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Update in Lung Cancer Treatment :

Afatinib in First Line Therapy for EGFRm+ NSCLC


First-Line Therapy with Context of EGFR Mutations

• Found in approximately 10% to 50% of pts with NSCLC


• More common in never smokers, adenocarcinomas, females, Asians
• Associated with response to EGFR TKIs
• Predominantly located in EGFR exons 18-21
‒ 86% of EGFR mutations are either deletions in exon 19 or a single-
point mutation in exon 21 (L858R)

Stewart EL, et al. Transl Lung Cancer Res. 2015;4:67-81.


Chan BA, et al. Transl Lung Cancer Res. 2015;4:36-54.
Mitsudomi T. Jpn J Clin Oncol 2010;40:101–6.
Wu YL, et al. Ann Oncol 2011;22(suppl 9):Abstract 33.
Herbst RS, et al. N Engl J Med. 2008;359:1367-1380.
Sequist LV, et al. J Clin Oncol. 2007;25:587-595 2
1st-, 2nd- and 3rd-Generation EGFR TKIs

• 1st-generation: Gefitinib and erlotinib, reversibly targeting EGFR


• 2nd-generation: Afatinib, irreversibly targeting EGFR/ErbB Family
• 3rd-generation: Osimertinib, irreversibly targeting EGFR T790M positive

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Complete blockade of the ErbB Family enhances the effect on
important signaling pathways

Doebele et al. Lung Cancer. 2010;69:1-12; Hynes and Lane. Nat Rev Cancer. 2005;5:341;
Li et al. Oncogene. 2008;27:4702; Spicer and Rudman. Target Oncol. 2010;5:245. 4
First-line Treatment with 1st- and 2nd-Generation EGFR TKIs vs
Chemotherapy in EGFR M+ NSCLC

EGFR ORR* PFS* OS*


EGFR TKI Trial N mutaiton (%) (months) (months)
71 vs 47 9.5 vs 6.3 21.6 vs 21.9
IPASS 1217 261
P<0.001 HR 0.48 (0.36-0.64) HR 1.00 (0.76-1.33)
74 vs 31 10.8 vs 5.4 27.7 vs 26.6
Gefitinib NEJ002 224 224
P<0.001 HR 0.32 (0.24-0.44) HR 0.89 (0.63-1.24)
62 vs 32 9.2 vs 6.3 36 vs 39
WJTOG 3405 172 172
First P<0.0001 HR 0.0.5 (0.34-0.71) HR 1.19 (0.77-1.83)
Generation
TKI 58 vs 15 9.7 vs 5.2 22.9 vs 19.6
EURTAC 173 173
P-value NR HR 0.37 (0.25-0.54) HR 0.92 (0.63-1.35)
83 vs 36 13.1 vs 4.6 22.8 vs 27.2
Erlotinib OPTIMAL 165 154
P<0.0001 HR 0.16 (0.10-0.26) HR 1.19 (0.83-1.71)
63 vs 34 11.0 vs 5.6 26.3 vs 25.5
ENSURE 217 216
P=0.0001 HR 0.42 (0.27-0.66) HR 0.91 (0.61-1.31)
69 vs 44 13.6 vs 6.9 31.6 vs 28.2
Second LUX-Lung 3 345 308
P=0.001 HR 0.41 (0.31-0.56) HR 0.78 (0.58-1.06)
Generation Afatinib
TKI 74 vs 31 13.7 vs 5.6 23.6 vs 23.5
LUX-Lung 6 364 324
P<0.0001 HR 0.26 (0.19-0.36) HR 0.83 (0.62-1.09)
PFS = progression-free survival; OS = overall survival. *Results described refer to common mutations only
.
Mok TS et al. N Engl J Med. 2009;361:947-57; Fukuoka M et al. J Clin Oncol. 2011;29:2866-74; Maemondo M et al. N Engl J Med. 2010;362:2380-98; Mitsudomi T et al. Lancet
Oncol. 2010;11:121-8; Yoshioka H et al. J Clin Oncol. 2014;32(suppl):abstract 8117; Rosell R et al. Lancet Oncol. 2012;13:239-46; Leon L et al. ESMO 2014. Abstract 1273P;
Zhou CC et al. Lancet Oncol. 2011;12:735-42; Zhou CC et al. J Clin Oncol. 2012;30(suppl):abstract 7520; Wu YL et al. Ann Oncol. 2015;26:1883-9; Sequist LV et al. J Clin
Oncol. 2013;31:3327-34; Wu YL et al. Lancet Oncol. 2014;15:213-22; Yang JC et al. Lancet Oncol 2015;16:141-51. 5
Ph III First-line Studies of 1st-Generation EGFR TKIs: No OS
benefit by sub-mutation in Meta-Analysis

Hazard ratio Hazard ratio


Trial n (95% CI) Trial n (95% CI)

Exon 19 deletion Exon 21 L858R

ENSURE 118 0.79 (0.48-1.30) ENSURE 98 1.05 (0.60-1.84)

EURTAC 115 0.94 (0.57-1.54) EURTAC 58 1.00 (0.56-1.79)

IPASS 163 0.86 (0.61-1.22) IPASS 129 1.40 (0.91-2.15)

NEJ002 117 0.82 (0.61-1.22) NEJ002 98 0.85 (0.50-1.42)

OPTIMAL 82 1.52 (0.91-2.52) OPTIMAL 72 0.92 (0.55-1.54)

WJTOG WJTOG
87 1.19 (0.65-2.18) 85 1.11 (0.60-2.05)
3405 3405

Overall 682 0.96 (0.79-1.16) Overall 540 1.06 (0.86-1.32)

0.05 1 5 0.05 1 5
Favors EGFR TKI Favors Chemotherapy Favors EGFR TKI Favors Chemotherapy

There was also no significant difference according to performance status (P-interaction=0.88), age (P-interaction=0.61),
ethnicity (P-interaction=0.63), histology (P-interaction=0.84), and cancer staging (P-interaction=0.43).

Lee CK et al. J Clin Oncol. 2015 (suppl.) Abstract 8072.


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LUX-Lung 3 & 6: First-line Afatinib vs Chemotherapy in EGFR
M+, Stage IIIB/IV NSCLC
Stage IIIB (wet)/IV lung adenocarcinoma
EGFR mutation in tumour
(central lab testing; TheraScreen® EGFR29a RGQ PCR)
Randomisation 2:1
Stratified by EGFR mutation
(Del19/L858R/other)

1 2
LUX-Lung 3 LUX-Lung 6
(n=345) (n=364; Asian pts)

Cisplatin + Pemetrexed Afatinib* Cisplatin + Gemcitabine


75 mg/m2 + 500 mg/m2 75 mg/m2 + 1000 mg/m2 D1, D8
IV q21d, up to 6 cycles 40 mg/db IV q21d, up to 6 cycles

Primary end point: PFS (RECIST 1.1, independent review)c


Secondary end points: OS, PROd, ORR, DCR, DOR, tumour shrinkage, safety
aEGFR29: 19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I.
bDose 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.
cTumour assessments: q6 weeks until week 48 and q12 weeks thereafter until progression/start of new therapy.
dPatient-reported outcomes: EQ-5D, EORTC QLQ-C30 and LC 13 at randomisation and q3 weeks until progression or new anticancer therapy.

Note: 24 patients in LUX-Lung 3 and 28 patients in LUX-Lung 6 were still on treatment as of December 2013.
RGQ = rotor-gene Q; PCR = polymerase chain reaction; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumours; ORR =
objective response rate; DCR = disease control rate; DOR = duration of response; OS = overall survival.
1. Sequist LV et al. J Clin Oncol. 2013;31:3327; 2. Wu YL et al. Lancet Oncol. 2014;15:213. 7
LUX-Lung 3 and 6: Primary Endpoint (PFS)
Independent Review ‒ All Randomised Patients

1.0
LUX-Lung 3,1 LUX-Lung 6,2
n=345 n=364
(A vs Cis/Pem) (A vs Gem/Cis)
Progression-free survival (probability)

0.8 Median PFS 11.1 vs 6.9 11.0 vs 5.6


HR for PFS 0.58 P<0.001 0.28 P<0.0001
12-month PFS 47% vs 22% 47% vs 2%
0.6

47% Afatinib LUX-Lung 6


Gem/cis LUX-Lung 6
47%
0.4
Afatinib LUX-Lung 3
Pem/cis LUX-Lung 3

0.2
22%

2%
0.0
0 3 6 9 12 15 18 21 24 27
Progression-free survival (months)
Number at risk
Afatinib (LL3) 230 180 151 120 77 50 31 10 3 0
Pem/cis (LL3) 115 72 41 21 11 7 3 2 0 0
Afatinib (LL6) 242 208 166 126 89 60 35 12 4 0
Gem/cis (LL6) 122 70 25 8 1 0 0 0 0 0
1. Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.
2. Wu et al. Lancet Oncol. 2014;15:213 8
VS Chemotherapy : PFS in Patients With and Without Brain Metastases
and Common Mutations (LUX Lung3)

With brain metastases Without brain metastases

Afatinib Cis/Pem Afatinib Cis/Pem


Median, mo 11.1 5.4 Median, mo 13.8 8.1
1.0 PFS in overall population 1.0 PFS in overall population
HR (95% CI) 0.54 (0.23-1.25) HR (95% CI) 0.48 (0.34-0.69)
P-value P=0.1378 P-value P<0.0001
Estimated PFS probability

Estimated PFS probability


0.8 0.8

0.6 Afatinib 0.6 Afatinib


CisPem CisPem

0.4 0.4

0.2 0.2

0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Time (months) Time (months)
No. at risk No. at risk
Afatinib 20 17 9 8 7 5 4 2 2 2 1 1 0 0 0 0 Afatinib 166 141 123 100 78 61 44 34 28 21 18 15 10 7 3 0
Cis/Pem 15 9 3 3 1 1 0 0 0 0 0 0 0 0 0 0 Cis/Pem 82 49 29 14 8 5 2 2 2 2 2 2 2 2 1 0

Schuler et al. J Thorac Oncol. 2016, 11(3):380-90. 9


VS Chemotherapy : PFS in Patients With and Without Brain Metastases
and Common Mutations (LUX-Lung 6)

With brain metastases Without brain metastases

Afatinib Cis/Gem Afatinib Cis/Gem


Median, mo 8.2 4.7 Median, mo 11.1
PFS in overall population 5.6
1.0 PFS in overall population 1.0
HR (95% CI) 0.47 (0.18-1.21) HR (95% CI) 0.22 (0.15-0.33)
P-value P=0.1060 P-value P<0.0001
Estimated PFS probability

Estimated PFS probability


0.8 0.8

0.6 Afatinib 0.6 Afatinib


CisGem CisGem

0.4 0.4

0.2 0.2

0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 0 3 6 9 12 15 18 21 24 27 30 33 36 39
Time (months) Time (months)
No. at risk No. at risk
Afatinib 18 22 16 11 10 8 7 4 3 3 2 0 0 0 Afatinib 185162 134102 76 54 43 33 27 21 15 9 1 0
Cis/Gem 18 7 2 0 0 0 0 0 0 0 0 0 0 0 Cis/Gem 86 52 17 6 1 0 0 0 0 0 0 0 0 0

Schuler et al. J Thorac Oncol. 2016, 11(3):380-90. 10


LUX-Lung 3 & 6: Individual OS in Common Mutations (del19 &
Leu858Arg combined) for Afatinib vs Chemotherapy

Overall survival LUX-Lung 3 OS LUX-Lung 6


Afatinib Cis/Pem Afatinib Cis/Gem
1.0 (n=203) (n=104) 1.0 (n=216) (n=108)
population
Median, mo 31.6
population 28.2 Median, mo 23.6 23.5
PFS in overall PFS in overall
HR (95% CI) 0.83 (0.62-1.09)
HR (95% CI) 0.78 (0.58-1.06) 0.8
0.8 P-value P=0.1756
P-value P=0.1090

Estimated OS probability
Estimated OS probability

Afatinib Afatinib
Cis/Pem Cis/Gem
0.6 0.6

0.4 0.4

0.2 0.2

0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Time (months) Time (months)


No. at risk No. at risk

Afatinib 203 197 188 181 171 162 143 133 121 108 101 90 58 49 32 9 1 0 Afatinib 216 214 202 190 172 158 141 118 104 93 80 51 19 9 1 0

Cis/Pem 104 98 92 86 81 71 63 55 52 47 40 35 26 20 10 5 1 0 Cis/Gem 108 101 93 87 81 70 61 55 49 36 30 17 8 3 0 0

Yang JC et al. Lancet Oncol. 2015; 16:141-51. 11


Overall Survival in Common Mutations: Subgroups

LUX-Lung 3 LUX-Lung 6

Patients HR Patients HR
Total 307 0.78 324 0.83
Gender
Male 103 0.73 111 0.70
Female 204 0.79 213 0.88
Age (years)
<65 189 0.82 246 0.87
≥65 118 0.73 78 0.60
EGFR mutation
Del19 169 0.54 186 0.64
L858R 138 1.30 138 1.22
Baseline ECOG score
0 115 0.96 78 0.82
1 191 0.71 246 0.83
Smoking history
Never smoker 210 0.75 251 0.71
<15 pack yrs, stopped >1 yr ago 29 0.79 11 1.22
Other current/ex-smoker 68 0.91 62 1.29
Race
Non-Asian 83 0.68
Asian 224 0.82

1/16 1/4 1 4 1/16 1/4 1 4 16


Favours Afatinib Favours Cis/Pem Favours Afatinib Favours Cis/Gem

Yang et al. Lancet Oncol. 2015; 16:141-51. 12


Del19 Patients: OS Gain of >1 Year With Afatinib vs
Chemotherapy
LUX-Lung 3 LUX-Lung 6
1.0 Afatinib Cis/Pem 1.0 Afatinib Cis/Gem
(n=112) (n=57) (n=124) (n=62)
Median, months 33.3 21.1 Median, months 31.4 18.4
HR (95% CI) 0.54 (0.36–0.79) HR (95% CI) 0.64 (0.44–0.94)
0.8 0.8
P-value P=0.0015 P-value P=0.0229
Estimated OS probability

Estimated OS probability
0.6 Afatinib 0.6 Afatinib
Cis/Pem Cis/Gem

0.4 0.4

0.2 0.2

0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

No. at risk: Time (months) No. at risk: Time (months)


Afatinib 112 108 105 102 96 93 83 80 72 62 58 51 34 30 21 6 1 0 Afatinib 124 122 118 115 106 99 90 80 73 69 59 39 16 8 1 0
Cis/Pem 57 55 50 46 43 37 33 27 25 22 20 16 10 6 1 1 0 0 Cis/Gem 62 58 53 49 44 35 30 28 26 21 18 11 4 3 0 0

Yang JC et al. Lancet Oncol. 2015; 16:141-51. 13


British Journal of Cancer (2015) 113, 1519-1528 | doi: 10.1038/bjc.2015.356

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Meta analysis for Overall Survival in del19 showed significant
difference in Afatinib vs. chemo (p<0.00001)

British Journal of Cancer (2015) 113, 1519-1528 | doi: 10.1038/bjc.2015.356


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LUX-Lung 7 - Study Design

• 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

Randomisation

Stratified by mutation type (Del19 vs L858R)


and presence of brain metastases (yes vs no)

1:1

Afatinib 40 mg once daily Gefitinib 250 mg once daily

Primary endpoints: PFS (independent review)#, TTF, OS

Secondary endpoints: ORR, time to and duration of response, duration of


disease control, tumour shrinkage, HRQoL, safety
# local or central test
# Tumor assessment performed at week 4, 8, every 8 weeks until w64 and every 12 weeks thereafter
Treatment beyond progression allowed if deemed beneficial by investigator.
Park K, et al. Lancet Oncol. 2016; 17(5): 577-589.
Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF® and in the U.S. under the brand name GILOTRIF® for use in patients with distinct types of
EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. 16
LUX-Lung 7: Patients with Afatinib are 2x more likely
progression free at 18 months vs Gefitinib
1.0 Afatinib Gefitinib
Gefitinib
Afatinib
(n=160) (n=159)
Median, mo 11.0 10.9
Median PFS (months) 11.0 10.9
HR (95% CI) 0.73 (0.57-0.95)
0.8
HR (95% CI)
P-value 0.73 (0.57–0.95)
0.0165
p value 0.0165
Estimated PFS probability

Afatinib
0.6 Gefitinib

p=0.0176
0.4 27%*
p=0.0184
18%†
0.2

15%
8%
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

No. at risk:
Time of progression free survival (months)
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

Park K, et al. Lancet Oncol. 2016; 17(5): 577-589. 17


LUX-Lung 7: Afatinib vs Gefitinib Improves ORR in TKI-Naive EGFR M+
NSCLC, Independent Review

80%
80
p=0.0083 Duration of response (DoR)
70%
60%
60 Afatinib Gefitinib
(n=112) (n=89)
56%
ORR (%)

Median DoR
10 .1 8.4
ORR

40%
40 (months)
95% CI (7.8–11.1) (7.4–10.9)

20%
20

0%0
Afatinib Gefitinib
Afatinib
n=112/160 n=89/159

Park KC et al. Lancet Oncol 2016;17:577–89.


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Management of Treatment-Related AEs: Afatinib
Tolerability-Guided Dose Adjustment

Standard dose of afatinib 40 mg/d

• Grade ≥3 AEs
• Prolonged grade 2 (≥7 consecutive days)
• Diarrhoea grade 2 >48 hours despite optimal care
• Worsening of renal function grade 2

Pause until recovery to grade ≤1 or baseline

Resume treatment at dose reduced by 10 mg

AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events.

GIOTRIF Local Product Information


20
No PFS Difference in Patients With or Without Dose
Reductions Within the First 6 Months
<40 mg in first ≥40 mg for first
6 months (n=105) 6 months (n=124)
Median PFS, months 11.3 11.0
PFS in overall population
1.0 HR (95% CI) 1.25 (0.91-1.72)
P-value
Estimated PFS probability
0.175
0.8
<40 mg in first 6 months
0.6 ≥40 mg in first 6 months

0.4

0.2

0
0 3 6 9 12 15 18 21 24 27
Time (months)
No. at risk
<40 mg in first 6 months 105 87 75 58 41 26 15 6 2 0
≥40 mg for first 6 months 124 93 76 62 36 24 16 4 1 0

53% of patients treated with afatinib reduced dose; 86% of dose reductions occurred within
the first 6 months of treatment
CI = confidence interval; HR = hazard ratio.
Yang et al. Annals of Oncology. 2016; 27(11): 2103-2110. 21
Severity of Diarrhoea and Rash/Acne Decreased over
Time (n=466)

Yang JC, et al. Poster Presented at the 38th Ann Cong of the European Society for Medical Oncology (ESMO), Amsterdam, 27 Sep – 1 Oct 2013 22
LUX-Lung 7: Overall Safety of Afatinib vs Gefitinib

Afatinib Gefitinib
Events, n (%)
(n=160) (n=159)

Any AE 158 (99) 159 (100)

Drug-related AEs 156 (98) 153 (96)

AEs leading to dose reduction* 67 (42) 3 (2)*

Related AEs leading to discontinuation 10 (6) 10 (6)

SAEs 71 (44) 59 (37)

Related SAEs 17 (11) 7 (4)§

Related fatal SAEs 0 1 (0.6)¶

*Dose adjustment for afatinib according to label. No dose reductions forseen for gefitinib according to prescribing information; §Including
4 patients with drug-related ILD (no drug-related ILD on afatinib); ¶One patient died of hepatic failure.
AE, adverse event; ILD, interstitial lung disease; SAE, serious adverse event.

Park KC et al. Lancet Oncol 2016;17:577–89.


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Molecular Mechanisms of Acquired Resistance to
First-/Second-Generation EGFR TKIs

Yu HA et al. Clin Cancer Res. 2013;19:2240. 24


3-year OS rates of Afatinib 1st line and Subsequent
Treatment with 3rd Gen TKIs up to 90%

1.0
Estimated Overall Survival

0.8

Afatinib Gefitinib
N=20 N=23
Probability

0.6
Median, mo NE 46.0

0.4 HR (95% CI) 0.51 (0.17-1.52)


P-value 0.22

0.2 Afatinib
Gefitinib

0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time to death (months)
No. at risk:
Afatinib 20 20 20 20 20 20 20 19 19 19 19 16 13 10 8 2 0
Gefitinib 23 23 23 22 22 22 21 20 20 20 19 19 19 15 7 4 0

Exploratory analysis of patients in LUX-Lung 7 receiving subsequently osimertinib or


olmutinib

Paz-Ares L et al. Ann Oncol, 2017 25


Molecular Characterization After Osimertinib First Line
Failure (All T790M Negative)

Kras
11% C797S
Kras and 23%
EGFR ampl
11%

Met ampl 11%


PIK3CA
11%

Her2 mut
11%
JAK2 11%
Mek 11%

Ramalingam SS et al. J Clin Oncol. 2017 26


Finding the Right Sequence

A) 3rd gen TKIs might show superiority compared with 1st-gen or 2nd gen TKI in terms of PFS
B)/C) upfront 1st or 2nd gen TKI with or without other target agents followed 3rd-gen TKIs can
be more effective
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Sun, J-M and Park K, Curr Opin Oncol 2017
Chemo-Free Multi-line Strategy for EGFR-M+ NSCLC
Time on treatment projections

Afatinib12-14 months1-3 Osimertinib 10 months4 > 24 months

?
19 months
Osimertinib ~19 months5

months on treatment

1.Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol.;2014;15:213.; 3. Park K et at., Lancet Oncol 2016;
4. Mok T NEJM 2016.; 5. Soria J NEJM 2017 28
Summary

• First-line afatinib significantly improved OS for more than 1 year


vs chemotherapy in EGFR Del19 patients
• Afatinib significantly improved PFS (independent review) and
ORR relative to Gefitinib in patients with EGFRm+ NSCLC
• EGFR TKI sequencing might be the most important determinant
of OS in patients with activating EGFR mutations.

• Afatinib followed by osimertinib may be the strongest option in


EGFR M+ NSCLC.

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