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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


EGFR TKIs vs ChemotherapyOutcomes by Smoking Status


EGFR TKIs vs ChemotherapyOutcomes by Sex


EGFR TKIs vs ChemotherapyOutcomes by Ethnicity


EGFR TKIs vs ChemotherapyOutcomes by Age


EGFR TKIs vs ChemotherapyOutcomes by Tumor Histology


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


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


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


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


• 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


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


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


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


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


NSCLC

EGFR Mutation Testing

How do the different technology platforms for detecting EGFR mutations

compare?


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

10

100

Alle

lic F

ract

ion

(%

)0.00

1N/D

0.01

0.1

1

10

100

Alle

lic F

ract

ion

(%

)

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

Advanced EGFR Mutation-Positive NSCLCd2qrtshcpf0x30.cloudfront.net/nodes/187/NSCLC Grand Rounds.pdf · •This slide deck in its original and unaltered format is for educational purposes

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