First Line Therapy in EGFR Mutant Advanced/Metastatic NSCLC

Selecting First-line Therapy in
the “EGFR Mutant”
Advanced/Metastatic NSCLC
Emad Shash MBBCh., MSc., MD.
Medical Oncology Department
National Cancer Institute, Cairo University

How to Hit a Target?
The art of “Precision” Medicine

NSCLC Pathology: From Traditional View to
more sub-molecular categorization
Evolution Of Knowledge

The EGFR Signal Transduction Pathway
Salomon, et al. Crit Rev Oncol Hematol 1995
Tyrosine kinase

EGFR Sub-Mutations in NSCLC
9%
exon 20
variants
3%
codon 719
variants
2%
other
variants
40%
L858R
substitution
46%
exon 19
deletions
Herbst RS, et al. N Engl J Med. 2008.
Sequist LV, et al. J Clin Oncol. 2007.

Advanced NSCLC: Evolution of Treatment
2000 - 2006 2006 - 2009 2010 2011 – 2017……..
EGFR mutation
ALK rearrangement
K-ras mutation
B-raf, HER2 mutation
ROS1, RET
Immunotherapy
Non-Squamous
Squamous
Targeting an Oncogenic Driver
EGFR mutation
Non-Squamous
Squamous
Non-Squamous
Squamous
NSCLC
Targeting EGFRTreating according histologyNSCLC

Adeno LCC-NOS SCC SCLC
EGFR mutants ALK ROS/RET
HER2
BRAF KRAS
KRAS
Changes in the Therapeutic Landscape of Stage IV
Lung Cancer: 2017
More individualization of therapy?

How’s The Story Began?
Can we get rid of chemotherapy administration?

Setting up the ground in Unselected
population: Previously Treated
Study EGFR TKI Used Phase Population OS Remark
ISEL Gefitinib VS
Placebo
III Previously
Treated
5.6 vs 5.1
months (p value
= 0.087)
Negative Trial
BR 21 Eroltinib VS
Placebo
III Previously
Treated
6.7 vs 4.7
months (p value
< 0.001)
Positive Trial
Adapted from Shash E et al. J Thorac Dis 2011.
Lessons Learnt & Identification of Subgroups that might benefit more
Study Subgroup analysis Results
ISEL Never Smokers 8.9 vs 6.1 months (p value = 0.012)
ISEL Asian Ethnicity 9.5 vs 5.5 months (p value = 0.01)
BR 21 Females, non-smokers &
Adenocarcinoma
Confirmed ISEL Subgroup analysis
More gaining evidence that those patients with EGFR Mutations yielded better RR, PFS & OS

Moving Forward with Selected
population Trial Designs!
Optimizing therapy for “EGFR Mutant” patients

Mok TS, et al. N Engl J Med. 2009.
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
Previously untreated pts
with stage IIIB/IV NSCLC,
adenocarcinoma, never or
ex-light smokers, WHO PS
0-2
(N = 1217)
Up to six
3-wk cycles
Gefitinib 250 mg/day PO
(n = 609)
Paclitaxel 200 mg/m2 IV on Day 1 +
Carboplatin AUC 5-6 mg/mL/min IV on Day 1
(n = 608)

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: 0.65-0.85; P < .001)
• EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs
carboplatin/paclitaxel
Mok TS, et al. N Engl J Med. 2009.
EGFR Mutation Positive
HR: 0.48
(95% CI: 0.36-0.64; P < .001)
ProbabilityofPFS
Mos Since Randomization
1.0
0.8
0.6
0.4
0.2
0
0 4 8 12 16 20 24
EGFR Mutation Negative
HR: 2.85
(95% CI: 2.05-3.98; P < .001)
ProbabilityofPFS
Mos Since Randomization
1.0
0.8
0.6
0.4
0.2
0
0 4 8 12 16 20 24
Gefitinib
Pac/carbo
Gefitinib
Pac/carbo

EURTAC: Erlotinib vs Chemo in EGFR Mutation–
Positive, Stage IIIB/IV NSCLC
• Primary endpoint: PFS (interim analysis planned at 88 events)
• Secondary endpoints: ORR, OS, location of progression, safety, EGFR-mutation analysis, QoL
Pts with no prior
chemotherapy, stage
IIIB/IV NSCLC, mutated
EGFR,* ECOG PS 0-2
(N = 174†)
PD
PD
Erlotinib 150 mg/day
(n = 86)
Platinum Doublet‡
Q3W x 4 cycles
(n = 87)
Stratified by mutation type,*
ECOG PS (0 vs 1 vs 2)
*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.
Rosell R, et al. Lancet Oncol. 2012.
 Randomized, open-label phase III trial

PFS in ITT Population
ProbabilityofPS
Erl (n = 86)
Chemotherapy (n = 87)
HR: 0.37 (95% CI: 0.25-0.54;
log-rank P < .0001)
Mos
0 3 6 9 12 15 18 21 24 27 30 33
Pts at Risk, n
Erl 86 63 54 32 21 17 9 7 4 2 2 0
Chemo 87 49 20 8 5 4 3 1 0 0 0 0
1.0
0.8
0.6
0.4
0.2
0
9.75.2
Rosell R, et al. Lancet Oncol. 2012;13:239-246.

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
(P < .0001)
22.8 vs 27.2
(HR: 1.19)
EURTAC[6] Erlotinib vs
platinum-based chemotherapy
174
9.7 vs 5.2
(P < .0001)
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
(P < .0001)
23.1 vs 23.5
(P = .61)
1 Maemondo M, et al. N Engl J Med. 2010. 2Mitsudomi T, et al. Lancet Oncol. 2010. 3Mitsudomi T, et al. ASCO 2012.
4 Zhou C, et al. Lancet Oncol. 2011. 5Zhou C, et al. Ann Oncol. 2015. 6Rosell R, et al. Lancet Oncol. 2012. 7Sequist LV, et
al. J Clin Oncol. 2013. 8Yang JC, et al. Lancet Oncol. 2015. 9Wu YL, et al. Lancet Oncol. 2014.

Lee CK, et al. J Natl Cancer Inst. 2013.
Favors EGFR TKI Favors Chemo
Meta-analysis of Randomized First-line EGFR
TKI Studies: Improved PFS
Study
HR
(95% CI)
HR
(95% CI)
EGFRmut(first-line therapy)
EURTAC
First-SIGNAL
GTOWG
INTACT1-2
IPASS
LUX LUNG3
NEJ002
OPTIMAL
TALENT
TOPICAL
TRIBUTE
WJTOG3405
Subtotal
0.37 (0.25-0.54)
0.54 (0.27-1.10)
1.08 (0.24-4.90)
0.55 (0.19-1.60)
0.48 (0.36-0.64)
0.58 (0.43-0.78)
0.32 (0.24-0.44)
0.16 (0.11-0.26)
0.59 (0.21-1.67)
0.90 (0.39-2.06)
0.49 (0.20-1.20)
0.52 (0.38-0.72)
0.43 (0.38-0.49)

Lee CK, et al. J Natl Cancer Inst. 2013.
Favors EGFR TKI Favors Chemo
First-line EGFR TKI Studies: Improved QoL
Study
HR
(95% CI)
HR
(95% CI)
EGFRmut(first-line therapy)
EURTAC
First-SIGNAL
GTOWG
INTACT1-2
IPASS
LUX LUNG3
NEJ002
OPTIMAL
TALENT
TOPICAL
TRIBUTE
WJTOG3405
Subtotal
0.37 (0.25-0.54)
0.54 (0.27-1.10)
1.08 (0.24-4.90)
0.55 (0.19-1.60)
0.48 (0.36-0.64)
0.58 (0.43-0.78)
0.32 (0.24-0.44)
0.16 (0.11-0.26)
0.59 (0.21-1.67)
0.90 (0.39-2.06)
0.49 (0.20-1.20)
0.52 (0.38-0.72)
0.43 (0.38-0.49)

Patients & Clinicians would like
to see SURVIVAL GAIN!!
The advancement of Diagnosis Knowledge & Drug Development: Can they yield
better results?

2nd
Generation
TKIs
3rd Generation
TKIs
1ST
Generation
TKIs
3 Generations of EGFR TKIs

One difference is how they bind to the EGFR protein
Receptor

Another Difference is their therapeutic
window
Gefitinib
EGFRm
T790M
Wt
Afatinib Osimertinib
EGFRm EGFRm
T790M
T790M
Wt
Wt
1x
10x
100xRelativeIC50
Li D, et al. Oncogene. 2008. Ranson M, et al. WCLC 2013. Moyer JD, et al. Cancer Res. 1997.
Kancha RK, et al. Clin Cancer Res. 2009.
Erlotinib
T790M
EGFRm
Wt

2nd Generation: LUX-Lung clinical trials and eligibility
*EGFR mutations detected by TheraScreen EGFR29 test:
• Common: 19 deletions in exon 19 and L858R in exon 21
• Uncommon: 3 insertions in exon 20, L861Q, T790M, G719S, G719A and G719C, S768I
Treatment
Line of
treatment
Mutation
test
LUX-Lung 2
Phase II
N=129
Afatinib
First- and second-
line (after chemo)
Direct sequencing
(central)
LUX-Lung 3
Phase III
N=345
Afatinib vs.
Pemetrexed/
cisplatin
First-line (Global)
EGFR29* (central)
LUX-Lung 6
Phase III
N=364
Afatinib vs.
Gemcitabine/
cisplatin
First-line (Asian)
EGFR29* (central)
2

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
Yang JC, et al. Lancet Oncol. 2012.
Measurable Tumor at Time of Best Response
MaximumDecrease
FromBaseline(%)
50
20
0
-30
-50
-100
200 40 60 80 100
Pt

LUX-Lung 3 Study Design
Randomization 2:1
Stratified by:
EGFR mutation (Del19/L858R/other)
Race (Asian/non-Asian)
Afatinib 40 mg/day†
Cisplatin + Pemetrexed
75 mg/m2 + 500 mg/m2
i.v. q21 days, up to 6 cycles
Primary endpoint: PFS (RECIST 1.1, independent review)‡
Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, PRO§, safety, PK
Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6)
EGFR mutation in tumor
(central lab testing; Therascreen EGFR29* RGQ PCR)
*EGFR29:19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I.
†Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10 mg decrements in case of related G3 or prolonged G2 AE.
‡Tumor assessments: q6 weeks until Week 48 and q12 weeks thereafter until progression/start of new therapy.
§Patient-reported outcomes: Q-5D, EORTC QLQ-C30 and QLQ-LC13 at randomization and q3 weeks until progression or new anti-cancer therapy.
Sequist et al. J Clin Oncol. 2013

Del l9/L858R mutations
AFATINIB– Superior first-line PFS vs pemetrexed/
cisplatin in common mutations (del 19/L858R)
• 53% reduction in relative risk of death or tumour progression in patients with common mutations
(HR 0.47; P<0.001)
• In ITT population, median PFS was 11.1 and 6.9 months for AFATINIB and pemetrexed/ cisplatin,
respectively (HR: 0.58; 95% CI, 0.43-0.78; P<0.001)
PFS by independent review (primary endpoint)
Preplanned subgroup analysis
PFSrate(%)
0.2
0.4
0.6
0.8
1.0
0.0
Time (months)
0 3 6 9 18 2112 15 24 27
Hazard ratio 0.47
(95% CI, 0.34-0.65)
P<0.001
AFATINIB®(n=204)
Pemetrexed/cisplatin (n=104)
13.6months
6.9months
Sequist et al. J Clin Oncol. 2013

Del 19 mutations
AFATINIB– Over 1 year extended OS vs
pemetrexed/cisplatin in subgroup of del19 patients
Hazard ratio 0.54
(95% CI, 0.36-0.79)
P=0.0015
AFATINIB (n=112)
Pemetrexed/cisplatin (n=57)
• 46% reduction in relative risk of death in del 19 patients (HR 0.54; P=0.0015)
• OS in ITT population (N=345) was 28.2 and 28.2 months for AFATINIB vs
pemetrexed/cisplatin, respectively (HR 0.88; P=0.39)
Overall survival (secondary endpoint)
Preplanned subgroup analysis
EstimatedOSprobability
0.2
0.4
0.6
0.8
1.0
0.0
Time of overall survival (months)
0 3 6 9 18 21 30 36 39 4512 15 24 27 33 42 48 51
33.3months
21.1months
>12
months
increase
median OS

LUX-Lung 31,2 / LUX-Lung 62,3, %
Afatinib LL3 (n=229) / LL6 (n =239 ) Cis/Pem (n=111) / Cis/Gem (n=113)
All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4
Rash/acnea 89.1 / 80.8 16.2 / 14.2 0.0 / 0.4 6.3 / 8.8 0 0
Diarrhoea 95.2 / 88.3 14.4 / 5.4 0 15.3 / 10.6 0 0
Paronychia/nail effecta 56.8 / 33.9 11.4 / 0.0 0 0 / 0 0 0
Stomatitis/mucositisa 72.1 / 51.9 8.3 / 5.4 0.4 / 0.0 15.3 / 5.3 0.9 / 0.0 0
Decreased appetite 20.5 / 10.0 3.1 / 1.3 0 53.2 / 40.7 2.7 / 1.8 0
Vomiting 17.0 / 9.6 3.1 / 0.8 0 42.3 / 80.5 2.7 / 15.9 0.0 / 3.5
Fatiguea 17.5 / 10.0 1.3 / 0.4 0 46.8 / 36.3 12.6 / 0.9 0
Nausea 17.9 / 7.5 0.9 / 0.0 0 65.8 / 75.2 3.6 / 7.1 0.0 /0.9
Dry skin/pruritusb 29.3 / 10.9 0.4 / 0.4 0 1.8 / 0.0 0 0
Neutropenia 0.9 / 2.1 0.4 / 0.4 0 31.5 / 54.0 15.3 / 17.7 2.7 / 8.8
Anaemia 3.1 / 5.4 0.4 / 0.4 0 27.9 / 27.4 4.5 / 7.1 1.8 / 1.8
Leukopenia 1.7 / 3.3 0.0 / 0.4 0 18.9 / 51.3 8.1 / 13.3 0.0 / 1.8
ALT increase 7.4 / 20.1 0.0 / 1.7 0 2.7 / 15.9 0.0 / 1.8 0.0 / 0.9
AST increase 5.2 / 15.1 0.0 / 0.4 0 1.8 / 10.6 0.0 / 1.8 0
Most Frequent Treatment-Related Adverse Events
(>20% Difference Between Treatment Arms)
aGrouped term for closely related AEs.
bIn LUX-Lung 3, the incidence for dry skin and pruritus were reported separately as 29.3% and 18.8%, respectively, for
all grades and 0.4% each for grade ≥3 in afatinib arm.
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Data on file. Boehringer Ingelheim; 3. Wu et al. Lancet Oncol. 2014;15:213.

2nd Generation EGFR TKI activity in Uncommon
Mutations “Explored analysis”
Patients with uncommon mutations treated with afatinib
n=23 n=26 n=26
Del19
n=408
L858R
n=330
Uncommon
n=100
LUX-Lung 2
Phase II
N=129
n=52
n=54
n=23
LUX-Lung 3
Phase III
N=345
n=170
n=138
n=37
LUX-Lung 6
Phase III
N=364
n=186
n=138
n=40
Uncommon
n=75

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 18-21 (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

Tumour shrinkage in patients with uncommon
mutations
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
Maximumchangefrombaseline(%) Exon 20 insertions (n=23)
De novo T790M (n=14):
T790M alone(*), T790M+Del19, T790M+L858R, T790M+G719X, T790M+L858R+G719X
Other (n=38):
L861Q, G719X, G719X+S768I, G719X+L861Q, E709G or V+L858R, S768I+L858R,
S768I, L861P, P848L, R776H+L858R, L861Q+Del19, K739_1744dup6
Independent review (n=67†)
*
*
*

Are 2nd Generation Agents
Superior to 1st Generation
Agents?
Time for Head-To-Head Comparison

LUX- LUNG 7
• Treatment beyond progression allowed if deemed beneficial by investigator
• RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until
Week 64, and every 12 weeks thereafter
• Stage IIIB/IV
adenocarcinoma of the
lung
• EGFR mutation (Del19
and/or L858R) in the
tumour tissue*
• No prior treatment for
advanced/
metastatic disease
• ECOG PS 0/1
Afatinib 40 mg
once daily†
Gefitinib 250 mg
once daily
Primary endpoints:
PFS (independent)
TTF
OS
Secondary endpoints:
ORR
Time to response
Duration of response
Duration of disease control
Tumor shrinkage
HRQoL
Safety
*Central or local test
†Dose modification to 50, 30, 20 mg permitted in line with prescribing information
Stratified by
• Mutation type (Del19/L858R)
• Brain metastases (present/absent)
1:1
N=319
Park K et al. Lancet Oncol 2016

Baseline Characteristics
Afatinib
160, N (%)
Gefitinib
159, N (%)
Median age, years (range) 63 (30–86) 63 (32–89)
Gender, % Female/Male 57/43 67/33
Race, %
Asian
Non-Asian
59
41
55
45
Brain metastases*, % 16 16
Smoking status, %
Never smoked
Light ex-smoker
Current/other ex-smoker
66
13
21
67
12
21
Baseline ECOG, %
0
1
32
68
30
70
NSCLC stage, %
IIIB
IV
5
95
2
98
EGFR mutation, %
Del19
L858R
58
42
58
42

PFS by Independent Review
No. at risk:
Afatinib 160 142 112 94 67 47 34 27 21 13 6 3 1 0 0
Gefitinib 159 132 106 83 52 22 14 9 7 5 3 3 1 1 0
1.0
0.8
0.6
0.4
0.2
0
0
Time of progression free survival (months)
EstimatedPFSprobability
Afatinib Gefitinib
Median, mo 11.0 10.9
HR (95% CI)
P-value
0.73 (0.57-0.95)
0.0165
27%
18%
15%
8%
3 6 9 12 15 18 21 24 27 30 33 36 39 42
P=0.0176
P=0.0184
Afatinib
Gefitinib

PFS for Subgroups by Independent Review
Total 319 0.732 (0.566, 0.947)
EGFR mutation
L858R 133 0.708 (0.475, 1.055)
Del19 186 0.764 (0.549, 1.063)
Brain metastases
Absent 268 0.739 (0.560, 0.976)
Present 51 0.764 (0.405, 1.439)
Baseline ECOG score
0 98 0.892 (0.542, 1.469)
1 221 0.705 (0.524, 0.948)
Gender
Male 122 0.876 (0.585, 1.312)
Female 197 0.653 (0.469, 0.910)
Age group
<65 years 177 0.681 (0.479, 0.968)
≥65 years 142 0.845 (0.585, 1.221)
Race group
Non-Asian 137 0.717 (0.487, 1.056)
Asian 182 0.756 (0.539, 1.060)
Smoking history
Never smoked 212 0.801 (0.584, 1.097)
<15 pack years + stopped >1 year before 40 1.094 (0.559, 2.140)
Other current or ex-smokers 67 0.477 (0.270, 0.845)
1/16 1/4 1 4 16
Favours Afatinib Favours Gefitinib
Factors Number of Patients Hazard Ratio (95% CI)

Deepening of Response!!
Does it matters??

Tumor Shrinkage by Independent Review
A
(n)
G
(n)
≥20% increase 1 4
0–<20% increase 6 6
0–<30% decrease 27 41
≥30–<50% decr. 50 46
≥50% decrease 65 54
Afatinib
Gefitinib
Based on maximum percentage decrease from baseline in the sum of target lesion diameters. A=Afatinib G=Gefitinib

Time to Treatment Failure
No. at risk:
Afatinib 160 148 133 113 91 68 56 48 40 25 18 9 5 0 0
Gefitinib 159 144 120 103 74 59 43 30 21 11 6 6 2 2 0
Time to treatment failure (months)
Estimatedprobabilityofbeingfreeof
treatmentfailure
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
25%
5%
P=0.0029
15%
13%
P=0.0067
Afatinib
Gefitinib
Afatinib Gefitinib
Median, mo 13.7 11.5
HR (95% CI)
P-value
0.73 (0.58-0.92)
0.0073
TTF = time from randomization to treatment discontinuation for any reason

TTF by Subgroups
Total 319 0.728 (0.576, 0.920)
EGFR mutation
L858R 133 0.748 (0.525, 1.065)
Del19 186 0.729 (0.535, 0.994)
Brain metastases
Absent 268 0.687 (0.533, 0.886)
Present 51 1.135 (0.635, 2.026)
Baseline ECOG score
0 98 0.784 (0.515, 1.195)
1 221 0.724 (0.547, 0.957)
Gender
Male 122 0.729 (0.499, 1.066)
Female 197 0.746 (0.554, 1.006)
Age group
<65 years 177 0.606 (0.443, 0.831)
≥65 years 142 0.902 (0.633, 1.286)
Race group
Non-Asian 137 0.660 (0.459, 0.949)
Asian 182 0.817 (0.603, 1.108)
Smoking history
Never smoked 212 0.752 (0.566, 0.998)
<15 pack years + stopped >1 year before 40 1.192 (0.621, 2.288)
Other current or ex-smokers 67 0.567 (0.334, 0.963)
Factors Number of patients Hazard Ratio (95% CI)
1/16 1/4 1 4 16
Favours Afatinib Favours Gefitinib

Objective Response and Disease Control Rate
by Independent Review
P = 0.0083
0%
20%
40%
60%
80%
Afatinib
112/160
Gefitinib
89/159
ORR
70%
Afatinib Gefitinib
Median DoR , months
(95% CI)
10.1
(7.8, 11.1)
8.4
(7.4 – 10.9)
Disease control rate (N) 91.3% (146) 87.4% (139)
56%

Toxicity of EGFR TKIs in NSCLC
EGFR TKI
 Study
Treatment-Related AEs, %
Diarrhea Rash Paronychia Stomatitis
Gr 1/2 Gr 3/4 Gr 1/2 Gr 3/4 Gr 1/2 Gr 3/4 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
0
0
Erlotinib
 OPTIMAL
 EURTAC
21
44
1
5
48
56
2
12
3
NR
0
NR
10
NR
1
NR
Afatinib
 LUX-Lung 3
 LUX-Lung 6
80
81
14.4
5.4
72
65
16.2
14.6
45
32
11.4
0
63
45
8.7
5.4
Burotto M, et al. Oncologist. 2015.
• Gefitinib and erlotinib have comparable toxicity
• Afatinib associated with more associated toxicity than gefitinib or erlotinib

Can 3rd Generation EGFR TKIs
offer much improvement in 1st
Line Setting?
The Future will tell

AURA: Osimertinib Efficacy by EGFR T790M
Status
• Phase I/II trial for pts with EGFR-positive NSCLC with progression after previous
treatment with EGFR TKIs
Median PFS: 2.8 mos Median PFS: 9.6 mos
Jänne PA, et al. N Engl J Med. 2015.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
ProbabilityofPFS T790M positive
T790M negative
Mos
0 3 6 9 12

Response Rates of EGFR T790M–Positive
Cohorts to Osimertinib
• DCR (CR, PR, or SD): 90% (95% CI: 84-94); activity in LM
Jänne PA, et al. New Engl J Med. 2015.
Yang, J C-H, et al. ASCO 2016.
n = 127 20 mg 40 mg 80 mg 160 mg 240 mg Total
n 10 32 61 41 13 157
ORR, % (95% CI)
50
(19-81)
59
(41-76)
66
(52-77)
51
(35-67)
54
(25-81)
59
(51-66)
*Imputed values for pts who died within 14 wks (98 days) of start of treatment and had no evaluable target lesion
assessments. DStudy discontinuation. T790M mutation determined by central test.
40 mg
80 mg
160 mg
240 mg
20 mg
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
40
50
D
D*D*
D
DDD
D
D DDD
DD
D
DD
D
D
D
D DD
DD D D
D DD
D D D DD DDD D DDD D
DD
D D
DD D D
D
D
DD
D
D
D
Best % Change From Baseline in Target Lesion
Osimertinib FDA approved (November 2015) for advanced EGFR T790M–positive NSCLC after PD on prior EGFR TKI

AURA 3: Osimertinib or Platinum–Pemetrexed
in EGFR T790M–Positive Lung Cancer
Mok T. et al. N Engl J Med 2017

Third-Generation EGFR TKIs
Agent N
RR, %
T790M-
RR, %
T790M+
PFS, mos Toxicity
Osimertinib[1] 253 21 61 ~ 8.2 Diarrhea
Rociletinib[2,3] 130 29
(17)
59
(45)
13.1
(6.1)
Hyperglycemia
Olmutinib[4] 62 NR 55 NR Dyspnea/rash
EGF816[5] 53  60 NR Rash
ASP8273[6] 47 ~ 33 61 NR Hyponatremia/
diarrhea
1. Jänne PA, et al. N Engl J Med. 2015.
2. Sequist LV, et al. N Engl J Med. 2015.
3. Sequist LV, et al. N Engl J Med. 2016.
4. Park K, et al. ASCO 2015.
5. Tan DS, et al. ASCO 2015..
6. Goto Y, et al. ASCO 2015.

AURA: AZD9291 in Previously Untreated
Advanced NSCLC
Predefined
expansion
cohorts
Sequential cohorts of pt
with previously
untreated LA/
metastatic NSCLC with
confirmed EGFR
mutation, WHO
PS 0-1
Cohort 5 (240 mg) T790M+
Cohort 4 (160 mg)
(n = 30)
T790M+/-
Cohort 3 (80 mg)
(n = 30)
T790M+/-
Cohort 2 (40 mg) T790M+/-
Cohort 1 (20 mg) T790M+
Ramalingam SS, et al. ASCO 2015
AZD9291 Dosing

AURA: Pt Population
Characteristic
80 mg
(n = 30)
160 mg
(n = 30)
Total
(N = 60)
Female, % 67 83 75
Median age, yrs (range) 63 (40-77) 65 (38-91) 64 (38-91)
EGFR mutation type,* %
 Exon 19 del
 L858R
 Other†
30
47
23
43
33
23
37
40
23
T790M status,* %
 Positive
 Negative
 Unknown
13
70
17
3
83
13
8
77
15
Ramalingam SS, et al. ASCO 2015
*Determined by central testing.
†Other includes other EGFR mutations, no mutation, or unknown result.

-70
-50
-30
-10
AURA: Tumor Response and PFS
Outcome
80 mg
(n = 30)
160 mg
(n = 30)
Total
(N = 60)
Maximum DoR, mos 13.8* 9.7*
PFS, % (95% CI)
 3 mos
 6 mos
 9 mos
 12 mos
90 (72-97)
83 (64-93)
83 (64-93)
73 (51-87)
97 (79-100)
90 (72-97)
78 (57-89)
NC
93 (83-97)
87 (75-93)
81 (68-89)
72 (55-64)
Ramalingam SS, et al. ASCO 2015.
*Ongoing.
50
40
30
20
10
0
-20
-40
-60
-80
-90
-100
80 mg
160 mg
BestPercentageChange
FromBaselineinTarget
Lesion
Individual Patients
D
D
DD D D DD
D
D
D*

clinicalTrials.gov
Third-Generation EGFR TKIs

Stewart EL, et al. Transl Lung Cancer Res. 2015;4:67-81.
Chan BA, et al. Transl Lung Cancer Res. 2015;4:36-54.
EGFR Mutations: Context To Memorize
• Found in approximately 10% to 30% of pts with NSCLC
• More common in never smokers, 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)

Summary of First-line EGFR TKIs in EGFR-
Mutated NSCLC
• 1st Generation & 2nd Generation TKIs improve PFS and QoL
• Afatinib PFS superior to first-generation EGFR TKIs
• Afatinib Showed OS in preplanned Subgroup (Further confirmations are warranted)
• Afatinib showed activity in both Common & Uncommon Mutations
• 3rd generation TKIs in 1st line setting may offer additional hope for
patients (All EGFR population & those with Specific Mutations)
• Choice of a specific EGFR TKI should consider toxicities and pt preferences

Choose Confidently for Your Patient!
Thank You

First Line Therapy in EGFR Mutant Advanced/Metastatic NSCLC

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