1. Selecting First-line Therapy in the EGFR Mutant NSCLC Setting
NSCLC, non-small-cell lung cancer.
This program is supported by an educational grant from Boehringer Ingelheim.

2. Faculty
Everett Vokes, MD John E. Ultmann Professor Chair, Department of Medicine Physician-in-Chief The University of Chicago Medicine and Biological Sciences Chicago, Illinois
Everett Vokes, MD, has disclosed that he has received consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, Genentech, Lilly, Merck, Synta, and VentiRx.

3. Background
EGFR mutation recognized as major determinant of response to EGFR TKIs
Mutation frequency approximately 10% to 30% of NSCLC
First-, second-, and third-generation drugs available
Not all mutations equally associated with response
Resistance patterns well described
NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.
Slide credit: clinicaloptions.com
Stewart EL, et al. Transl Lung Cancer Res. 2015;4:67-81.

4. EGFR Mutations in NSCLC
9% exon 20 variants
3% codon 719 variants
2% other variants
40% L858R substitution
46% exon 19 deletions
NSCLC, non-small-cell lung cancer.
Herbst RS, et al. N Engl J Med. 2008;359:
Sequist LV, et al. J Clin Oncol. 2007;25:
Slide credit: clinicaloptions.com

5. Screening for EGFR Mutations
Parameter
Direct DNA (Sanger) Sequencing
Next-Generation
Sequencing
DNA source
Tissue from biopsy/resection
Tissue, blood/plasma, urine
Sensitivity
Low: mutant variant must be ≥ 20% of sample to be detectable
High: mutant variant can be as low as 5% of input sample
Specificity
High
High (equivalent to Sanger)
Turnaround time
Within 10 working days of receipt
Up to several wks
Advantages
Gold standard: well defined, readily available methodology
High throughput; simultaneously test multiple targets/genes of interest; quantitative; decreased cost per bp
Limitations
Tumor tissue samples often too small or heterogeneous; low throughput; limited in detecting gene copy number changes
Clinical standards not yet established; complex workflow and analysis
bp, base pair
Khoo C, et al. Transl Lung Cancer Res. 2015;4: Lindeman NI, et al. J Thorac Oncol. 2013;8: Luthra R, et al. Cancers. 2015;7: Rizzo JM, et al. Cancer Prev Res. 2012;5: Chin EL, et al. BMC Genet. 2013;14:6.
Slide credit: clinicaloptions.com

6. Lung Cancer Mutation Consortium: Single Driver Mutations in NSCLC
No mutation detected
ERBB2 3%
KRAS 25%
MET AMP < 1%
EGFR 17%
MEK1 < 1%
EML4-ALK 8%
NRAS < 1%
Double mutants 3%
AKT1 0%
BRAF 2%
PIK3CA < 1%
Mutations found in 64% (466/733) of tumors completely tested
NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com
Kris MG, et al. JAMA. 2014;311:

7. EGFR Mutations: Context
Found in approximately 10% to 30% of pts with NSCLC
More common in neversmokers, adenocarcinomas, females, Asians
Associated with response to first-, second-, and third-generation TKIs
Predominantly located in EGFR exons 18-21
85% of EGFR mutations are either deletions in exon 19 or a single-point mutation in exon 21 (L858R)
The specific EGFR mutation identified is important
There are sensitive mutations, primary resistance mutations (often exon 20), and acquired resistance mutations (T790M)
NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.
Stewart EL, et al. Transl Lung Cancer Res. 2015;4:67-81.
Chan BA, et al. Transl Lung Cancer Res. 2015;4:36-54.
Slide credit: clinicaloptions.com

8. IPASS: First-line Gefitinib vs Paclitaxel/ Carboplatin in Stage IIIB/IV NSCLC
Open-label phase III trial
Primary endpoint: PFS
Secondary endpoints: OS, ORR, quality of life, symptom reduction, safety
Study conducted in Asian countries
Up to six
3-wk cycles
Gefitinib 250 mg/day PO
(n = 609)
Previously untreated pts with stage IIIB/IV NSCLC, adenocarcinoma, never or ex-light smokers, WHO PS 0-2
(N = 1217)
Paclitaxel 200 mg/m2 IV on Day 1 +
Carboplatin AUC 5-6 mg/mL/min IV on Day 1
(n = 608)
AUC, area under the curve; NSCLC, non-small-cell lung cancer; PS, performance status; WHO, World Health Organization.
Slide credit: clinicaloptions.com
Mok TS, et al. N Engl J Med. 2009;361:

9. Gefitinib vs Paclitaxel/Carboplatin in Advanced NSCLC: PFS by EGFR Status
PFS: gefitinib superior to carboplatin/paclitaxel in ITT population
HR for progression/death: 0.74 (95% CI: ; P < .001)
EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs carboplatin/paclitaxel
EGFR Mutation Positive
EGFR Mutation Negative
1.0
1.0
Gefitinib
Pac/carbo
Gefitinib
Pac/carbo
0.8
0.8
HR: (95% CI: ; P < .001)
HR: (95% CI: ; P < .001)
0.6
Carbo, carboplatin; ITT, intent to treat; NSCLC, non-small-cell lung cancer; Pac, paclitaxel.
0.6
Probability of PFS
Probability of PFS
0.4
0.4
0.2
0.2 4 8 12 16 20 24 4 8 12 16 20 24
Mos Since Randomization
Mos Since Randomization
Slide credit: clinicaloptions.com
Mok TS, et al. N Engl J Med. 2009;361:

10. Mos From TKI Initiation
EGFR TKIs in EGFR-Mutant Metastatic Lung Adenocarcinoma: 5-Yr PFS and OS
Pts (N = 137) treated with erlotinib or gefitnib were included
PFS OS
1.0
1.0
0.8
0.8
0.6
0.6
Probability of PFS
Median PFS: 12.1 mos
Probability of OS
Median OS: 30.9 mos
0.4
0.4
EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.
0.2
0.2 10 20 30 40 50 60 20 40 60 80
Mos From TKI Initiation
Mos From Treatment Initiation
Slide credit: clinicaloptions.com
Lin JJ, et al. J Thorac Oncol. 2016;11:

11. Stratified by mutation type,* ECOG PS (0 vs 1 vs 2)
EURTAC: Erlotinib vs Chemo in EGFR Mutation–Positive, Stage IIIB/IV NSCLC
Randomized, open-label phase III trial
Stratified by mutation type,* ECOG PS (0 vs 1 vs 2)
Erlotinib 150 mg/day
(n = 86) PD
Pts with no prior chemotherapy, stage IIIB/IV NSCLC, mutated EGFR,* ECOG PS 0-2
(N = 174†)
Platinum Doublet‡
Q3W x 4 cycles
(n = 87) PD
Primary endpoint: PFS (interim analysis planned at 88 events)
Secondary endpoints: ORR, OS, location of progression, safety, EGFR-mutation analysis, QoL
AUC, area under the curve; ECOG, Easter Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status; QoL, quality of life.
*Exon 19 deletion or exon 21 L858R mutation. †1227 pts screened; 174 pts with mutated EGFR enrolled; 1 pt withdrawn. ‡Cisplatin 75 mg/m2 Day 1/docetaxel 75 mg/m2 Day 1; cisplatin 75 mg/m2 Day 1/ gemcitabine 1250 mg/m2 Days 1, 8; carboplatin AUC = 6 Day 1/docetaxel 75 mg/m2 Day 1; carboplatin AUC = 5 Day 1/gemcitabine 1000 mg/m2 Days 1, 8.
Slide credit: clinicaloptions.com
Rosell R, et al. Lancet Oncol. 2012;13:

12. PFS in ITT Population 1.0 Erl (n = 86) 0.8 Chemotherapy (n = 87) 0.6
0.4
0.2
Erl (n = 86)
Chemotherapy (n = 87)
HR: 0.37 (95% CI: ;
log-rank P < .0001)
Probability of PS
5.2
9.7
Erl, erlotinib; ITT, intent to treat.
Mos
Pts at Risk, n
Erl Chemo
Slide credit: clinicaloptions.com
Rosell R, et al. Lancet Oncol. 2012;13:

13. First-line Treatment With EGFR TKIs vs Chemotherapy in EGFR-Mutated NSCLC
Study
Treatment N
Median PFS, Mos
Median OS, Mos
Maemondo[1]
Gefitinib vs carboplatin/ paclitaxel
230
10.8 vs 5.4
(P < .001)
30.5 vs 23.6
(P = .31)
Mitsudomi[2,3]
Gefitinib vs
cisplatin/docetaxel
172
9.2 vs 6.3
(P < .0001)
35.5 vs 38.8
(HR: 1.19)
OPTIMAL[4,5]
Erlotinib vs
carboplatin/gemcitabine
165
13.1 vs 4.6
22.8 vs 27.2
EURTAC[6]
platinum-based chemotherapy
174
9.7 vs 5.2
19.3 vs 19.5
(P = .87)
LUX-Lung 3[7,8]
Afatanib vs
cisplatin/pemetrexed
345
11.1 vs 6.9
(P = .001)
28.2 vs 28.2 (P = .39)
LUX-Lung 6[8,9]
Afatinib vs cisplatin/gemcitabine
364
11.0 vs 5.6
23.1 vs (P = .61)
NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.
1. Maemondo M, et al. N Engl J Med. 2010;362: Mitsudomi T, et al. Lancet Oncol. 2010;11: Mitsudomi T, et al. ASCO Abstract Zhou C, et al. Lancet Oncol. 2011;12: Zhou C, et al. Ann Oncol. 2015;26: Rosell R, et al. Lancet Oncol. 2012;13: Sequist LV, et al. J Clin Oncol. 2013;31: Yang JC, et al. Lancet Oncol. 2015;16: Wu YL, et al. Lancet Oncol. 2014;15:
Slide credit: clinicaloptions.com 13

14. Meta-analysis of Randomized First-line EGFR TKI Studies: Improved PFS
HR (95% CI)
HR (95% CI)
Study
EGFRmut (first-line therapy)
EURTAC
First-SIGNAL
GTOWG
INTACT1-2
IPASS
LUX LUNG3
NEJ002
OPTIMAL
TALENT
TOPICAL
TRIBUTE
WJTOG3405
Subtotal
0.37 ( )
0.54 ( )
1.08 ( )
0.55 ( )
0.48 ( )
0.58 ( )
0.32 ( )
0.16 ( )
0.59 ( )
0.90 ( )
0.49 ( )
0.52 ( )
0.43 ( )
TKI, tyrosine kinase inhibitor.
Favors EGFR TKI
Favors Chemo
Slide credit: clinicaloptions.com
Lee CK, et al. J Natl Cancer Inst. 2013;105:

15. 3 Generations of EGFR TKIs
T790M
Erlotinib
T790M
EGFRm Wt
100x
Afatinib
Osimertinib
EGFRm
T790M Wt
10x
Relative IC50 Wt
m, mutated; TKI, tyrosine kinase inhibitor; Wt, wild type. 1x
EGFRm
Gefitinib
Li D, et al. Oncogene. 2008;27: Ranson M, et al. WCLC Abstract MO Moyer JD, et al. Cancer Res. 1997;57: Kancha RK, et al. Clin Cancer Res. 2009;15:
Slide credit: clinicaloptions.com 15

16. LUX-Lung 2: High Response of EGFR-Mutated, TKI-Naive NSCLC to Afatinib
Phase II: 61% (79/129) pts achieved ORR (2 CR; 77 PR) regardless of type of EGFR mutation
Measurable Tumor at Time of Best Response 50 20
Maximum Decrease From Baseline(%)
-30
NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.
-50
-100 20 40 60 80
100 Pt
Slide credit: clinicaloptions.com
Yang JC, et al. Lancet Oncol. 2012;13:

17. Cisplatin/Pemetrexed (n = 104)
LUX-Lung 3: Afatinib vs Chemo Improves PFS in TKI-Naive EGFR-Mutated NSCLC
Phase III study of afatinib vs cisplatin-pemetrexed in EGFR-mutant NSCLC adenocarcinoma (N = 345)
Median PFS by del(19) and L858R EGFR Mutation Status
Afatinib (n = 204)
Cisplatin/Pemetrexed (n = 104)
1.0
Events, n (%) Median, mos
130 (64) 13.6
61 (59) 6.9
0.8
Afatinib Cisplatin/pemetrexed
0.6
Probability of PFS
(HR: 0.47; 95% CI: ; P < .001)
0.4
NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.
0.2 3 6 9 12 15 18 21 24 27
Mos
Slide credit: clinicaloptions.com
Sequist LV, et al. J Clin Oncol. 2013;31:
Sequist et al, JCO, 2013

18. Estimated OS Probability Estimated OS Probability
LUX-Lung 3+6: OS by del(19) and L858R Mutation Status for Afatinib vs Cisplatin/Pemetrexed
del(19)
Afatinib (n = 236)
Chemo (n = 119)
Median, mos
31.7
20.7
HR (95% CI)
0.59 ( ) P = .0001
L858R
Afatinib (n = 183)
Chemo (n = 93)
Median, mos
22.1
26.9
HR (95% CI)
1.25 ( ) P = .1600
1.0
1.0
0.8
0.8
0.6
0.6
Estimated OS Probability
Estimated OS Probability
0.4
0.4
0.2
0.2
Mos
Mos
Slide credit: clinicaloptions.com
Yang JC, et al. Lancet Oncol. 2015;16:

19. Is OS With Afatinib in LUX-Lung 3/6 Superior to That of Other EGFR TKIs?45
EGFR TKI
Chemo 40 35 30 25
Median OS (Mos) 20 15 10 5
TKI, tyrosine kinase inhibitor.
Mitsudomi (N = 172)
Maemondo (N = 230)
EURTAC (N = 174)
OPTIMAL (N = 165)
LUX-Lung-3 (N = 345)
LUX-Lung-6 (N = 364)
Terminated
early after
interim analysis?
Gefitinib
Erlotinib
Afatinib
Mitsudomi T, et al. Lancet Oncol. 2010;11: Maemondo M, et al. N Engl J Med. 2010;362: Rosell R, et al. Lancet Oncol. 2012;13: Zhou, et al. Lancet Oncol. 2011;12: Yang JC, et al. Lancet Oncol. 2015;16:
Slide credit: clinicaloptions.com

20. LUX-Lung 2+3+6: Afatinib in NSCLC Pts With Uncommon EGFR Mutations
Combined post hoc, ITT analysis of data on pts with uncommon EGFR mutations (n = 100) prospectively collected from the LUX-Lung 2, 3, and 6 trials
Afatinib: n = 75; chemotherapy: n = 25
Pts with uncommon EGFR mutations given afatinib categorized into 3 cohorts
Cohort n
Uncommon Mutations
Group 1 38
Point mutations or duplications in exons (L861Q, G719S, G719A, G719C, S768I, rare others) alone or in combination with each other
Group 2 14
De novo T790M mutations in exon 20 alone or in combination with other mutations
Group 3 23
Exon 20 insertions
ITT, intent to treat; NSCLC, non-small-cell lung cancer.
Slide credit: clinicaloptions.com
Yang JC, et al. Lancet Oncol. 2015;16:

21. Afatinib in NSCLC Pts With Uncommon EGFR Mutations: Tumor Shrinkage
Decreases in tumor size in response to afatinib associated with an increase in PFS
Tumor Shrinkage and PFS
120 40
100
Group 1 Group 2 Group 3 35 30 80 25 60 20
PFS (Mos) 15 40 10
Maximum Decrease From Baseline (%) 20 5
-20
NSCLC, non-small-cell lung cancer.
-40
-60
-80
-100 5 10 15 20 25 30 35 40 45 50 55 60 65 70
Pt Index Sorted by Maximum % Decrease in Descending Order
Slide credit: clinicaloptions.com
Yang JC, et al. Lancet Oncol. 2015;16:

22. Afatinib in NSCLC Pts With Uncommom EGFR Mutations: Response
Outcome
Afatinib
Group 1
(n = 38)*
Afatinib Group 2
(n = 14)†‡
Group 3
(n = 23)‡
Chemotherapy
Group
(n = 25)§
ORR, % (95% CI)
71.1
( )
14.3
( )
8.7
( ) 24
( )
Median DOR, mos (95% CI)
11.1
( )
8.2
( )
7.1
( ) --
Disease control, % (95% CI)
84.2
( )
64.3
( )
65.2
( )
Median PFS, mos (95% CI)
10.7
( )
2.9
( )
2.7
( )
( )
Median OS, mos (95% CI)
19.4
( )
14.9
( )
9.2
( )
30.2
( )
DOR, duration of response; NSCLC, non-small-cell lung cancer.
*Consists of pts with all point mutations or duplications in exons †Consists of pts with de novo T790M mutations. ‡Consists of pts with exon 20 insertions. §Consists of pts with mutations falling into groups 1/2/3 (n = 18/3/2).
For chemotherapy cohort, median PFS/median OS longer for pts in group 1 (8.4/40.8 mos) vs pts in groups 2 (6.7/22.2 mos) or 3 (5.2/31.0 mos)
Slide credit: clinicaloptions.com
Yang JC, et al. Lancet Oncol. 2015;16:

23. LUX-Lung 7: PFS With First-line Afatinib vs Gefitinib in EGFR-Mutated NSCLC
100 80
Afatinib Gefitinib HR: 0.73 (95% CI: ; P = 0.017) 60
PFS (%) 40 20
NSCLC, non-small-cell lung cancer. 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Mos
Pts at Risk, n Afatinib Gefitinib
94 83
67 52
47 22
34 14
27 9
21 7
13 5
6 3
3 3
1 1
0 1
0 0
Slide credit: clinicaloptions.com
Park K, et al. Lancet Oncol. 2016;[Epub ahead of print].

24. Estimated Probability of Being on Treatment (%)
LUX-Lung 7: Time-to-Treatment Failure With First-line Afatinib vs Gefitinib
100 80
Afatinib Gefitinib HR: 0.73 (95% CI: ; P = .0073) 60
Estimated Probability of Being on Treatment (%) 40 20
NSCLC, non-small-cell lung cancer. 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Mos
Pts at Risk, n Afatinib Gefitinib
91 74
68 59
56 43
48 30
40 21
25 11
18 6
9 6
5 2
0 2
0 0
Slide credit: clinicaloptions.com
Park K, et al. Lancet Oncol. 2016;[Epub ahead of print].

25. Mos From Treatment Initiation Mos From Treatment Initiation
5-Yr OS in EGFR-Mutated NSCLC Treated With Either Erlotinib or Gefitinib
Prolonged survival associated with exon 19 vs exon 18 or 21 deletions
No extrathoracic mets (n = 79) Extrathoracic mets (n = 58)
1.0
1.0
Exon 18 (n = 4)
Exon 19 (n = 76) Exon 21 (n = 21)
0.8
0.8
0.6
0.6
Median OS: 26.7, 41.4
Median OS: 23.9, 33.6, 27.0
Probability of OS
Probability of OS
0.4
HR: 0.55 (P = .001)
0.4
HR: 0.52 (P = .001)
0.2
0.2
NSCLC, non-small-cell lung cancer. 20 40 60 80 20 40 60 80
Mos From Treatment Initiation
Mos From Treatment Initiation
Slide credit: clinicaloptions.com
Lin JJ, et al. J Thorac Oncol. 2016;11:

26. Toxicity of EGFR TKIs in NSCLC
Study
Treatment-Related AEs, %
Diarrhea
Rash
Paronychia
Stomatitis
Gr 1/2
Gr 3/4
Gefitinib
Mitsudomi
Maemondo 47 38
1.1
0.9 72 75
2.3
5.3 27 NR
1.2
2.6 19 11
Erlotinib
OPTIMAL
EURTAC 21 44 1 5 48 56 2 12 3 10
Afatinib
LUX-Lung 3
LUX-Lung 6 80 81
14.4
5.4 65
16.2
14.6 45 32
11.4 63
8.7
AE, adverse event; Gr, grade; NR, not reported; NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.
Gefitinib and erlotinib have comparable toxicity
Afatinib associated with more severe toxicity than gefitinib or erlotinib
Slide credit: clinicaloptions.com
Burotto M, et al. Oncologist. 2015;20:

27. First-line Erlotinib ± Carboplatin/Paclitaxel in EGFR-Mutated NSCLC
CALGB trial of first-line combination therapy in clinically selected pts (N = 181)
40% (66 of 164 evaluable pts) had EGFR mutations
PFS OS
1.0
1.0
E (n = 33)
ECP (n = 33)
E (n = 33)
ECP (n = 33)
0.8
0.8
0.6
0.6
Proportion Progression Free
Probability of OS
0.4
0.4
0.2
0.2
HR: 0.77 (95% CI: ; log-rank P = .3490)
HR: 0.97 (95% CI: ; log-rank P = .9227)
C, carboplatin; E, erlotininb; Gr, grade; NSCLC, non-small-cell lung cancer; P, paclitaxel. 6 12 18 24 30 36 42 6 12 18 24 30 36 42 48 54 60
Mos
Mos
Addition of chemotherapy only served to increase toxicity
Gr 3/4 hematologic: 2% vs 49%; Gr 3/4 nonhem: 24% vs 52%; P < .001
Slide credit: clinicaloptions.com
Jänne PA, et al. J Clin Oncol. 2012;30:

28. Phase II Study: Erlotinib ± Bevacizumab in Advanced NSCLC With EGFR Mutations
Erlotinib 150 mg QD +
Bevacizumab 15 mg/kg q3w (n = 77)
Pts with chemo-naive, nonsquamous NSCLC and EGFR mutations (del 19, L858R), no brain mets
(N = 154)
Treat until disease progression or unacceptable toxicity
Erlotinib 150 mg QD
(n = 77)
Open-label study
Primary endpoint: PFS (independent review; RECIST)
Secondary endpoints: OS, tumor response, QoL, safety
NSCLC, non-small-cell lung cancer; QoL, quality of life; RECIST, Response Evaluation Criteria In Solid Tumors.
Seto T, et al. Lancet Oncol. 2014;15:
Kato T, et al. ASCO Abstract 8005.
Slide credit: clinicaloptions.com

29. Erlotinib ± Bevacizumab in Advanced NSCLC With EGFR Mutations: PFSEB E
Median PFS, mos
16.0
9.7
HR (95% CI)
0.54 ( )
P value
.0015
1.0
0.8
0.6 EB E
Probability of PFS
0.4
0.2
B, bevacizumab; E, erlotinib; NSCLC, non-small-cell lung cancer; PFS, progression-free survival.
9.7
16.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Mos
Pts at Risk, n EB 75 72 69 64 60 53 49 38 30 20 13 8 4 4 E 77 66 57 44 39 29 24 21 18 12 10 5 2 1
Seto T, et al. Lancet Oncol. 2014;15:
Kato T, et al. ASCO Abstract 8005.
Slide credit: clinicaloptions.com

30. Summary of First-line EGFR TKIs in EGFR- Mutated NSCLC
Erlotinib, gefitinib, and afatinib improve PFS and QoL
Active in pts with poor PS
Afatinib PFS superior to first-generation EGFR TKIs
Choice of a specific EGFR TKI should consider toxicities and pt preferences
Combination with bevacizumab under investigation
NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor.
Slide credit: clinicaloptions.com

31. Go Online for More CCO Coverage of NSCLC!
Downloadable slidesets of key studies from ASCO 2016 selected by expert faculty Expert Analysis of key presentations from ASCO 2016
clinicaloptions.com/oncology