolongation 7 (2) 3 (<1) 4 (1) 14 (3)
AURA pooled Phase II data cut off - 1 November 2015; Population: full analysis set*Total median treatment duration 13.2 months; †As of June 1, 2015, of more than 1200 patients across all studies dosed with osimertinib, ILD grouped term events were reported in approximately 2.9% of patients (35 events): nine Grade 1, six Grade 2, 18 Grade ≥3, two currently ungraded. Of these, a total of four patients are reported to have died due to ILD (Grade 5).
AURA3 Phase III TrialITT Population: PFS
Mok TS, et al. N Engl J Med. 2017.
AURA3 Phase III TrialSubgroup Analyses of PFS
Mok TS, et al. N Engl J Med. 2017.
Sequist LV, et al. JAMA Oncol. 2016.
Osimertinib After Disease Progression on Rociletinib
RociletinibOsimertinib
Pe
rce
nta
ge C
han
ge F
rom
Bas
elin
e Tu
mo
r B
urd
en
30
20
10
0
-10
-20
-30
-40
-50
-60
Time (days)0 100 200 300 400 500 600
Pt 2
Pt 1
Pt 3
Pt 4
Pt 5
Pt 6
Longitudinal response for each patient who transitioned directly from rociletinib to osimertinib
Tan DS, et al. ASCO. 2015.
EGF816 First Human Phase I/II Study
Best Percentage Change from Baseline in Target Lesions
Be
st P
erc
en
tage
Ch
ange
Fro
m B
ase
line 40
20
0
-20
-40
-60
-80
n/N(%)=40/53 (75.5%)
** * * *
Treatment Group
75 mg QD 150 mg QD 225 mg QD 300 mg QD 350 mg QD
* *
Tan DS, et al. ASCO. 2015.
EGF816 Phase I/II StudyDrug-Related AEs (>10% of Pts)
Adverse event, n (%)
Dose group
All (n=53)75mg QD (n=7)
150mg QD (n=16)
225mg QD (n=16)
300mg QD (n=5)
350mg QD(n=9)
All Grades
Grade 3/4
All Grades
Grade 3/4
All Grades
Grade 3/4
All Grades
Grade 3/4
All Grades
Grade 3/4
All Grades
Grade 3/4
Maculopapular rash 3 (43) 0 3 (19) 1 (6) 8 (50) 5 (31) 4 (80) 2 (40) 5 (56) 3 (33) 23 (43) 11 (21)
Diarrhea 0 0 2 (13) 0 8 (50) 0 2 (40) 0 5 (56) 1 (11) 17 (32) 1 (2)
Dry skin 1 (14) 0 5 (31) 0 4 (25) 0 3 (60) 0 2 (22) 0 15 (28) 0
Stomatitis 4 (57) 0 4 (25) 0 4 (25) 0 1 (20) 0 1 (11) 0 14 (26) 0
Pruritus 1 (14) 0 4 (25) 0 5 (31) 0 2 (40) 0 1 (11) 0 13 (25) 0
Decreased appetite 1 (14) 0 2 (13) 0 2 (13) 0 1 (20) 0 3 (33) 0 9 (17) 0
Dermatitis acneiform
0 0 3 (19) 0 4 (25) 0 0 0 2 (22) 0 9 (17) 0
Nausea 1 (14) 0 2 (13) 0 2 (13) 0 1 (20) 0 1 (11) 0 7 (13) 0
Paronychia 0 0 2 (13) 0 2 (13) 0 1 (20) 0 1 (11) 0 6 (11) 0
Vomiting 1 (14) 0 1 (6) 0 2 (13) 0 1 (20) 0 1 (11) 0 6 (11) 0
Wang S. J Hematol Oncol. 2016.
EGF816Ongoing Trials
Phase Study Population NCT no.
I/II Patients with EGFR mutated solid malignancies
02108964
IB/II Patients with EGFR mutated NSCLC 02335944
II Patients with EGFR mutated and cMET-positive NSCLC
02323126
Wang S. J Hematol Oncol. 2016.
ASP8273Ongoing Trials
Phase Study Population NCT no.
I NSCLC patients who have EGFR mutations and received prior treatment with EGFR TKI
02113813
I/II NSCLC with EGFR mutation and had progressive disease after previous treatment with EGFR TKIs
02192697
II NSCLC with EGFR mutation and TKI naïve patients
02500927
III Stage IIIB/IV NSCLC with EGFR mutations 02588261
EGFR TKI ResistancePotential Clinical Algorithm
Tan DS, et al. J Thorac Oncol. 2016.
NSCLC
EGFR Mutation Testing
How do the different technology platforms for detecting EGFR mutations
compare?
Tan DS, et al. J Thorac Oncol. 2016.
EGFR Mutation TestingMethods and Applications
Technique Sensitivity (% Mutant DNA) Mutations IdentifiedDetection of Co-
mutationsPotential
Applications
Direct sequencing 10-25% Known and new No Tissue
Pyrosequencing 5-10% Known only No Tissue
Multiplex PCR (SnaPshot) 5% Known only Yes (hotspots) Tissue
cobas 3-5% Known only No Tissue, Plasma
WAVE-surveyor 2% Known only No Tissue, Plasma
Mass spectrometry based 1-10% Known only Yes (hotspots) Tissue, Plasma
High-depth NGS (at least 200x depth)
1-10%(depending on error rates and
sequencing depth)Known and new Yes Tissue, Plasma
Therascreen 1-5% Known only No Tissue, Plasma
Scorpions ARMS 1% Known only No Tissue, Plasma
Locked nucleic acid clamp 1% Known only No Tissue, Plasma
TAm-Seq 2% Known and new Yes Tissue, Plasma
BEAMing <0.1% Known only No Tissue, Plasma
Digital droplet PCR <0.1% Known only No Tissue, Plasma
CAPP-Seq ~0.02% Known and new Yes Plasma
Shinde R, et al. J Manag Care Spec Pharm. 2016.
EGFR Mutation TestingUtilization Patterns: 2009-2012
Retrospective claims database analysis of patients treated with erlotinib who received biomarker testing procedures (N=634)
The low frequency of EGFR mutation testingsuggests a need for increased awareness of the importance
of biomarker testing for guiding treatment decisions.
Year n (%)
2009 71 (11.2)
2010 168 (26.5)
2011 226 (35.6)
2012 169 (26.7)
Levy BP, et al. Oncologist. 2015.
EGFR Mutation TestingImplementing Guidelines
1. Staying current with rapidly evolving practice standardsA. Consider promoting a local physician “champion” to educate colleagues in their
region or community B. Establish formal venues for the communication of biomarker education
2. Managing resources and communication between stakeholdersA. Every patient suspected of having advanced-stage disease should, ideally, be
evaluated by a multidisciplinary teamB. Each institution should establish a molecular testing policy that covers reflex
testing.C. Nurse “navigators” may help streamline patient care and facilitate consistent
communication amount multidisciplinary teamsD. Electronic health records should be maintained and shared among the
multidisciplinary teams
3. Optimizing tissue acquisition and processing A. Tissue acquirers and pathologists should communicate effectively to ensure that
tissue obtained for molecular testing is of sufficient quantity and qualityB. Decision on the optimal diagnostic procedure for molecular testing should be
individualized and include risk-benefit analysis.C. Ensure timely identification of actionable biomarkersD. Efficient use of pleural fluid may facilitate molecular testing
Liquid BiopsyGenotyping Circulating Tumor DNA
• Tumor cells release small fragments of cell-free plasma DNA (cfDNA) into circulation by multiple mechanisms
− Cell-free DNA (cfDNA) includes normal and circulating tumor DNA (ctDNA)
− Size: Average 180-200 base pairs
− Half-life: ~2 hours
Diaz LA Jr., Bardelli A. J Clin Oncol. 2014.
Liquid BiopsyApplications
Diaz LA Jr., Bardelli A. J Clin Oncol. 2014.
• Early disease detection
• Assessment of molecular heterogeneity of overall disease
• Monitoring of tumor dynamics
• Identification of genetic determinants for targeted therapy
• Evaluation of early treatment response
• Monitoring of minimal residual disease
• Assessment of evolution of resistance in real time
Detection of T790MTumor Biopsy vs Liquid Biopsy
Sundaresan TK, et al. Clin Cancer Res. 2016.
No single diagnostic test for acquired resistance,including tumor biopsy, can be considered a "gold standard."
Comparison Agreement (%) 95% CI Kappa
CTC vs all biopsy 74 54-89 0.485
ctDNA vs all biopsy 61 42-78 0.228
CTC/ctDNA vs all biopsy 69 52-84 0.35
0.060.04
0.060.04
AURA Phase I StudyPlasma EGFR Genotyping
Oxnard GR, et al. J Clin Oncol. 2016.
Specificity Sensitivity
19 deln = 136
L858Rn = 73
T790Mn = 158
19 deln = 80
L858Rn = 143
T790Mn = 58
82.3% 86.3% 70.3% 97.5% 96.5% 69.0%
0.001
N/D
0.01
0.1
1
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1N/D
0.01
0.1
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Use of Plasma EGFR GenotypingPotential New Paradigm
Oxnard GR, et al. J Clin Oncol. 2016.
Acquired resistance to EGFR TKI
FDA-approved plasma assay for T790M and sensitizing mutations
T790M+ T790M-
Skip biopsy, start 3rd gen EGFR TKI
Biopsy, FDA approved FFPE assay for T790M
T790M+ T790M-
Chemo3rd gen
EGFR TKI
EGFRm+ NSCLC
The Role of PD-1 Pathway Blockade
EGFRm+ NSCLCResponses to PD-1 Pathway Blockade
Gainor JF, et al. Clin Cancer Res. 2016; Herbst RS, et al. Lancet. 2016; Borghaei H, et al. N Engl J Med. 2015; Rizvi NA, et al. Science. 2015.
• EGFRm+ NSCLC seems to be associated with low responses to PD-1/PD-L1 inhibitors.
− This may be partly due to the low rates of concurrent PD-L1 expression and CD8+ tumor-infiltrating lymphocytes within the tumor microenvironment, as well as the lower mutational load associated with EGFRm+ NSCLC.
• Although these findings will need to be validated in future prospective studies, they are clinically relevant with regard to the existing treatment paradigm of EGFRm+ NSCLC, including molecular testing and the prioritization of therapies already available.
Lung CancerFuture
Seoane J, De Mattos-Arruda L. J Intern Med. 2014.
Precision Medicine ChallengesTumor Heterogeneity
Intertumor heterogeneity Intratumor heterogeneity
Intratumor genomic heterogeneity
Intratumor epigenomic heterogeneity
Intratumor microenvironment heterogeneity
Subclone X
Subclone Y
Fibroblast
Immune cells
Blood vessel
Advancing Precision MedicineNovel Clinical Trial Designs
Politi K, Herbst RS. Clin Cancer Res. 2015.
Lung CancerPrecision Oncology Future
Tan WL. Lancet Oncol. 2016.
Evolutionary trajectoryNatural clinical history of cancerPaired tumor-circulating tumor cells-plasmaMultisector profilingLongitudinal sampling
Other traitsDNA damage repairMetabolic stateStemness of tumor
ImmunophenotypingImmune checkpoint biomarkersMutational burdenNeoantigen predictionHLA typingT-cell repertoire sequencingInflammatory state
Past historyEtiology – eg, smoking statusPrior response to therapyMutational signatures
Multidimensional profilingTargeted sequencing for driversWhole exome/whole genome sequencingRNA sequencingProteomic profilingChromatin state
Patient-derived modelsHigh throughput screening for therapeutic vulnerabilitiesEx vivo immune killing assays
EGFRm+ NSCLCCase Studies
• 55 WF 2 pk-yr remote smoker presents with dyspnea on exertion, and chronic, rapidly escalating cough.
• Previously treated for pneumonia with azithromycin and levofloxacin without resolution in symptoms.
• Also complains of increasing pain in right side, low grade fevers, malaise, and 10 lb weight loss over 2 month period.
• Set up for outpatient fiber optic bronchoscopy (FOB), but then presents in extremis, with diffuse right-sided pulmonary infiltrate on chest x-ray in the ED, prompting admission on 9/23/15 after CT chest reveals extensive lymphangitic disease at the right lung base as well as numerous hepatic lesions.
• Placed back on ABOs.
Case 1Presentation
• FOB with transbronchial needle aspiration biopsy consistent with lung adenocarcinoma, TTF1 (+)
• PET CT scan (10/5/15): metastatic neoplasm, including lymphangitic carcinomatosis in the right lung, thoracic and cervical metastatic lymphadenopathy, and liver, bilateral adrenal and osseous metastases; likely miliary metastatic involvement of the left lung as well.
• Brain MRI (-)
• About to start systemic chemo, but biopsy returned (+) for Del 19 EGFR mutation.
Case 1Diagnosis
A. Afatinib
B. Erlotinib
C. Gefitinib
D. All of the above
E. None of the above
Which agent(s) have been shown to improve overall survival compared with chemotherapy in TKI-naïve patients?
2012
• 60 y/o female presented with stage III left lower lobe (stations 7, 4L, 11L LΝ+) lung adenocarcinoma.
• Treated with induction chemotherapy (cisplatin-pemetrexed) followed by chemo-radiation (70 Gy in 35 fractions).
2013 (January)
• PET negative
• Baseline biopsy: EGFR exon 19 del.
Case 22012-2013
2014 (January)
• Development of fluorodeoxyglucose (FDG) avidity in left hilar region, progressively worsening; biopsy-positive adenocarcinoma.
• Started on erlotinib.
2014 (July)
• Response-isolated brain metastasis treated with stereotactic body radiation therapy (SBRT); continued response.
• Increasing FDG avidity of left hilar lesion and new right upper lobe ground-glass opacity; bilateral small lung nodules with bony disease.
Case 22014
2015 (April)
• Bronchoscopy-endobronchial ultrasound: 11L+ metastatic adenocarcinoma; quantity not sufficient for mutation testing.
• Plasma DNA next generation sequencing: T790M+
• Started on osimertinib.
2016 (February)
• PET/CT: decrease in size and soft tissue uptake in left hilar region.
• Response of bony metastases
Case 22015-2016
Key Take Home Points
• Recently, there has been a lot of progress in NSCLC.
− A number of sophisticated tools and targeted agents have been developed, including the FDA-approved second-line TKI, osimertinib, for T790M+ disease.
• As we continue making advancements, molecular testing will become increasingly important.
− Tumor heterogeneity poses a substantial diagnostic and therapeutic challenge that will need to be overcome for the successful application of precision treatment.
− Non-invasive or minimally invasive diagnostic methods will prove particularly useful for longitudinal molecular characterization of tumors, enabling effective sequential therapies.
Key Take Home Points (cont.)
• Despite guideline recommendations, the frequency of biomarker testing is low highlighting the need for more awareness of testing to guide treatment decisions.
• Strategies for improving guidelines implementation
− Stay current with rapidly evolving practice standards
− Manage resources and communication between stakeholdero Ideally, every patient suspected of having advanced NSCLC
should be evaluated by a multidisciplinary team
− Optimize tissue acquisition and processingo Ensure timely identification of actionable biomarkers